Original Article A New Vaginal Gel for Femalegenital Wellness and Disease Prevention: Rationale of a Multi-Herbal Derived Treatment on a High-Tech Pharmaceutical Perspective
Beniamino Palmieri*, Maria Vadalà, Nicol Fornabaio and Carmen Laurino
Department of General Surgery and Surgical Specialties, University of Modena and Reggio Emilia Medical School, Surgical Clinic, Modena, Italy
ABSTRACT
The folk ethno-medicine describes some useful herbal remedies for vaginal hygiene, whose knowledge goes back to previous centuries; unfortunately, only few of them have been submitted to clinical trials and fulfilled the evidence-based medicine rules thus being successfully introduced into the routine use; as a matter of fact actually the consumer is quite sensitive to the message that historical natural active principles revisited by positive recent investigations can have a role in the disease prevention and treatment. Salvia, Melaleuca and Calendula have been selected by us among a certain number of natural compounds to be introduced in the formula of our vaginal gel, because their complementary properties synergize Address for each other, achieving, altogether the best clinical results. The Correspondence mechanism of actionof the 3 herbs extracts in combination, takes control of the vaginal surface integrity and mucosa restoration after Department of mechanical, chemical or microbiological damage, especially through General Surgery and the well-known Calendula contributes to body defenses against Surgical Specialties, external agents, has anti-inflammatory, antioxidant and healing University of Modena properties; Salvia expresses altogether a wide and selective control, and Reggio Emilia supports the natural mechanism for body´s purification and promotes Medical School, the toxin elimination; Melaleuca expresses altogether a wide and Surgical Clinic, selective control of pathogenic microflora enclosing the often Modena, Italy relapsing Candida albicans super-infections. E-mail: [email protected] Keywords: Vaginal wellness, Sage, Marigold, Tea Tree oil, Vaginal gel.
American Journal of Phytomedicine and Clinical Therapeutics www.ajpct.org Palmieri et al______ISSN 2321 – 2748
INTRODUCTION Vaginal Gel Based upon Herbal extracts and introduced in the formula of our vaginal gel, HPMC because their complementary properties “The vaginal gel” is a water-based synergize each other, achieving, altogether vaginal gel with a lubricant action, thanks to the best clinical results. The dry powder of the synergy of hydroxypropyl each plant extract was in amount of 100 mg methylcellulose (HPMC) associated with and added to 500 ml of distilled water then distilled waters of Salvia officinalis L. and boiled for one minute to obtain the aqueous Calendula officinalis L., useful to keep extract, therefore the plant concentration is lubricated and protected the vaginal surface. lower and it not explicates pharmacological The Melaleuca alternifolia (tea tree oil) with action. Chlorhexidine has been added at the the other components, gives to the gel a concentration of 0, 02%, this low soothing and refreshing properties. To the concentration is addressed to prevent formula is added chlorhexidine, with contamination of the gel and packaging by antifungal and bacteriostatic properties just bacteria and protozoa. Hydroxypropyl with preservative purpose to inhibit micotic methylcellulose, a polymer with muco- and bacteria contamination in the mimetic properties has been added to induce preparation. a protective, transparent and viscoelastic The natural herbal resources are very shield on the mucosa upon which the active helpful in maintaining a well balanced principles can express their mixed properties environment when topically delivered in the at the best being. Salvia and Calendula in mucosal cavities of the human body because the soluble form of water extracts, of the multifactorial interferences of the Melaleuca (tea tree oil) as essential oil. phytocomplexes with the biological background. Specifically an healthy vaginal Individual clinical background for homeostasis has multi-steps rebounds, either Melaleuca, Salvia and Calendula mixed in the endocrine and immunological setting, formula or in the mucosa cells turnover and trophic activation, in the maintenance of acidic pH, Calendula officinalis Linn (Marigold) optimal hydration or finally in the symbiotic Calendulaofficinalis L. (Asteraceae) microscopic flora control. The folk ethno- iscommonly used for quickening the wound medicine describes some useful herbal healing process due to its anti-inflammatory, remedies for vaginal hygiene, whose anti-virus, antimicrobial and antifungal knowledge goes back to previous centuries; activity, anti-cancer, antioxidant and healing unfortunately, only few of them have been properties1. The major classes of Calendula submitted to clinical trials and fulfilled the phytoconstituents are triterpene alcohols, evidence-based medicine rules thus being triterpene saponins, flavonoids, carotenoids successfully introduced into the routine use; and polysaccharides. Some of these as a matter of fact actually the consumer is compounds are able to permeate the stratum quite sensitive to the message that historical corneum, and so to penetrate into deeper natural active principles revisited by positive skin layers2,3. Preparations of C. officinalis recent investigations can have a role in the are mainly applied in the form of infusions, ailment prevention and treatment. tinctures and ointments as wound healing Salvia, Melaleuca and Calendula remedies for inflammation of the skin, have been selected by us among a certain mucous membranes, to prevent infection and number of natural compounds to be to soothe inflamed and damaged skin4, but
