Actual Topics on Women’s Health Актуальные Вопросы Женского Здоровья ქალთა ჯანმრთელობის აქტუალური საკითხები

ISSN 2298-0091

w ww .Actual to pi cswo men’s hea l th.o rg

The 6th Volume of Journal is published by financial support of Sukhishvili Teaching University

Пятый номер журнала издан при финансовой поддержки Учебного Университета Сухишвили

Jurnalis meqvse nomeri ibeWdeba suxiSvilis saswavlo universitetis finansuri mxardaWeriT

N6 (2014) Tbilisi UDC (uak) 061.231:614.253-055.2(479.22) +618.1 q-189 Editorial Board N. Zhvania Editor in Chief Kh.Kaladze Deputy Editor in Chief L. Skuratovskaia (Russia), Deputy Editor in Chief

Sh. Avaliani, M. Balavadze, M. Beridze, K. Chelidze, K. Doklestic (Serbia), C. Griffioen (Netherland), M. Jebashvili, T. Kezeli, A. Khomassuridze, D. Metreveli, B. Pfleiderer (Germany), T. Sanikidze, M. Shakarashvili, E. Sukhishvili, Y. Tizabi, T. Vakhtangadze, M. Zodelava

Proof Reader: D. Sokhadze

Редакционная коллегия Н. Жвания – Главный Редактор Х.Каладзе – Зам. Гл. Редактора Л. Скуратовская (Россия), – Зам. Гл. Редактора

Ш. Авалиани, М. Балавадзе, М. Беридзе, Т. Вахтангадзе, Ц. Грифиоен (Нидерланды), М. Джебашвили, К. Доклестик (Сербия), М. Зоделава, Т. Кезели, Д. Метревели, Б. Пфлейдерер (Германия), Т. Саникидзе, Е. Сухишвили, Дж. Тизаби, А. Хомасуридзе, К. Челидзе, М. Шакарашвили

Корректор: Д. Сохадзе

saredaqcio kolegia n. Jvania – mTavari redaqtori x. kalaZe – mT. redaqtoris moadgile l. skuratovskaia (ruseTi) – mT. redaqtoris moadgile

S. avaliani, m. balavaZe, m. beriZe, c. grifioeni (niderlandebi), k. doklestik (serbeTi), T. vaxtangaZe, m. zodelava, T. kezeli, d. metreveli, b. pfleidereri (germania), T. sanikiZe, e. suxiSvili, j. tizabi, m. SaqaraSvili, a. xomasuriZe, k. WeliZe, m. jebaSvili koreqtori: d. soxaZe Dear Readers,

Warm Greetings from Georgia! It’ s our great pleasure to present the new 6 th volume of the journal “Actual Topics on Women’s Health” to you. I express wish and hope of all the members of Journal Editorial Board that the information given in this Journal is important and interesting for you. We try to publish the scientific articles, which contain really new and actual information. Despite the actuality of problems on women’s health, it is not easy to get the articles in such a small country as Georgia. So, we are cordially inviting our readers - the doctors, biologists, and people of other professions from different countries to present their articles for the exchange of knowledge, experience and information. We are also ready to take into account your wishes, comments, interests, etc. for easier continuation of our work. We hope the information given in our Journal would be important and interesting for you. Thank you once again that you are the readers of our journal.

With respect and best wishes, Nino Zhvania, MD. PhD., Editor in Chief President of Georgian Medical Women’s Association Associate Professor at Tbilisi Petre Shotadze Medical Academy

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Since 1995 Sukhishvili University has been formed as one of the most successful universities of Georgia and took important place in educational system. The main mission of the university is to undertake educational policy obtained by the Ministry of Education and Science of Georgia and to contribute reforms in educational sphere implemented by the government. The main task of the university is to prepare contemporary, high-qualified, competitive specialists, to deepen their knowledge and to form practical skills.

4 სუხიშვილის სასწავლო უნივერსიტეტი განათლება უკეთესი მომავლისთვის აირჩიე სუხიშვილის უნივერსიტეტი შემოხაზე 058

სწავლის საფასური # აკადემიური პროგრამის ადგილების დასახელება ქვოტა თბილისი გორი 1 ბიზნესის ადმინისტრირება 115 2250 2000 2 საერთაშორისო ურთიერთობები 75 2250 2000 3 ტურიზმი 120 2250 2000 4 საჯარო მმართველობა 100 2250 2000 5 ინგლისური ფილოლოგია 30 2000 1700 6 ფარმაცია 30 2000 1700 7 ეკოლოგია 35 2000 1700 8 აგრონომია 20 1800 1700 9 სატყეო საქმე 35 2000 1700 10 სასურსათო ტექნოლოგიები 20 1800 1700 11 საინფორმაციო ტექნოლოგიები 20 2000 1700 12 ქართული ენა 30 2000 2000 აზერბაიჯანულენოვანთათვის 13 ქართული ენა 30 2000 2000 სომხურენოვანთათვის 2015-2016 სასწავლო წლის მიღება აკრედიტებულ საბაკალავრო პროგრამებზე

მისამართი: გორი, ცხინვალის გზ.#9 ტელ: 0370 27 05 57; თბილისი, ა. პოლიტკოვსკაიას ქ. #9ა 032 2 51 94 95 E-mail: [email protected] www. Sukhishvili.edu.ge 1995 წლიდან სუხიშვილის უნივერსიტეტი თავისი მრავალწლ-იანი გამოცდილებით ჩამოყალიბდა ერთ- ერთ წარმატებულ უნივერსიტე-ტად და მყარი ადგილი დაიკავა საგანმანათლებლო სივრცეში. უნივერსიტეტის ძირითად მისიას წარმოადგენს საქართველოს განათლებისა და მეცნიერების სამინისტროს საგანმანათლებლო პოლიტიკის გატარება და განათლების სფეროში სახელმწიფოს მიერ განხორციელებული რეფორმების ხელშეწყობა. უნივერსიტეტის მთავარი ამოცანაა თანამედროვე, მაღალკვალიფიციური, კონკურენტუნარიანი სპეციალისტების მომზადება, მათი აზროვნების გაღრმავება და პრაქტიკული უნარ-ჩვევების ჩამოყალიბება.

5 Admission at BA programs for 2015-2016 academic year

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6 CONTENTS P

GENDER DIFFERENCES IN RESPONSE TO ALCOHOL AND NICOTINE - Washington, DC, USA ------8 ALTERATION OF OXIDATIVE METABOLISM UNDER THE INFLUENCE OF UVA IN WOMEN OF DIFFERENT AGES K. Berianidze, A. Katsitadze, T. Sanikidze, Tbilisi, Georgia ------26 SOME ASPECTS OF PATHOGENESIS OF HYPERTENSION IN MENOPAUSAL WOMEN M. Buleishvili, N. Lobjanidze, G. Ormotsadze, L. Ratiani, T. Sanikidze, Tbilisi, Georgia ------32 CITRUS EXTRACT IN PROPHYLACTIC OF CHRONIC DISEASES Gvilava, I. Chkvishvili. M. Giorgobiani, T. Sanikidze ------44 SUGGESTED PROGRAM OF TRAINING EXERCISES FOR PREGNANT WOMEN AT "SCHOOL OF MOTHERHOOD" O. V. Goncharova, Moscow, Russia ------54 SEX BASED DIFFERENCES ON THE TREATMENT OF CARDIOVASCULAR DISEASES N. Zhvania, Tbilisi, Georgia ------67 THE EFFICACY OF HUMAN PAPILLOMAVIRUS VACCINES IN PREVENTING THE DEVELOPMENT OF CERVICAL CANCER: A SUMMARIZED REVIEW OF SELECTED RANDOMIZED CONTROLLED CLINICAL TRIALS. Iyad F. Jaber, Palestine, Jerusalem ------86 FROM OUTRAGE TO COURAGE, by Anne Firth Murray (The review of the book) L. Skuratovskaya, G. Drozdova, L. Cornelius Denver, USA, Moscow, Russia ---- INFORMATION FOR AUTHORS ------95

 GENDER DIFFERENCES IN RESPONSE TO ALCOHOL AND NICOTINE Y. Tizabi, O. Prospéro- García, R. Moratalla Department of Pharmacology, College of Medicine, Howard University, Washington, DC, USA Laboratory of Cannabinoids, Department of Physiology, Faculty of Medicine. UNAM Universidad Nacional Autónoma de México, Mexico. Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

Although earlier publications on sex differences in response to ethanol tolerance were noted in late 1950’s [126], more serious attention to the issue of gender differences in alcohol effect and addiction to this age-old substance have been recognized more recently [33]. Part of the reason for absence of such studies was likely the reluctance of the investigators to include female subjects due to inadequate understanding of the influence of estrous cycle and consequent hormonal effects on drugs including alcohol. Initial studies of gender-related differences concentrated more on alcohol metabolism and sleep response where significant differences between old male and female mice were observed [26]. It is now well established that not only there are sex differences in pharmacokinetic effects of alcohol (e.g. metabolism and tolerance) but also in pharmacodynamic effects (e.g. the influence on the central nervous system and interactions with various neurotransmitters and/or receptors). These distinctions have been observed both in human as well as in animal studies [36, 37]. Thus, significant sex differences in actions at the molecular as well as the behavioral level including ethanol seeking and drinking, dependence and withdrawal have been reported. For example in an ethanol oral self-administration paradigm in rats, it was shown that whereas males and females initiated alcohol drinking at similar rates, females maintained their preference for ethanol over a longer duration. This difference was attributed to dihydrotestosterone levels in male and estradiol levels in females [2]. It has also been observed that female rats display a shorter time for recovery from ethanol withdrawal and that their GABAA receptor function is differentially altered compared to male rats [37]. Moreover, neurosteroids which are differentially expressed in males vs females and have been shown to modulate GABA function may also respond differently to ethanol [5, 46, 78]. Indeed, it is hypothesized that fluctuations in GABAergic steroid levels (and the resultant change in GABAergic inhibitory tone) alter sensitivity to ethanol, leading to changes in the positive motivational or withdrawal-related effects of ethanol [46].

8 An important aspect of gender-alcohol interaction may be manifested in relationship between depression and alcoholism where a high rate of co-morbidity of these 2 disorders exist. Although there are two primary viewpoints on how these diseases interact, the exact neurobiological substrates are far from clear. In one case, it has been hypothesized that chronic alcohol use through interactions with neurotransmitter systems that regulate mood, precipitates depression [1, 38, 48, 58, 91, 98, 123] and that the resulting depressive-like characteristics may even worsen after cessation [55, 102]. In another case, it is hypothesized that depression precedes alcoholism, and that alcohol may be used initially to counteract some symptoms of depression. This scenario may be particularly true in female alcoholics as depression is more common in women [106]. In this regard, we have observed antidepressant- like effects of low alcohol doses in WKY rat model of depression [60], a result consistent with findings of antidepressant effects of alcohol in alcohol-preferring Sardinia rats [24]. However, with chronic use and development of tolerance, the symptoms of depression may even worsen in alcoholics [38, 95, 108]. Therefore, it is possible that the initial antidepressant effect of low doses of alcohol may contribute to eventual co-morbidity of alcoholism and depression, particularly in women. Although the detrimental effects of alcoholism are well known, it is of interest to note that, given in moderate to low doses alcohol provides neuroprotection. Thus, ethanol protects in-vitro and ex-vivo neural cultures exposed to toxins such as HIV-1 glycoprotein gp120 [26], homoquinolinic acid [21] and NMDA [21, 22, 127] all of which may cause neurodegeneration. Similarly, we have observed that pre-treatment of SH-SY5Y cells, a cell line commonly used to model nigral dopaminergic neurons for Parkinson's disease, with ethanol attenuates salsolinol-induced toxicity [90]. Although the exact neuroprotective mechanism of low alcohol concentration is not known, several mechanisms including alcohol causing increased release of heat shock proteins [10, 25, 57, 105] and a possible anti- inflammatory effect [25, 10, 74] have been proposed. It would be very curious to investigate whether gender differences may play a role in the overall effects of alcohol and its postulated mechanisms. Moreover, it appears that despite all the current investigations characterizing sex differences in the actions of ethanol, it is unlikely that a unified theory could explain all the gender differences. The complex and multimodal effects of ethanol at molecular, cellular and behavioral circuitries underscore this premise. Nonetheless it is now accepted that treatment of alcoholism should be managed differently in women than in men [37, 51, 64] and that future studies should include both males and female subjects. The importance of gender consideration in research was emphasized recently in NIH guidelines in preclinical as well as clinical studies [118-121].

9 NICOTINE AND GENDER The tremendous health hazards of smoking are well established. Moreover, considerable evidence of gender differences in smoking habit, relapse to smoking and consequence of smoking in general, and response to nicotine in particular, is provided in the literature. A more recent study has shown that variation in nicotine dependence between the two genders may be attributable to the differences in nicotine metabolism [101]. Thus, gender differences in pharmacokinetic and pharmacodynamic effects of nicotine are very important consideration in design and prevention of smoking across the two genders [12, 77, 83, 101]. Nicotine, unlike alcohol (see above) is believed to interact primarily with specific nicotinic receptors that are widely distributed in the central nervous system and may be differentially expressed in females vs males. Nicotinic receptors have been directly implicated not only in reward pathway and addiction to nicotine, but also in a variety of central functions such as cognitive and attention processes, pain and mood regulation. In addition, their role in neuronal plasticity may be responsible for the neuroprotective effects as well as mood regulating effects of nicotine [3, 13, 20, 57, 72, 17, 85, 114, 116, 117]. Interestingly, extensive interactions of alcohol with nicotinic receptors have also been reported [42, 89, 93, 113-115]. Although similar to the co-morbidity of alcoholism and depression, nicotine addiction (from tobacco products) and depression are also highly co-expressed, the reasons for such association are still not fully elucidated. One possibly is that nicotine demonstrates antidepressant qualities, as often depression relapses when cessation is attempted, leading to “self-medication hypothesis” [26, 71, 109]. A second possibility is that excessive nicotine use induces depression itself, but this is only seen consistently in adolescence [125, 75, 110, 34]. Third, nicotine withdrawal induces depression, which likely contributes to the failure rate of smoking cessation [15, 31 44, 49, 122]. Preclinical as well as clinical studies suggest an antidepressant-like effect of nicotine that could result from the euphoric effects experienced by new smoker [84]. However, it is clear that nicotine (from patch or smoking) may have a direct effect in alleviating anhedonia and improving mood in depressed patients [28, 67, 99]. In studies using animal models, nicotine has been shown to reduce depressive-like symptoms such as helplessness and anhedonia [39, 60, 103, 116, 117, 120, 121. 1999, 2000, 2009, 2010]. Therefore, depressed individuals may use nicotine as an anti-depressant at first, but continued use can worsen depression particularly during withdrawal [15, 27, 49, 122]. This varied relationship between nicotine and depression may explain the varied relationship depressed patients experience with nicotine usage [79, 80]. Beyond its anti-depressant qualities, nicotine may also have a neuroprotective effect as suggested by a number of

10 epidemiological and empirical studies. Thus, an inverse relationship between Parkinson's disease and smoking has been consistently demonstrated in a number of epidemiological studies [41, 73, 6, 8, 96, 112]. Moreover, in-vivo and in-vitro studies have shown that nicotine protects against nigrostriatal damage induced by various compounds. For example, in cell models of Parkinson's disease nicotine protects against endogenous toxic substances such as salsolinol and aminochrome that selectively damage dopaminergic cells [29, 30, 39, 72, 90]. Further studies using primary and immortal cell cultures, have shown nicotine to protect against or attenuate toxicity induced by inflammatory mediators such as LPS and cytokines, as well as a variety of other toxicants such as glutamate, alcohol, N-methyl-D-aspartate (NMDA) and hypoxia [33, 53, 54, 62, 65, 111, 113, 118, 119, 74]. Similarly, in animal studies including non-human primates it has been shown that nicotine delays Parkinson's disease-like symptoms induced by MPTP [87, 88]. A mechanism of nicotine protection against Parkinson's disease may involve inhibition of astrocyte activation [66]. The primary targets of nicotine as mentioned above are nicotinic receptors [28, 29, 33, 54, 82, 87] and the signal transduction mechanism(s) underlying the neuroprotection is likely to involve direct or indirect nicotinic receptor modulation of calcium and other anti-apoptotic mechanisms [16, 40, 62, 65, 92, 111]. Regardless of the pathway, it is evident that nicotine or nicotinic agonists may be suitable drugs for treating some neurodegenerative diseases, depression, or both. Such effects may occur via suppression of neuroinflammation and modulation of innate immune pathway primarily due to activation of alpha7 nicotinic receptors [32, 81, 104, 128]. Interestingly, vagal stimulation, which may result in modulation of the immune response through alpha7 nicotinic receptors, also confers an antidepressant effect [124], although further studies are needed to confirm this contention [27, 94]. In addition to neurodegenerative and neuropsychiatric diseases, the anti-inflammatory effects of nicotine maybe applicable to variety of conditions including ulcerative colitis, septic kidney injury and obesity all of which can be precipitated or exacerbated by inflammatory processes [23, 63]. A major remaining question pertinent to this review is whether gender differences may affect any of these outcomes. Thus, further studies on gender effects on final outcome of nicotinic interventions are necessary. ALCOHOL - NICOTINE AND GENDER Although detrimental effects of heavy drinking or smoking alone are well established, the combination of the two may have much more dramatic health consequences. For example, either heavy drinking or smoking may increase the risk of various cancers (e.g. head, neck and esophagus) or ulcer of the duodenum by 5–6-fold, whereas their combination could raise these risks to as high as 25–30-fold [97]. Despite this knowledge, simultaneous, consumption

11 of these two substances is widespread [4, 18, 34, 43, 50, 68]. It is also known that alcohol may increase the craving for nicotine and nicotine may increase the craving for alcohol [7, 51, 69, 70]. Indeed, it is now well recognized that alcohol may be a major risk factor for relapse during smoking cessation [14, 19, 56] and conversely smoking may be a major risk factor for alcoholism relapse [19, 107]. To date a number of plausible explanations for the desire to combine drinking and smoking have been provided. These include a strong genetic predisposition, enhanced rewarding effect of the combination, possible analgesic effects of the combination, metabolic interactions between the two substances and more recently mood effects of the two [60]. Nicotine, as discussed above may exert antidepressant effects. Interestingly, recently we observed that the depressogenic effects of high alcohol dose in Wistar rats can be blocked be pretreatment with nicotine. Moreover, alcohol-induced depression was associated with an increase in hippocampal BDNF that was also blocked by nicotine pretreatment. Thus, it could be suggested that counteraction of alcohol-induced mood dysregulation by nicotine might also contribute to their co-abuse [60]. To date, very few studies have looked at gender differences in relation to combined use of alcohol and nicotine [9, 45, 64]. Greenfield et al, 2010 [51], provided a comprehensive review of substance abuse in women with emphasis that further research in this area could provide very useful information for prevention and/or treatment of substance use disorder in women. This notion can be extended to studies dealing with concomitant problem of drinking and smoking as detailed in our current review. It is hoped that through such understandings better treatment for both genders, but especially for women in respect to drug abuse in general, and concomitant use of alcohol and nicotine in particular, will be achieved. Acknowledgment: Supported by: NIH/NIAAA R03AA022479 (YT), IN224314 from DGAPA-UNAM (OPG) and SAF2013-48532 (RM)

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GENDER DIFFERENCES IN RESPONSE TO ALCOHOL AND NICOTINE Y. Tizabi, O. Prospéro-García, R. Moratalla Department of Pharmacology, College of Medicine, Howard University, Washington, DC, USA Laboratory of Cannabinoids, Department of Physiology, Faculty of Medicine. UNAM Universidad Nacional Autónoma de México, Mexico. Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

SUMMARY Alcohol and nicotine have differential effects in males and females. Although some risk factors associated with depression are well established, the neurobiological substrates of such associations remain elusive. Despite the very high co-morbid incidence of smoking and depression, differential influence of nicotine in male vs. female are not fully elucidated. These gender issues become more important as they are compounded in comorbid condition of drinking and smoking. The detrimental risk factors are significantly higher in alcoholism and smoking alone and in combination they become synergistic. In this review, the mechanisms of action of alcohol and nicotine are given briefly and the gender differences in responses to this substances, are discussed. It’s concluded that alcohol and nicotine, individually or in combination, have differential CNS effects in male vs. female. For improved therapy, further investigation of gender dichotomy in alcohol and nicotine effects as well as dependence on these substances are warranted. Key Wards: alcohol, nicotine, gender.

23 ГЕНДЕРНЫЕ РАЗЛИЧИЯ В ОТВЕТ НА АЛКОГОЛЬ И НИКОТИН И. Тизаби, О. Просперо-Карция, Росарио Мораталла Департамент Фармакологии Медицинского Коледжа Говардского Университета, Вашингтон, США Лаборатория каннабиноидов, Департамент Физиологии Факультета Медицины, Мехико Каджал Университет, Верхний Совет Научных Исследований, Мадрид, Испания

РЕЗЮМЕ Алкоголь и никотин, два наиболее легально широко используемых вещества, имеют различные эффекты у мужчин и женщин. Это важное различие не изучено надлежащим образом. Хотя такие факторы риска, у женщин с депрессией, как семейная история депрессии и алкоголизм хорошо известны, их нейробиологические субстраты не изучены. Несмотря на высокую частоту сопутствующих заболеваений при курении и депрессиях, гендерное различие влияния никотина полностью не выяснены. Гендерные различия курения и алкоголизма становятся более важными, поскольку они усугубляются сопутствующими заболеваниями. Алкоголизм и курение являются вредными факторами риска, при различные видах рака, вместе они имеют синергетический эффект. В данном обзоре, после краткой презентации механизма действия алкоголя и никотина и гендерных различий в ответ на их действие, обсуждаются возможные способствующие факторы. Сделан вывод, что алкоголь и никотин, по отдельности или в комбинации, имеют различные эффекты на ЦНС у мужчин и женщин. Для улучшения терапии, оправданно дальнейшее изучение гендерной дихотомии эффектов спирта и никотина, и зависимости от этих веществ. Ключев ые слова : алкоголь, никотин, гендер.

