DOCSLIB.ORG

Towards Improved Treatment Outcomes for Tuberculosis Meningitis - Rethinking the Regimen

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Towards Improved Treatment Outcomes for Tuberculosis Meningitis - Rethinking the Regimen Mini Review Article Open Access J Neurol Neurosurg Volume 8 Issue 2- August 2018 DOI: 10.19080/OAJNN.2018.08.555734 Copyright © All rights are reserved by Rajeswari Ramachandran Towards Improved Treatment Outcomes for Tuberculosis Meningitis - Rethinking the Regimen Rajeswari Ramachandran1* and Muniyandi M2 1Consultant Neurologist, Dr Kamakshi Memorial Hospital, India 2Scientist-C, National Institute for Research in Tuberculosis, Indian Council of Medical Research, India Submission: December 16, 2017; Published: August 16, 2018 *Corresponding author: Rajeswari Ramachandran, Consultant Neurologist, Dr. Kamakshi Memorial Hospital, Tamil Nadu, India; Tel: ; Email: Abstract Tuberculosis (TB) ranks as the second leading cause of death from an infectious disease worldwide. TB meningitis (TBM) is the most destructive extra-pulmonary form of TB. The current recommended treatment prevents death or disability in less than half of the patients. TB meningitis still represents an important problem by contributing to a huge number of years of life lost. The management of TBM remains a big challenge. In this context, this manuscript discusses anti TB drugs and treatment regimens that make a difference in the treatment outcomes of TBM considering the pharmacokinetics parameters of anti TB drugs with special reference to the Blood-Brain Barrier (BBB) which is unique to Central Nervous System (CNS). It was observed that generally the treatment outcomes are poor with the recommended regimens (mortality rate ranging from 6.3 to 48.1%). In view of the poor treatment outcomes with standard regimens, different studies were carried out to strengthen in reducing mortality. There is an urgent need to rethink TBM treatment regimens and to strengthen it considering the following factors: PK parametersthe regimen of and the improve anti TB thedrugs treatment including outcomes their ability by using to penetrate different the interventions. BBB and drugs Most that of achieve the studies good did CSF not concentrations, show a significant drugs improvement that achieve CSF concentrations above the MIC value, considering new drugs, retooling old drugs, using second line drugs for TBM as first line drugs, and optimummodifying duration the host of response. treatment. In the management of TBM we need clinical trials to evaluate the efficacy of regimens containing drugs like isoniazid, pyrazinamide, levofloxacin, linezolid, ethionamide, rifampicin and injectable aminoglycoside and trials are also needed to assess the Keywords: Virus; CSF: CerebroSpinal Fluid TB: Tuberculosis; TBM: TB Meningitis; CNS: Central Nervous System; BBB: Blood-Brain Barrier; HIV: Human Immunodeficiency Introduction worldwide with up to half of surviving patients presenting with Infectious diseases still pose a major problem for public irreversible sequelae, including paraplegia, blindness, motor and health, mainly in developing countries, where they are the most common reasons contributing to both mortality morbidity and the family. The current recommended treatment prevents death disability. This results in enormous economic burden to the cognitive deficits [4], resulting in enormous economic burden to or disability in less than half of the patients. TB meningitis still patient, family and the country. Tuberculosis (TB) remains a represents an important problem by contributing to a huge major global health problem, responsible for ill health among millions of people each year. TB ranks as the second leading cause of death from an infectious disease worldwide, after the numberIn this of yearsmanuscript of life lostwe discuss[5]. anti TB drugs and treatment regimens