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also for poorly healing wounds, bruises, increased survival time compared to boils and rashes, e.g., pharyngitis and leg control15.Triterpeneslikefaradiol and ulcers5. In the mixed lymphocyte reaction, taraxasterol inhibit experimental tumor 70% ethanol extract showed stimulatory promotion and are consequently considered effects at 0.1-10 μg/ml, followed by inhibitors of tumor growth16. A saponin rich inhibition at higher concentrations6. Human fraction given orally at 50 mg/kg body granulocytes phagocytosis was stimulated weight to hyperlipemic rats reduced the by polysaccharides isolated from Calendula serum lipid level17,18.Oral administration of flowers aqueous extract7. Extracts of C. officinalis extract is effective to inhibit Calendula flowers of differing polarities serum glucose levels increase in glucose- exhibited anti-oxidative effects on liposomal loaded mice; gastric emptying and finally lipid peroxidation induced by Fe2+ and shows a potent gastro-protective effect in ascorbic acid8,9. Isorhamnetin 3-glycosides rats, inhibiting ethanol and indomethacin- from Calendula flowers inhibited induced gastric lesions in this one19. The lipoxygenase from rat lung cytosol at a aqueous alcohol extract of C. officinalis concentration of 1.5 × 10-5 M10. In a test exhibited central nervous system inhibitory system based on porcine buccal membranes, effect with marked overall sedative activity strong concentration-dependent adhesive as well as hypotensive effect20. The alcohl processes were observed with a low extract of C. officinalis flowers, instead, viscosity polysaccharide enriched extract possesses anti-HIV properties, it seems that (98% carbohydrates) of Calendula flowers. may inhibit early events in the HIV These findings suggest that the replication cycle, suppressing cell polysaccharides may contribute to fusion21and is also able to inhibit the therapeutic effects in the irritated mucosa Epstein-Barr virus early antigen activation22 treatment11. Lycopene, saponins, and to suppress the replication of herpes triterpenoids and flavonoids, like quercitin simplex in vitro23. A cream containing prevent from releasing of harmful and Calendula extract has been showed to be histamine enzymes, which cause sensitivity effective in dextran and burn edemas as well and inflammation, heal the redness and pain, as in acute lymphedema in rats. Activity and inhibits plasma release to the tissue, against lymphedema was primarily ascribed decreasing the capillary permeability. At the to macrophage proteolytic activity same time, terpenoids reduce the enhancement24. The flowers essential oil immigration of white blood cells into inhibited the growth in vitro of Bacillus inflamed area12 (Eghdampour et al., 2013) subtilis, Escherichia coli, S. aureus, and lycopene consistently reduces transcript Pseudomonas aeruginosa and Candida levels of pro-inflammatory cytokines13. In albicans25,26. Acetone, ethanol or water animal studies, Calendula has showed to extracts inhibited the growth in vitro of the stimulate granulation and increase fungus Neurospora crass27. A flavonoid glycoproteins and collagen at wound fraction isolated from the flowers inhibited sites14,1. Calendula officinalis extract could the in vitro growth of S. aureus, enhance the collagen content whether by Sarcinalutea, E. coli, Klebsiella pneumonia increasing synthesis or decreasing and Candida monosa28.The 50% ethanol catabolism of collagen1. A fraction enriched extract of the plant showed spermicidal in triterpene administered orally to mice activity in rats at 2% concentration29. inoculated with Ehrlich mouse carcinoma Flavonoids and saponins prevent from prevented the as cites development and releasing of harmful and histamine enzymes,
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which cause sensitivity and inflammation; individual scores for each symptom heal the redness and pain; and inhibit plasma improved33. Local application of a mixture discretion to the tissues by decreasing the containing 70% oily extract of capillary permeability. Triterpenoids provide Hypericumperforatum and 30% oily extract the anti-inflammatory activity. The essential of C. arvensisin women with surgical oil from C. officinalis flowers exhibits good wounds improved the rate of healing, sun protection activity due to its antioxidant compared with controls34.In a phase III activity30. Cutaneous application of a cream randomized single blinded trial C. containing essential oil of Calendula (at 4% officinalisis compared with trolamine in the and 5%) prevents UV-B-induced alterations prevention assessment of acute dermatitis in the level of antioxidants in rat skin tissue, during irradiation for breast cancer. Patients with increasing in superoxide dismutase who had been operated on for breast cancer (SOD), catalases (CAT), ascorbic acid level and who were to receive post-operative (ASC) and total protein (TP) level, and radiation therapy were randomly allocated to simultaneously reduction in application of either Calendula ointment malondialdehyde (MDA) content, a marker containing 20% of fresh Calendula aerial of lipid peroxidation31. The photo-protective parts in petroleum