24 alkoholisa da nikotinis zemoqmedebaze organizmis pasuxis genderuli Taviseburebani i. tizabi, o. prospero-karcia, r. morotala hovardis universitetis samedicino kolejis farmakologiis epartamenti, vaSingtoni, aSS kanabinoidebis laboratoria, medicinis fakultetis fiziologiis departamenti, mexiko kajalis universitetis samecniero kvlevebis umaRlesi sabWo, madridi, espaneTi reziume alkohols da nikotins, or yvelaze farTod legalurad gamoiyenebad nivTierebas, aqvT gansxvavebuli efeqtebi qalebsa da mamakacebSi. es mniSvnelovani genderuli gansxvaveba ar aris saTanadod Sefasebuli. dadgenilia depresiasTan asocirebuli riskis faqtorebi qalebSi, romelTac saojaxo istoriaSi aReniSnebaT depresia da alkoholizmi, Tumca am kavSirebis neirobiologiuri substratebi jer kidev Seuswavlelia. miuxedavad mowevis da depresiis Tanmxlebi daavadebebis Zalian maRali sixSirisa, nikotinis diferenciuli gavlena mamakacebSi da qalebSi ar aris srulyofilad Seswavlili. genderul gansxvavebebi metad mniSvnelovania, radgan isini Rrmavdeba alkoholizmis da mowevis Tanmxlebi mdgomareobebiT. mavne Cvevebi, rogoric alkoholizmi da mowevaa sxvadasxva formis avTvisebiani simivnis risk faqtorebs warmoadgenen, Tumca maTi moqmedeba sinergiulia orive risk faqtoris Serwymis Semdeg. mocemul statiaSi moyvanilia alkoholis da nikotinis moqmedebis meqanizmebis da maTze organizmis reagirebis genderuli gansxvavebebis mokle mimoxilva, ganxilulia am nivTierebaTa moxmarebis xelSemwyobi faqtorebi. miRebulia daskvna, rom alkohols da nikotins, calcalke da/an kombinaciaSi, gansxvavebuli gavlena aqvT qalisa da mamakacis centralur nervul sistemaze. mkurnalobis gaumjobesebis mizniT, aucilebelia alkoholis da nikotinis gavlenis genderuli diqotomiis da maT mimarT damokidebulebis Semdgomi detaluri Seswavla. skvanZo sityvebi: alkoholi, nikotini, genderi 25 ALTERATION OF OXIDATIVE METABOLISM UNDER THE INFLUENCE OF UVA IN WOMEN OF DIFFERENT AGES K. Berianidze, A. Katsitadze, T. Sanikidze Tbilisi State Medical University, Georgia

Ultra violet (UV) radiation represents 5% of the total solar radiation reaching the earth's surface, and is divided into two spectral regions: UVA (320–400 nm) and UVB (290– 320 nm) constituting ~96% and ~4%, respectively [6]. Differently from UVB, UVA rays are able to penetrate further into the dermal layers of skin where they are absorbed by skin chromophores triggering the generation of reactive oxygen species (ROS) in the resident dermal fibroblasts and in extra-cellular structures, which are responsible for oxidative damage, alterations in gene expression, DNA damage, leading to cell inflammation, photo- ageing/-carcinogenesis [2, 7, 8, 10]. Therefore is a clear need for biological protection of UVA underlying skin. Purpose of the study was to investigate the oxidative metabolism in blood of women of reproductive and menopausal age, after a course of UVA irradiation. MATERIALS AND METHODS 20 women have been investigated (group I – 10 menopausal women, aged 40-55years (menopause confirmed by 12 monthly amenorrhea [9]), and Group 2 – 10 women of reproductive age, 25-35years old). In order to study influence of UV rays on oxidative metabolism women exposed to radiation 320-400 nm wave length for 5-10 minutes in the solarium during 6 days per month 3 months in total. Parameters of oxidative metabolism - activity of red blood cells (RBC) antioxidant - / enzymes (catalase (CAT), superoxiddismutase (SOD), reactive oxygen (O2 ) and lipid (LOO ) radicals content in whole blood were studied in women blood by spectrophotometric and Electron Paramagnetic Resonance (EPR) methods. Statistical analysis of the results was performed by soft ware package SPSS (version 20.0). The difference between the values of the parameters evaluated criteria STUDENT-and statistical significance was determined by P values<0.05. RESULTS AND DISCUSSION Results of the study are shown in Table 1. Indicators of blood redox parameters did not statistically significantly differ among women of reproductive and menopausal period (Table 1), there was a statistically non significant trend increase the activity of CAT and SOD in women of menopausal period, indicating the intensification of oxidative processes in this

26 age group. After a course of UV irradiation in women of reproductive age activity of antioxidant enzymes was not statistically significant changed from baseline values, there was a tendency to increase in catalase activity. Table 1. Oxidative metabolism parameters before and after the influence of solariumin womenof different ages

Women in Reproductive Women in menopause Parameters age (25-35y) (40-55 y)

Cat Before 13,43±5,3 17,8±2,7 Act/mg. prot 38,41±12,3* After 16,25±4,8

18,93±1,8 SOD Before 14,81±2,3 Act/mg.prot After 15,54±2,5 24,32±1,5* LOO. Before 0 0 mm/mg After 0 1,5±0,2 - O2 Before 0 0 mm/mg After 0 0 In menopausal women after the course of UV irradiation catalase activity increased by 200%, SOD activity-24%compared to initial parameters. In the blood of reproductive age women oxygen and lipid reactive species have been recorded neither before, no after the exposure. Whereas in the blood of menopausal women after the course UV irradiation EPR signal of spin trapped lip peroxide and superoxide radicals were detected. Oxidative stress results from increased concentrations of reactive oxygen species and/or a reduction in antioxidants. The antioxidant enzymes form the primary defense system against reactive species and oxidative stress [5]. SOD converts superoxide (O2−) to hydrogen peroxide (H2O2) and its isoform (Cu Zn SOD have been identified in RBCs (11). Catalase converts H2O2 to water and oxygen and is present in all aerobic cells, with the highest levels in the liver, kidney and RBC [4]. It is estimated that UVA radiation promotes increase activity of free-radical oxidation and lipid peroxidation, is responsible for DNA damage initiation. UVA rays induce in human skin NOS gene expression and increase of NO-'s production, inhibition of fibroblast proliferation [2]. These processes contribute to skin aging. It is estimated that the UV

27 radiation-induced skin lesions significantly depending on the type of skin (photo tip) and patient age [1]. Our research results shown that UVA rays cause a particularly strong influence on the oxidative metabolism in the women of II group, represented by menopausal age women (according the Glogaus international classification this is a group of women, which are beginning to express photo aging symptoms). On the basis of above mentioned data, we need to recommended for women of menopausal age to avoid UV among them the UVA radiation.

REFERENCES 1. Baumann L. Cosmetic dermatology. New York: McGraw-Hill; 2002. 226 p. 2. Bickers DR, Athar M (2006) Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol 126: 2565–2575. 3. Chen M, Zhang G, Yi M, Chen X, Li J, Xie H, Chen X. Effect of UVA irradiation on proliferation and NO/iNOS system of human skin fibroblast. Zhong Nan Da XueXueBao Yi Xue Ban. Aug; 34(8):705-11. 4. Deisseroth A, Dounce AL. Catalase: physical and chemical properties, mechanism of catalysis, and physiological role. Physiol Rev 1970;50:319-75 5. Mates JM. Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology. Toxicology 2000;153:83-104 6. Sarasin A (1999) The molecular pathways of ultraviolet-induced carcinogenesis. Mutat Res 428: 5–10. 7. Scharffetter-Kochanek K, Wlaschek M, Brenneisen P, Schauen M, Blaudschun R, et al. (1997) UV-induced reactive oxygen species in photocarcinogenesis and photoaging. BiolChem 378: 1247–1257. 8. Vile GF, Tyrrell RM (1995) UVA radiation-induced oxidative damage to lipids and proteins in vitro and in human skin fibroblasts is dependent on iron and singlet oxygen. Free RadicBiol Med 18: 721–730 9. Women Health,2006, p. 23 10. Wondrak GT, Roberts MJ, Cervantes-Laurean D, Jacobson MK, Jacobson EL (2003) Proteins of the extracellular matrix are sensitizers of photo-oxidative stress in human skin cells. J Invest Dermatol 121: 578–586. 11. Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free RadicBiol Med 2002;33:337-349

28 ALTERATION OF OXIDATIVE METABOLISM UNDER THE INFLUENCE OF UVA IN WOMENOF DIFFERENT AGES K. Berianidze, A. Katsitadze, T. Sanikidze TSMU, Georgia

SUMMARY Purpose of study was to investigate the oxidative metabolism in blood of women of reproductive and menopausal age, after a course of UVA irradiation. 2 groups of women (I- menopausal, 2 – reproductive age) were exposed to radiation 320-400nm wave length, for 5-10 min. in the solarium, during 6 days per month, 3 months totally. Activity of red blood cells (RBC), -catalase (CAT), superoxiddismutase (SOD), - / reactive oxygen (O2 ) lipid radicals (LOO ) content, were studied in blood by Spectrophotometric and Electron Paramagnetic Resonance methods. In menopausal women after the course of UVA irradiation CAT activity increased by 200%, SOD -by 24%, EPR signals of spin trapped lipoperoxide radicals, were detected. In the blood of reproductive age women, oxygen and lipid reactive species were no recorded. We recommend for women in menopause to avoid UV, among them the UVA radiation. Key words: ultraviolet (UVA) radiation, oxidative stress, menopausal women, reproductive women

ИЗМЕНЕНИЯ ОКИСЛИТЕЛЬНОГО МЕТАБОЛИЗМА ПО ДЕЙСТВИЕМ УФА ОБЛУЧЕНИЯ У ЖЕНЩИН РАЗНОГО ВОЗРАСТА К. Берианидзе, А. Кацитадзе, Т. Саникидзе ТГМУ, Грузия

Целью исследования явилось изучение окислительного метаболизма в крови женщин репродуктивного и менопаузного возраста, после курса облучения в солярии (УФА лучи). Женщины (I группа – менопаузный возраст, 2 группа – репродуктивный возраст) подвергались 5-10 минутному облучению, длиной волны 320-400 нм в солярии, в течение 6 дней в месяц (в продолжении 3-х месяцев). Параметры окислительного метаболизма-активность антиоксидантных ферментов эрироцитов (каталазы (CAT), супероксиддисмутазы (СОД), содержание реактивных радикалов

29 - / кислорода (О2 ) и липидов (LОО ) в крови изучались методами спектрофотометрии и электронного парамагнитного резонанса (ЭПР). У женщин в менопаузе после курса УФА облучения активность каталазы увеличилась на 200%, активность СОД–на 24%, по сравнению с исходными значениями. В крови женщин репродуктивного возраста- активные формы кислорода и липидов не регистрировались, тогда как в крови женщин в менопаузе после курса УФА облучения были зарегистрированы сигналы ЭПР спин меченных радикалов липопероксидов. Выявлено особенно сильное воздействие УФА лучей на окислительный метаболизм женщин в период менопаузы. Рекомендуем женщинам постменопаузного возраста избегать УФ в том числе УФА облучения. Ключев ые с лова : ультрафиолетовое (UVA) облучение, окислительный стресс, женщины в менопаузе, репродуктивные женщины

UVA zemoqmedebiT gamowveuli oqsidaciuri metabolizmis cvlilebebi sxvadaxva asakis qalebSi q. berianiZe, a. kacitaZe, T. sanikiZe Tssu, saqarTvelo

reziume winamdebare kvlevis mizans warmoadgenda reproduqciuli da menopauzuri qalebis sisxlSi JangviTi metabolizmis procesebis Seswavla ultraiisferi A (UVA) sxivebiT zemoqmedebis Sedegad. qalebi (I jg. – menopauzis asakis, II jg. – reproduqciuli asakis qalebi) eqvemdebarebodnen solariumSi dasxivebas, 320-400 nm talRis sigrZis sxivebiT 5-10 wT-iT, TveSi 6 dRis ganmavlobaSi (sul 3Tve). gamokvleuli qalebis sisxlSi vikvlevdiT JangviTi metabolizmis parametrebs – eriTrocitebis antioqsidanturi fermentebis (katalazas, superoqsiddismutazas (sod), sisxlSi reaqtiuli Jangbadis (O2-) aqtivobas da lipidebis (LOO/) radikalebis Semcvelobas speqtrofotometruli da eleqtronuli paramagnituri rezonansis (EPR) meTodebiT. menopauzur qalebSi, UVA sxivebis zemoqmedebiT, katalazas aqtivoba izrdeboda 200%-iT, sod-is aqtivoba – 24%-iT, reproduqciul

30 qalebSi es maCveneblebi sawyisTan SedarebiT mniSvnelovnad ar Secvlila. menopauzuri qalebis sisxlSi UVA dasxivebis Semdeg aRiniSneboda lipoperoqsidebis EPR signali. kvlevis Sedegad dadginda, rom UVA sxivebi mniSvnelovan gavlenas axdens meopauzuri asakis qalebis JangviTi metabolizmis parametrebze (glogaus klasifikaciis Sesabamisad, qalebis am jgufSi ukve gamoixateba fotodaberebis simptomebi). miRebuli monacemebis safuZvelze, rekomendacias vaZlebT menopauzur qalebs moeridon UV, maT Soris UVA dasxivebis zemoqmedebas. sakvanZo sityvebi: ultraiisferi dasxiveba, oqsidaciuri stresi, qalebi menopauzaSi, reproduqciuli qalebi

31 SOME ASPECTS OF PATHOGENESIS OF HYPERTENSION IN MENOPAUSAL WOMEN M. Buleishvili, N. Lobjanidze, G. Ormotsadze, L. Ratiani, T. Sanikidze Tbilisi State Medical University, Georgia Davit Agmashenebeli University, Georgia INTRODUCTION Arterial hypertension (AH) is a common cause of cerebral stroke, myocardial infarction and heart failure. Risk of hypertension increases with age. Blood pressure in women of reproductive age, is usually lower than in age-matched men. After menopause increase of the systolic blood pressure is more common, so in menopausal women the frequency of AH is equal to that in men. The causes and pathogenesis of AH in menopause are not established yet. It ‘s proposed an important role of hormonal changes that develope during menopause and significantly contribute to the development of AH in this period of women’s life. A lot of studies reveal effects of estrogens on regulation of cardiovascular system [4, 13, 17]. These effects are connected with endotelium-dependent and independent vazodilatation. It’s well known that estrgen inhibits vascular smooth muscle proliferation (blocking collagen secretion), reduce permiability of potassium-dependent calcium channels [7], resulting in antihypertensive activity. The aim of our investigation was to establish the role of estrogens in the pathogenesis of AH during menopause. MATERIALS AND METHODS Clinical research were conducted on the patients who had been admitted to the to the Central Clinic of Tbilisi State Medical University during 2011-2013. Above-mentioned research complies with the norms of the bio ethic’s Foundations. The local ethics committee approved the protocol, and informed consent was obtained from all participants. Two groups (I group – reproduction age (35-50 years old – 20 patients), II group – menopause age (45-60 years old – 25 patients) of women with arterial hypertension were investigated and compared with each other. Inclusion in the menopausal group was performed according to the mark of 12 months of amenorrhea. Women with cystic disease, ovarioectomy, or using hormone replacement therapy, were excluded from studding group. Subjects were undergone preliminary screening for body mass index, dislipidemia, history of arterial hypertension, diabetes mellitus, myocardial infarction, stroke, angina pectoris, family history of coronary artery disease. Extensive data were collected regarding

32 smoking, alcohol intake, diet, physical activity, lifestyle factors, exposure to toxic materials, - . etc. In each group blood content of estradiole, oxygen (O2 ), lipid (LOO ) reactive species, NO, endothelin and antioxidant enzymes superoxide dismutase (SOD) catalase (CAT) glutation reductase (GR) activity were investigated. In order to determine activity of antioxidant enzymes packed red blood cell lysate of patients’ blood was prepared. The antioxidant enzymes activity (SOD, CAT, GR) was measured according standard spectrophotometric methods [4]. - . Free nitric oxide (NO), Free oxygen radicals (O2 ) and Peroxil radicals (LOO ) was measured by Electron Paramagnic Resonance (EPR) method on the rediospectrometre РЭ- 1307 (Russia). For the detection of free NO spin-trap natrium diethildithiocarbamate (DETC) 2+ (Sigma) was used. EPR spectres of NO-Fe -(DETC)2 complexes are measured at the temterature of liquid nitrogen at microwave power 20 mVt. Peroxil radicals (LOO.) was measured with spin-trapα-phenyl-tertbutilnitron (PBN) (SIGMA). Free oxygen radicals (O2) was measured with spin-trap 5, 5-dimethyl-I-pyrolin-IV-oxide (DMPO) (Sigma). Spintrapped - . O2 and LOO EPR spectres are measured at room temperature at microwave power 20 mVt.

Density of inactive form of β2–adrenoreceptors (β2AR) wasdetected according intencity of EPR signal g=2, 01 [15]. Endothelin–1 content in blood was measured by immune enzymatic assay with DRG (German-USA) standard –test reagents. Statistical analyses of the obtained results were performed by SPSS (version 10.0) program package. Result was obtained in form of standard deviation of average values. Difference between groups was assessed by student t+ criterion. In all cases statistical confidentiality was defined according to < 0.05 index. In order to determine the relationship between the obtained parameters correlation analyses were carried out. RESULTS It was revealed statistically significant changes of the redox - homeostasis parameters, in menopausal women (in relation to reproductive age): activity of catalase increased from 12,08±0,711 mcat/mlto 18,02±2,299 mcat/ml(50%), GR reduced significantly from 9,03±0,421 U/gHbto 5,63±0,387U/gHb(38%) and SOD didn’t significantly changed(reproductive age – 2,34±0,471U/ml; menopause – 3,02±0,274U/ml); lipoperoxide – . - . (LOO ) and superoxide-radicals (O2 ) content increases (LOO – from 0,36±0,039mm/mg to - 0,63±0,073 mm/mg; and O2 – from 0,06±0,016 mm/mg to 0,26±0,206 mm/mg) (Table 1).

33 Table 1. Activity of pro- and antioxidant system in blood of reproductive and menopausal aged women

. - LOO O2 Cat SOD GR (mm/mg) (mm/mg) (mcat/ml) (U/ml) (U/gHb) Reproductive 0,36±0,039 0,06±0,016 12,08±0,711 2,34±0,471 9,03±0,421 Menopause 0,63±0,073* 0,26±0,206* 18,02±2,299* 3,02±0,274 5,63±0,387* • P < 0,05

We have identified, as well decrease free nitric oxide (from 2,26±0,112 mm/mg to 1,89±0,050 mm/mg) and increase on endothelin content (from 5,4±0,2 pg/ml to 6,4±0,5 pg/ml)in the blood of menopausal women (Table 2). Table 2. Free nitric oxide (NO) and endothelin content in blood of reproductive and menopausal aged women NO Endotelin N (mm/mg) (pg/ml) Reproductive 20 2,26±0,112 5,4±0,2

Menopause 25 1,89±0,050* 6,4±0,5*

• P < 0,05

Density of inactivated β2AR (corresponding to the intensity of the EPR signal g = 2,01 [15]) on the surface of RBCs membranes in menopausal women was greater than the corresponding parameters in women of reproductive age (decreased from 0,51±0,008 mm/mg to 0,40±0,06 mm/mg) (Figure 1). This result indicates the decrease activity of adrenergic regulation during menopause. In some patients it was detected low intensity of NO hemoglobin NOHb EPR signal in blood (~1,5±0,07 mm/mg) (data is not shown). At the same time no statistically significant correlation was revealed between NOHb EPR signal intensity an estradiol blood concentration in reproductive (r = -0,60, p = 0.03) and menopause age (r = -0,29, p = 0,12) (Figure 2).

34 Figure 1.

Density of inactivated β2AR on the surface of erythrocyte membranes in reproductive and menopausal aged women 1 – reproductive age; 2 – menopausal age

Figure 2.

Scatterplot of ESTRONI against HbNO; categorized by AGE Tamriko_Levani 28v*49c AGE: 1 HbNO:ESTRONI: r = -0.6030; p = 0.0292 AGE: 1 ESTRONI = 0.5441-0.1613*x AGE: 2 HbNO:ESTRONI: r = -0.2939; p = 0.1290 AGE: 2 ESTRONI = 0.3746-0.016*x 0.8

0.7

0.6

0.5 NI O

R 0.4 T ES 0.3

0.2

0.1 -1 0 1 2 3 4 5 6 -1 0 1 2 3 4 5 6

AGE: 1 AGE: 2 HbNO

Correlation between the NOHb EPR signal intensity and estradiole content in blood of reproductive and menopause aged women (AGE 1 – reproductive age; AGE 2 – menopausal age)

35 DISCUSSION - . Free radicales includ in oxigen (O2 , OH, H2O2) and nitrogen (NO) reactive species, are the products of normal celular metabolism and exist in cells at low concentrations[8].Imbalance in their generation and clearence processes inducing by endogenous antioxidant system, increases the content of free radicals in organism and promotes the development of oxidative stress. Oxidative stress plays a central role in the pathogenesis of numerous different diseases. Results of investigations were revealed the disbalance between pro- and antioxidant systems activity in the menopausal women blood, characterized by increase of oxygen and . - lipids free radicals (LOO , O2 ) content, alterations in activity of antioxidant enzymes (CAT, GR) and reduction in estrogens level. The important role of estrogens in regulation of women redox metabolism is well known. Regarding to the results of numerous studies estrogens might protect tissue from oxidative stress by the receptor-dependent (increase expression and activity of endogenous antioxidant enzymes) and receptor independent (direct scavenging of reactive oxygen species) pathways. Direct receptor-independent antioxidative effects of estrogens is due to existence in their structure specific unsubstituted A-ring phenolic hydroxyl group with one or two adjacent methoxy groups, which provide strongest antioxidant protection. It was shown that estrogens increase manganese (MnSOD) and extracellular SOD (ecSOD) expression and enzyme’s activity [19]. Significantly lower GR activity has been seen in blood samples from menopausal women compared with that seen in reproductive aging women. Prolonged oral contraceptive use, increased GR activity [12]. In our study it was revealed, that in menopause GR activity was significantly lower and activity of SOD didn’t changed in comparison to the same parameters in reproductive women. These results appear to confirm findings regarding the stimulatory effect of estrogens on glutathione content [11] and the glutation cycle enzimes, but not SOD and CAT activities [12]. Significant increase of catalase activity may be considered as a compensatory against falling of GR activity. Butin contrast to CAT GR in addition to the detoxification of superoxide radicals implements neutralization of contributes to the development of oxidative stress. Therefore, estrogen deficiency in menopausal women causes the accumulation of free - . oxygen (O2 ) and lipid (LOO ) radicals in blood due to the reduction of antioxidant enzymes activity and failure of their scavenging potential. Many facts indicate on the important role of estrogens in the development of hypertension in post menopausal women. There are numerous evidence of the association between endothelial dysfunction and reduced endogenous production of estrogens [6]. Endothelial dysfunction is characterized by an impairment of endothelium-dependent

36 vasodilatation, which has been linked to imbalance between the endothelial-derived vasoactive factors, like nitric oxide and endothelin [3]. Nitric oxide (NO) is an extremely pleiotropic molecule, and there are many contradictory reports in the literature concerning its phisiological and pathophisiological role. These in consistencies may be due to the multiple cellular actions of this molecule, the level and site of NO production, and surround in redox environment. Decrease free NO content concentration in menopausal women’s blood detected in our study may be conditioned to the decrease of NO synthesis (at the expense of the reduction constitution endothelial NO sinthase (eNOS-ase) activity, or enzyme content), as well as the oxidative degradation of NO (transformation to peroxinitrite in the oxidative stress conditions), or deposition in form of HbNO complexes. β-adrenoreceptors β2AR involve in regulation of mechanical properties of red blood cells( RBCs) through the influence on the deformability of the membrane integral/skeleton proteins. These findings suggest that β-adrenergic agonists may improve in the RBCs passage through microvasculature [20]. Increasing the density of inactivated β2AR (the intensity of the corresponding EPR signal g = 2,01) on the surface of RBCs membranes of menopausal women in comparison of the corresponding data in women of reproductive age, revealed in our studies, indicates on the decrease activity of adrenergetic regulation during menopause and therefore the rheological properties of the blood.