that make a difference in the treatment outcomes of HumanTuberculosis Immunodeficiency meningitis Virus (TBM) (HIV) is the [1]. most destructive extra- of anti TB drugs with special reference to the Blood-Brain TBM. Specifically, we consider the pharmacokinetics parameters Barrier (BBB) which is unique to Central Nervous System (CNS). the membranes that envelop the brain and the spinal cord. The pulmonary form of TB. It is an inflammation of the meninges, We have looked at chemotherapy in terms of choice of drugs, reports from India indicate that one tenth of EPTB cases were optimum dosage, ability to penetrate the BBB and the possible inclusion of immune modulators such as steroids and the role of meningial, spinal and bone TB [2]. Reported long term case shunt surgery. fatality due to TBM ranges from 20 to 69% [3], in different settings Open Access J Neurol Neurosurg 8(2): OAJNN.MS.ID.555734 (2018) 001 Open Access Journal of Neurology & Neurosurgery Current Treatment for TBM done during 1969 to 2010. It was observed that generally the treatment outcomes are poor with the recommended regimens The treatment of EPTB follows standard treatment -mortality rate ranging from 6.3 to 48.1%. The pooled estimate of guidelines depending on the categorization and is consistent with international recommendations by WHO and the of childhood-TBM reported treatment regimens used and their International Union Against Tuberculosis and Lung Disease mortality was 19.1% [8]. A systematic review and meta-analysis outcomes. The pooled estimates based on 19 studies, with reported treatment outcomes on 1636 children in ten countries and treated with two months isoniazid, rifampicin, pyrazinamide (IUATLD) [6,7]. TBM patients are considered to be seriously ill between 1952 and 2005 showed a risk of death in 19.3% and and streptomycin followed by 7 months of continuation phase probability of survival without neurological sequelae was only treated with isoniazid and rifampicin. The recommended anti TB drugs and the duration of treatment for TBM is described for antimicrobial combinations were studied. These studies did TBM in Box-1. 36.7% [9]. In these studies 27 regimens were used and multiple not show any associations between outcomes and study-level Poor Treatment Outcomes treatment characteristics such as treatment duration, number Figure 1 & Figure 2 describes the treatment outcomes of intensive-phase drugs, isoniazid dose, rifampicin dose, and such as mortality and morbidity reported by different studies use of rifampicin, streptomycin, pyrazinamide, ethambutol, or corticosteroids. Figure 1: Treatment outcomes of childhood tuberculous meningitis (mortality) Figure 2: Treatment outcomes of childhood tuberculous meningitis (morbidity) How to cite this article: Rajeswari R, Muniyandi M. Towards Improved Treatment Outcomes for Tuberculosis Meningitis - Rethinking the Regimen. 002 Open Access J Neurol Neurosurg. 2018; 8(2): 555734. DOI: 10.19080/OAJNN.2018.08.555734. Open Access Journal of Neurology & Neurosurgery In view of the poor treatment outcomes with standard adding steroids, management of hydrocephalus, etc. Majority of regimens (Table 1), different studies were carried out to strengthen the regimen and improve the treatment outcomes mortality. It is disappointing that there was no advantage the studies did not show a significant improvement in reducing by using different interventions such as high dose rifampicin, adding newer quinolones, adding ethionomide, adding linezolid, with regard to overall mortality and most measures of illness. associated with the use of these intensified treatment regimens, addingTable1: bothEfforts rifampicin taken to improve and levofloxacin, the treatment high outcome dose moxifloxacin, in TBM - Interventions and treatment outcomes. Interventions Outcomes Higher rifampin (13mg per kg) administered intravenously Linezolid