jelly (126 patients) or effect of topical gel formulation of C. trolamine (128 patients) on the irradiated officinalis is thought to be associated with fields after each session. The primary end an improvement in collagen synthesis in the point was the occurrence of acute dermatitis sub-epidermal connective tissue, topical of grade 2 or higher. Secondary end points application accelerates the biological events were the occurrence of pain, the quantity of involved in the photo-damaged dermal the topical agent used and the patient healing process1,3. Furthermore the presence satisfaction. The occurrence of acute in the Calendula extract of β-carotene, dermatitis of grade 2 or higher was quercitin13, 1,8-cineole and α-pinene, significantly lower (41% vs. 63%; p< 0.001) compounds with scavenge free radicals with the use of Calendula than with activity, conferring it a good antioxidant trolamine. Moreover, patients receiving potential2,31. In a randomized, open Calendula had less frequent radiotherapy controlled study, were compared the effects interruption and significantly reduced of three ointments after topical treatment of radiation-induced pain35.Furthermore the patients with 2nd or 3rd degree burns for 17 clinical relevance of this finding is days: Calendula flower ointment (prepared emphasized by the significant improvement by digestion in vaseline) (n = 53) or vaseline in self-assessed patient satisfaction with only (n = 50) or a proteolytic ointment (n = regard to pain and dermatitis35. Another 53). The success rates were considered to be study led to healthy volunteers has reported 37/53 for Calendula flower ointment, 27/50 that C. officinalis as a cream preparation for vaseline and 35/53 for the proteolytic protects skin from irritant contact dermatitis ointment32. In an open uncontrolled pilot caused by exposure to sodium lauryl study, 30 patients with burns or scalds were sulfate36. In 34 patients with venous leg treated 3 times/day for up to 14 days with a ulcer was carried out clinical examination of hydrogel containing 10% of a hydro-ethanol an ointment with C. officinalis extract. A extract. The symptoms like reddening, total of 21 patients with 33 venous ulcers swelling, blistering, pain, soreness and heat were treated with ointment, applied twice a sensitivity were scored before, during and at day for 3 weeks. Control group that the end of treatment. Total score and consisted of 13 patients with 22 venous
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ulcers were treated with saline solution (n=1) and experimental (n=2) groups. The dressings, applied to ulcers for 3 weeks. In women in experimental group used Aloe the experimental group, the total surface of vera and Calendula ointment every 8 hours all the ulcers at the beginning of the therapy and the control group used hospital routine was 67,544 mm2. After the 3rd week, the on episiotomy for 5 days12. The data were total surface of all the ulcers was 39,373 collected by demographic questionnaire and mm2 (a decrease of 41.71%). In seven redness, edema, ecchymosis, discharge and patients, complete epithelialization was approximation scale (REEDA) which achieved. In the control group, the total investigated the episiotomy healing before surface of all ulcers at the beginning of the and five days after intervention in two therapy was 69,722 mm2. After the 3rd week, groups. REEDA scale in five days after the total surface of all ulcers was 58,743 delivery showed statistically significant mm2 (a decrease of 14.52%). In four difference between control and experimental patients, complete epithelialization was groups. Aloe vera and Calendula ointment achieved. There was a statistically considerably increase independently, the significant acceleration of wound healing in speed of episiotomy wound healing39. the experimental group (p< 0.05), Another protocol has been published suggesting the positive effects of the randomly comparing topical Aloe Vera ointment with marigold extract on venous against Calendula Officinalison diaper ulcer epithelialization37.Schmidgall and dermatitis in 63 children and infants with a coworkers (2000)11 evaluated on an protocol encompassing 3 cream delivery experimental ex vivo pig mucosal patch the /daily for 10 days. The severity of dermatitis bio-adhesiveness of herbal polysaccharides was graded at baseline as well as at the end extracts to the epidermal layer, confirming of trial using a 5-point scale. The adverse that Calendula officinalis has this specific effects of study medications were assessed property11. during the trial. Both treatment groups In a recent study of Tedeschi et al. (p<0.001) had positive results on the (2012)38, Calendula officinalis extract was symptoms but Calendula ointment improves enclosed in a gel formula including significantly the number of rash sites isoflavones, Lactobacillus sporogenes, and compared to Aloe group (p =0.001). No lactic acid and challenged to 186 women adverse effect was reported from either of mean age 53.7 years, postmenopausal for the medications. 4.1 years, using standardized oral Lavagna and colleagues (2001)34 isoflavones, 103 of which introducing the estimated the benefits of Hypericum and vaginal gel and 83 without topical treatment. Calendula oils in the epithelial The itching, burning, vulvovaginal reconstruction of surgical wounds in 24 erythema, vaginal dryness and dyspareunia childbirth with caesarean section, stating intensity were compared in the two groups; that the combined compounds were very the use of the gel gave a definite symptoms effective in reducing the wounds diameter34. relieve compared with no local treatment38. Calendula officinalis hydroalcoholic Eghdampour et al. (2013)12 evaluated the extract has not shown acute toxicity effect of Aloe vera and Calendula on following administration in rats and perineal episiotomy healing with a mice21,23. The main adverse event is allergic randomized clinical trial involving 111 contact dermatitis40,23. No serious adverse primiparous women. They were randomly effects have been signaled, and it is categorized into three groups of control considered safe to use both topically and