It was established that β2AR play an important role in mediating β-adrenergic vasorelaxation in a variety of blood vessel types through stimulation of NO production. β2AR stimulate both the protein kinase A (PKA) and PI3K-Akt phosphatidylinositide 3 kinases/Protein kinaseB (PKB) also known as Akt pathways, which can give rise to phosphorylation on serine-1177 – and hence Ca2+-independent activation of endothelial NO- synthase (eNOS). This increase in eNOS activity augments NO biosynthesis. NO-induced hyper polarization of the plasmalemma activates CAT-1 (cationic amino acid transporter-1), which transportates extracellular L-arginine. Increased uptake of L-arginine (extra- and intracellular) by eNOS, substantially induces rising of NO production and mediation of vaso relaxation [16]. It was shown also, that estrogens involve in the regulation of β2-AR vasodilator effects through β2-adrenergic activation of NO synthesis via estrogen receptor α /estrogen receptor-β) ERα/ERβ pathway. Estrogen initiated cytoplasmic signaling events upon binding to estrogenic receptor, leading to cyclic Adenosine monophosphate (cAMP) production and phosphorylation of factors such as extracellular-signal-regulated kinases1/2 (ERK1/2), p38, and Akt, (Protein kinase B (PKB), also known as Akt, is a serine/threonine- specific protein kinas, that plays a key role in multiple cellular processes

37 such as glucose

38 metabolism, apoptosis, cell proliferation, transcription and cell migration) which ultimately induce activation of eNOS [12]. Therefore, reduction in estrogen levels during menopause causes the decrease the level of β2AR induced NO production and contributes disruption the mechanism of β2-AR vasodilator effect. In addition to direct vasodilatatory activity of NO it reveals vasoactive effect via regulation of RBCs deformability. Under in vivo conditions NO-dose-dependent biphasic effect is revealed: in presence of NO at physiological concentration in the blood, it participates in the maintenance of normal deformability of RBCs, but at higher concentrations NO adversely affects cellular mechanical behavior. It is yet unknown the target structure of that adverse mechanism; most probable site for this effect is altered phosphorylation of the RBCs cytoskeleton proteins with further changing of Na+-K+-ATP-ase and Ca2+-ATP-ase activities [4]. Increased synthesis of NO usually takes place as a result of activation inducible NO-synthase (iNOS) in conditions of influence of various proinflammatory factors. It should be mentioned that the estrogens stimulate eNOS enzymatic activity mediated by plasma membrane estrogen receptors [18], but suppress the indusible NO-sinthase (iNOS) [14] activity [9]. The inhibitory effects of estrogens on iNOS activity might be conditioned to their suppressive effects on proinflammatory cytokine activity. The mentioned leads to variations of NO level and instability of blood circulation and RBCs deformability during the period of menopause. In normal metabolic conditions approximately 10% of the daily turnover of RBCs (6000–8000 RBCs per 1 mm3 of blood) is removed from the circulation by reticule- endothelial system, which accompanied by release of free hemoglobin from these RBCs into the plasma. During impairment deformability of RBCs (induced by aging, disorder of membrane composition, inactivation of β2AR, or alteration of NO content) concentration of released free hemoglobin increases; it involves in regulation of vasoactivity of blood vessel due to its ability to bind nitric oxide and by this way which contributes to reduction of free nitric oxide content [3]. Decrease in nitric oxide content usually is associated with hypertension. Endothelin-1 is a potent vasoconstrictor peptide and increases its synthesis/release activity is associated with vaso-occlusion. Being an important mediator of vascular dysfunction, endothelin has also been identified as one of the targets for estrogen action in the vasculature. Estradiol and its major endogenous metabolites inhibit endothelin-1 synthesis by an estrogen receptors-independent mechanism [4, 10]. Consequently, lack of estrogen content during menopause is responsible to age related vasoconstriction and development of hypertension in menopause.

38 As it seems from the results of our study, lack of blood estrogens content in menopausal women is one of the major causes of impairment RBCs membranes deformability, decrease activity of adrenergic structures and the subsequent decrease of the

β2-AR-stimulated NO production. These factors contribute to reducing deformability of RBCs membrane and impairment of mechanical properties of the blood. This results do not give us the opportunity to get complete picture of development of hypertension in menopausal women, but provide an important novel information regarding the particularly physiological mechanisms underlying estrogen NO-dependent and β-adrenergic regulation of vascular tone in menopausal women. CONCLUSION From the above mentioned it is clear, that in menopausal women insufficiency of estrogens contents is the main factor, which stipulates probability of imbalance between the endothelial-derived vasoactive factors (nitric oxide and endothelin, β2-AR) and development hypertension. In women of reproductive age probability and risk of hypertension grows in the presence of additional risk factors, such as, oxidative stress and/or fluctuations in estrogens level towards insufficiency, which leads reduction of nitric oxide content due to its oxidative transformation in peroxinitrite, or enhanced inclusion in HbNO complexes.

REFERENCES 1. Bor-Kucukatay M., Wenby R. B., Meiselman H. J., Baskurt O. K. Effects of nitric oxide on red blood cell deformability. AJP Heart and Circulatory Physiology. 2003; 284, 5: H1577-H1584 2. Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med. 1995; 332: 1589–1593. 3. Dobarro D, Gómez-Rubín MC, Sanchez-Recalde A, Moreno R, Galeote G, Jimenez-Valero S, Calvo L, López de Sá E, López-Sendón JL. Current pharmacological approach to restoreendothelialdysfunction. Cardiovasc Hematol Agents Med Chem. 2009; 7(3):212-22. 4. Dubey R. K., Jackson E. K. Keller P. J. Imthurn B., Rosselli M. Estradiol Metabolites Inhibit Endothelin Synthesis by an Estrogen Receptor-Independent Mechanism. Hypertension. 2001;37:640-644, 5. Dubey RK, Oparil S, Imthurm B, Jackson EK. Sex hormones and hypertension. Cardiovasc Res. 2002; 53: 688-708.

39 6. Duerrschmidt N, et al. 2000; Yura T, et al. 1999; Griendling KK, et al., 2000, Yanes LL, Reckelhoff JF. Postmenopausal hypertension. Am J Hypertens. 2011; 24(7):740-9. 7. Grossini E., Molinari C., Mary D. A. S. G., Intracoronary Genistein Acutely Increases Coronary Blood Flow in Anesthetized Pigs through β-Adrenergic Mediated Nitric Oxide Release and Estrogenic Receptors. Endocrinology. 2008; 149: 2678–2687 8. Halliwell B, Gutteridge JM Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol. 1990; 186:1-85 9. Karpuzoglu E, Ahmed SA. Estrogen regulation of nitric oxide and inducible nitric oxide synthase (iNOS) in immune cells: implications for immunity, autoimmune diseases, and apoptosis. Nitric Oxide. 2006;15(3):177-86 10. Lekontseva O., Chakrabarti S., Davidge S. T. Endothelin in the female vasculature: a role in aging? AJP - Regu Physiol. 2010; 298, 3: R509-R516. 11. Liu H., Wang H., Shenvi S., Hagen T. M., Liu R.-M,Glutathione Metabolism during Aging and in Alzheimer Disease. Annals of the New York Academy of Sciences. 2004; 1019: 346–349. 12. Massafra C, D Gioia1, C De Felice1, E Picciolini, V De Leo, M Bonifazi and ABernabei. Effects of estrogens and androgens on erythrocyte antioxidant superoxide dismutase, catalase and glutathione peroxidase activities during the menstrual cycle. Journal of Endocrinology. 2000; 167:447–452. 13. Pelzer T, de Jaeger T, Muck J., Stimpel M, Neyses L. Oestrogen action on the myocardium in vivo: specific and permissive for angiotensin-con-verting enzyme inhibition. J Hypertens. 2002; 20:1001-1006. 14. Pfeilschifter J., Ditz R., Pfohl M., Schatz H. Changes in Proinflammatory Cytokine Activity after Menopause. Endocrine Reviews. 2002; 23(1):90–119. 15. Pulatova M.K., Richireva G.T, Kuroptieva Z.V. EPR in rafiobiology. 1989 (in Russian 16. Queen L. R, Ji Y., Xu B., et al., Mechanisms underlying β2-adrenoceptor- mediated nitric oxide generation by human umbilical vein endothelial cells. J Physiol. 2006; 15, 576( 2): 585–594 17. Ratiani L, Parkosadze G, Koptonashvili L, Ormotsadze G, Sulaqvelidze M, Sanikidze T. Correlation of atherogenetic biomarkers and estradiol changes in postmenopause. Georgian Med News. 2011; 195:100-5. 18. Stirone C., Boroujerdi A., Duckles S. P., Krause D. N. Estrogen Receptor Activation of Phosphoinositide-3 Kinase, Akt, and Nitric Oxide Signaling in Cerebral Blood Vessels: Rapid and Long-Term Effects. Molecular Pharmacology. 2005; 67. 1: 105-113.

40 19. Strehlow K, Rotter S, Wassmann S, Adam O, Grohé C, Laufs K, Böhm M, Nickenig G. Modulation of antioxidant enzyme expression and function by estrogen. Circ Res. 2003;25; 93(2):170-7. 20. Tuvia S., Moses A., Gulayev N., Levin S., Korenstein R. β-Adrenergic agonists regulate cell membrane fluctuations of human erythrocytes. The Journal of Physiology, 1999; 516: 781-792

SOME ASPECTS OF PATHOGENESIS OF HYPERTENSION IN MENOPAUSAL WOMEN M. Buleishvili, N. Lobjanidze, G. Ormotsadze, L. Ratiani, T. Sanikidze Tbilisi State Medical University, Georgia Davit Agmashenebeli University, Georgia

SUMMARY The aim of investigation is to establishthe role of estrogens in the pathogenesis of hypertention in menopause. Clinical researches were conducted on the patients who had been admitted to the Central Clinic of Tbilisi State Medical University during 2011-2013. Two groups (I group – reproduction age (35-50 years old – 20 patients), II group – menopause age (45-60 years old – 25 patients)) of women with hypertension were investigated. The results of study reveal increased blood superoxide and lipoperoxide radicals, and endothelin content and decreased of free Nitric Oxide (NO) content in menopausal women blood. At the same time activity of catalaseincreased (from 12,08±0,711 mcat/ml to 18,02±2,299 mcat/ml (50%)) Glutathione Reductase (GR) reduced (from 9,03±0,421 U/gHb to 5,63±0,387U/gHb (38%)) significantly and Superoxide Dismutase (SOD) didn’t change in relation to reproductive aged group. Negative correlation between the complexes of NO with hemoglobin (Hb) and estradiole content in blood of reproductive aged (r = -0,60, p = 0.03) was revealed. In menopausal women insufficiency of estrogens isthemain factor, which stipulates probability of imbalance betweentheendothelial-derivedvasoactivefactors (nitric oxide and endothelin, β2-AR) and developmentof hypertension. In women of reproductiveageprobability and risk of hypertensiongrows in thepresence of additionalriskfactors, such as, oxidativestress and/orfluctuations in estrogens level towards insufficiency, which leads reduction of nitric

41 oxide content due to its oxidative transformation in peroxinitrite, or enhanced inclusion in HbNO complexes. Key words: menopause, nitric oxide, endothelin, oxidative stress

НЕКОТОРЫЕ АСПЕКТЫ ПАТОГЕНЕЗА АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИИ У ЖЕНЩИН В МЕНОПАУЗЕ М.Булеишвили, Н. Лобжанидзе, Г.Ормоцадзе, Л. Ратиани, Т. Саникидзе Тбилисский Государственный Медицинский Университет, Грузия Университет им. Давида Агмашенебели, Грузия

РЕЗЮМЕ Целью исследования явилось установление роли эстрогенов в патогенезе артериальной гипертензии (АГ) в период менопаузы. Исследованы две группы женщин с АГ (I группа – репродуктивный возраст 35-50 лет – 20 пациенток), II группа – менопауза (возраст 45-60 лет – 25 пациенток) Было выявлено увеличение содержание супероксид и липопероксид радикалов и эндотелина и снижение содержания свободного оксида азота (NO) в крови пациенток периода менопаузы. Активность каталазы увеличилась (с 12,08±0,711 MCAT/мл до 18,02±2,299 Mcat/мл (50%)), GR снизилась (с 9,03±0,421U/ГОМК в 5,63±0,387 U/ГОМК(38%)), SOD не изменилась по сравнению со значениями в крови пациенток репродуктивного возраста. Выявлена отрицательная корреляция между содержанием комплексов NO с гемоглобином и эстрадиолом в крови женщин репродуктивного возраста (R = -0,60, р =0,03). Недостаточность эстрогенов способствует развитию дисбаланса между вазоактивными факторами эндотелия и развитию АГ. У женщин репродуктивного возраста риск АГ растет в присутствии окислительного стресса и колебания уровня эстрогенов в крови, что приводит к снижению содержания оксида азота (в силу его окислительной трансформации в пероксинитрит, или включения в комплексы HbNO). Ключевые слова: менопауза, нитрит азота, эндотелин, окислительный стресс.

42 arteriuli hipertenziis paTogenezis zogierTi aspeqtebi menopauzis periodSi m. buleiSvili, n. lobJaniZe, g. ormocaZe, l. ratiani, T. sanikiZe Tssu, saqarTvelo daviT aRmaSeneblis universiteti, Tbilisi, saqarTvelo

reziume kvlevis mizani iyo, arteriuli hipertenziis paTogenezSi estrogenebis rolis dadgena menopauzis periodSi.

Seswavlil iqna arteriuli hipertenziis mqone qalebis ori jgufi. I jgufi – reproduqciuli asakis 35-50 wlis 20 pacienti, II – menopauzis jgufi, asaki – 45-60 weli, 25 pacienti. kvlevis Sedegebma aCvena sisxlSi superoqsidis da lipoperoqsidis zeJanguri radikalebis da endoTelinis zrda da Tavisufali azotis oqsidis (NO) donis Semcireba menopauzis asakis pacientebSi. katalazas aqtivoba (12,08±0,711 MCAT/ml-dan 18,02±2,299Mcat/ml-mde (50%) gaizarda. GR Semcirda (9,03±0,421 U/GOMK-­‐dan 5,63±0,387 U/GHB-­‐mde (38%), SOD ar Secvlila reproduqciuli asakis qalebTan SedarebiT. reproduqciuli asakis qalebSi aRiniSna uaryofiTi korelacia sisxlSi NO kompleqsebis, hemoglobinis da estradiolis SemcvelobaSi (R = -­‐0,60, p = 0.03). zemoTqmulidan gamomdinare, SegviZlia davaskvnaT, rom estrogenebis nakleboba xels uwyobs endoTeluri vazoaqtiuri faqtorebis disbalanss da arteriuli hipertenziis ganviTarebas reproduqciuli asakis qalebSi. arteriuli hipertenziis risks zrdis oqsidaciuri stresi da estrogenis donis Semcireba sisxlSi, rac iwvevs azotis oqsidebis Semcirebas maTi peroqsinitritad oqsidanturi transformaciis an HbNO kompleqsebSi CarTvis gamo. sakvanZo sityvebi: menopauza, azotis nitriti, endoTelini, oqsidaciuri stresi

43 CITRUS EXTRACT IN PROPHYLACTIC OF CHRONIC DISEASES Gvilava, I. Chkvishvili. M. Giorgobiani, T. Sanikidze Tbilisi State Medical University (Review Article)

60% of deaths in worldwide are caused by chronic diseases (CD) – (chronic heart disease, chronic respiratory disease, stroke, cancer, diabetes, rheumatoid attrite, neurodegenerative diseases, mental disorders , trauma, etc.). In 2005, more than 35 million people died as a result of CD [33]. The average age-old (65 years) persons, of the world's population, has increased in the last 20 years, which is accompanied by a significant increase in the number of CD [32]. At the same time, the modern urbanization and the technical progress on our planet, is accompanied with grow in geochemical and radioactive contamination background, as a result of abundance of modern industrial (nuclear power plant), medical (diagnosis and therapy), military (nuclear terrorism) sources and geo- ecological and political factors – earthquakes, cosmic radiation, the social and political explosions [10, 31]. CD deaths occurred in 80% of population of low and middle-income countries [34]. In the developing countries health care system is focused, primarily, to provide emergency medical system, and less attention is paid to prevention and management of CD. CD are complex, depending on the trigger factors, as well as the conditions, are characterized by long duration (more than 6 months), resistance, a huge number of complications and sudden exacerbations [33], The health care system is creating problems for growth of medical costs, and service conditions in the field of CD prevention. Created the need to be focused from emergency medicine on the CD management (65+-population) [32]. CD are accompanied by the components: inflammation, free radical oxidation and oxidative stress. This triad is not a disease, rather the result of a normal cellular process, but at the same time, active participant of chronic heart disease, chronic respiratory disease, stroke, cancer, diabetis, rheumatoid athritis, neurodegenerative diseases, mental disorders, trauma, aging and other processes. As CD incidence and its tendency to lethality are projected to increase for decades all over the world, there is a need for effective preventive strategies. Evidence continues to mount that altering dietary habits is an effective and cost-efficient approach for reducing CD risk. There is growing interest in the ability of phytochemicals to preventCD. While

44 optimizing the intake of specific foods and/or their bioactive components seems a prudent, non-invasive and cost-effective strategy for reducing the cancer burden, is far from a simple process [19]. The magnitude of the problem in identifying critical dietary components, is evident by the literally thousands of compounds consumed each day [7, 19]. Plants are known to synthesize a diverse array of phytochemicals, including flavonoids, polyphenols and anthocyanins that assist a plant to resist pathogens. It is important to note that though each of these phytochemicals is potent in influencing on the signal system of cell-cell interaction and genes expression [28]. These compounds are strong inhibitors of oxidative stress development, they are also non-toxic to the normal cells [24]. What really sets apart their differential effects in abnormal cells versus, normal cells is their ability to regulate oxidative metabolism cells and at the same time, manipulate levels of metabolizing enzymes and induce detoxifying enzymes rendering them non-toxic to normal cells. Flavonoids of food plants have high potent neurotropic activity [28]. There is growing interest in the ability of phytochemicals to prevent CD [5, 9, 13, 16, 23, 29]. Furthermore, the dearth of quantitative information about some food constituents limits the ability to unravel which constituents are most important. Unfortunately many food phytochemicals remain largely uncharacterized and this can lead to confusion about the true role of diet in determining health. Interactions between the different components within a food, may explain why isolated components do not always result in similar biological outcomes to the intact food [7]. Over the recent 15 years, scientists are very much interested in natural compounds, that are characterized by antioxidant properties (propolis extract, various herbal products – citrus hesperidin, tea polyphenol compounds, red grape extract, etc. [11, 12], that are able to protect cells from radio-induced effects. Protective activity of herbal compounds is determined by high content of compounds with bioactive, antioxidant, immunemodulator activity. Separated from citrus active compounds (polymetoxiated flavones) characterized by antioxidant, immunomodulative, antibacterial, antivirus, anticancerogen activities. Separated from citrus hersperidin, in combination with other flavonoids, is used in Europe for the treatment of various CD; there are some evidence upon protective, DNA-stabilizing activity of hesperidins [2, 12, 14, 37]. Polymetoxilated flavones antyatherogenic activivty was established, which revealed in their antioxidant and lipid metabolism, the regulatory activity – they involve in neutralization of oxygen free radicals, accelerate the dissorganisation of low density lipoproteins and prevent the development of atherosclerotique plaques. [6, 25, 35]. It