supplementationMorality 34% [19]has a remarkable Addition of linezolid therapeutic benefit for TBM, as shown by rapid consciousness recovery, in the first 4 Intensified regimen Higher doseweeks of oral of rifampin treatment than [15] the standard dose (15mg per kilogram of body weight vs. 10 mg per kilogram) and the addition Addition of rifampicin, levofloxacin [20] mortality (28%) of levofloxacin to the standard regimen: Intrathecal administration levofloxacin amikacin Successful outcomeMorality (Case 63% report) [11] Moxifloxacin IsoniazidHigh dose (15 moxifloxacin to 20mg per 800mgkg) + rifampin [19] (20mg per kg) + pyrazinamide (40mg per 26% at stage III and 6% at stage II died before Ethionomide kg) + ethionamide (20mg per kg), all given completion of therapy. 6 months rifampicin, isoniazid, pyrazinamide, throughout 6 months [13] 80% children had a good outcome Mortality Ethionomide ethambutolfor HIV-uninfected and the same 3.8% Corticosteroidsdrugs 9for months have no for effect HIV-infected on people [14] who survive TBM with disabling neurological Steroids reduce deaths by almost one quarter Role of corticosteroids death. However, this small possible harm is deficit,unlikely but to thisbe quantitatively outcome is less important common when than compared to the reduction in mortality. (RR 0.75) [18] Surgery is required for patients with Management of hydrocephalus including obstructive hydrocephalus and those in poor 10.5% to 57.1% depending on various clinical diuretics & shunt surgery grades, requiring repeated revisions. Outcome variable[i]associated Mortality factors varied from months in both treatment cohorts, which Increasing duration of treatment suggestedMost deaths that the occurred difference during in death the first rate 6 was 6 months vs longer than 6 months [22] not directly related to duration of ATT Seven patients died during the treatment Directly observed treatment Intermittent short course chemotherapy There is a need to rethink on TBM treatment regimens resulting
Load more

Recommended publications
  • Para-Aminosalicylic Acid – Biopharmaceutical, Pharmacological
    Para-aminosalicylic acid – biopharmaceutical, pharmacological... PHARMACIA, vol. 62, No. 1/2015 25 PARA-AMINOSALICYLIC ACID – BIOPHARMACEUTICAL, PHARMACO- LOGICAL, AND CLINICAL FEATURES AND RESURGENCE AS AN ANTI- TUBERCULOUS AGENT G. Momekov*, D. Momekova, G. Stavrakov, Y. Voynikov, P. Peikov Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria Summary: Para-aminosalicylic acid (INN aminosalicylic acid; PAS) is a bacteriostatic chemo- therapeutic agent used in the therapy of all forms of tuberculosis, both pulmonary and extrapul- monary, caused by sensitive strains of the mycobacteria resistant to other antituberculotics or if the patient is intolerant towards other drugs. Since its clinical introduction in the late 1940s aminosalicylic acid (PAS) has been a mainstay in the treatment of TB into the 1960s. Along with isoniazid and streptomycin, it was a ‘first-line’ agent for tuberculosis. However, it was plagued by poor gastro-intestinal tolerance and rare but severe allergic reactions. Ethambutol was later shown to be approximately equivalent to PAS in potency, and generally better tolerated than PAS when ethambutol was used at dosages of 25 mg/kg/day or less. Therefore, PAS was replaced by etham- butol as a primary TB drug. However, because of the relative lack of use of PAS over the past 3 decades, most isolates of TB remain susceptible to it. Thus, PAS has experienced a renaissance in the management of patients with multi-drug resistant tuberculosis. Key words: Aminosalicylic acid, Antituberculous agents, MDR-TB, XDR-TB Introduction of treatment the cure rate improved up to 90%. The In 1943 the Swedish chemist Jörgen Lehmann combination of both drugs reduced the selection of (1898-1989) addressed a letter to the managers of resistant strains tremendously [3].