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orally14,31, even though systemic selectively regulate cell function during administration of marigold products should inflammation, in particular monocyte be avoided during early stages of pregnancy activity and after topical application it may because of its ability to stimulate menstrual regulate inflammatory responses to foreign flow41. antigens in the skin; then it is able to repressmonocyte superoxide production and Melaleuca alternifolia (Tea Tree oil) consequently it prevents oxidative tissue Melaleuca alternifolia essential oil damage that may be seen in more chronic (Myrtaceae) is used since ancient time for inflammatory states51. A clinical study has treating a wide variety of medical diseases reported that TTO lid scrubbing is able to and conditions. It -is promising as an essentially reduce the tear levels of antimicrobial and is effectiveness in a inflammatory cytokines (IL-1β, IL-17) several of dermatologic condition including involved in various immune response and dandruff, acne, head lice, herpes and other inflammatory processes in ocular cutaneous infections like tonsillitis, demodecosis patients52. Several in vivo stomatitis and vaginitis42,43. Tea tree oil is studies have shown that TTO has inhibitory currently incorporated into various range of effects on inflammatory processes, such as pharmaceutical and cosmetic products for reduction of histamine-induced oedema and the treatment of sores, blisters, spots, rashes, contact hypersensitivity after topical TTO warts, burns and acne44. Tea treeoil (TTO) application in mice53,54. Furthermore, contains approximately 100 compounds, clinical studies of human volunteers have mainly terpene hydrocarbons, demonstrated that TTO can reduce monoterpenes, sesquiterpenes and their significantly the histamine-induced skin corresponding alcohols14,45 as well as inflammation (developing oedema aromatic compounds. Many of this histamine-induced)55 and nickel-induced compounds penetrate skin and enhance the contact hypersensitivity in human dorsal penetration of other substances, this may skin after topical application of 100% boost TTO medical effects, but it may also TTO56. Moreover, TTO hydrogel exhibits potentiate the opportunities of toxicity46.The effectiveness in cooling burn wounds and in composition of tea tree oil has been increasing the rate of wound healing in a regulated by the International Organization porcine model57. In a clinical study led on for Standardization (Oil of Melaleuca- 49 humans with chronic gingivitis, terpinene-4-ol type) (ISO4730:2004), that Soukoulis and Hirsch (2004)58 have reported specifies compositional limits for 15 of the the efficacy of topically application of TTO- approximately 100 compounds47,45,48. Tea containing gel in reducing gingival tree oil is comprised of at least 30% inflammation58. terpinen-4-ol which causes most of its Tea tree oil has also antiviral biological activity, although in practice this activity: in vitro studies have demonstrated is often approximately 40% of the oil and a the TTO virucidal activity and TTO efficacy maximum content of 15% of 1,8-cineole49. in viral plaque formation reduction against Terpinen-4-ol and α–terpineol, the herpes simplex virus (HSV-1 and HSV-2) mainly bioactive TTO compounds, show and influenza virus subtype H1N1. It seems anti-inflammatory activity when applied that TTO interferes with an early step of the topically in a carageenan-induced hind paw viral replicative cycle59. Furthermore the oedema rat model50. Furthermore terpinene- TTO antiviral activity has been confirmed in 4-ol has been demonstrated that TTO may a randomized, placebo-controlled trial on
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patients with self-reported history of svaginalis. The wide range of TTO recurrent herpes labialis60. At a later stage susceptible organisms proposes that this Millar and Moore (2008)61 have reported the agent may be useful for skin antisepsis and successful of TTO treatment in pediatric to facilitate healing in chronic patients with warts on their right middle Staphylococcus-infected wounds. Moreover finger. In this trial TTO was applied many pathogenic organisms have been topically once daily to the lesions for 12 shown to be more susceptible to tea tree oil days with a favourable outcome, including than commensal organisms64,46,65. Clinical complete re-epithelization of the infected studies have demonstrated the efficacy of areas, highlighting the potential use of TTO percutaneous application of TTO in in the treatment of common warts due to resolution of osteomyelitis due to MRSA human papilloma virus (HPV)61. infection in adult male66, and MRSA- Greay et al. (2010)62 have described infected wounds, showing fast healing, for the first time TTO antitumor