45 is very interesting effect of flavonoids on benzopirens detoxification and its derivatives formation processes in animal liver [34]. In particular, flavonon’s derivatives, have ability to by 3-4 folds increase hydroxilation of benzpirenis in animal liver microsomes. Tangeretin and nobiletin increase monooxigenas activity during benzopiren detoxification; nobelitin cellular signal transduction factors (cAMP, ERK/MAPK, CREB) stimulatory activity was established [1, 20, 36]. A large quantities of the nobilitin are found in citrus peel [21]. As for citrus extracts influence on women’s health. We investigated tangerine extract (TE), in the laboratory of Department of Medical Physics and Biophysics of Tbilisi State Medical University. The experimental and clinical studies, revealed ability of TE to correct carbohydrate, lipid and oxidative metabolism, decrease body mass index, epididymal fat mass and body weight in women with metabolic syndrome and over faded female rats [3, 6, 38, 39]. A 4-month clinical trials have shown that TE is an effective remedy for the correction of metabolic syndrome components: reduces abdominal obesity by decrease waist circumference; corrects dislipidemy – normalizes elevated levels of plasma triglycerides and reduced plasma levels of High Density Cholesterol (HDL), effectively corrects carbohydrate metabolism disorders – reduction of glycated hemoglobin (HbA1c) in patients with impaired glucose tolerance/diabetes mellitus type 2 [26]. In human peripheral blood limphocites stimulative activity of polymetoxilated flavones (nobelitine) on copper oxidation in the cytochrome oxidase, was established. We propose that the modulatory ability of nobeline on the activity of mitochondrial enzymes determines imunomodulative and anticancerogenic activity of this compound. The mechanisms of action of nobiletin, identified in investigations indicates on new pharmacological approaches of citrus flavonoids [6]. In another research, flavonoids of tangerine peel extract, prevented liver damage through supression activity of regulatory Th - cells and anti-inflammatory cytokines (TNFα, INF-γ), and activation of IL-10 expression. These studies indicate the new ways in treatment of chronic hepatitis and other autoimmune diseases through the use of the citrus flavonoids [22]. Tangerins peel is exspesially rich with polymetoxilated flavonoids. Ten polymetoxilated flavonoids were extracted, among them two newly discovered plavons 7- hydroksy-3,5,6,3',4"-pentametoxiflavones and and 7-hydroksy-3,5,6,8,3',4"- hexametoxiflavone. Many of them (5,6,7,8,3",4"-hexametoxy-flavone (nobiletine), 5,6,7,8,3,4"-pentametoxyflavone (tangeretin) and 5,6,7,4'-tetrametoxiflavone (tetra-0- metylizoscutelarein) has antycancerogenic activity, 5,6,7,3',4"-pentametoxyflavone (sinensetine) and 5,6,7,8,3",4"-hexametoxy-plavone (nobiletine) reduce erytrocites aggregation and sedimentation in vitro [4]. Structure-dependent antycancerogenic, antioxidant, antiinflammatory activity of this compounds was established. In particular 5 -

46 OH, 3 - OCH [3] 8 - OCH [3] containing compaunds revialed high actiity, wheares 3 - OH and 3'-OCH (3) containing – low activity [15, 17, 25]. New natural flavonoids-6-oxy-3, 5, 7, 8, 3’, 4’-hexametoxyflavone, 3, 5, 7, 3’, 4’- pentaoxy-8-metoxyflavone and 3, 5, 7, 8, 4’-pentaoxy-3’-metoxyflavone, were extracted by us from citruses (tangerine peel) [43]. Among them 3, 5, 7, 3’, 4’-pentaoxy-8-metoxyflavone and 3, 5, 7, 8, 4’-pentaoxy-3’-metoxyflavone in citrus famili were detected the first. We first identifited 5-oxyi-3, 7, 8, 3’, 4’-pentametoxiflavone, 5-oxyi-6, 7, 8, 3’, 4’- pentametoxyflavone, 3, 5, 6, 7, 3’, 4’-hexametoxiflavone, 3, 6, 7, 8, 4’-pentametoxyflavone, 3, 5, 7, 8, 3’, 4’-hexametoxyflavone, 5, 7, 8, 4’-tetrametoxyflavone and 5, 7, 8, 3’, 4’- pentametoxyflavone from most common sort of tangerine, unshiu [41, 42]. Numerous studies establish, that partly hydroxylated flavones are characterizid by high biological activity. Polimetoxilated flavones inhibit human cancer cells proliferation [25, 36]. Special interest attract 5-oxyentametoxy flavones (characterized by expessially high activity, as fully metylated derivates (noniletine, tangerine)). 5-oxy-6, 7, 8, 3’, 4’- pentametoxyflavone, 5-oxyi- 3,6,7,8,3’,4’-hexametoxy-flavone and 5-oxy-6, 7, 8, 4’- tetrametoxyflavone revialed regulatory activity on the cell proliferation and apoptosis signal proteins (Pp21Cip1/Waf1, CDK-2, CDK-4, phosphor-Rb, Mcl-1, caspases 3 & 8, and PAR) [Qiu P, et al. 2010, Xiao H, et al. 2009]. We believe that the investigation of plant products and their identification will stimulate creation of high quality plant production. The prophylactic use of safe edible plants, among them the TE, will help us to reduce and avoid risk factors, that can lead to cancer, circulatory, diabetes, obesity and other CD.

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CITRUS EXTRACT IN PROPHYLACTIC OF CHRONIC DISEASES Gvilava, I. Chkvishvili. M. Giorgobiani, T. Sanikidze TSMU Review Article

SUMMARY 60% of deaths in worldwide are caused by chronic diseases (CD). CD are complex, depending on the trigger factors, as well as the conditions, are characterized by long -more than 6 months duration, resistance, a number of compititions and sudden exacerbations. The health care system is creating problems for growth of medical costs, and service conditions in the field of CD prevention. Created the need to be focused on the CD management and need of effective preventive strategies. Evidence continues to mount that altering dietary habits is an effective and cost-efficient approach for reducing CD risk. There is growing interest in the ability of phytochemicals, characterized by antioxidant properties to prevent CD. From the citrus, exspesially tangerine are separated active compounds -polymetoxiated flavones, which are characterized by antioxidant and immunomodulative activity. Tangerine Peel Extract (TPE) obtained in laboratories LTD “Irakli Chkhikvishvili”. Prophylactic use of safe, edible TPE will help us to reduce and avoid risk factors that can lead to CD. Key words: Citrus, Tangerine peel extract, chronic diseases.

51 ЦИТРУСОВЫЙ ЭКСТРАКТ В ПРОФИЛАКТИКЕ ХРОНИЧЕСКИХ ЗАБОЛЕВАНИЙ И. Гвилава, И. Чхиквишвили, М. Гиоргобиани, Т. Саникидзе ТГМУ

РЕЗЮМЕ 60% смертности в мире вызваны хроническими заболеваниями (ХЗ). ХЗ являются комплексными, зависят от провоцирующих факторов, окружающих условий, характеризуются длительностью-более 6 месяцев течения, высокой резистентностью и в ряде случаев- внезапными обострениями. В результате, в системе здравоохранения создаются проблемы связанные с ростом медицинских расходов, а также необходимостью создания условий купирования и профилактики ХЗ. Возникает необходимость сосредоточения здравохранения на проблеме лечении ХЗ, разработке эффективных профилактических стратегий. В настоящее время существуют многочисленные доказательства об эффективности коррекции питания в профилактике ХЗ. Внимание привлекают различные фитохимические соединения, обладающие антиоксидантной, иммуномодуляторной активностью, как средства профилактики ХЗ. Цитрусуы, особенно мандарины особенно богаты биологически активными полиметоксилированными соединениями, характеризующимися антиоксидантной и иммуномодуляторной активностью. Экстракт из кожуры мандарина получено в лаборатории ООО «Ираклий Чхиквишвили». Профилактическое применение пищевых продуктов содержащих экстракт из кожуры мандаринов будет способствовать снижению риска развития ХЗ. Ключев ые с лова : цитрусы, экстракт кожуры мандарина, хроническое заболевания.

52 citrusebis eqstraqti qronikul daavadebaTa prevenciaSi i. gvilava, i. CxikviSvili m. giorgobiani, T. sanikiZe Tssu

reziume msoflioSi sikvdilianobis 60% gamowveulia qronikuli daavadebebiT (qd). qd damokidebulia maprovocirebel faqtorebze, garemo pirobebze, xasiaTdeba xangrZlivi – 6 Tveze meti mimdinareobiT, maRali mdgradobiT mkurnalobis mimarT, da rig SemTxvevebSi, uecari garTulebebiT. Sedegad, izrdeba qd mkurnalobis xarjebis zrdasTan dakavSirebuli problemebi jandacvis sistemaSi, iqmneba qd efeqturi prevenciis da mkurnalobis strategiis Seqmnis aucilebloba. amJamad dadasturebulia kvebis wesis koreqciis efeqturoba qd prevenciis mizniT. yuradRebas ipyrobs sxvadasxva fitoqimiuri naerTebi, romelTac gaaCniaT antioqsidanturi da imunomodulat oruli moqmedeba, rac, SesaZloa, gamoyenebul iqnes qd prevenciisTvis. citrusebi, gansakuTrebiT mandarini, mdidaria biologiurad aqtiuri polimetoqsilirebuli naerTebiT, romelTac axasiaTebs antioqsidanturi da imunomodulatoruli moqmedeba. mandarinis eqstraqti miRebulia Sps "irakli CxikviSvili"-s mier. mandarinis kanis eqstraqtis Semcveli sakvebi danamatebis gamoyeneba qd profilaqtikis mizniT Seamcirebs maTi ganviTarebis risks. saakvanZo sityvebi: citrusi, mandarinis kanis eqstraqti, qronikuli daavadebebi

53 SUGGESTED PROGRAM OF TRAINING EXERCISES FOR PREGNANT WOMEN AT "SCHOOL OF MOTHERHOOD" O. V. Goncharova SEI Department at I. M. Sechenov First Moscow Medical University President of the All-Russia Public Institution

In the Russian Federation nowadays much attention is paid to development of service for diseases prevention, especially in the field of protection of motherhood and childhood, with the service providers in the Russian Federation generally presented by “Motherhood Schools”, antenatal clinics in Maternity Welfare Centers and “Healthy Child Rooms” in children's policlinics [1, 2]. It should be noted however, that, despite the observed improvement in demographic situation in the Russian Federation noted by 2010, the outlined growth of birth rate and decrease in infantile mortality cannot lead to decrease in natural losses of the population [4, 5]. Every third child, according to Federal State Budgetary Institution, the Science Centre of children’s health care RAMS, already from the period of neonatality, has various diseases and deviations from the state of health; every twelfth baby is born with low body weight. Morbidity rate of newborns in general increased over the last 5 years by 20%. And among the 15-17-years old groups of children there is noticeable increase in prevalence of chronic diseases; therefore there was developed the actual system of the measures directed on prevention of children's morbidity since the antenatal period [3]. “MOTHERHOOD SCHOOLS” IN MATERNITY WELFARE CENTERS According to the Order by Ministry of Health of the Russian Federation No. 50 dd. 10.02.2003 "Concerning approval of instructive-methodological directions for organization of work schedule in maternity welfare centers", in the field of providing out-patient and polyclinic obstetric and gynecologic assistance, the leading role is played by maternity welfare centers. Preparation for childbirth and motherhood in maternity welfare centers is carried out individually as well as at “Motherhood Schools”. Basic principles to functioning of “Motherhood Schools”. 1. Creation of the programs for "School of the motherhood" including 3 practice lessons given by obstetrician-gynecologist doctors, 2 - by pediatrician and 1 by a legal consultant (if there is any professional consultant or advisor available); 2. Providing personnel structure of "School" including doctors, accoucheurs and nurses taking care for newborns (being medical assistants when carrying out exercises);

54 3. Selection of groups for exercises for 15-20 women, it is desirable to have in the same groups women with identical term of pregnancy; 4. Implementation of a manager of consultation functions of control under organization of work of the whole "School"; 5. Organization of methodical materials ensuring work of "School" through communication with the territorial authority services to medical prevention centers. One of effective forms of teaching is helping to make the whole family ready for the child's birth, directed to involvement of all the family members into active participation in prenatal preparation. The trainers use for teaching demonstration materials, visual aids, technical means and subjects of care of the child, in various forms of interactive training. All the women, starting from the Ist trimester of pregnancy, are invited to visit the School of motherhood, and it is desirable them to be there together with future fathers or close relatives. Part 1. Training program of Exercises suggested by obstetrician-gynecologist doctors for pregnant women at school of motherhood Exercise 1. Anatomic and physiology changes taking place in mother's organism during pregnancy  Brief information concerning the structure and functioning of privates system and organs.  Female and man's genital organs.  Development of a pre-natal fetus (Fertilization. First signs of pregnancy. Development of a fetus during the months of pregnancy, its reaction to external irritants. The role of placenta and amniotic fluids supporting the life of a fetus. Physiological changes in the woman's organism, during pregnancy periods).  Risk factors of pregnancy (What are the risk factors? Influence of health of parents onto health of the future child. Heredity factors role. Addiction to alcohol, smoking, narcotic drugs and toxic substances by parents as harmful risk factors of pathology of a fetus. Influence of other adverse factors onto fetus: ecology, industry, infectious, medicinal, radiation background, etc. Complications during pregnancy).  Medical supervision (Importance of early visits of a pregnant woman to maternity welfare centers. Frequency of visits by obstetrician doctors, gynecologists, accoucheurs. Necessity to carry out in obligatory volume medical examinations through all the period of pregnancy. Acquaintance with modern tool methods of tracking the state of health of mother and fetus. Trainings for pregnant women participating in some tests for certain assessments of progress of pregnancy and condition of the fetus).

55 Exercise 2. Hygiene guidelines to be followed during pregnancy  Change in life style (Recommendations about the labor regimes at work and at home. Legislative rights of pregnant women. Day regimen. Sexual life during pregnancy).  Food (Concept about caloric content of food and balanced diet nutrition. Drinks and water consumption. A role of vitamins and microelements for health of mother and fetus. Features of food at pathological states: early toxicosis, constipations, arterial hypertension, diseases of kidneys, etc.).  Personal hygiene (Value of observance of body cleanliness: care for skin, teeth, mammary glands, genitals, etc. Clothes, footwear, underwear. The role of breastfeeding during the first 6 months of the child’s life. Use of natural factors for straightening and tempering of women’s organism).  The role of gymnastic exercises during pregnancy (Training in a complex of physical exercises according to pregnancy term. Training improving the ability to relax - "quick rest").  Features of psycho-emotional conditions of pregnant women (Psychological adaptation of the woman to pregnancy. The role of family in psychological and physical support of the woman during pregnancy, childbirth and after the child's birth). Exercise 3. Preparation to "childbirth without fear" . Calendar terms of approaching time of childbirth. . Harbingers of started childbirth activity. . Preparation for going to maternity hospital. . Labor periods of childbirth and duration. . Behavior at delivery (Importance of correct and calm behavior of the woman at childbirth. Role of partnership in childbirth. Trust to the medical personnel and necessity to follow all recommendations given by the doctors. Training in various ways of breathing for the safe course of childbirth. Training in administration and taking of labor pain relief. Auto- training and local self-massage for strengthening of the psycho-emotional condition at childbirth). . First hours after the child delivery. Value of immediate applying the child to breast right in the delivery room. . Remedial gymnastics in postnatal period. . Contraception after the child delivery. . Legislative rights of motherhood.

56 Part 2. Program of Exercises suggested by pediatricians for pregnant women at "school of motherhood" Exercise 1. The baby is born  Signs of the mature child.  Anatomic and physiologic features of the newborn.  Hormonal crisis in newborns.  Importance of staying together for the mother and child in maternity hospital.  Rules of personal hygiene at intercourse contact with the newborn.  Techniques of putting the child to breast.  Advise on preparing sets of linen and things for the newborn at going home from maternity hospital. Exercise 2. Care for the newborn child in the family . Preparation and hygiene of "dedicated corner" for the child in the family. . Items to care for the child. . Rules of taking care for the child (Daily hygienic procedures, washing the child. Care for skin and umbilical wound. Loose swaddling. Day regimen). . Feeding of the newborn (Importance of breastfeeding role formation good health of the child. Artificial (bottle) feeding). . Influence of harmful factors on health of the child (Inadmissibility of addictions in the family: smoking, alcohol, consumption of narcotic and toxic substances). . Councils and training in carrying out medical recommendations (Methods of massage and elements of gymnastics for the newborn. Technique of measurement of temperature. Instillation of nasal drops, and drops for ears and eyes. Putting cleansing enemas and introduction of gas vent pipes. Use of warming pans and hot-water bottles, rules to use warming compresses. Preparation and Technique of giving medicines prescribed by the doctor, danger of self-prescribed treatment). Exercise Example "Breastfeeding" At School Of Motherhood Women's milk, in comparison with its artificial substitutes, has major advantages which include:  optimum and balanced level of nutrition,  high assimilability in child's organism of nutrition contained in women's milk,  contained in milk wide range of biologically active agents and protective factors (enzymes, hormones, immunoglobulins, lactoferrin, leukocytes, etc.),  beneficial effect on intestinal microflora,  sterility, 57  optimal temperature. Women's milk completely corresponds to features of a metabolism of child’s organism at early age and has positive impact on its growth, development, resilience to infections, intellectual potential, behavioural and mental reactions. Nature of feeding on the first year of life substantially defines the state of health of the child not only at early age, but also during the subsequent periods of his life. Poses when feeding First of all choose for yourself and the child a convenient pose to carry out feeding in relaxing circumstances. It is important as your fatigue can lower or block lactation. In the first days after delivery you feed the baby in bed, lying on one side and having placed a small pillow under this side as a form of support (or having put the baby on it). You can, especially if childbirth was carried out by Cesarean section, feed the child lying on the back. Place the baby onto your stomach, supporting the forehead as it is still difficult for the child to hold the head for long time. In such position the child can suck the milk long as the baby can easily breathe. And it is better when feeding the baby to sit in a low chair or on a chair, having placed under your leg a small stool in accordance with the breast with which you feed. But at any pose we recommend "skin to skin" and "eyes in eyes" contact, therefore before feeding, undress to waist, leave the kid in a diaper and cover with a warm diaper. In such a situation the child will touch your breast and proximity of mother will wake in the baby all necessary reflexes. And closeness of the baby, touching the breast, in turn, will be favorable to influence quantity of hormones in your blood: the prolactinum stimulating production of milk and oxytocin, promoting contractions of uterus and extraction of milk from breast. 1. Before breast-feeding, with the purpose of infection prevention, follow the rules of personal hygiene: nails have to be cut short, hands always washed with soap. Daily, at least once a day, use special antiseptic wipers or wash breast with warm water and soap, and before each feeding – always use special clearing wipers or just simply wash with water. Put some cream onto glands located round nipple, when breast-feeding to create for breast a protective film working like a shield against bacteria and preventing the skin of nipples from drying; if you wash your breast too often, the breast nipple and the skin of areola around it will lose the most part of greasing, then glands can become blocked or inflamed, there might be cracks appearing on nipples. 2. Decant the first 2-3 drops of milk and pour out as in outer departments of ferruterous channels it can be polluted.

58 3. Touch the baby’s lips with the nipple (better the upper lip) for stimulation of grabbing reflex. 4. With your hand raise up the breast, holding it between the thumb and the other fingers (the breast lies on the palm) and direct the nipple towards the child. Some mothers prefer to hold the breast with finger close to the child's nose. It is not necessary to do it as thus milk channels would be squeezed and the milk flow weakens. The child freely breathes even without the breast hold with the finger. 5. Make sure the child took the round-nipple areola together with the nipple, it prevents the baby from swallowing air and cracks on skin of nipples. You can support the child holding the back and shoulders, but not the nape. His head has to lean back freely, slightly leaned back. For how long breast feeding of the child has to last? The child’s sucking on average about 15-20 minutes. We don't recommend to leave the child with the breast for more than 20-30 minutes as long sucking of breast can lead to damaged integrity of nipples skin and appearance of cracks. There are "lazy eaters" who suck slowly and inertly, fall asleep at breast. Stimulate such loafers: when falling asleep – slightly pat on the cheek, try to make attempt of taking out the nipple, the child would suck again. The first and last portions of breast milk have different structure: the first portion contains more lactose (dairy sugar), less fat and protein, and, as to say, more "diluted", and the last portions are fat-rich therefore don't take off prematurely the baby from one breast to give another, more filled with milk, thus it loses so-called "back", more high-calorie milk. Is it necessary to observe the feeding regime? For the healthy full-term newborns we recommend "free mode of feeding", that is, on request of the child, including at night. At such type of feeding the child well gains on the weight, sleeps fast, and you stimulate more expressed milk and ability to its secretion remains is longer. "Demands of the child" can arise come up to 10-12 times a day in the beginning. It is important that you correctly define the "hungry call" crying you hear from the child. In process of growth of the kid and with your help there will be developed the timetable of feeding – from 6 to 8 times a day. But if your kid was born before term, has some deviations in state of health, only the doctor can decide about the mode of feeding. For each breast, is better to alternate feeding to provide their maximum depletion. If there is not enough milk in one breast, it is emitted with rare drops, finish feeding the child from the other breast. Begin the following feeding with the side which in the previous time was the second.

59 One of frequent causes of cracks could be taking the breast off in the wrong way upon feeding is over. To wean the child, carefully implant the finger into a corner of a mouth of the baby, between two gums, unclenching them so that the nipple itself "left" its mouth. After feeding slightly squeeze out some milk, grease with it a nipple and areola and then let it dry. Milk contains the active agents promoting healing of cracks not obligatory to wash nipples water after feeding. In addition, for the purpose of prevention of cracks on nipples, apply some cream or ointment recommended by your pediatrician onto the breast, nipples and areola (for example, "Bepanthen", "Pantoderm", "Purelan 100", etc.) with massage movements from outside to inside by the palms. Eructing after feeding Each child during feeding swallows some volume of air and it needs to let out as "an air bubble" formed in stomach, through the mouth. For this purpose hold the child in arms, having lent him under chin your shoulder covered with a diaper or a napkin. It isn't obligatory to pat the kid on the back. Silently sit down and slightly, without any pressing, stroke the baby’s head. Putting to bed the child after feeding, put the baby onto left or right side (this way there will be no danger that it could choke with casting), alternating the sides, but more often - onto the right side which facilitates depletion of stomach. Roll a towel and put it between the back of the child and mattress. Modern German researches showed that if babies sleep on one side and back, and when vigilant they vomit, this simple measure often reduces risk of occurrence of the syndrome of sudden death. Is decantation of milk after breast-feeding necessary? The recent researches showed that when feeding the child according to the child’s demand, which means the child’s regime of feeding is flexible and free, and thus the breaks between the meal intakes don't exceed two hours in the afternoon and four hours at night, then the necessary amount of milk remains in breast. However, considering the fact that mastitis occurs not only when infection enters through the cracks on nipples, but also when the milk’s stagnated in the breast, therefore during the first month we recommend you to decant some milk after each feeding even if you decant only 3 spoons. After that "critical period" expression of milk will become regular and you afterwards will feed the child "on demand", without decanting the remains. The decanted milk is necessary for the child if it is impossible to directly give the breast to the baby because of some birth trauma, or for deep prematurity of the child, or due to some illness of mother, her day work and other reasons.