    [Show full text]
  • Targeting Intracellular P-Aminobenzoic Acid Production
    www.nature.com/scientificreports OPEN Targeting intracellular p-aminobenzoic acid production potentiates the anti-tubercular Received: 08 July 2016 Accepted: 03 November 2016 action of antifolates Published: 01 December 2016 Joshua M. Thiede1,*, Shannon L. Kordus1,*, Breanna J. Turman1, Joseph A. Buonomo2, Courtney C. Aldrich2, Yusuke Minato1 & Anthony D. Baughn1 The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance. Herein, we demonstrate that disruption of PABA biosynthesis potentiates the anti-tubercular action of DHPS inhibitors and PAS by up to 1000 fold. Disruption of PABA biosynthesis is also demonstrated to lead to loss of viability over time. Further, we demonstrate that this strategy restores the wild type level of PAS susceptibility in a previously characterized PAS resistant strain of M. tuberculosis. Finally, we demonstrate selective inhibition of PABA biosynthesis in M. tuberculosis using the small molecule MAC173979. This study reveals that the M. tuberculosis PABA biosynthetic pathway is responsible for intrinsic resistance to various antifolates and this pathway is a chemically vulnerable target whose disruption could potentiate the tuberculocidal activity of an underutilized class of antimicrobial agents. Tuberculosis (TB) causes over 1.7 million deaths per year and an estimated two billion people latently infected with Mycobacterium tuberculosis provides a large reservoir for ongoing reactivation and transmission of disease1,2.
    [Show full text]
  • Treatment of Tuberculosis in Adults and Children Guideline Version 3.0 March 2021
    Treatment of tuberculosis in adults and children Guideline Version 3.0 March 2021 Treatment of tuberculosis in adults and children - Guideline Version 3.0 March 2021 Treatment of tuberculosis in adults and children - Guideline Version 3.0 March 2021 Published by the State of Queensland (Queensland Health), March 2021 This document is licensed under a Creative Commons Attribution 3.0 Australia licence. To view a copy of this licence, visit creativecommons.org/licenses/by/3.0/au © State of Queensland (Queensland Health) 2020 You are free to copy, communicate and adapt the work, as long as you attribute the State of Queensland (Queensland Health). For more information contact: Communicable Diseases Branch, Department of Health, Queensland Health, GPO Box 48, Brisbane QLD 4001, email [email protected], phone (07) 3328 9718. An electronic version of this document is available at https://www.health.qld.gov.au/clinical-practice/guidelines-procedures/diseases- infection/diseases/tuberculosis/guidance/guidelines Note, updates after May 2021 are amended in the online version of Treatment of tuberculosis in adults and children ONLY — printed copies may not be current Treatment of tuberculosis in adults and children — Guideline Version 3.0 March 2021 Printed copies may not be current see online version for most recent version ii Contents What this guideline covers 1 What this guideline does not cover 1 Standard regimens for drug susceptible pulmonary tuberculosis 2 Six-month 2 Extended duration 2 Additional considerations for children (age 0
    [Show full text]
  • Estonian Statistics on Medicines 2016 1/41
    Estonian Statistics on Medicines 2016 ATC code ATC group / Active substance (rout of admin.) Quantity sold Unit DDD Unit DDD/1000/ day A ALIMENTARY TRACT AND METABOLISM 167,8985 A01 STOMATOLOGICAL PREPARATIONS 0,0738 A01A STOMATOLOGICAL PREPARATIONS 0,0738 A01AB Antiinfectives and antiseptics for local oral treatment 0,0738 A01AB09 Miconazole (O) 7088 g 0,2 g 0,0738 A01AB12 Hexetidine (O) 1951200 ml A01AB81 Neomycin+ Benzocaine (dental) 30200 pieces A01AB82 Demeclocycline+ Triamcinolone (dental) 680 g A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+ Thymol (dental) 3094 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+ Cetylpyridinium chloride (gingival) 227150 g A01AD81 Lidocaine+ Cetrimide (O) 30900 g A01AD82 Choline salicylate (O) 864720 pieces A01AD83 Lidocaine+ Chamomille extract (O) 370080 g A01AD90 Lidocaine+ Paraformaldehyde (dental) 405 g A02 DRUGS FOR ACID RELATED DISORDERS 47,1312 A02A ANTACIDS 1,0133 Combinations and complexes of aluminium, calcium and A02AD 1,0133 magnesium compounds A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 811120 pieces 10 pieces 0,1689 A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 3101974 ml 50 ml 0,1292 A02AD83 Calcium carbonate+ Magnesium carbonate (O) 3434232 pieces 10 pieces 0,7152 DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 46,1179 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 2,3855 A02BA02 Ranitidine (O) 340327,5 g 0,3 g 2,3624 A02BA02 Ranitidine (P) 3318,25 g 0,3 g 0,0230 A02BC Proton pump inhibitors 43,7324 A02BC01 Omeprazole