activity. reduction in inflammation, pain and wound They have shown that topical 10% odor. Furthermore TTO appeared more TTO/DMSO, thanks to its abundance in efficacious than the standard treatment and terpenes, has in vivo antitumor activity, better tolerability by patients65. In a recent inducing regression and growth inhibition of study Malic et al. (2014)67 have tested and aggressive, subcutaneous, chemo-resistant, proved the TTO biocide activity against melanoma mice model, highlighting topical urinary catheter pathogens (several strain of TTO as a possible alternative topical Proteus mirabilis and Proteus vulgaris) antitumor treatment62. Afterwards, Bozzuto suggesting that TTO may be a good et al. (2011)63 have supported this finding, alternative approach to incorporating into showing that TTO is able to inhibit the biomaterials used in catheter development to growth of melanoma cells and it is even able inhibit growth and swarming of P. mirabilis to overcome multidrug resistance (MDR), in long-term-catheterized patients67. TTO indicating that TTO can also interfere with antibacterial activity has been proved also the migration and invasion processes of against mutans streptococci and other oral drug-sensitive and drug-resistant melanoma microorganism in a clinical study to cells63. compare the antimicrobial activity of tea tree Tea tree oil is widely used topically oil and chlorhexidine solutions against oral for the treatment of bacterial and fungal microorganisms68,69. Beforehand, Jandourek infections because of its broad antimicrobial et al. (1998)70 have been demonstrated the activity against several strains of bacteria, efficacy of TTO oral solution as an fungi and protozoan. The antimicrobial alternative regimen for AIDS patients with activity of TTO has been proved against oropharyngeal candidiasis refractory to many organisms, including Staphylococcus fluconazole70. The fungicidal activity of aureus, coaugulase-negative staphylococci, TTO has been confirmed also by Ramage et Staphylococcus spp. (methiccillin-resistant al. (2012)71 in a study in which they and –-sensitive S. aureus MRSA and evaluate the efficacy of TTOagainst C. MSSA), vancomycin-resistant enterococci, albicans clinical strains isolated from a Acinetobacterbaumannii, Escherichia coli, variety of patients, to support the Propionibacterium acnes, Staphylococcus forcefulness of a putative application of epidermidis, Klebsiella pneumonia, Candida TTO in prophylaxis and treatment of albicans, Candida spp., Trichophytonspp, oropharyngeal candidiasis71. A multicenter, Malessezia furfur and Trichomona- randomized controlled trial have reported
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that tea tree oil is highly effective in the terpinen-4-ol, alpha-terpinene, gamma- treatment of superficial fungal infections terpinene and alpha-terpineolas effective such as onychomycosis72. In this last study anti-bacterial, anti-fungal and anti-protozoal on 117 patients, it has been compared a compounds; previous in vitro studies77. 100% tea tree oil solution with 1% Preceding study has reported that treatment clotrimazole solution in the treatment of with TTO vaginal pessaries of bacterial onychomycosis. After 6 months of vaginosis patients was effectiveness in treatment, the 2 groups showed comparable removing symptoms without affecting results on the basis of mycologic cure (11% vaginal flora commensal lactobacilli, for clotrimazole and 18% for tea tree oil) suggesting a target effect of tea tree oil and clinical assessment and subjective rating against pathogenic microorganisms. These of appearance and symptoms (61% for data have been confirmed by Hammer et al. clotrimazole and 60% for tea tree oil)72. A (1999)78 in a study in which they tested tea previous clinical study has reported that a tree oil susceptibilities of lactobacilli and 10% tea tree oil cream works about as well organisms associated with bacterial as tolnaftate 1% cream in treating symptoms vaginosis. They reported indeed that all of athlete's foot, although being less lactobacilli tested are appreciably more effective than clotrimazole or terbinafine73. resistant to tea tree oil then organisms Later in a randomized, controlled, double- associated with bacterial vaginosis78. blinded trialto determine the efficacy and Mondello et al. (2006)79on experimentally safety of 25% and 50% tea tree oil in the infected oophorectomized rats confirmed the treatment of interdigital tinea pedis, Satchell positive fungicide effect of terpinen-4-ol, the et al. (2002)74 have reported that there is a main bioactive component of Melaleuca marked clinical response seen in 68% of the alternifolia Cheel against azole sensitive 50% tea tree oil group and 72% of the 25% candida species. In vitro and in vivo studies tea tree oil group, compared to 39% in the have showed the efficacy of TTO in the placebo group after 4 weeks of treatment74. treatment of vaginal candidiasis in rat These data suggest that TTO may have a experimental model. These studies have role in at least symptomatic treatment of demonstrated that TTO has fungicidal dose- tinea pedis and onychomycosis and other dependent activity against superficial wounds. Furthermore, in vitro fluconazole/itraconazole-susceptible and - studies have demonstrated the TTO efficacy resistant strains of Candida albicans and against various dermatophyte species against C. glabrata, C. neoformans and C. including Malessezia species, the etiological parapsilosis. The