Alkaloids with Anti-Onchocercal Activity from Voacanga africana Stapf (Apocynaceae): Identification and Molecular Modeling.

A new iboga-vobasine-type isomeric bisindole alkaloid named voacamine A (1), along with eight known compounds-voacangine (2), voacristine (3), coronaridine (4), tabernanthine (5), iboxygaine (6), voacamine (7), voacorine (8) and conoduramine (9)-were isolated from the stem bark of Voacangaafricana. The structures of the compounds were determined by comprehensive spectroscopic analyses. Compounds 1, 2, 3, 4, 6, 7 and 8 were found to inhibit the motility of both the microfilariae (Mf) and adult male worms of Onchocerca ochengi, in a dose-dependent manner, but were only moderately active on the adult female worms upon biochemical assessment at 30 µM drug concentrations. The IC50 values of the isolates are 2.49-5.49 µM for microfilariae and 3.45-17.87 µM for adult males. Homology modeling was used to generate a 3D model of the O. ochengi thioredoxin reductase target and docking simulation, followed by molecular dynamics and binding free energy calculations attempted to offer an explanation of the anti-onchocercal structure-activity relationship (SAR) of the isolated compounds. These alkaloids are new potential leads for the development of antifilarial drugs. The results of this study validate the traditional use of V. africana in the treatment of human onchocerciasis.

Sub-Standard Pharmaceutical Services in Private Healthcare Facilities Serving Low-Income Settlements in Nairobi County, Kenya.

Background: Quality pharmaceutical services are an integral part of primary healthcare and a key determinant of patient outcomes. The study focuses on pharmaceutical service delivery among private healthcare facilities serving informal settlements within Nairobi County, Kenya and aims at understanding the drug procurement practices, task-shifting and ethical issues associated with drug brand preference, competition and disposal of expired drugs. Methods: Forty-five private facilities comprising of hospitals, nursing homes, health centres, medical centres, clinics and pharmacies were recruited through purposive sampling. Structured electronic questionnaires were administered to 45 respondents working within the study facilities over an 8-week period. Results: About 50% of personnel carrying out drug procurement belonged to non-pharmaceutical cadres namely; doctors, clinical officers, nurses and pharmacy assistants. Drug brand preferences among healthcare facilities and patients were mainly pegged on perceived quality and price. Unethical business competition practices were recorded, including poor professional demeanour and waiver of consultation fees veiled to undercut colleagues. Government subsidized drugs were sold at 100% profit in fifty percent of the facilities stocking them. In 44% of the facilities, the disposal of expired drugs was not in conformity to existing government regulatory guidelines. Conclusions: There is extensive task-shifting and delegation of pharmaceutical services to non-pharmaceutical cadres and poor observance of ethical guidelines in private facilities. Strict enforcement of regulations is required for optimal practices.

Medicine Prices, Availability, and Affordability in Private Health Facilities in Low-Income Settlements in Nairobi County, Kenya.

Medicine prices are a major determinant of access to healthcare. Owing to low availability of medicines in the public health facilities and poor accessibility to these facilities, most low-income residents pay out-of-pocket for health services and transport to the private health facilities. In low-income settlements, high retail prices are likely to push the population further into poverty and ill health. This study assessed the retail pricing, availability, and affordability of medicines in private health facilities in low-income settlements within Nairobi County. Medicine prices and availability data were collected between September and December 2016 at 45 private healthcare facilities in 14 of Nairobi's low-income settlements using electronic questionnaires. The International Medical Products Price Guide provided international medicine reference prices for comparison. Affordability and availability proxies were calculated according to existing methods. Innovator brands were 13.8 times more expensive than generic brands. The lowest priced generics and innovator brands were, on average, sold at 2.9 and 32.6 times the median international reference prices of corresponding medicines. Assuming a 100% disposable income, it would take 0.03 to 1.33 days' wages for the lowest paid government employee to pay for treatment courses of selected single generic medicines. Medicine availability in the facilities ranged between 2% and 76% (mean 43%) for indicator medicines. Prices of selected medicines varied within the 14 study regions. Retail medicine prices in the low-income settlements studied were generally higher than corresponding international reference prices. Price variations were observed across different regions although the regions comprise similar socioeconomic populations. These factors are likely to impact negatively on healthcare access.

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.

A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively.

Artemisinin derivatives: a patent review (2006 - present).

INTRODUCTION: The isolation of artemisinin from an ancient Chinese remedy in the early 1970s heralded the beginning of a new era in antimalarial drug therapy culminating in artemisinin-based combination therapies currently being the mainstay of malaria treatment worldwide. Ongoing research on this compound and its derivatives has revealed its potential use in treating other infectious and noninfectious diseases. AREAS COVERED: This review provides a summary of patents published globally from January 2006 to June 2012 covering promising artemisinin derivatives and artemisinin-based drug combinations developed for use in various therapeutic areas. EXPERT OPINION: The diversity of semi-synthetic artemisinin derivatives has been limited to the same design strategy of modifying the artemisinin molecule at the same positions due to inherent synthetic challenges. To address this, future endeavors should include: the use of biotransformation strategies to modify other positions in the sesquiterpene ring while retaining the endoperoxide bridge; the design and synthesis of synthetic ozonides based on the pharmacophoric endoperoxide motif and drug repositioning approaches to artemisinin-based combination therapy. A better understanding of the mechanism of action of artemisinin derivatives and their biomolecular targets may provide an invaluable tool for the development of derivatives with a wider array of activity and greater clinical utility than currently appreciated.

Benzoheterocyclic amodiaquine analogues with potent antiplasmodial activity: synthesis and pharmacological evaluation.

The synthesis and evaluation of antiplasmodial activity of benzothiazole, benzimidazole, benzoxazole and pyridine analogues of amodiaquine is hereby reported. Benzothiazole and benzoxazole analogues with a protonatable tertiary nitrogen atom possessed excellent activity against the W2 and K1 chloroquine resistant strains of Plasmodium falciparum, with IC(50)s ranging from 7 to 22 nM.