    [Show full text]
  • 1 Application to 21St WHO Expert Committee on the Selection And
    Application to 21st WHO Expert Committee on the Selection and Use of Essential Medicines to include the childhood TB fixed-dose combinations into the WHO model list of Essential Medicines for Children Summary This application is about inclusion of the following two childhood TB fixed dose combinations into the core list of the WHO model list of Essential Medicines for Children: For the intensive phase of TB treatment: Rifampicin 75 mg + Isoniazid 50 mg + Pyrazinamide 150mg For the continuation phase of TB treatment: Rifampicin 75mg + Isoniazid 50 mg General items 1. Summary of statement of the proposal for inclusion, change or deletion At least 1 million children become ill with TB every year. In 2015, 210,000 children died of TB including 40,000 children who were HIV-infected. Children represent about 10- 11% of all TB cases annually (1). Researchers estimate that nearly 67 million children are globally infected with TB and therefore at risk of developing disease in the future (2) . Until recently, there were no appropriate first-line TB medicines designed for treatment of TB in children. Then, treatment of childhood TB faced two major challenges namely: i) inadequacy of the dosage of INH in the existing FDC (rifampicin60mg, isoniazid30mg, pyrazinamide150mg); and ii) difficulties in administering solid non-dispersible medications to children. However, updated WHO guideline development group recommendations as reflected in the WHO Guidance for national TB programmes on the management of tuberculosis in children: second edition, 2014 provided the framework for the dosage adjustment to the appropriate levels. Sustained advocacy for child-friendly formulations of anti-TB drugs resulted in the development of the new FDCs in recommended doses; and as dispersible formulations for easy administration through an initiative led by the TB Alliance and WHO (Essential Medicines and Health Products Department and the Global TB Programme), and funded by UNITAID and USAID.
    [Show full text]
  • Treatment of Drug-Resistant Tuberculosis an Official ATS/CDC/ERS/IDSA Clinical Practice Guideline Payam Nahid, Sundari R
    AMERICAN THORACIC SOCIETY DOCUMENTS Treatment of Drug-Resistant Tuberculosis An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline Payam Nahid, Sundari R. Mase, Giovanni Battista Migliori, Giovanni Sotgiu, Graham H. Bothamley, Jan L. Brozek, Adithya Cattamanchi, J. Peter Cegielski, Lisa Chen, Charles L. Daley, Tracy L. Dalton, Raquel Duarte, Federica Fregonese, C. Robert Horsburgh, Jr., Faiz Ahmad Khan, Fayez Kheir, Zhiyi Lan, Alfred Lardizabal, Michael Lauzardo, Joan M. Mangan, Suzanne M. Marks, Lindsay McKenna, Dick Menzies, Carole D. Mitnick, Diana M. Nilsen, Farah Parvez, Charles A. Peloquin, Ann Raftery, H. Simon Schaaf, Neha S. Shah, Jeffrey R. Starke, John W. Wilson, Jonathan M. Wortham, Terence Chorba, and Barbara Seaworth; on behalf of the American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America THIS OFFICIAL CLINICAL PRACTICE GUIDELINE WAS APPROVED BY THE AMERICAN THORACIC SOCIETY, THE EUROPEAN RESPIRATORY SOCIETY, AND THE INFECTIOUS DISEASES SOCIETY OF AMERICA SEPTEMBER 2019, AND WAS CLEARED BY THE U.S. CENTERS FOR DISEASE CONTROL AND PREVENTION SEPTEMBER 2019 Background: The American Thoracic Society, U.S. Centers for was judged to be very low, because the data came Disease Control and Prevention, European Respiratory Society, and from observational studies with significant loss to follow-up Infectious Diseases Society of America jointly sponsored this new and imbalance in background regimens between comparator practice guideline on the treatment of drug-resistant tuberculosis groups. Good practices in the management of MDR-TB are (DR-TB). The document includes recommendations on the described. On the basis of the evidence review, a clinical strategy treatment of multidrug-resistant TB (MDR-TB) as well as tool for building a treatment regimen for MDR-TB is also isoniazid-resistant but rifampin-susceptible TB.