60 In these cases the decanted milk can be given to the kid from a spoon or a cup and if it is necessary to give it from a small bottle, you watch that the opening was small, milk followed separate drops with a speed of 1 a drop in a second, otherwise, having got used to easy receiving food through a pacifier, he will refuse to suck the breast. If during some illness you take medicines which gets into breast milk, consult the doctor: perhaps, it is better to feed the child during this period with some artificial mixed milk, and with it, you need to decant milk in order to maintain lactation. Technique of milk decantation 1. Before decantation or a milk, sterilize all the ware for milk, by boiling within 20 minutes, carefully wash the hands. The nipple and areola should be washed by the wipers. 2. Decant the first 5-10 ml of milk in separate ware and pour out. 3. At first, make some light massing movements by your fingers, moving from the breast basis towards the areola: the movements have to be soft and wavering, slightly pressing with finger-cushions, making gentle vibration. Having pushed milk towards areola, softly take the area around the nipple and press it towards the nipple. In the beginning milk will be expressed in drops, and then, at repeated manipulations, as streams. 4. Slowly move your fingers clockwise so that the breast was completely freed from milk. Decantation of milk using a manual milking pump After each use wash, the milking pump and let it dry, and before decantation sterilize. Collect the decanted milk in a sterile small bottle, close it and before placing it to refrigerator where it has to be stored no more than three hours, leave it for 30 minutes to sit at the room temperature for preservation of valuable properties of milk. It can be frozen in special bags, and before giving to the child warmed in special heater up to the temperature of 37-40 ºС. According to the last scientific recommendations, if your kid, receiving breast milk, is doing well, gains the weight, develops, has no symptoms of rachitis, anemia and other deviations in a state of health, it will not be needed to add any additional food for about four months. It should be noted that in the majority of the countries of the world introduction of alternate feeding is usually begun later, at the age of six months, providing the normal development of the child. Many Russian pediatricians also tend now to "world practice". In order to watch development of the child and to be sure that it proceeds normally, you should regularly measure the baby’s growth and weigh on scales. If you want to know, how much milk the child consumed, weigh it before feeding and after, then difference in weight will make the amount of the milk consumed. If you weigh the child regularly – every

61 week or once a day on the same scales, same time, better in the evening, before feeding – this way you will know exact increase in weight. The data provided in tables 1 and 2 will help you to estimate, whether sufficient amount of milk is consumed by the child and make sure the growth is going on in right direction. Table 1 Daily amount of breast milk or mixed artificial milk with normal physical development of the baby Total daily volume of feeding consumed Age (breast milk, mixes, additional food) up to 2 months 1/5 of the body mass or 700-750 ml 2-4 months 1/6 of the body mass or 750-800 ml 4-6 months 1/7 of the body mass or 800-900 ml Older than 6 months 1/8 – 1/9 or 1000-1100 ml of the body mass Example: The baby is 1 month old, and its weight amounts to 3500 g, daily volume of consumed feeding should amount to 1/5 of the body weight, i.е. 700 ml, for one meal – 100 ml (at 7-time feeding). Table 2 Gaining the body weight and growth during the first year of a child’s life Gaining the Gaining the growth Monthly gaining body weight Monthly gaining in No. during the period, in weight, g during the growth, cm cm period, g 1. 600 600 3 3 2. 800 1400 3 6 3. 800 2200 2,5 8,5 4. 750 2950 2,5 11 5. 700 3650 2 13 6. 650 4300 2 15 7. 600 4900 2 17 8. 550 5450 2 19 9. 500 5950 1,5 20,5 10. 450 6400 1,5 22 11. 400 6800 1,5 23,5 12. 350 7150 1,5 25

62 Proceeding from the aforesaid it is obviously very important to develop the system of actions directed to prevention of children's incidence since the antenatal period, and it is also possible to conclude, that despite coordination of approaches to advance the policy of prevention has to be carried out at the federal level; while now problems of prevention of diseases in population, including mothers and newborn children, more often are considered to be connected with the solution of questions at the regional level with coordinating role of Ministry of Health, that gives the chance to reflect dynamics of developing the decease- prevention service in the country, and to provide its stability.

REFERENCES 1. http://www.mosgorzdrav.ru/mgz/komzdravsite.nsf/va_WebPages/page_n070?Ope nDocument. Правительство Москвы. Программа занятий с беременными в "Школе материнства". 2. http://www.med-pravo.ru/PRICMZ/pricmz2003/50/50_2-1.htm. Приказ Минздрава РФ от 10.02.2003 N 50. Приложение № 2. Схемы динамического наблюдения беременных и родильниц. Медицина и Право. Приложение N 1. Инструкция по организации работы женской консультации 3. http://www.nczd.ru/. Федерадьное Государственное Бюджетное Учреждение «Научный Центр Здоровья Детей» 4. http://www.gks.ru/wps/wcm/connect/rosstat_main/rosstat/ru/statistics/population/ demography/ю Федеральная Служба Государственной Статистики. Реализация федерального закона от 8.05.2010г. №83-ФЗ. 5. Министерство Здравоохранения Российской Федерации, Департамент Мониторинга, Анализа и Стратегического Развития Здравоохранения. ФГБУ «Центральный Научно-Исследовательский Институт Организации и Информатизации Здравоохранения» Министерства Здравоохранения Российской Федерации. Медико- Демографические Показатели Российской Федерации, 2012 Год. Статистические Материалы. Москва 2013.

63 SUGGESTED PROGRAM OF TRAINING EXERCISES FOR PREGNANT WOMEN AT "SCHOOL OF MOTHERHOOD" O. V. Goncharova SEI Department at I. M. Sechenov First Moscow Medical University President of the Russian Medical Women’s Association SUMMARY In the Russian Federation much attention is paid to development of service for diseases prevention, especially in the field of protection of motherhood and childhood, with the service providers generally presented by “Motherhood Schools” in Maternity Welfare Centers and “Healthy Child Rooms” in children's policlinics. Preparation for childbirth and motherhood in maternity welfare centers is carried out individually as well as at “Motherhood Schools”. One of effective forms of teaching is helping to make the whole family ready for the child's birth, directed to involvement of all the family members into active participation in prenatal preparation. The trainers use for teaching demonstration materials, visual aids, technical means and subjects of care of the child, in various forms of interactive training. All the women, starting from the 1st trimester of pregnancy, are invited to visit the School of motherhood, and it is desirable them to be there together with future fathers or close relatives. The 1st part of training program includes exercises, suggested by obstetrician-gynecologist doctors for pregnant women, 2nd part – exercises suggested by pediatricians for pregnant women at "school of motherhood" It is obviously very important to develop the system at the regional level of actions directed to prevention of children's incidence since the antenatal period, with coordinating role of Ministry of Health that gives the chance to reflect dynamics of developing the decease- prevention service in the country, and to provide its stability. Key Words: Pregnancy, childbirth, healthy newborn

64 ПРИМЕРНАЯ ПРОГРАММА ЗАНЯТИЙ С БЕРЕМЕННЫМИ ЖЕНЩИНАМИ В «ШКОЛЕ МАТЕРИНСТВА» Гончарова О.В. Кафедра ГБОУ «Первого Московского Медицинского Университета им. И.М.Сеченова, Президент Ассоциации Женщин-Медиков России РЕЗЮМЕ В Российской Федерации в настоящее время большое внимание уделяется развитию службы профилактики в области охраны материнства и детства, которая в основном представлена «Школами Материнства» в женских консультациях и кабинетами здорового ребенка в детских поликлиниках. Подготовка к родам и материнству в женских консультациях проводится индивидуально и в «Школах Материнства». Эффективной формой занятий является семейная подготовка к рождению ребенка, направленная на привлечение членов семьи к активному участию в дородовой подготовке. На занятиях используются демонстрационные материалы, наглядные пособия, технические средства и предметы ухода за ребенком, формы интерактивного обучения. К посещению «Школы Материнства» привлекаются все женщины с I триместра беременности, желательно вместе с будущими отцами или близкими родственниками. Первая часть программы включает в себя занятие акушера-гинеколога с беременными женщинами, а вторая часть – занятие педиатра с беременными женщинами в «Школе Материнства». Большую значимость имеет разработка системы мероприятий на региональном уровне, направленных на профилактику детской заболеваемости, начиная с антенатального периода, при координирующей роли Министерства Здравоохранения и гарантированной поддержки со стороны государства. Ключев ые слова : беременность, роды, здоровый новорожденный

65 orsuli qalebis samSobiarod mosamzadebeli programa «orsulTa skolaSi» o. gonCarova i. seCenovis sax. moskovis pirveli samedicino universiteti ruseTis eqim qalTa asociaciis prezidenti reziume ruseTis federaciaSi didi mniSvneloba eniWeba dedaTa da bavSvTa dacvis samsaxuris ganviTarebas, romelic warmodgenilia qalTa konsultaciebTan arsebuli "orsulTa skolebiT" da "janmrTeli bavSvis" kabinetebiT. mSobiarobisTvis da dedobisTvis momzadeba qalTa konsultaciebSi tardeba rogorc individualurad, agreTve "orsulTa skolis" programis farglebSi. Zalian efeqturia "jaxuri momzadeba", romelic gulisxmobs ojaxis wevrebis momzadebas orsulis mSobiarobis wina periodisTvis. mecadineobebze gamoiyeneba sademonstracio masalebi, TvalsaCinoebani, manekenebi, interaqtiuli swavlebis formebi. "orsulTa skolaSi" saswavlo kursi iwyeba orsulobis pirveli trimestridan. survilis SemTxvevaSi, mecadineobebSi erTveba momavali mama da sxva axlo naTesavebic. programis pirvel nawils axorcielebs mean-ginekologi, meore nawils ki – pediatri. unda aRiniSnos, rom programis farglebSi aRiniSneba bavSvTa daavadebebis klebadobis dadebiTi dinamika. Zalian mniSvnelovania regionebSi bavSvTa daavadebebis profilaqtikaze zrunvis samsaxuris organizeba antenataluri periodidan, jandacvis saministrosTan koordinirebeli TanamSromlobis da misgan garantirebuli mxardaWeris pirobebSi.

sakvanZo sityvebi: orsuloba, mSobiaroba, janmrTeli axalSobili

66 SEX BASED DIFFERENCES ON THE TREATMENT OF CARDIOVASCULAR DISEASES Reviewe Article N. Zhvania Petre Shotadze Tbilisi Medical Academy

INTRODUCTION. Cardiovascular Vascular Disease (CVD) became number 1 killer of women in developed countries. Concerning 2012 statistical data, 1 out of 3 women died from heart diseases in USA – approximately one woman every minute. This fact causes the more interest for peculiarities on diagnosis, course and treatment of those diseases, taking into account sex based differences of the drugs effect [3]. The goal of proposed article is to rewire the sex based differences (SBD) of some drug’s effectiveness in the treatment of CVD. The data concerning the SBD in treatment of CVD are not complete. Most of studies have the conflicting, various results. Partially, it can be explained by the insufficient participation of women in clinical researches. The necessity of further assessed SBD in pharmacokinetics and pharmacodynamics was underlined in the “Agenda for Research on Women’s Health for the 21st Century,” published by National Institutes of Health in 1999 [43]. The situation was changed during the last years. Several researches were performed by support of FDA Office of Women’s Health (OWH) for getting more information on sex differences of FDA- regulated drug’s effectiveness, used for treatment of CVD [13]. In the NIH Biennial Report of the Director of 2006-2007 was shown that in 2006, 624 of extramural and intramural phase III clinical research protocols [499, 430] participants – 63% were women [52]. There are many factors, which determine the SBD in treatment of CVD. Besides the genetically determined differences on biochemical processes and the specific periods in women’s life – puberty, menstruation, pregnancy, menopause, there are anatomical and physiological differences, which have an influence on drugs effectiveness and different therapeutic responses in men and women. ANATOMICAL AND PHYSIOLOGICAL DIFFERENCES. As usually, the women’s heart is smaller and the coronary arteries are shorter as compared to men’s of the same stature, race and age. Body weight and distribution volumes are higher in men. The level of glomerulofiltration and especially, the creatinine clearance are age-dependent and are lower in women as compared to men. The resting hearts rate in women is higher than in men – on average 3-5 beats per minute; however, cardiac output in women is

67 smaller by 10%-30%. Ejection fraction in women is higher than in men. The duration of the cardiac cycle in men is longer [25, 58, 68]. The amount of fluid in women is different during periods of the menstrual cycle. Percentage of tissue fluid fluctuates during the menstrual cycle, as the high estradiol concentrations are associated with fluid and sodium retention. High blood concentration of estradiol in women, opposite to the high concentration of testosterone in men with the corresponding muscle metabolism, also influences on the drugs difference pharmacodynamics and pharmacokinetics in women and men [36, 38, 50, 58, 68, 71]. The activity of isoenzymes CYP1A, the drug efflux transporter P-glycoprotein, is higher in men. Drug’s glucuronidation and by this way, the inactivation of epinephrine, norepinephrine and dopamine, is more rapid in men [51]. In children PQ interval duration does not depend on sex, but during and after puberty it is slightly shortened in boys, as compared to girls, due to changes in repolarization. Women observed long duration of the corrected QT interval and longer recovery time of the sinus node function. Some studies have shown that QT interval is prolonged, especially during the first ovulatory phase of menstrual cycle, and it is connected with a higher concentration of estradiol in plasma [53]. The prolonged QT interval raises the risk of drugs adverse reactions (DAR) in women as compared to men. This prolong cardiac repolarization – the development of arrhythmias, including life threatening arrhythmia – torsade des ‘pointes, and ventricular tachycardia, which can lead to ventricular fibrillation. The QT-interval-prolonging antiarrhythmic drugs, such as quinidine, amiodaron, sotalol, disopiramide ibutilide, and non- antiarrhythmic drugs – erythromycin, halofantrine have more proarithmic effect in women, which can be connected with the regulation of potassium channel expression by sex steroids [2, 7, 33, 43, 64, 81]. It’s well known that the clinically significant DAR are more common and severe in women, as compared to men [8, 80]. According to the FDA Adverse Events Reporting System (AERS) – a voluntary database of adverse events, women have more and generally more serious adverse events than men. Eight out of ten drugs were withdrawn from the market during the period from January 1 1997 through December 2000, due to adverse effects in women [8]. The results of analysis of 48 cohort studies in Great Britain have shown a 1,5 to 1,7-fold higher risk for drugs side effects in women, as compared to men [35]. As usually, it is connected with higher plasma concentration of some drugs in women. The drugs plasma concentration depends on volume distribution and systemic clearance. Women’s body weight and distribution volumes are less than men’s, but they often receive higher doses of drugs, which cause high plasma concentration of drugs. As compared to men, the lower level of glomerulofiltration and creatinine’s clearance in women perhaps create preconditions to the

68 accumulation of medicines, and therefore, raise its possible side effects. Women have more fatty tissues, so, the volume of hydrophilic drugs distribution is less, which increases their level in plasma. Opposite to it, the duration of lipophilic drugs activity became longer and the concentration – less [35, 57, 58, 81]. All these facts influence on drugs concentration in blood and on its possible side effects in women [5, 16, 21, 43, 51, 63, 81]. An example of this is the higher blood concentration of digoxin in women after the treatment of women and men with its equal doses. This fact increases the possibility of the likelihood of arrhythmias [1]. The DAR may be increased during the specific periods of women life, such as pregnancy, menopause and menstruation [39, 43]. As usual, women take more different drugs in comparison with men that probably can increase possible side effects of drugs because of their interaction [43]. Concerning the objective, studies related data, women are more attentive to their body discomfort, more often report their symptoms of physical illness, and evaluate discomfort such as illness symptoms, as compared to men [4]. 17-44 years old women twice often visit physician and have twice more hospital stay than men. After the age of 45, when sex-specific conditions are excluded, women visit physician about 10-20% often than men. The frequency of women hospitalization is also higher, as compared to men in this age group. These facts also influence on the rate of DAR in women [4, 20]. INFLUENCE OF SEX HORMONES. The big meaning have the SBD in activities of metabolic enzymes. Some studies have shown higher activity of Hepatic enzyme CYT P450 (CYP3A4) in women that influence on drug response. Women have higher clearance of CYP3A4 substrates. The liver biopsy in women has shown the higher expression of informative RNA – CYP3A4, and twice more level of CYP3A4 in plasma, comparing with men [19, 51, 70]. Enzyme CYP3A4 participates in first- pass metabolism of more that 50% of drugs, often used in patients with CVD. The following drugs used for treatment of CVD are the substrate of this enzyme: atorvastatine, dilthiazem, nimodipine nisoldipione chinidine, lovastatine, verapamile, symvastatine. The activity of these ferment is regulated by sex hormones so, it can be change during the menopause [82]. The activeness of CYP1A2 and CYP2E1 enzyme is higher in men, as compared to women [10, 68, 82]. The data about activeness of CYP2D6, the substrates of which are enkainide, flekainide, mexiletine, propafenon, metoprolol and thimolol in women appear to be conflicting. There are data concerning higher levels of this drug in women blood plasma, because of the lower sensitivity of CYP2D6 to these drugs [67]. The menstruation, pregnancy and ovarioectomy can affect the activity of the enzyme CYP2D6, however this changes in

69 enzyme activity not always cause the clinically significant drug effects in men and women [7, 53]. No sex-specific differences exist for CYP2C9 and CYP2C19 [51]. Among the factors affecting SBD in the treatment of CVD, an important role belongs to the sex hormones. Despite this, some authors contest the presence of receptors for estrogen and progesterone in rodent myocardium [22]. The majority of reports agree to the presence and activity of ERs in mouse, rat and human hearts Two receptors of estrogen – ERs – ERα and ERβ, which have been found in the human and rodent hearts, can be responsible for the drugs sex different effects in cardiovascular system [32, 37, 51]. Some experimental studies suggest that estrogens, such as βestradiol reduce infarction size and improve cardiac remodeling [47]. In experimental studies, the ERα- knockout in male mice caused more severe ischemia reperfusion damage than in male wild- type mice that suggests a protective role of ERα against ischemia-reperfusion damage in males. Knockout of ERβ and its isoform in female animals increase mortality and aggravate markers of heart failure that suggests a protective role for ERβ in females [47, 79]. The metabolites of estradiol-catechol-estradiols and methoxy-estradiols directly influence on vascular cells, and their influence is believed to be protective [17, 37]. Experimental studies have shown the protective effect of estrogens on the myocardial hypertrophy in ovariectomized female mice with aortic stenosis [69]. The sex differences in the development of myocardial hypertrophy and heart failure inducted in the rat model showed different genomic response in male and female [59, 71]. The different response on heart hypertrophy in women with aortic stenosis was shown in clinical studies [42]. Clinical studies have shown that cardiac function is better preserved in women with aortic stenosis, than in men [9]. The effects of ER receptors are not completely studied, however it‘s clear that the contribution of ER subtypes is sex different. Estrogens in men and women influence on rapid vasodilatation, reduce the adhesion-molecule expression, increase the synthesis of vascular endothelial growth factor, and improve endothelial-mediated vasodilatation. The protective effects of estrogens on vascular s ystem are performed via NO. Estrogens increase NO synthesis by increasing the activity of endothelial NO synthase, reduce the leukocyte adhesion a n d inhibit the vascular smooth muscle cells proliferation [18, 37, 38, 54]. However, two biggest trials WHI and HERS performed on women for adjust the influence of hormone replacement therapy on CHD and other diseases, have shown that despite the beneficial physiological effects of estrogens in the development of heart diseases,

70 the hormone replacement therapy does not always have a beneficial effect on development and treatment of CHD and these results depend on many other factors [52]. Despite the mechanisms connected with sex differences in the incidence and progression of CVD are unknown, the studies of the role of sex hormones in modulating the activity of several regulatory systems, including the renin-angiotensin system (RAS), have been suggested. Sex differences in CVD have been shown in spontaneously hypertensive rats, Dahl salt-sensitive rats and ischemia-reperfusion injuries Results demonstrate the importance of AT2 receptors in mediating sex differences in vascular injury. The results demonstrate the importance of AT2 receptors in mediating sex differences in vascular injury [15, 34, 44, 59,

77]. It was described the differential expression of angiotensin II type 2 AT2 receptors in vascular remodeling, induced by polyethylene cuff placement around the femoral artery in the wild-type (Agtr2+) and AT2 receptor null (Agtr2−) mice. AT2 receptor expression was enhanced more deeply in the injured artery of the Agtr2+, in the females. In the Agtr2+ mice, no significant differences in the expression of the AT1 receptor were observed in males and females [44, 59]. The degree of vascular injury, in the injured artery, was greater in males than in females. The authors suggest that the lower expression of AT2 receptors in the injured arteries of male rats can be the main cause of this sex difference. They also suggest that the

AT2 receptors have more protective effect on vascular injury in females [79].