researchers have also agents in many superficial skin diseases reported that TTO effectiveness is such as seborrheic dermatitis, suggesting comparable to that of fluconazole in drug- that tea tree oil ointment may be a good susceptible organisms and is not influenced alternative in the therapy of fungal by low pH. These findings suggest that TTO infections of the skin and mucous may be a putative therapeutic agent in the membranes as well as in the treatment of treatment of acute and recurrent forms of dandruff, a mild form of seborrheic vulvovaginitis42,79. dermatitis75,76. Banes-Marshall et al. (2001)80 A recent phytotherapy review onthe explored the antibacterial antifungal action issue: “vaginitis” addressed to find new of tea tree oil against methicillin-resistant trends in pharmacological treatments, Staphylococcus aureus (MRSA), S. aureus, outlined the role of tea tree oil including faecal streptococci, beta-haemolytic
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streptococci, coagulase-negative staphy- Association (COLIPA) in 2002 has lococci, Pseudomonas spp. and coliform recommended that tea tree oil should not be bacilli. Eleven Candida spp. isolated from used in cosmetic products in a way that skin and vaginal swabs. In 64 specimens results in a concentration greater than 1% oil TTO produced an inhibitory and bactericidal being applied to the body44 (SCCP, 2004). effect at 3% and 4% (v/v), respectively. S. Adverse reactions may be minimized by aureus and Candida spp. were the most avoiding ingestion, applying only diluted oil susceptible to TTO, with MICs and MBCs topically, using oil that has been stored of 0.5% and 1%, respectively. P. aeruginosa correctly or using only the TTO isolated and the faecal streptococci isolated, with bioactive ingredients47. MICs and MBCs of >8%, were resistant to TTO80. Salvia officinalis Linn (Sage) Watson and coworkers Salvia officinalis L.(Lamiaceae) is a (2012)81performed a sixty-six health Mediterranean species, naturalized in many professionals (medical practitioners, countries.The traditional medical experience dermatologists, nurses and allied health comprises several thousand years of internal professionals) survey to evaluate the quality and external application and nowadays the of complementary and alternative preparation of dried leaves of S. officinalis is prescriptions in recurrent vulvovaginal registered as a medicinal drug83,84. Salvia candidiasis; the caregivers in the medical officinalis has been used for encouraging and ob/gyn area collected info about healing, excessive menstrual bleeding, hot complementary alternative medicine (CAM) flashes (menopausal sweats) hyperhidrosis, management enclosing lactobacillus, which vaginal discharge and improving memory85. was the most self-described, oral and In Jordan, it is used in traditional medicine vaginal yogurth, vinegar, garlic, Chinese as antiseptic, antiscabies, antisyphilitic, and medicine and tea tree oil; TTO was anti-inflammatory, being frequently used documented to be largely used in the folk against skin disorders. It is applied both medicine, even if Lactobacillus was the externally and internally as anti-phlogistic most common remedy reported in this and astringent drug84. The main compounds survey81. of S. officinalis oils were 1,8-cineole (39.5- Traditional evidence from almost 80 50.3%) and camphor (8.8-25.0%) alpha- years of use indicates that topical use of tea thujone, beta-thujone, borneol, and tree oil is relatively safe, and that adverse viridiflorol and phenolic diterpenesCarnosic events are minor and occasional in absence acid (CA) and carnosol (CS) which are of ingestion82. There are few reports of inhibitors of Peroxisome proliferator- allergy and contact dermatitis in predisposed activated receptor gamma (PPARgamma), a individuals47,49,82; evidences of poisoning if ligand activated transcription factor, taken internally in higher doses and skin belonging to the metazoan family of nuclear irritation at higher concentrations46,47. hormone receptors. Activation of However, degradation products of PPARgamma increases the transcription of monoterpenes in tea tree oil actually appear enzymes involved in primary metabolism, to be sensitizing agents. It seems that the leading to lower blood levels of fatty acids prevalence of allergy is approximately 5% and glucose. Animal experiments and in 76. Therefore TTO topical treatment is vitro studies have reported that Salvia considered safe14;82, though the European officinalis extracts may significantly Cosmetic Toiletry and Perfumery decrease serum glucose in diabetic rats and
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normoglycemic mice86,87;furthermore it is management of acute viral pharyngitis88,92. safe and effective in the improvement of The astringent activity of sage (active lipid profile, including a decrease on the ingredient of dental-care herbal medicinal highly atherogenic LDL-C particles and an preparations) promotes the reduction in increase in the HDL-C particles in healthy plaque growth, the inhibition of gingival humans; of antioxidant defenses, increasing inflammation and has positive effects on superoxide dismutase (SOD) and catalase caries prophylaxis93. Furthermore, gurgle (CAT) activities in human erythrocytes; and solutions with sage leaf are typically applied of lymphocyte Hsp70 protein expression in in acute laryngopharyngitis94. Many studies human volunteers, contributing to stress have shown that Salvia