    [Show full text]
  • RIFATER (Rifampin, Isoniazid and Pyrazinamide)
    RIFATER® (rifampin, isoniazid and pyrazinamide) Tablets WARNING Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after many months of treatment. The risk of developing hepatitis is age related. Approximate case rates by age are: 0 per 1,000 for persons under 20 years of age, 3 per 1,000 for persons in the 20 to 34 year age group, 12 per 1,000 for persons in the 35 to 49 year age group, 23 per 1,000 for persons in the 50 to 64 year age group, and 8 per 1,000 for persons over 65 years of age. The risk of hepatitis is increased with daily consumption of alcohol. Precise data to provide a fatality rate for isoniazid-related hepatitis is not available; however, in a U.S. Public Health Service Surveillance Study of 13,838 persons taking isoniazid, there were 8 deaths among 174 cases of hepatitis. Therefore, patients given isoniazid should be carefully monitored and interviewed at monthly intervals. Serum transaminase concentration becomes elevated in about 10% to 20% of patients, usually during the first few months of therapy, but it can occur at any time. Usually enzyme levels return to normal despite continuance of drug, but in some cases progressive liver dysfunction occurs. Patients should be instructed to report immediately any of the prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, or vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected, isoniazid should be discontinued promptly since continued use of the drug in these cases has been reported to cause a more severe form of liver damage.
    [Show full text]
  • Efficacy and Tolerability of Ethionamide Versus Prothionamide: a Systematic Review
    ERJ Express. Published on June 10, 2016 as doi: 10.1183/13993003.00438-2016 RESEARCH LETTER | IN PRESS | CORRECTED PROOF Efficacy and tolerability of ethionamide versus prothionamide: a systematic review To the Editor: To treat multidrug-resistant tuberculosis (MDR-TB), the World Health Organization recommends to include, during the intensive phase of treatment, at least a parenteral agent, a later-generation fluoroquinolone, ethionamide (Eth) (or prothionamide (Pth)), cycloserine (Cs) or p-aminosalicylic acid (PAS) if Cs cannot be used, and pyrazinamide (Pzd) (which is not considered among the aforementioned four probably effective drugs) [1, 2]. In particular, among the four drugs likely to be effective, at least two essential or “core” drugs (one with a good bactericidal and one with a good sterilising activity) and two other “companion” drugs should be administered [3, 4]. In most of the countries where drug susceptibility testing cannot be performed to guide treatment regimen design, standardised second-line treatment regimens are prescribed, based on kanamycin (Km), levofloxacin (Lfx), Eth, Cs and Pzd. Although the regimen is built following the international recommendations, the outcomes remain poor globally [5, 6]. Less than 50–70% of the cases, in fact, achieve treatment success [5, 6], resulting in insufficient control of MDR-TB. It is widely recognised that one frequent cause of poor outcome is treatment default, which is mostly due to the low tolerability of the antituberculosis drugs employed [7]. One of the less tolerated antibiotics is Eth, because of the serious and frequent gastric adverse events [8 9] or of hypothyroidism, which is frequently subclinical. Eth and Pth are thionamide drugs, characterised by a structure similar to isoniazid (Inh).