AT1 receptor antagonist Valsartan (in the dose 1 mg/kg per day) decreased vascular injury more in female than male Agtr2+ mice [75]. This study suggests that more pronounced vascular injury in males than females, may be partially explained by the enhanced expression of AT2 receptors in the female femoral arteries and by the AT2receptors mediated protective effect of angiotensin II in vascular injury. So, sex hormones, via interaction with other regulatory systems, including the RAS, play an important role in the development of CAD

[34, 44]. This study of Okumura et al suggests that AT2 receptors mediate a protective effect of angiotensin II in vascular injury, more in females comparing with mails. Because of estrogen regulates the RAS, it possible to predict that ARB would be especially beneficial in postmenopausal women in whom the estrogen modulation of the RAS is lost [49]. However not always is clear the protective effect of female sex hormones and the damaged effect of male sex hormones on vascular wall [34]. The clinical data, concerning the sex-based differences on effectiveness of ACEI and ARB, is conflicting. The authors studied the analysis of thirteen randomized cohort trails that used ACEIs, and nine trials that used ARBs for treatment of AH, shown that sex-specific outcome data was reported in six of the ACEI trials and in three of the ARB trials. Total women involvement in these trials was 39.1%. This study also shown that in women

71 involvement on trails was not complete and only 43% of large hypertension clinical trials reported sex-specific data. The result of seven of the nine trials shown that effectiveness of ACEIs and ARBs was slightly more effective in men [48]. Some authors studied this subject, have not shown the sex differences on effectiveness of ACEI during the treatment of arterial hypertension [6]. The results of cohort study of 19,698 elderly women and men with CHF, prescribed ARB or ACEI, shown that women on ARBs had significantly better survival compared to women on ACE inhibitors, whether hypertensive or not. At the same time results suggested that ARB was comparable with ACE inhibitors, in hypertensive men, but ACEI were associated with better survival in non-hypertensive men. The difference on men’s survival prescribed ARBs or ACE inhibitors, was no shown [24]. The Second Australian National Blood Pressure Study (SANBPS) has shown that despite of similar effect of ACE inhibitors for treatment of AH in elderly patients, the case of cardiovascular events and death was more frequent in women than in men [73]. Authors studied the antihypertensive drugs cessation in patients with AH concluded that it was slightly more often in men [41]. Authors studied 350 patients, with HF – 256 men, with a mean age of 65 ± 10,6 years, treated at a multidisciplinary HF unit, shown that 83% of men (vs. 68%, p < 0.001) were treated by ACEI, women more often received ARB (18% vs. 8%, p = 0.006). Authors concluded that mortality after one-year treatment analysis despite differences in age, etiology and co-morbidities, was similar in men and women (10.4% vs. 10.5%). The results of treatment treated at a multidisciplinary HF unit also were almost similar [30]. The bioequivalence study of sex differences of pharmacokinetic and pharmacodynamics of enalapril performed on 24 healthy volunteers – 12 men and women, shown significantly smaller basal plasma activity of ACE and maximum ACE inhibition in women. The same study shown, that women at the follicular phase had significantly less activity of ACEI comparing with men [78]. The results of investigations of 120 patients (20-45 years old) with grade 1 and 2 hypertension, shown more efficiency of losartan for treatment of AH in women, comparing with men. The same study shown more efficiency of losartan comparing with enalapril in women of this age as the starting therapy. No differences were shown in effectiveness of lozartan and enalapril in women who have continued treatment of AH [85]. The authors analyzed the prescription and using of ACEI and ARB for treatment of CAD and HF in men and women, shown that men more often take ACEI versus women, who more often take ARB. Partially it can be explained with more often side effects of ACEI, such as cough in women, comparing with men [26, 28, 45, 66]. Some authors have shown the higher efficacy of ARB comparing with ACEI in treatment of AH and CHF among women

72 [12, 24, 85]. However authors concluded that it is necessary additional trials for recommend ARBs as the drug of choice in women [12, 24]. The genetic studies were performed for investigate the effect of the polymorphism on bradykinin type 1 (B1)-receptor-mediated coronary artery dilation and peripheral blood mononuclear cell activation. The rs12050217 A/G single nucleotide polymorphism in the B1 receptor gene is associated with the efficacy of the ACEI perindopril in treatment of coronary artery disease. The study shown increased expression of the pro-inflammatory factors CXCL5 (CXC chemokine ligand 5) and IL6 (interleukin-6) in fresh human mononuclear cells (1 μmol/l des-Arg(9)-bradykinin). These responses occurred in blood cells of women, were not affected by genotype and correlated with their plasma 17β-oestradiol levels (r (2)=0.32, P=0.02; n=17). This difference in responses to B1 receptor stimulation in blood mononuclear cells indicates to the possible SBD in the effectiveness of ACEI therapy [74]. In accordance with above-mentioned data, there are many questions concerning SBD of ACEI and ARB effectiveness in treatment of CVD, which needs to be specified. The sex related differences of beta-blockers effectiveness in treatment of CVD is much better studied. The sympathetic activity is less and the parasympathetic activity is more in women comparing with men. The blood concentration of norepinephrine is higher in women [25]. The frequency of DAR due to CYP2D6- dependent β-blockers such as metoprolol, is also higher in women. The cause is the lower sensitivity of CYP2D6 to the drugs, and as a result, higher plasma levels of metoprolol, which can be approximately 100% higher in women. Some authors proposed for women to use β blockers such as carvedilol and nebivolol, which are less metabolized by CYP2D6 [16, 31, 43, 67, 76, 84]. There is conflicting data concerning the effectiveness of beta blockers for treatment of CVD in men and women. After the analysis of 1602 patients prescriptions for treatment of CVD, no evidence was shown, suggested that women obtain less benefit from beta-blockers administration. Additionally, women exposure to metoprolol increases while taking oral contraceptives [31, 39, 62]. The results of meta-analysis of 4 large clinical studies about action of the metoprolol, have shown the similar effectiveness of BB in the prevention of acute coronary events, in men and women. The data about that some beta-blocker is superior to another in different gender, for treatment of CVD, was not found [23]. According to the results of meta-analysis of 5 randomized clinical trials with a total number of patients involved over 5,000 (including women accounted for 1/5), the effects of metoprolol on mortality, after myocardial infarction, revealed a decrease in the incidence of cardiovascular death equally, among women and men [23]. Contrary the detailed gender-specific analysis for the CIBIS II study, shown that, bisoprolol was significantly more effective in women,

73 with not significantly unadjusted effect on mortality in women than in men [11, 60]. The results of study MERIT-HF (Metoprolol Controlled Release / Extended Release Randomized Intervention Trial in Chronic Heart Failure), as well as in the study COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival), shown that the treatment of symptomatic heart failure with beta-blockers reduces mortality in both women and men, but reduction in mortality of the subgroup of women, were not statistically significant [46, 65]. However post-hoc analysis studies CIBIS II (Cardiac Insufficiency Bisoprolol Study II) found that BB reception prognostic advantages for women were more significant and even higher than in men [11, 26 55, 56]. Thus, the data concerning beta- blockers effectiveness in men and women due to some inconsistency needs of further study. The sex related differences of Calcium Channel Blockers (CCB) effectiveness in treatment of CVD. The data concerning SBD in effectiveness of CCB for treatment of CVD is also conflicting. There is no enough data about sex-based effectiveness of CCB in treatment of CVD. After a first series pass metabolism in the liver, CCB often retain a higher concentration in plasma in men than in women, due to increased activity of the latter CYP3A4. Especially it concerns the nifedipine and verapamil after intravenous administration [14, 28]. Several studies to determine pharmacokinetic differences in CCB significant clinical impact in men and women were performed. Main clinical studies of the effect of CCB on AH, comprises approximately the same number of men and women, and in some studies, the number of women even exceeded the number of men [51]. The study ACCT (Amlodipine Cardiovascular Community Trial) found that antihypertensive efficacy of amlodipine after adjustment for age and body mass, was more pronounced in women, and depended on the reception of hormone replacement therapy [26, 51]. In addition, the study HOT (Hypertension Optimal Treatment), which studied the effect of aspirin and effectiveness of intensive blood pressure lowering on felodipine, found that while taking felodipine, CCB clinical consequences for women were the best at a marked reduction in the level of diastolic blood pressure, whereas for men this pattern was not significant [27]. The study in which gender-sensitive vasomotor endothelial function, pulse wave velocity and gender based effectiveness of amlodipine in treatment of AH were investigated, shown the more effectiveness of amlodipine such as monotherapy in women, who have reached the target values of blood pressure in 60% of cases [84]. At the same time some studies do not prove gender-specific differences on effectiveness of CCB in the treatment outcomes of cardiovascular disease [28, 51]. During last years the investigations of genetic mechanisms of sex differences in drugs response were performing. V. Regitz- Zagrosek intensively working in the field of gender differences in peculiarities and treatment

74 of CVD proposed the Strategies for study the gender-specific effects of drug effectiveness. She underlined the necessity of study of this subject at all levels-from the preclinical investigations in animal models, especially necessary in the case of new drugs, including the III and 1V phase of clinical investigations. V. Regitz Zagrojek suggested that gender based differences in drugs effects, might to be study at the cellular, molecular and genetic levels and at all levels the differences, which influence on drugs pharmacokinetics and pharmacodynamics can be found. The special interest have the drugs which interact with the influence of sex hormones, or with genes which are located on the X- or Y- chromosome, and h a v e d i f f e r e n t e f f e c t s i n m e n a n d w o m e n . S u c h d r u g s c a n c a u s e t h e g e n d e r d i f f e r e n t e f f e c t s i n t r e a t m e n t o f d i f f e r e n t d i s e a s e s [ 5 1 ] . T h e m a i n g o a l o f t h e a b o v e - m e n t i o n e d s t u d i e s i s t h e s u c c e s s f u l f u t u r e u s e o f o b t a i n e d d a t a i n t h e c l i n i c a l p r a c t i c e . A t t h e c o n c l u s i o n o f t h i s a r t i c l e , w e c a n s u g g e s t t h a t , d e s p i t e t h e e x i s t e n c e o f s e x b a s e d d i f f e r e n c e s o f d r u g s i n t h e t r e a t m e n t o f h e a r t d i s e a s e s , t h e r e a r e m a n y q u e s t i o n s w h i c h r e q u i r e d e t a i l e d c l a r i f i c a t i o n .

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SEX BASED DIFFERENCES ON THE TREATMENT OF CARDIOVASCULAR DISEASES N. Zhvania Tbilisi P. Shotadze Medical Academy Reviewe Article SUMMARY

Cardiovascular Disease (CVD) became number 1 killer of women in developed countries. This fact causes the more interest for peculiarities on treatment of those diseases, taking into account sex based differences (SBD) of the drugs effect. Many factors – anatomical, physiological, sex hormones, genetically determine factors, influence on SBD in treatment of CVD. The article contains the results of different studies concerning SBD of effectiveness of angiotensin converting enzymes inhibitors, angiotensin receptor blockers, beta blockers, calcium channels blockers in treatment of CVD. The results of most studies are conflicting, there are many questions which need clarification. The suggestion of V. Regitz Zagrojek cocerning the necessity of studies of this subject at the cellular, molecular and genetic levels, from preclinical studies in animals models including all levels of clinical investigations is done. The main goal of these studies is the successful use of the obtained data in clinical practice. Key Wards: cardiovascular disease, gender based differences, drug’s effectiveness. 83 ПОЛОВЫЕ РАЗЛИЧИЯ ЛЕЧЕНИЯ СЕРДЕЧНО-СОСУДИСТЫХ ЗАБОЛЕВАНИЙ (Обзорная Статья) Н. Жвания Тбилисская медицинская академия им Петре Шотадзе РЕЗЮМЕ

Сердечно-сосудистые заболевания (ССЗ) являются убийцами номер 1 женщин в развитых странах. Этот факт вызывает больший интерес для изучения особенностей лечения указанных заболеваний, принимая во внимание половые различия (ПР) эффективности препаратов. Многие факторы – анатомические, физиологические, половые гормоны, генетические факторы, влияют на ПР эффективности препаратов в лечении сердечно-сосудистых заболеваний. Статья содержит результаты различных исследований, касающихся ПР эффективности ингибиторов ангиотензин превращающего фермента, блокаторов рецепторов ангиотензина, бета-блокаторов, блокаторов кальциевых каналов в лечении сердечно-сосудистых заболеваний. Результаты большинства исследований противоречивы. Есть много вопросов, которые нуждаются в уточнении. В статье приведено соображение V. Regitz Zagrojek о необходимости исследований на эту тему на клеточном, молекулярном и генетическом уровнях, от доклинических исследований на животных моделях, включая все уровни клинических исследований. Основной целью этих исследований является успешное использование полученных данных в клинической практике. Ключев ые с лова : кардиоваскулярные заболевания, гендерное различия, эффективность препаратов.

84 gul-sisxlZarRvTa daavadebebis mkurnalobis sqesze dafuZnebuli gansxvavebebi (mimoxilviTi statia) n. Jvania petre SoTaZis saxelobis Tbilisis samedicino akademia reziume

ganviTarebuli qveynebis statistikis mixedviT, gul-sisxlZarRvTa daavadebebi “nomer pirveli mkvleli” gaxda qalebisTvis. Aqedan gamomdinare, did interess iwvevs am daavadebebis mkurnalobis Taviseburebebis Seswavla, wamlebis sqesze dafuZnebuli efeqturobis gansxvavebebis gaTvaliswinebiT. gul sisxlZarRvTa daavadebebis mkurnalobis procesSi, mravali faqtori (anatomiuri, genetikuri, fsiqologiuri, sqesobrivi hormonebi) axdens gavlenas medikamentebis efeqturobis sqesobriv gansxvavebaze. statiaSi moyvanilia sxvadasxva kvlevebis Sedegebi angiotensin- gardamqmneli fermentis inhibitorebis, angiotenzinis receptorebis blokatorebis, beta-adrenoblokatorebis, kalciumis arxebis blokatorebis sqesze dafuZnebuli efeqturobis gansxvavebis Sesaxeb. kvlevebis umravlesobis Sedegebi winaaRmdegobrivia – arsebobs bevri sakiTxi, romelic moiTxovs garkvevas. statiaSi moyvanilia V. Regitz Zagrojek-is mosazreba am sakiTxze. is miiCnevs, rom aucilebelia rogorc preklinikuri (cxovelTa modelebze), ise klinikuri kvlevebis Catareba ujredul, molekulur da genetikuri doneebze. am kvlevebis mTavari mizania miRebuli monacemebis warmatebuli gamoyeneba klinikur praqtikaSi. skvanZo sityvebi: gul-sisxlZarRvTa daavadebebi, genderuli gansxvavebebi, medikamentebis efeqturoba

85 THE EFFICACY OF HUMAN PAPILLOMAVIRUS VACCINES IN PREVENTING THE DEVELOPMENT OF CERVICAL CANCER: A SUMMARIZED REVIEW OF SELECTED RANDOMIZED CONTROLLED CLINICAL TRIALS. Iyad F. Jaber Caucasus International University Tbilisi, Republic of Georgia Palestine, Jerusalem

INTRODUCTION The Human Papillomavirus (HPV) is a non-enveloped, circular double-stranded DNA virus, and is a member of the family of Papillomaviridae. The genomic structure of the HPV contributes to its virulence and disease pathogenesis. HPV has an icosahedral capsid which contains eight genes categorized as Early and Late, these are gene encoding proteins (E1,E2,E4,E5,E6,E7,L1,L2) known as the Open Reading Frames(ORFs) [6]. Each one of these proteins has a specific role in the viral mechanisms of pathogenicity, infectivity, replication, transcription and immune evasion. HPV infection and replication occurs intracellularly in the mucosal and cutaneous epithelial tissues like those tissues lining the oropharynx, cervix and skin, respectively. An HPV infection of the skin epithelial keratinocytes can lead to the classic genital warts formation, and the infection of the cervical mucosal epithelium can develop into a precancerous cervical lesion which is almost always a determinant factor for a progression into a cervical cancer. There are over 100 types of HPV strains, with the most clinically significant causative organisms of cervical cancer, being HPV type 16 and type 18 [1]. Out of these HPV strains, about 40 can cause epithelial infections and not all strains infections result in diseases [8]. The HPV vaccines Gardasil® and Cervarix® are made from purified L1 protein which is a major component of the HPV capsid. The self-assembling of L1 is the main mechanism in the immunization effect against HPV. In vitro L1 self-assembling process generates different types of Virus-like particles (VLP). VLP are nonpathogenic particles that resembles the surface of the HPV virion, they do not carry the active HPV viral DNA, and therefore, they do not cause diseases or lesions [12]. Gardasil® is a quadrivalent vaccine manufactured by Merck for the immunization against HPV types 6, 11, 16 and 18, it contains specific amounts of VLPs L1 protein in

86 micrograms and it’s the only one licensed for HPV immunization in males. Cervarix® is a bivalent vaccine manufactured by GlaxoSmithKline for the immunization against HPV types 16 and 18, it is a combination of specific amounts of HPV 16 and 18 L1 VLP proteins in micrograms. These vaccines are routinely administered as a series of 3 doses at 0, 2, and 6 months [11]. Both vaccines are made with the use of recombinant DNA technology. The virulence factors of the HPV virus have been removed. The VLP as the name suggests, virus like particles, successfully stimulate the T lymphocytes and the B lymphocyte, particularly Memory B cells, in initiating an important immune response in which the immune system acts as if there is a real virulent HPV viral infection. [11] Upon a post-HPV vaccination HPV infection, the Memory B cells identify the HPV by its capsid proteins, having been exposed to the L1 VLP of the vaccines, which looks very similar to the invading virulent HPV L1 proteins. Activation of B cell lymphocytes into plasma cells occurs, the plasma cells then release a series of immunoglobulin antibodies (IgM, IgG, IgA) directed against the HPV capsid’s antigens with the IgM being the first antibody secreted to act against the HPV [10] IgG antibody plasma titer is increased in chronic infection and during the disease process. Therefore, in clinical trials, HPV antibody titers are always monitored to evaluate the efficacy of the vaccine in adopting to the immune system [11]. Cervical cancer is the second most common cancer in females around the globe. Around 270,000 women die every year because of cervical cancer. It has been documented that HPV 16 and 18 infections account to 70% of cervical cancer cases [14]. The Human Papillomaviruses, particularly, the high risk HPV types 16 and 18 cause different forms of cervical dysplasia including the precancerous Cervical Intraepithelial Neoplasia (CIN) graded as CIN1, CIN2 and CIN3 with the latter being the most severe form of precancerous lesions. Almost 100% of all cervical cancers are caused by a persistent infection from high risk HPV genotypes, HPV type 16 is the most common HPV carcinogenic genotype (55% to 60% of all cervical cancer cases) followed by HPV type 18 which accounts for 10% to 15% of all cervical cancer cases [7, 13]. CIN3 is the last stage for a precancerous lesion formation to proceed into an invasive cervical squamous cell carcinoma. About 80% to 85% of cervical cancers are squamous cell carcinomas, followed by adenocarcinomas (15%). EVIDENCE-BASED DISCUSSION. Numerous clinical trials and researches have studied the vaccines Gardasil® and Cervarix® for their efficacies, side effects, outcomes, kinetics, dosages, immunogenicity, immunological characteristics and mechanisms of action.

87 In a major randomized double blind placebo-controlled trial done in 28 sites in the United States, Canada and Brazil, conducted between November 2003 and July 2004, 776 women vaccinated with the bivalent vaccine Cervarix® against HPV type 16 and 18 were included in an extended follow-up study to determine the efficacy and safety of the bivalent vaccine. The satisfactory results showed a sustained high levels of HPV 16 and HPV 18 circulating antibodies and a 100% efficacy of the bivalent vaccine in preventing the development of HPV associated lesions up to 4.5 years post vaccination, with less than one log10 decline in the vaccine Geometric Mean Titers (GMT) from the peak values up to the end of the follow-up [2]. Findings from a large international Phase III double blind randomized controlled study that involved the assessment and evaluation of 18,644 women participants who got vaccinated with the HPV Bivalent vaccine showed an outstanding efficacy of the bivalent vaccine in protecting against the development of CIN. Only 23 women developed CIN2+ lesions, 2 women from the vaccine group and 21 from the control group. The vaccine efficacy was 90.4% with a 97.9% Confidence Interval (97.9% CI 53 .4-99.3, p<0.0001).[9] This study was further followed-up in the PATRICIA trial which lasted for 4 years and is considered one of the largest multinational randomized controlled clinical trials designed for the evaluation of HPV vaccines efficacies. In another multinational double blind placebo-controlled randomized trial, named FUTURE II, conducted from June 2002 to May 2003 at 90 different research sites in 13 countries, 12,167 women participants between the ages of 15 and 26 years, were included and were grouped into two groups, the vaccine group (n=6087) they received the quadrivalent vaccine Gardasil®, and the placebo group (n=6080) [3]. The statistical analysis of this trial was based on the power of the interim analysis being identified as a power of 80 to 90% with a one sided alpha of 0.02055. The results of the per-protocol susceptible population (n=10,565 at 87% randomization) demonstrated a 100% efficacy of the quadrivalent vaccine against the HPV 16,18-induced cervical intraepithelial neoplasia, after 1.5 years of post Dose 3 follow-up in the vaccine group (no CIN development in the vaccine group participants), 21 placebo group participants developed CIN putting the Confidence Interval at 97.96% CI [3]. At the end of the trial, 3 years after Dose 1, results demonstrated that the quadrivalent vaccine prevented 98% of HPV 16,18 related cervical lesions. Only one women in the vaccine group developed a cervical lesion, compared to 42 women in the placebo group who developed CIN2, CIN3, and cervical adenocarcinomas. In the unrestricted susceptible population (n=11,728), the efficacy for prevention of HPV type 18 related lesions was 100% [3].

88 A Costa Rican community based randomized control trial was established to evaluate the efficacy of the bivalent HPV vaccine in preventing the HPV 16,18 associated cervical intraepithelial neoplasias CIN and CIN2+. The total number of 7,466 women participants aged between 18-25 years were enrolled in the trial and were grouped into 2 groups, the HPV arm group (N=3727) received the 3 doses of HPV bivalent vaccine and the control arm group (N=3739) received 3 doses Hepatitis A vaccine over 6 month. Cytological assessments were based on the Bethesda system: Low grade squamous Intraepithelial Lesion (LSIL) and High grade Squamous Intraepithelial Lesion (HSIL). HPV 16/18 IgG antibodies were detected and quantified using the Enzyme linked Immunosorbent assay (ELISA). Polymerase Chain Reaction (PCR) was used to detect HPV 16/18 viral DNA. Vaccine efficacy was well established as the results showed a 89.8% efficacy (95% CI 31.3-99.5) against HPV 16/18 CIN2+ with a rate reduction of 3.0/1000 [5]. The GlaxoSmithKline Vaccine HPV-007 Study Group performed a double blind randomized placebo-controlled study that involved 1113 women at the initiation of the study (n=560 vaccine group) and (n=553 placebo group) from 3 countries at 27 sites. The follow-up study, up to 6.4 years, had 393 participants in the vaccine group and 383 in the placebo group. HPV antibody titers were continuously monitored and cervical samples were collected every 6 months. Results showed a vaccine efficacy of 95.3% (95 CI 87.4-98.7) against HPV 16/18 infections, and a 100% efficacy against CIN2+ [4]. CONCLUSION Based on the aforementioned clinical trials results, HPV vaccines, have proven their efficacies in preventing the development of cervical neoplasias, and in limiting the HPV associated persistent infections. Further studies are needed for the correlation between these various results, and a long term incidence rate monitoring among the participant populations should be assigned to reevaluate the longevity, efficacy and immunogenicity of the tested vaccines.