officinalis essential tolerance and cytoprotection87,88. oil exhibits strong or moderate antimicrobial The anti-inflammatory and activity against various strains of antiphlogistic properties of Salvia extract are bacteriaand yeast, including Candida due to triterpenesoleanolic, ursolic acid and albicans and dermatomycetes, depending on diterpenecarnosol. A study that investigates sage chemical composition95,96,97. Mosafa et topical anti-inflammatory activity of Salvia al. (2014)98 have led a study to test officinalis leaves, obtained from four plant antibacterial activity of sage ethanol extract populations of different origins extracted in through well diffusion and microdilution two different ways, revealed that ursolic method against multidrug resistant bacteria. acid is sage component that exhibits the In this study they have showed that not only stronger anti-inflammatory properties and it essential oil has higher antimicrobial effects, could explain anti-phlogistic activity of the but also ethanol extract of sage leaves and official plant drug Salviae folium. In this last stems have antibacterial effects both Gram report anti-inflammatory activity of the two negative and Gram positive multidrug sage extracts is tested by evaluation of resistant bacteria, such as Staphylococcus extracts inhibiting ability of the Croton oil- aureus, Escherichia coli, Pneumoniae induced ear oedema in mice. The anti- aeruginosa and Klebsiella pneumoniae. inflammatory effect of ursolic acid is They have also reported that sage compared with that of a reference non- antimicrobial activity is dose-dependent, steroidal anti-inflammatory drug, with increased effect increasing indomethacin. The ursolic acid activity concentration98. Salvia officinalis oil is appears two fold more potent than that of equally useful at countering bacterial indomethacin89. infections, since it kills bacteria and inhibits The antibacterial properties of sage their growth. This property can also be used oils have been attributed to the presence of to heal ailments like bacterial infections in 1,8-cineole, thujone, and camphor90. the ears, nose, throat, eyes, genitals, urethra, However in 2007, Pinto et al.91 declaredthat colon, intestines as well as on the skin and in thujones do not play an important role wounds. This oil is also capable of inhibiting against yeasts and filamentous fungi. This fungal infections both internally and work also suggests 1,8-cineole and camphor externally, and gives relief from fungal as the main responsible for the antifungal infections like dysentery, skin diseases, activity in the tested strains91. A Athlete’s Foot, or dermatitis. In a study of randomized, double-blind, placebo- Abu-Darwish (2013)99, the oils revealed controlled study has demonstrated clinical antifungal activity against dermatophyte efficacy of a spray, containing 15% of a strains and significantly inhibited Salvia fluid extract, in the symptomatic pain inflammation generated by NO production
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LPS-induced in macrophages, without adult rats101. Sage efficacy for the treatment affecting cell viability, in concentrations up of hot flushes during menopause and of the to 0.64 μL/mL. This is the first report associated menopausal symptoms (e.g. regardingthe in vitro anti-inflammatory insomnia, irritability, dryness of vagina etc.) potential of S. officinalis oil. These findings was demonstrated in an open multicenter demonstrated that mammalian macrophages clinical trial88,102. Conserning the anti-fushes and keratinocytes viability is not affected by Salvia extract effect, Rathe et al.(2013)103 bioactive concentrations of S. officinalis identified with the vacuum liquid oilmaking itsuitable to be incorporated in chromatography, luteolin-7-O-glucuronide skin care formulations for cosmetic and (EC₅₀129 µg/mL) as the active putative pharmaceutical purposes99. In the clinical estrogenic principle; flavonoids are safe and setting a wide observational study of commonly used herbal medicinal product Guaschino and Benvenuti (2008)100 during the menopause involved in the anti- reviewedvaginalpH, lifestyle and correct hot flush effect of Salvia officinalis103. intimate hygiene in women of different ages Several studies have shown that the and in different physiopathological consumption of Salvia officinalis extract is conditions. Different randomized subgroups safe and non-toxic88,92,102,104,105. of 2641 women (prepubertal, fertile, pregnancy, breastfeeding, premenopause CONCLUSION and menopause). In this survey, the most appropriate detergent for the woman's Rationale for the combined formula of the intimate hygiene was recommended by 264 hydroxypropilmetilcellulose and 3 herbal gynecologists on the basis of age and extracts in a vaginal gel. physio-pathological status of the patients, The combination of HPMC and and extract of Salvia officinalisto be used Calendula, Melaleuca, and Salvia once or twice a day for four weeks was Officinalis in a single topical delivery mainly, spontaneously prescribed for system is a unique opportunity to face adolescents, child-bearing age and pre- vaginal care with an exhaustive integrated menopause; this investigation highlights the mucosal defense strategy. Basically the traditional role of Salvia in routine female vaginal epithelium is exposed to different intimate hygiene like the natural plant and complexes stressor agents producing extracts favoring the reduction of vaginal epithelial