    [Show full text]
  • Synthesis and Characterization of Nano-Sized 4-Aminosalicylic Acid–Sulfamethazine Cocrystals
    pharmaceutics Article Synthesis and Characterization of Nano-Sized 4-Aminosalicylic Acid–Sulfamethazine Cocrystals Ala’ Salem 1 , Anna Takácsi-Nagy 1,Sándor Nagy 1, Alexandra Hagymási 1, Fruzsina G˝osi 1, Barbara Vörös-Horváth 1 , Tomislav Bali´c 2, Szilárd Pál 1,* and Aleksandar Széchenyi 1,2,* 1 Institute of Pharmaceutical Technology and Biopharmacy, University of Pécs, 7622 Pécs, Hungary; [email protected] (A.S.); [email protected] (A.T.-N.); [email protected] (S.N.); [email protected] (A.H.); [email protected] (F.G.); [email protected] (B.V.-H.) 2 Department of Chemistry, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; [email protected] * Correspondence: [email protected] (S.P.); [email protected] (A.S.) Abstract: Drug–drug cocrystals are formulated to produce combined medication, not just to modu- late active pharmaceutical ingredient (API) properties. Nano-crystals adjust the pharmacokinetic properties and enhance the dissolution of APIs. Nano-cocrystals seem to enhance API properties by combining the benefits of both technologies. Despite the promising opportunities of nano-sized cocrystals, the research at the interface of nano-technology and cocrystals has, however, been de- scribed to be in its infancy. In this study, high-pressure homogenization (HPH) and high-power ultrasound were used to prepare nano-sized cocrystals of 4-aminosalysilic acid and sulfamethazine in order to establish differences between the two methods in terms of cocrystal size, morphology, polymorphic form, and dissolution rate enhancement. It was found that both methods resulted in the Citation: Salem, A.; Takácsi-Nagy, formation of form I cocrystals with a high degree of crystallinity.
    [Show full text]
  • Customs Tariff - Schedule
    CUSTOMS TARIFF - SCHEDULE 99 - i Chapter 99 SPECIAL CLASSIFICATION PROVISIONS - COMMERCIAL Notes. 1. The provisions of this Chapter are not subject to the rule of specificity in General Interpretative Rule 3 (a). 2. Goods which may be classified under the provisions of Chapter 99, if also eligible for classification under the provisions of Chapter 98, shall be classified in Chapter 98. 3. Goods may be classified under a tariff item in this Chapter and be entitled to the Most-Favoured-Nation Tariff or a preferential tariff rate of customs duty under this Chapter that applies to those goods according to the tariff treatment applicable to their country of origin only after classification under a tariff item in Chapters 1 to 97 has been determined and the conditions of any Chapter 99 provision and any applicable regulations or orders in relation thereto have been met. 4. The words and expressions used in this Chapter have the same meaning as in Chapters 1 to 97. Issued January 1, 2019 99 - 1 CUSTOMS TARIFF - SCHEDULE Tariff Unit of MFN Applicable SS Description of Goods Item Meas. Tariff Preferential Tariffs 9901.00.00 Articles and materials for use in the manufacture or repair of the Free CCCT, LDCT, GPT, UST, following to be employed in commercial fishing or the commercial MT, MUST, CIAT, CT, harvesting of marine plants: CRT, IT, NT, SLT, PT, COLT, JT, PAT, HNT, Artificial bait; KRT, CEUT, UAT, CPTPT: Free Carapace measures; Cordage, fishing lines (including marlines), rope and twine, of a circumference not exceeding 38 mm; Devices for keeping nets open; Fish hooks; Fishing nets and netting; Jiggers; Line floats; Lobster traps; Lures; Marker buoys of any material excluding wood; Net floats; Scallop drag nets; Spat collectors and collector holders; Swivels.
    [Show full text]
  • Are Mycobacterium Drugs Effective for Treatment Resistant Lyme Disease, Tick-Borne Co-Infections, and Autoimmune Disease?