REFERENCES 1. CDC. Human Papillomavirus. Epidemiology and Prevention of Vaccine- Preventable Diseases. The Pink Book: Course Textbook - 12th Edition Second Printing (May 2012). Centers for Disease Control and Prevention, USA. 2. Diane M. Harper et al. Sustained efficacy up to 4·5 years of a bivalent L1 virus- like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. The Lancet, Volume 367, Issue 9518, Pages 1247 - 1255, 15 April 2006. 3. FUTURE II Study Group. Quadrivalent Vaccine against Human Papillomavirus

89 to Prevent High-Grade Cervical Lesions. . N Engl J Med 2007; 356:1915-1927May 10, 2007DOI: 10.1056/NEJMoa061741. 4. GlaxoSmithKline Vaccine HPV-007 Study Group. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomized placebo-controlled trial up to 6·4 years. The Lancet, Volume 374, Issue 9706, Pages 1975 - 1985, 12 December 2009. 5. Hildesheim A, et al. Efficacy of the HPV-16/18 vaccine: Final according to protocol results from the phase of the randomized Costa Rica HPV-16/18 vaccine trial. Vaccine (2014). http://dx.doi.org/10.1016/j.vaccine.2014.06.038 6. Longworth Michelle S, Laimins Laimonis A. Pathogenesis of Human Papillomaviruses in Differentiating Epithelia. Microbiol. Mol. Biol. Rev, June 2004 vol.68 no.2 362-372. American Society for Microbiology 7. Munoz N, Bosch FX, de Sanjose S, et al; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003; 348: 518-527 8. NCIRS. Human papillomavirus (HPV) vaccines for Australians. NCIRS Fact sheet: March 2013, National Center for Immunisation Research & Surveillance, Australia. 9. Paavonen J et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like- particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. 10. The Lancet, Volume 369, Issue 9580, Pages 2161-2170, 30 June 2007 11. Ruiz W, McClements WL, Jansen KU, Esser MT. Kinetics and isotype profile of antibody responses in rhesus macaques induced following vaccination with HPV 6, 11, 16 and 18 L1-virus-like particles formulated with or without Merck aluminum adjuvant. Journal of Immune Based Therapies and Vaccines 2005;3:2. doi:10.1186/1476-8518-3-2. 12. SAGE/WHO Evidence based recommendations on Human Papilloma Virus (HPV) Vaccines Schedules. The WHO’s Strategic Advisory Group of Experts (SAGE) on Immunization, March 11, 2014. 13. Sankaranarayanan, R., 2 vs 3 doses hpv vaccine schedule: low- and middle- income countries, in Eurogin 2013 International Multidisciplinary Congress. 2013: Florence, Italy. 14. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999; 189: 12-19. 15. World Health Organization (WHO) Fact sheet N°380: Human papillomavirus (HPV) and cervical cancer. September 2013

90 THE EFFICACY OF HUMAN PAPILLOMAVIRUS VACCINES IN PREVENTING THE DEVELOPMENT OF CERVICAL CANCER: A SUMMARIZED REVIEW OF SELECTED RANDOMIZED CONTROLLED CLINICAL TRIALS. I. F. Jaber Caucasus International University Tbilisi, Georgia Palestine, Jerusalem Summary Human papilloma virus (HPV) is a common virus that causes a variety of diseases in women. HPV has been extensively studied for its linkage to the development of cervical cancer in females of different ages. HPV vaccines have already proven their efficacies in preventing the development of certain types of female reproductive organ cancers such as cervical cancer, vaginal, and vulvar cancers. This review emphasizes on the benefits, outcomes and efficacy of using HPV vaccines, namely Gardasil® and Cervarix®, in limiting the progression from HPV infection to precancerous cervical lesions and cervical cancer. A summarized review of several highly renowned and peer-reviewed randomized controlled clinical trials that were designed for the evaluation of the HPV vaccines efficacies in different populations. A scientific review of HPV microbiology, carcinogenesis and vaccines mechanisms of action based on a variety of materials that are related to the topic. Keywords: Human Papillomavirus, HPV, cervical cancer, vaccines, efficacy.

91 ЭФФЕКТИВНОСТЬ ВАКЦИНЫ ЧЕЛОВЕЧЕСКОГО ПАПИЛОМАВИРУСА В ПРЕВЕНЦИИ РАЗВИТИЯ РАКА ШЕЙКИ МАТКИ: СУМИНОВАННЫЙ ОБЗОР ИЗБРАННЫХ РАНДОМИЗИРОВАННЫХ КЛИНИЧЕСКИХ ИССЛЕДОВАНИЙ И. Ф. Джабер Кавказский интернациональный университет. Тбилиси, Грузия Палестина, Иерусалим РЕЗЮМЕ Вирус папилломы человека (ВПЧ, или HPV - human papilloma virus) – это широко распространенный вирус, вызывающий разнообразные заболевания у женщин. Подробно изучено действие ВПЧ и ее связь с развитием рака шейки матки у женщин разных возрастов. Вакцины против ВПЧ уже доказали свою эффективность в предотвращении развития некоторых типов рака женских репродуктивных органов: шейки матки, влагалища, вульвы. В обзоре подчеркнуты результаты, эффективность и успехи использования вакцин против ВПЧ, а именно ® Гардасил и Церварикс ®. После вакцинации резко уменьшается количество случаев перехода ВПЧ-инфекции в предраковые и раковые поражения шейки матки. В статье, на основе различных материалов, объяснены механизмы действия вакцины, приведены данные о микробиологии и канцерогенезе ВПЧ. Показаны результаты нескольких очень известных и рецензируемых рандомизированных клинических испытаний, которые были проведены для оценки эффективности вакцин против ВПЧ в различных популяциях. Ключев ые слова : Вирус папилломы человека, ВПЧ, рак шейки матки, вакцины, эффективность.

92 adamianis papilomavirusis sawinaaRmdego vaqcinis efeqturoba saSvilosnos yelis kibos prevenciisTvis: SerCeuli randomizebuli klinikuri kvlevebis Semajamebeli mimoxilva i. f. jaberi kavkasiis saerTaSoriso universiteti Tbilisi, saqarTvelo palestina, ierusalimi adamianis papilloma virusi adamianis papiloma virusi (apv) farTod gavrcelebuli virusia, romliTac uamravi qalia msoflioSi daavadebuli. detalurad aris Seswavlili apv da misi kavSiri saSvilosnos yelis kibos ganviTarebasTan sxvasasxva asakis qalebSi. apv-s sawinaaRmdego vaqcinis efeqturoba ukve dadasturebulia qalis reproduqciuli organoebis (saSvilonos yeli, saSo, vulva) kibos profilaqtikis mizniT. mimoxilvaSi gamokveTilia apv-s sawinaaRmdego vaqcinis Sedegebi, maTi efeqturoba da warmateba am virusis mkurnalobis mizniT (kerZod, gardasilis da cervariqsis). vaqcinaciis Sedegad mkveTrad mcirdeba apv infeqciiT saSvilosnos yelis prekanceruli da kanceruli dzianebis SemTxvevebi. statiaSi, sxvadasxva masalaze dayrdnobiT, axsnilia vaqcinis moqmedebis meqanizmebi, moyvanilia monacemebi apv-s mikrobiologiisa da kancerogenezis Sesaxeb. naCvenebia ramdenime cnobili da recenzirebadi randomizebuli klinikuri kvlevebis Sedegebi, romlebic Catarda sxvadasxva populaciaSi apv sawinaaRmdego vaqcinis efeqturobis Sesafaseblad. sakvanZo sityvebi: admianis papilloma virusi (apv), saSvilosnos yelis kibo, vaqcinebi, vaqcinis efeqturoba.

93 94 FROM OUTRAGE TO COURAGE, by Anne Firth Murray (The review of the book) L. Skuratovskaya, G. Drozdova, L. Cornelius The Institute of General pathology and Pathophysiology of RAMS, Russia Peoples Friendship University of Russia Oncology RDC, Denver, Co., USA

In 1980s Dr. Jonathan Mann published several articles about protection of human rights of AIDS victims thus drawing attention to gender-related aspects of the right to health [1]. These papers triggered studies of this problem. In 1993, UN held a conference on Human Rights in Vienna when member states began to consider rape and domestic violence as Human Rights violations (advocates of women’s rights proclaimed: “Women's Rights are Human Rights and Human Rights are Women's Rights”). In 1994, the International Summit on Population and Development (Cairo, Egypt) has equated reproductive rights with Human Rights for the first time [2]. A lot of excellent articles and books summarizing evidence of violations of women’s rights in different parts of the Earth have been published since then. Among organizations for protection of women’s rights established in different countries, there is the Global Fund for Women founded by Anne Firth Murray in 1987 [3]. Its aim is to “provide fund internationally to seed, strengthen, and link groups committed to women’s well-being”. As Anne Firth Murray wrote, her vision of this Fund was that it would be a place where women could come to be helped, a place where their hopes and dreams for positive changes and empowerment might come true. She defined empowerment as “having a vision, having a plan to make this vision a reality, and having the capacity to take the steps toward implementing the plan.” Over all these years, Anne Firth Murray was an example of how to achieve this goal [4]. She wrote: ”As a person who had a vision and saw it became reality through the creation and development of the Global Fund for Women and through dynamic interaction with idealistic and committed student, I wish similar experiences for others.” (In 2000, Anne Firth Murray became a consulting professor in human biology at Stanford University, where she lectures on international women’s health and human rights, and on love as a force for social justice). She summarized all her experience in organizing women’s groups by means of the Global Fund for Women in order to protect women’s rights in different parts of the world since 1987; and today we have a wonderful opportunity to read this experience her book From Outrage to Courage, second edition, published in 2013. The

95 book has the following subheading: ”The Unjust and Unhealthy Situation of Women in Poorer Countries and What They are doing About it”. As Mary Robinson, ex-President of Ireland, UN High Commissioner for Human Rights (1997-2002) wrote: “This book illuminates the details of women’s lives – their struggles, their resilience, and the ability of so many to respond with practical and visionary solutions. A rare combination of clear analysis and inspiration”. The book consists of 346 pages and 10 chapters. It is dedicated “to the women who teach courage and resilience” and its main goal is expressed in Gandhi’s words: In the midst of Death, life persists; In the midst of untruth, truth persists; In the midst of darkness, light persists. The book has an introduction named Darkness and Light. From the very first sentence of this book you understand that this book is about women’s health:”Being born female is dangerous to your health”. This is true for many readers, but for most women living in developing countries it is a real tragedy. Sex selective abortion is widespread, as parents decide, for various reasons that they cannot bring another girl to the world. Hundreds of thousands girls have “disappeared” resulting in misbalanced male/female ratio in such countries as China, India, and Korea. Seventy seven million girls worldwide do not go to school as compared with sixty five million boys. Some three million girls, most of them in Africa, are at risk of being genitally mutilated each year. HIV/AIDS is spreading faster among adolescent girls and young women. More than 350,000 women die each year from almost completely preventable childbirth-related injuries and illnesses. From one fourth to one half women worldwide suffer from violence of their intimate partners. Three out of four victims of war are women and children. Most elderly women in poor countries are illiterate and suffer from different illnesses, challenges also faced by many men. But unlike their male counterparts, these women are more isolate and often are saddled with arduous care-giving roles [5, 6]. As for us, members of the Medical Women's International Association, and all healthcare professionals, working on the development of health as women’s rights, this book is a very valuable resource. From the very beginning, the author wrote: ”Women’s health is so much more than a medical issue, it is cultural, political, economic, and – above all - an issue of social justice. Improving women’s health and advancing the status of women is often seen as powerful means to solve economic problems rather that as route toward through justice. It is both, to be sure”.

96 The book begins with a chapter about women poverty and human rights because many women at the grassroots levels identify it as a critical issue of their life and their health is the next one. Demeaning and disempowerment of girls and women, persistence of poverty, unequal access to education, food, health care, and money, as well as pervasive violence affect woman’s health. All events of woman‘s life affects her health, especially if we define health in a broad sense, as does the World Health Organization (WHO): “the state of complete physical, mental and social well-being and not merely the absence of disease and infirmity”’... In all chapters of this book Anne First Murray shows her readers how important is to include an “economic factor” in the WHO definition. When we merely use WHO definition of health alone, we encounter problems in assessment of health status in various societies and groups that are worlds apart in their culture, economy, history, demography, and medical history. Nevertheless, the United Nations and others multinational agencies have attempted to measure health status. If we combine their data, we will obtain the best possible statistics and information currently available on the subject. They all have shown no doubt that in modern society, women do enjoy the same opportunities as men. Gro Brutland, an ex-head of the WHO, in was quoted in a 1998 press release: “Never have so many had such broad and advanced access to healthcare. But never have so many been denied access to health care.” The UN report called The World’s Women 2000: Trends and Statistics showed persisted disparities between women and men worldwide in six areas: health, human rights and political decision making, work, education and communication, population and families“ (developing world carries 90% of disease burden, yet poorer countries have access to only 10% of the resources that go to health”) [7, 8]. Author explain why focus on women health is so important at present: it is not only because the gender’s inequality is injustice but also because women, whether healthy or not, are in the heart of family and society. Women’s health affects every area of her life and, therefore, of her family and community. Women are not just productive members of family; often they are a kind of a safety net. The inequalities – violations of the human rights of women – stem from basic dislocation in society that distorts the life both men and women. To improve women’s health, we must treat specific health problems, but conditions of women’s lives must also be changed so that women can gain more power over their lives and their health. We should do our best to make that justice possible for everybody. Many very sad stories are collected in this book. Author wrote:”Through stories and descriptions, poetry and statistics, I seek to augment the overview provided by this book.

97 Many issues of women’s health have long been invisible and considered too private to discuss. Book help us to make injustice visible”. All chapters of book are very informative, contain much statistic data and many personal experiences dedicated to violation of rights to health. Let’s consider just one example, namely, chapter 6 Violence against Women: Abuse or Terrorism? It analyzes the report of the first global study of domestic violence based on research done by London School of Hygiene and Tropical Medicine. This report shows that violence against women is widespread, with far reaching health consequences. Women who are physically abused by their partners are likely to experience health problems, regardless of whether they live in a modern industrialized city or a rural area in developing nation. The Center for Gender Equity describes violence against women as “the most pervasive yet least recognized human rights abuse in the world” as well as a “profound health problem sapping women’s energy, compromising their physical health, and eroding their self-esteem”. Men against their female partners perpetrate the vast majority of partner abuse. Women are shoved, slapped, punched, beaten, burned, kicked and killed every day in every country around the world. Author quoted the United Nation Secretary General Ban Ki-Moon: “Violence against women and girls continues unabated in every continent, country and culture. It takes a devastating toll on women’s lives, on their families and on society as a whole. Most society prohibits such violence yet the reality is that too often, it is covered up or tacitly condoned”. In her book, Anne Firth Murray suggests that we should consider using the term “terror” instead of “abuse”, since this is exactly what it is happening on a global scale. It is difficult disagree with her suggestion. The researchers who produced this study (published in 2005 by WHO) for which 24,000 women in ten countries had been interviewed found that “victims are about twice as likely as non-victims to suffer from poor health, and that such effects persist long after the violence stopped”. This health impact of domestic violence went beyond injuries, as women who had experienced physical or sexual violence by their partners were more likely to have pain, dizziness and mental health problems. Victims were also more likely to have considered suicide and to have suffered miscarriages. According to different reports issued in 2002 and based on data from the United Kingdom and the United States, domestic violence toward woman might begin or escalate during her pregnancy. One US study showed that 37% of obstetric patients were suffering violence, and that 30% of domestic violence actually started during her pregnancy. Domestic “abuse/terror” was identified as a major health issue for pregnant women. The author of From Outrage to Courage wrote that consequences of domestic violence were not just a matter of individual’s health, but rather was an issue of

98 public healthcare. A study named The Economic Dimensions of Interpersonal Violence published by WHO in 2004 noted that in addition to devastating individual families, interpersonal violence also results in major economic costs to societies. For example, the USA spends 3.3% of GDP (5.8 billion dollars) on violence-related matters. This idea runs all through the whole book. In her Global Fund for Women, Anne Firth Murray has been working hard to emphasize the problems of violation of women’s rights to health. Thus, we, healthcare professionals, must support her more actively: both personally, and as a group. Readers of Urgent Problems of Women’s Health are not surprised that in this book Ann Firth Murray highlights the problem of woman’s health describing both general and specific health issues. She also demonstrates how many factors affect women and men differently. We, healthcare professionals, have been trying to promote these ideas for years. Although the process was not very fast, we were able to achieve some success in May 2014, when the US National Institutes of Health (NIH) published new standards that would require inclusion of female cells in pre-clinical research. The Society for the Women‘s Health Research (SWHR)-(2) wrote in their letter: “The word is spreading women‘s health matters! After nearly 25 years of advocacy and education, women’s health and biological sex differences are becoming more a priority in clinical research and then despite the fact that biological sex differences are well noted in scientific literature, many researches have been slowed to incorporate female equity in clinical research...” This information and Anne Firth Murray’s book From Outrage to Courage give us new stimuli to pursue our goal: to participate in building a true democratic society in our common home, i.e. the planet Earth, but first of all, in our own home and in our motherland. We hope to translate this book into different languages. Now it is available at: Amazon.com, Amazon Europe, Create Space e Store, Create Space Direct, bookstores and online retailers [4].

99 ОТ ОТЧАЯНИЯ К ОТВАГЕ Рецензия на книгу Энн Фёрт Мюррей Л. Скуратовская, Г. Дроздова, Л. Корнелиус, НИИ Общей патологии и патофизиологии РАМН, Россия Российский Университет Дружбы народов, Россия Группа онкологов г. Денвер, Колорадо, США (Перевод с англ. - Иван Борщевский)

В последние годы проблеме многочисленных нарушения прав женщин уделяется всё больше внимания [1]. Интерес усилился с 1993 года, когда ООН провела в Вене конференцию по правам человека - тогда страны-участницы впервые назвали такие действия, как изнасилование и домашнее насилие, «нарушением прав человека « (Права женщин - это права человека, а права человека - это права женщин), - а также с 1994 года, когда Международная конференции по народонаселению и развитию (Вена) впервые приравняла репродукционные права к правам человека. С тех пор было опубликовано много замечательных книг и статей, авторы которых собрали множество свидетельств о случаях нарушения прав женщин, в том числе вскрыли проблему домашнего насилия в разных уголках нашей планеты [2]. Особое внимание проблемам соблюдения права на здоровье, стали уделять с конца 80-х годов прошлого века, когда доктор Джонатан Манн напечатал несколько статей о защите прав жертв СПИДа и ВИЧ инфицированных [3]. Для защиты прав женщин во многих странах были учреждены различные неправительственные организации, и среди них - Международный женский фонд, основанный в 1987 году Энн Фёрт Мюррей. Его цель - «спонсировать создание, развитие и взаимодействие групп, занимающихся благополучием женщин». Как писала Энн Фёрт Мюррей, она представляет себе этот фонд как место, где женщины могут найти помощь, место, где все их мечты и чаяния о переменах к лучшему, а также о расширении возможностей женщин наконец-то сбудутся [4]. Согласно ее определению, «расширение возможностей женщин» (empowerment) – это значит, что «у женщины должна быть мечта, у нее должен быть план, чтобы эту мечту осуществить, а также у нее должны быть возможности реализовать этот план». В течение многих лет Энн Фёрт Мюррей служила живым примером того, как добиваться этой цели. Она пишет: «У меня была мечта и я видела, как она сбылась – Международный женский фонд существует и развивается! Я сотрудничаю со

100 студентами, у которых горят глаза и которые желают трудиться! Поэтому я хочу, чтобы ту же радость испытали и другие» (в 2000 году Энн Фёрт Мюррей стала профессором- консультантом по биологии человека в Стэнфордском университете, где она читает лекции о здоровье женщин и правах человека, а также о том, что любовь - та сила, которая позволит добиться социальной справедливости). Она обобщает свой опыт по созданию женских групп в рамках Международного женского фонда для защиты прав женщин в разных уголках земного шара с 1987 года. И сегодня у нас есть замечательная возможность познакомиться с этим опытом благодаря книге «От отчаяния к отваге», второе, переработанно издание которой опубликовано в 2013 году. У книги есть подзаголовок: «Несправедливое и нездоровое положение женщин в бедных странах - что они делают, чтобы исправить его». Как писала Мэри Робинсон, бывший Президент Ирландии, Верховный комиссар Организации Объединенных Наций по правам человека (1997-2002): «Эта книга освещает подробности жизни женщины – их борьбу, их стойкость, способность принимать правильные и дальновидные решения. Редкое сочетание четкого анализа и вдохновения!» В книге 346 страниц. Она посвящена «женщинам, которые учат нас отваге и стойкости», а ее цель выражена в словах Ганди: «Посреди смерти остается жизнь; Посреди лжи остается истина; Посреди тьмы остается свет». Книга состоит из десяти частей, а предисловие называется «Тьма и свет». С самого первого предложения книги понятно, что она посвящена женскому здоровью: «Родиться женщиной опасно для вашего здоровья». И это печальная истина верна в отношении многих читательниц, однако для многих женщин в развивающихся странах это настоящая трагедия. Аборты в зависимости от пола будущего ребенка очень распространены, поскольку родители, по разным причинам, считают, что они не могут допустить появления на свет еще одной девочки. Сотни тысяч девочек «исчезли», из-за чего в таких странах, как Китай, Индия и Корея соотношение женщин и мужчин нарушено. Семьдесят семь миллионов девочек во всем мире не ходят в школу (в сравнении с шестьюдесятью пятью миллионами мальчиков). Около трех миллионов девочек каждый год подвергаются так называемому «женскому обрезанию», большинство из них живет в Африке. ВИЧ/СПИД быстрее распространяется среди девочек-подростков и молодых женщин. Каждый год более 350 000 тысяч женщин умирают от заболеваний

