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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.

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 analogs, 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 4×10 mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. KEYWORDS: amodiaquine, benzoxazole, antiplasmodial activity, antimalarial activity, malaria, reactive metabolite, 4-aminoquinolines; bioactivation; structure-activity relationship; β-hematin; quinone imine. INTRODUCTIONMalaria remains a leading cause of morbidity and mortality globally. In 2012, there were an estimated 207 million cases of malaria and 627 000 deaths worldwide, with 90% of all malaria deaths occurring in sub-Saharan Africa. 1 One of the biggest challenges facing malaria chemotherapy is the rapid emergence of resistance to existing antimalarial drugs. 2 This challenge underscores the need for the continued search for new antimalarials.Chloroquine (1) (structure shown in Figure 1), was undoubtedly one of the most successful antimalarials ever owing to its good efficacy and low cost which made it affordable especially in the developing countries with high malaria endemicity. 3 Chloroquine was replaced as first line therapy by the sulfonamide antimalarials and, later on, artemisinin combination therapy (ACT), following the development of widespread resistance against the drug by Plasmodium falciparum. 4An aromatic side chain analogue of chloroquine, amodiaquine (2), however, retains activity against chloroquine-resistant Plasmodium strains. 5 Besides, it is an established fact that resistance against these 4-aminoquinolines is not a result of target modification but is caused by impaired accumulation of the drug at the target. 6,7 Consequently, amodiaquine is an attractive lead compound in the search for new antimalarials. Despite the desirable antimalarial efficacy of amodiaquine, chronic use especially during prophylaxis has been found to precipitate severe hepatotoxicity, myelotoxicity and agranulocytosis. 8,9 This toxicity has been attributed to the bioactivation of amodiaquine to reactive quinone imine (3) and aldehyde quinone imine (4) metabolites (figure 1) which covalently bind to cellular macromolecules causing drug-induced toxicity and cell damage di...