disruption, inflammation and pH, the improvement of symptoms and the cancer, especially when the hormonal quality of sexual activity in all trophic action is reduced by the advancing age/conditions observed100.The estrogenic menopause; recurrent parasitic infections, activity of Salvia officinalis has been such as Trichomonas, bacteria, fungi and demonstrated experimentally and a team of viruses contagions, when vaginal pH has investigators has shown the herb has strong been modified to basic levels alter the effects in cases of oligomenorrhea and microflora, inducing dramatic inflammatory amenorrhea; therefore, sage can be used for reactions, often turning to chronic stage, that hormone imbalances as premenstrual may lead to epithelial dysplasia. tension, endometriosis, cysts and for The action mechanism of the 3 herbs stimulate, regulate and promote a normal extracts in combination, takes control of the menstrual flow. It seems that sage tea vaginal surface integrity and mucosa drinking, via hypothalamic-pituitary-ovarian restoration after mechanical or chemical or axis, may be improves female fertility in microbiological damage, especially through the well-known Calendula contributes to
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body defenses against external agents, has 3. Fonseca Y.M., Catini C.D., Vicentini F.T., anti-inflammatory, antioxidant and healing Cordeiro Cardoso J., Cavalcantide properties; Salvia expresses altogether a Albuquerque J.R.L. and Vieira Fonesca M.J. wide and selective control, supports the Efficacy of marigold extract-loaded natural mechanism for body´s purification, formulations against UV-induced oxidative stress. J. Pharm. Sci.2011; 100(6):2182- promotes the toxin elimination; Melaleuca 2193. expresses altogether a wide and selective 4. Khalid K.A. and Teixeira da Silva J.A. control of pathogenic microflora enclosing Biology of Calendula Officinalis Linn.: the often relapsing Candida albicans super- Focus on Pharmacology, Biological infections. Furthermore, Salvia and Activities and Agronomic Practices. Med. Calendula promote an estrogen –like trophic and Aromatic Plant. Sci. and Biotech.2012; effect upon the vaginal mucosa, enhancing 6(1):12-27. Review. the natural lubricating properties of the 5. Bisset N.G. and Wichtl M. Herbal Drugs and mucins secretion. Obviously the modern Phytopharmaceuticals; 2nd ed. Medpharm drug-manufacturing technology strongly Scientific Publishers 2001;118-20. Stuttgart, emphasizes the quality of such a gel with Germany. 6. Amirghofran Z., Azadbakht M. and Karimi long standing bioavailability upon the M.H. Evaluation of the immunomodulatory vaginal mucosa, and of the mixed herbal effects of five herbal plants. J extracts with specific and well balanced Ethnopharmacol. Sep2000; 72(1-2):167-72. eutrophic and infections preventing 7. Varljen J.L.A. and Wagner H. Structural properties; HPMC has been proven a quite analysis of a rhamno-arabinogalactan and effective background for active principles arabinogalactans with immuno-stimulating delivery, and lactic acid stabilizes the acidic activity from Calendula officinalis. pH of the medium promoting homeostasis of Phytochemi.1989; 28:2379-83. indigenous microflora. 8. Popovic M., Kourinovic B., Mimica-Dukic The table 1 summarizes the N., Vojinovic-Miloradav M. and Cupic V. contribution of each active principle to Combined effects of plant extracts and xenobiotics on liposomal lipid peroxidation. maintenance of vaginal mucosahomeost as Part I. Marigold extract-ciprofloxacin/ is through protective, lubricant and soothing pyralene. Oxid Commun.1999; 22:487-94. functions. 9. Popovic M., Kourinovic B, Mimica-Dukic N., Vojinovic-Miloradav M. and Djordjevic REFERENCES A. Combined effects of plant extracts and xenobiotics on liposomal lipid peroxidation. 1. Chandran P.K. and Kuttan R. Effect of Part II. Marigold extract-CCl4/fullerenol. . Calendula Officinalis Flower extract on OxidCommun.2000; 23:178-86. Acute Phase Proteins, Antioxidant Defense 10. Bezakova L., Masterova I, Paulikova I. and Mechanism and Granuloma Formation Psenak M. Inhibitory activity of During Thermal Burns. J. Clin. Biochem. isorhamnetin glycosides from Calendula Nutr.; Sep. 2008; 43(2):58-64. officinalis L. on the activity of lipoxygenase. 2. Bernatoniene J., Masteikova R., Davalgiene Pharmazie.; Feb1996; 51(2):126-7. J., Peciura R., Gauryliene R., Bernatoniene 11. Schmidgall J., Schnetz E. and Hensel A. R., Majiene D., Lazauskas R., Civinskiene Evidence for bioadhesive effects of G., Velziene S., Muselik J. and Chalupova Z. polysaccharides and polysaccharide- Topical application of Calendula officinalis containing herbs in an ex vivo bioadhesion (L.): Formulation and evaluation of assay on buccal membranes. Planta Med. hydrophilic cream with antioxidant activity. Feb2000; 66(1):48-53. J. Med. Plant. Res.2011; 5(6): 868-877. 12. Eghdampour F., Jahdie F., Kheyrkhah M., Taghizadeh M., Neghizadeh S. and Hagani
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Table 1. Female genital wellness and disease prevention PROTECTIVE LUBRICANT SOOTHING Maintenance of vaginal Estrogenic-like property Anti-inflammatory microflora Melaleuca Calendula Calendula Salvia Melaleuca Calendula Salvia Antimicrobial property Trophic effect Antioxidant Melaleuca Calendula Salvia Calendula Salvia Calendula Salvia Melaleuca Antioxidant Moisturizing Healing property Calendula Salvia Melaleuca Calendula Calendula Melaleuca
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