101 и осложнений в родах, которые можно было бы предотвратить. От четверти до половины всех живущих сегодня (!) женщин, страдают от насилия со стороны спутников жизни и половых партнеров. Трое из четырех жертв войны - женщины и дети. Многие взрослые женщины в бедных странах неграмотны и страдают от различных заболеваний - от этого конечно, страдают и мужчины, однако в отличие от мужчин, женщины чаще остаются один на один со своими проблемам. На них также лежит тяжкий груз домашнего хозяйства [5, 6]. Для нас, членов Международной Ассоциации Женщин-Врачей и всех медицинских работников, которые считают, что забота о здоровье женщины - это соблюдение ее прав- прав человека, эта книга представляет собой очень ценное пособие. В самом начале автор пишет: «Здоровье женщины - это вопрос не одной лишь медицины. Это вопрос культуры, политики, и экономики, и, в первую очередь, вопрос социальной справедливости. Улучшение здоровья женщины и повышение ее статуса зачастую воспринимается как мощное средство для решения экономических проблем, нежели как путь к общей справедливости. Однако, несомненно, это и то, и другое». Книга начинается с главы о бедности женщин как нарушении прав человека, потому что простые женщины именно эту проблему считают главной в своей жизни, а на втором месте стоит здоровье. На здоровье женщины влияет всё, что происходит в ее жизни, особенно если мы расширим понятие Всемирной Организации Здравоохранения (ВОЗ): «Здоровье - это состояние полного физического, психического, социального и духовного благополучия, а не просто отсутствие болезней и физических дефектов...» Во всех главах книги Энн Фёрт Мюррей показывает читателям, как важно включать в определение ВОЗ и «экономический фактор». Используя определение ВОЗ, при определении состояния здоровья представителей различных групп населения, которые значительно отличаются друг от друга по культуре, экономическому положению, истории, демографии и медицинскому обслуживанию, мы сталкиваемся с определенными проблемами. Тем не менее, ООН и другие международные организации приводят данные которые позволяют оценить состояние здоровья населения в разных странах.. И если мы объединим все полученные ими данные- получим самую достоверную информацию. А она гласит, что в современном обществе, несомненно, у женщин должны быть те же возможности для реализации своих прав, что и у мужчин, но их нет… В пресс-релизе 1998 года приведены слова Гру Харлем Брутланд, бывшей главы ВОЗ: «Никогда прежде здравоохранение не было так доступно. Но никогда прежде столь многим в этом доступе отказывали». В отчете ООН

102 «Положение женщин в мире: тенденции и статистика. 2000» показано, что во всем мире по-прежнему наблюдается неравенство между мужчинами и женщинами в шести областях: здоровье, права человека и участие в политике, работа, образование, коммуникация, семья (90% от общего количества заболеваний наблюдаются в развивающихся странах, однако этим странам доступно лишь 10% от мировой системы здравоохранения) [7, 8]. Энн Фёрт Мюррей объясняет, почему сегодня так важно уделять внимание здоровью женщин- не только потому, что половое неравенство несправедливо, но еще и потому, что женщины, здоровые или больные, - это сердце любой семьи и всего общества. Здоровье женщины влияет на все области ее жизни и, как следствие, на ее семью и на всё общество. Женщины не просто активные члены семьи, зачастую они ее ангелы-хранители. А неравенство - нарушение прав женщин - происходит из-за древних предубеждений, навязанных обществу, которые разрушают жизнь как мужчин, так и женщин. Чтобы улучшить здоровье женщин, конечно, нужно лечить определенные заболевания, однако нужно менять и условия их проживания, чтобы женщины полнее могли распоряжаться совей жизнью и здоровьем. Мы можем сделать выбор- жить по вселенским законам справедливости. Но мы можем решить изменить мир так, чтобы справедливость была доступна для всех. Восьмая глава посвящена труду женщин в эпоху глобализации. В этой книге собрано много грустных историй. «С помощью рассказов и примеров, лирики и статистики, я хочу подчеркнуть основную мысль моей книги. Многие вопросы женского здоровья долгое время выпадали из поля нашего зрения, их также считали слишком личными для публичных обсуждений. Книга же поможет обличить эту несправедливость». Все десять глав книги очень информативны, содержат много статистических данных, а также множество рассказов от первого лица в главах, посвященных нарушению прав на здоровье. Рассмотрим один пример - главу 6 «Женщины: дурное обращение или терроризм?» Она анализирует первое международное исследование домашнего насилия, проведенное Лондонской школой гигиены и тропической медицины. В отчете указано, что насилие против женщин широко распространено, что не может не сказаться на здоровье. У женщин, подвергшихся физическому насилию, очевидно, будут проблемы со здоровьем независимо от того, живет ли она в большом современном городе экономически развитой страны или в деревне страны третьего мира. Центр полового равенства описывает насилие против женщин как «самое частое, но, вместе с этим, наиболее скрываемое в мире нарушение прав женщин», а также как

103 «серьезную угрозу здоровью, которая истощает женщин, вредит их здоровью и лишает их самоуважения». Чаще всего семейное насилие совершается мужчинами против своих спутниц. Затрещины, пощечины, удары, избиения, ожоги и убийства - это происходит с женщинами каждый день, в каждой стране, во всем мире. Автор цитирует Генерального секретаря ООН Пан Ги-Муна: «Насилие в отношении женщин и девочек не прекращается ни на одном континенте, ни в одной стране или культуре. Последствия этого насилия для жизни женщин, для их семей, а также для общества, в целом, просто разрушительны. Большинство сообществ запрещают такое насилие, но на деле, увы, его покрывают или даже потворствуют». В своей книге Энн Фёрт Мюррей предлагает использовать слово «террор» вместо «жестокое обращение», поскольку именно это мы наблюдаем во всем мире. И с этим предложением трудно не согласиться. Авторы этого исследования (опубликованного ВОЗ в 2005 году) опросили 24 000 женщин в десяти странах и выяснили, что «проблемы со здоровьем возникают у жертв насилия в два раза чаще, чем других женщин, и проблемы эти остаются еще долго после того, когда насилие прекратилось». Проблемы со здоровьем у жертв домашнего насилия не ограничиваются лишь травмами, поскольку женщины, подвергшиеся сексуальному или физическому насилию со стороны своих партнеров, чаще страдают от боли, головокружения и эмоциональных расстройств. Жертвы насилия чаще задумываются о суициде, у них чаще бывают выкидыши. Согласно различным сообщениям, опубликованным в 2002 году на основании данных из США и Великобритании, домашнее насилие в отношении женщин усиливается в период беременности. Одно американское исследование показало, что 37% беременных женщин сталкивались с насилием, а в 30% случаев домашнее насилие началось именно во время беременности. Домашнее насилие./террор - главная угроза здоровью беременных женщин. Автор книги «От отчаяния к отваге» пишет, что последствия домашнего насилия не ограничиваются лишь здоровьем отдельного человека, это проблема здоровья всего общества. Исследование «Экономические вопросы межличностного насилия», опубликованное ВОЗ в 2004 году показало, что кроме разрушительного влияния на семью, межличностное насилие также дорого обходится обществу. Например, в США 3,3% ВВП (5,8 миллиардов долларов) тратится на вопросы, связанные с насилием. С помощью Международного Женского Фонда Энн Фёрт Мюррей старается обратить внимание на нарушение прав женщин и в частности, на здоровье. Мы ,каждый врач, и все медицинское сообщество, в целом, должны активнее

104 пропагандировать необходимость соблюдения прав человека и особенно право на здоровье. Читатели журнала «Актуальных проблем женского здоровья» не будут удивлены, что в своей книге Энн Фёрт Мюррей освещает проблему женского здоровья, описывая как общие, так и частные медицинские проблемы, подчеркивая их гендерные различия. Мы, медицинские работники многие годы пропагандировали эту идею. Хоть и медленно, но успех приходит и в этом направлении: в мае 2014 года Национальный институт здоровья США опубликовал новое руководство, которое « позволит включать в доклинические исследования клетки, взятые у женщин». Общество по исследованию женского здоровья (Society for the Women‘s Health Research, SWHR) написало в своем письме: «Наконец-то важность здоровья женщин признали и говорят об этом! Спустя 25 лет постоянных усилий и просвещения, проблемы женского здоровья и различия полов наконец-то стали учитываться в клинических исследованиях, потому что несмотря на то, что биологическое различие полов хорошо описано в медицинской литературе, многие исследователи не торопятся учитывать его на практике» [4]. Эти данные, также как и книга Энн Фёрт Мюррей «От отчаяния к отваге» придает нам сил и дальше стремиться к цели - построению настоящего демократического общества в нашем большом доме – на планете Земля, а также в нашем собственном доме и в нашей стране. Мы надеемся перевести эту книгу на разные языки. Сейчас ее можно купить в интернете: на сайтах Amazon.com, Amazon Europe, Create Space eStore, CreatSpace Direct, а также в книжных магазинах.

REFERENCES: 1. "From Outrage to Courage" The Unjust and Unhealthy Situation of Women in Poorer Countries and What They Are Doing About It ANNE FIRTH MURRAY Foreword by Paul Farmer New and Revised Second Edition 2. Anne Firth Murray, Menlo Park, California, USA, 2013, www.annefirthmurray.com 3. Mann J.M. et all. "Surveillance for AIDS in Central African City: Kinshasa,Zaire" Journal of the American Medical Association 1986, 255; 3255-59. (Full references of Johnathan Mann"s articles about Health and Human Rights published in Edwin Cameron "the Deafening Silence of AIDS" ,Health and Human Rights(An International Journal) vol.5, N 1, pp.7 – 24 4. Society for Women's Health Researche – mail form Society for Women's Health Research , May 2014.

105 5. Hogeman M.C; Foreman KJ et al "Maternal mortality for 181 countries 1980-2008: a systematic analysis of progress toward Millennium Development Goal 5"In Lancet. 2010 ;M ay8; vol 375,N9726; 6. 2009 "Global Facts and Figures un Pitanguy, Jacueline, ed. 7. 2007 Violence Against Women in the International Context, CEPIA, Rio de Janeiro, June 8. 2005 WHO Multi- Country Study on Women's Health And Domestic Violence Against Women http://www. who.int/gender/violence/who-multicountry-study/en/index.html.

FROM OUTRAGE TO COURAGE, by Anne Firth Murray (The review of the book) L. Skuratovskaya, G. Drozdova, L. Cornelius The Institute of General pathology and Pathophysiology of RAMS, Russia Peoples Friendship University of Russia Oncology RDC, Denver, Co.,USA SUMMARY In 1980s Dr. Jonathan Mann published several articles about protection of human rights of AIDS victims thus drawing attention to gender-related aspects of the right to health. These papers triggered studies of this problem. Among organizations for protection of women’s rights established in different countries, there is the Global Fund for Women founded by Anne Firth Murray in 1987. Its aim is to “provide fund internationally to seed, strengthen, and link groups committed to women’s well-being”. Over all these years, Anne Firth Murray was an example of how to achieve this goal She summarized all her experience in organizing women’s groups by means of the Global Fund for Women in order to protect women’s rights in different parts of the world since 1987.mAnd today we have a wonderful opportunity to read this experience her book From Outrage to Courage, second edition, published in 2013. The book has the following subheading: ”The Unjust and Unhealthy Situation of Women in Poorer Countries and What They are doing About it”. All chapters of book are very informative. They contain much statistic data and many personal experiences dedicated to violation of rights to health. Key wards: women's rights, women's health, domestic violence, sexual violence

106 ОТ ОТЧАЯНИЯ К ОТВАГЕ Рецензия на книгу Энн Фёрт Мюррей Л. Скуратовская, Г. Дроздова, Л. Корнелиус, НИИ Общей патологии и патофизиологии РАМН, Россия Российский Университет Дружбы народов, Россия Группа онкологов г. Денвер, Колорадо, США

РЕЗЮМЕ В последние годы проблеме многочисленных нарушения прав женщин уделяется всё больше внимания. Особое внимание проблемам соблюдения права на здоровье, стали уделять с конца 80-х годов прошлого века, когда доктор Джонатан Манн напечатал несколько статей о защите прав жертв СПИДа и ВИЧ инфицированных. Для защиты прав женщин во многих странах были учреждены различные неправительственные организации, и среди них – Международный женский фонд, основанный в 1987 году Энн Фёрт Мюррей. Его цель – «спонсировать создание, развитие и взаимодействие групп, занимающихся благополучием женщин». В течение многих лет Энн Фёрт Мюррей служила живым примером того, как добиваться этой цели. Она обобщает свой опыт по созданию женских групп в рамках Международного женского фонда для защиты прав женщин в разных уголках земного шара с 1987 года. И сегодня у нас есть замечательная возможность познакомиться с этим опытом благодаря книге «От отчаяния к отваге», второе, переработанно издание которой опубликовано в 2013 году. Все десять глав книги очень информативны, содержат много статистических данных, а также множество рассказов от первого лица в главах, посвященных нарушению прав на здоровье. Ключев ые слова : женские права, женское здоровье, семейное насилие, сексуальное насилие

107 recenzia en fert mureis wignze sasowarkveTilebidan gambedaobamde l. skuratovskaia, g. drozdova, l. korneliusi zogadi paTologiis da paTofiziologiis ssk, ruseTi ruseTis xalxTa megobrobis universiteti, ruseTi q. denveris onkologTa jgufi, kolorado, aSS

reziume ukanaskneli wlebis ganmavlobaSi, qalTa uflebebis darRvevebs sul ufro meti yuradReba eqceva. qalTa janmrTelobis uflebebiT gansakuTrebiT mas Semdeg dainteresdnen, rac gasuli saukunis 80-iani wlebSi, jonaTan manma gamoaqveyna ramdenime statia SidsiTa da aiv inficirebulTa uflebebis dacvis Sesaxeb. qalTa uflebebis dasacavad msoflioSi bevri arasamTavrobo organizaciaa Seqmnili, maT Soris, en fert mureis mier 1987 wels dafuZnebuli qalTa saerTaSoriso fondi. fondis mizania, daasponsoros qalTa keTildReobis problemebiT dakavebuli jgufebi – maTi moRvaweoba, ganviTareba da urTierTkavSirebi. didi xnis ganmavlobaSi, TviT en fert murei, imis cocxal magaliTs warmoadgenda, Tu rogor SeiZleba am miznis miRweva. 1987 wlidan is aqtiurad moRvaweobda qalTa saerTaSoriso fondis farglebSi da Tavis gamocdilebas uziarebda qalTa uflebebis damcav sxvadasxva organizaciebs, msoflios yvela kuTxeSi. Aswored am udidesi gamocdilebis Sedegia mis mier Seqmnili wigni «sasowarkveTilebidan gambedaobamde», romlis meore, gadamuSavebuli gamocema 2013 wels gamoica. wignis yvela (10-ve) Tavi informatiulia, Seicavs bevr mniSvnelovan statistikur monacems, agreTve Zaladobis msxverplTa monaTxrobebs, janmrTelobis uflebebis darRvevis Sesaxeb. sakvanZo sityvebi: qalTa uflebebi, qalTa janmrTeloba, ojaxuri Zaladoba, seqsualuri Zaladoba

108 INFORMATION FOR AUTHORS Journal “Actual Topics on Women’s Health” is peer-reviewed multidisciplinary journal, which publishes research and review articles related to women's health and health care. The articles should be submitted in English or Russian Languages. In any case articles must be accompanied by the Abstracts in English, Russian and Georgian Languages (not more than 150 words). The content of articles as of the abstracts should be strictly identical and consist: the introduction, objectives, methods, results, discussion, conclusions and 4-6 key words. The total volume of articles with Abstracts and list of references should be at list pages (A4 format). The articles must be printed on the standard typing paper (A4 format). Typeface – Times New Roman, Cyrillic, AcadNusx. Fonts size – 12, line spacing – 1, 5; margins: top and bottom – 2,5cm, left – 3cm; right – 1, 5. The articles must be followed by the list of references. The list of references is located at the end of articles. All references cited in the text must be listed. References are numbered in the text by numbers given in the square brackets. In the case of necessity the numbers are repeated throughout the text. The list of references should be arranged alphabetically in accordance with the surname of the first author and include: authors surname and initials, name of the Journal (book), year of publication, volume, number, and the first and the last pages. In the case of book the place and publisher should be provided. The list of references includes: Georgian, Cyrillic and Latin scripts. Articles should be presented in the printed form and on CD as electronic version. It is also possible to send articles by email. Black and white graphics should be submitted in MS Excel format, the other black and white drawings can be submitted in the form of JPG files. The print of color graphics or photos needs the special permission of Journal Editorial board. In the beginning of the article, should be listed the authors and their place of work. Manuscript must be signed by all authors. The contact information (phone number and e-mail of corresponding author) should be indicated. Printing of articles in the journal is provided by the expense of the authors. Contact information: Nino Zhvania: Tel: (+995 551) 44 90 94; E-mail: [email protected] Khatuna Kaladze: Tel: (+995 593) 149626; E-mail: [email protected] [email protected]

109 ИНФОРМАЦИЯ ДЛЯ АВТОРОВ Журнал “Actual Topics on Women’s Health” является рецензируемым, многопрофильным журналом, публикующим статьи, по вопросам женского здоровья и его обеспечения. Статьи в журнале публикуются на Английском и Русском языках. В любом случае статьи должны сопровождаться резюме на Английском, Русском и Грузинском языках (не более 150 слов). Статьи должны быть напечатаны на стандартной бумаге для печатанья (A4 формата). Для печатанья следует использовать шрифты Times New Roman, Cyrillic, AcadNusx. Размер фонта – 12, интервал между строками – 1,5 см, верхние и нижние поля – 2,5 см, справа – 1,5 см, слева – 3см. Содержание статей и резюме должно быть строго идентичным и содержать: введение, цель работы, методы исследования, результаты, обсуждение, выводы, 4-6 ключевых слов. Общий объем статей, включая резюме и список использованной литературы, должны составлять не меньше 5 страниц (А 4 формат). Статьи должны сопровождаться списком использованной литературы. Вся цитированная литература должна быть приведена в списке. Список использованной литературы должен находиться в конце статьи. Вся цитированная литература должна быть указана в тексте соответствующим номером в квадратных скобках. В списке литературы должны быть указаны фамилии и инициалы имен авторов, название журнала, книги, год издания, том, номер, номера первой и последней страниц. В случае книги должны быть указаны город и название издательства. В списке литературы сперва должны быть указаны грузинские источники, затем русские и латыноязычные. Статьи для печатанья в журнале должны представляться в напечатанном виде и на компакт диске виде электронной версии, а также можно переслать работы по электронной почте. Черно-белые графики должны быть представлены в виде файлов формата MS Excel; другие черно-белые рисунки в виде файлов формата JPG. Для печатанья цветных графиков и рисунков необходимо специальное разрешение редакционной коллегии. В начале статьи должны быть указаны авторы статьи и их место работы. Статья должна быть подписана всеми авторами и сопровождаться контактной информацией одного из соавторов (номер телефона, адрес Электронной почты). Печатанье статей в журнале осуществляется за счет авторов. Контактная информация: Нино Жвания: (+995 551) 44 90 94; E-mail: [email protected] Хатуна Каладзе: (+995 593) 14 96 26; E-mail: [email protected], [email protected]

110 informacia avtorebisTvis

Jurnali “Actual Topics on Women’s Health” warmoadgens recenzirebad, mravalprofilian Jurnals, romelSic ibeWdeba statiebi qalis janmrTelobisa da janmrTelobis dacvis Sesaxeb. statiebi JurnalSi ibeWdeba inglisur da rusul enebze. nebismier SemTxvevaSi, statias Tan unda axldes reziumeebi qarTul, rusul da inglisur enebze (ara umetes 150 sityvisa). teqsti unda daibeWdos standartul sabeWd qaRaldze (А 4 formati). dasabeWdad gamoyenebul unda iqnas fontebi: Times New Roman, Cyrillic, AcadNusx. Sriftis zoma – 12, intervali strofebs Soris – 1,5sm; teqstis zeda da qveda sazRvrebi – 2,5 sm; marjvena sazRvari – 1,5 xolo marcxena – 3sm. statiis da reziumes Sinaarsi unda iyos mkacrad identuri da moicavdes: Sesavals, kvlevis mizans, kvlevis meTodebs, miRebul Sedegebs da maT ganxilvas, daskvnebs da 4–6 sakvanZo sityvas. statiis saerTo moculoba (reziumeebis da gamoyenebuli literaturis CaTvliT), ar unda iyos 5 gverdze naklebi (А 4 formati). statiebs Tan unda axldes gamoyenebuli literaturis sia. citirebuli literatura unda iyos miTiTebuli teqstSi, numeraciis Sesabamisad, kvadratul frCxilebSi. literaturis siaSi unda iyos miTiTebuli avtorebis gvarebi da maTi saxelebis inicialebi, Jurnalis (wignis) saxelwodeba, gamocemis weli, tomi, nomeri, pirveli da bolo gverdebi. wignis SemTxvevaSi aucilebelia qalaqis da gamomcemlobis miTiTeba. gamosaqveynebeli statiebi redaqciaSi mowodebuli unda iyos akrefili teqstis da kompaqt diskze Senaxuli eleqtronuli versiis saxiT, aseve SesaZlebelia masalis eleqtronul fostaze gamogzavna. teqstSi gamoyenebuli Sav-TeTri grafikebi warmodgenili unda iyos MS Excel failis, xolo Sav TeTri suraTebi – jpg failis saxiT. feradi grafikebis da suraTebis dabeWdvas esaWiroeba Jurnalis saredaqcio kolegiis specialuri nebarTva. statiis dasawyisSi ganTavsebuli unda iyos misi avtorebis da maTi samuSao adgilis CamonaTvali. statiebi xelmowerili unda iyos yvela avtoris mier da unda axldes sakontaqto piris (erTerTi Tanaavtoris) sakontaqto informacia (telefoni, el–fosta). statiebi JurnalSi ibeWdeba avtorebis xarjiT. sakontaqto informacia: nino Jvania: (+995 551) 44 90 94; nin.zhvania27@gmail. com xaTuna kalaZe: (+995 593) 14 96 26; [email protected], [email protected]

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