    Central JSM Arthritis Bringing Excellence in Open Access Case Report *Corresponding author Richard I. Horowitz, Hudson Valley Healing Arts Center, 4232 Albany Post Road, Hyde Park, New York 12538, Are Mycobacterium Drugs USA, Tel: 845-229-8977; Fax: 845-229-8930; Email: Submitted: 15 June 2016 Effective for Treatment Accepted: 14 July 2016 Published: 16 July 2016 Resistant Lyme Disease, Tick- Copyright © 2016 Horowitz et al. Borne Co-Infections, and OPEN ACCESS Keywords Autoimmune Disease? • Lyme disease • Bartonella Richard I. Horowitz* and Phyllis R. Freeman • Tularemia Hudson Valley Healing Arts Center, USA • Behçet’s Disease/Syndrome • Rheumatoid arthritis • Dapsone Abstract • Pyrazinamide Introduction: PTLDS/chronic Lyme disease may cause disabling symptoms with • Persister bacteria associated overlapping autoimmune manifestations, with few clinically effective published treatment options. We recently reported on the successful use of a mycobacterium drug, Dapsone, for those with PTLDS. We now report on the novel use of another mycobacterium drug, pyrazinamide, (PZA), in relieving resistant symptomatology secondary to Lyme disease and associated co-infections, while decreasing autoimmune manifestations with Behçet’s syndrome. Method: Disabling multi-systemic/arthritic symptoms persisted in a Lyme patient with co-infections (Bartonella, tularemia) and overlapping rheumatoid arthritis/ Behçet’s disease, despite several rotations of classic antibiotic and DMARD regimens. Dapsone, a published treatment protocol used for Behçet’s syndrome, recently has been demonstrated to be effective in the treatment of PTLDS/chronic Lyme disease and co-infections. It was superior to prior treatment regimens in relieving some resistant chronic tick-borne/autoimmune manifestations; however, it did not effectively treat the skin lesions and ulcers secondary to Behçet’s disease, nor significantly affect the granuloma formation, joint swelling, and pain associated with Lyme, Bartonella, and RA.
    [Show full text]
  • Alphabetical Listing of ATC Drugs & Codes
    Alphabetical Listing of ATC drugs & codes. Introduction This file is an alphabetical listing of ATC codes as supplied to us in November 1999. It is supplied free as a service to those who care about good medicine use by mSupply support. To get an overview of the ATC system, use the “ATC categories.pdf” document also alvailable from www.msupply.org.nz Thanks to the WHO collaborating centre for Drug Statistics & Methodology, Norway, for supplying the raw data. I have intentionally supplied these files as PDFs so that they are not quite so easily manipulated and redistributed. I am told there is no copyright on the files, but it still seems polite to ask before using other people’s work, so please contact <[email protected]> for permission before asking us for text files. mSupply support also distributes mSupply software for inventory control, which has an inbuilt system for reporting on medicine usage using the ATC system You can download a full working version from www.msupply.org.nz Craig Drown, mSupply Support <[email protected]> April 2000 A (2-benzhydryloxyethyl)diethyl-methylammonium iodide A03AB16 0.3 g O 2-(4-chlorphenoxy)-ethanol D01AE06 4-dimethylaminophenol V03AB27 Abciximab B01AC13 25 mg P Absorbable gelatin sponge B02BC01 Acadesine C01EB13 Acamprosate V03AA03 2 g O Acarbose A10BF01 0.3 g O Acebutolol C07AB04 0.4 g O,P Acebutolol and thiazides C07BB04 Aceclidine S01EB08 Aceclidine, combinations S01EB58 Aceclofenac M01AB16 0.2 g O Acefylline piperazine R03DA09 Acemetacin M01AB11 Acenocoumarol B01AA07 5 mg O Acepromazine N05AA04
    [Show full text]