Epidemic of Plasmodium falciparum malaria involving substandard antimalarial drugs, Pakistan, 2003.

Because of instability in eastern Afghanistan, new refugees crossed into the federally administered tribal areas of northwestern Pakistan in 2002. In 2003, we investigated an epidemic of Plasmodium falciparum malaria in 1 of the camps. Incidence was 100.4 cases/1,000 person-years; in other nearby camps it was only 2.1/1,000 person-years. Anopheline mosquitoes were found despite an earlier spray campaign. Documented clinical failures at the basic health unit prompted a drug resistance survey of locally manufactured sulfadoxine-pyrimethamine used for routine treatment. The in vivo failure rate was 28.5%. PCR analysis of the P. falciparum dihydrofolate reductase and dihyropteroate synthase genes showed no mutations associated with clinical failure. However, chemical analysis of the drug showed that it was substandard. As global incidence decreases and epidemics become more of a threat, enhanced quality assurance of control interventions is essential.

The quality of antimalarials available in Yemen.

BACKGROUND: Malaria has always been a major public health problem in Yemen. Several studies in developing countries have demonstrated ineffective and poor quality drugs including antimalarials. Therefore, quality assessment of antimalarial drugs is of crucial importance. This study aimed to assess the quality of antimalarials (chloroquine and sulfadoxine/pyrimethamine) available in Yemen and to determine whether the quality of these products was related to the level of the distribution chain at which the samples were collected or related to the manufacturers. METHODS: Four samples from each antimalarial product were collected from each of the various levels of the distribution chain. One sample was kept with the research team. Two were tested at Sana'a and Aden Drug Quality Control Laboratories. The fourth was sent to the Centre for Quality Assurance of Medicines in Potchefstroom, South Africa, for analysis. Quality indicators measured were the content of the active ingredient and dissolution rate (for tablets only) in comparison to standard specifications for these products in the relevant pharmacopoeia. RESULTS: The results identified several problems of sub-standard products within the drug distribution chain. They included high and low failures in ingredient content for chloroquine tablets and chloroquine syrup. There was some dissolution failure for chloroquine tablets, and high sulfadoxine/pyrimethamine tablets dissolution failures. Failures with the dissolution of the pyrimethamine were found at most of the collection points. No clear relationship neither between the quality products and the level of the distribution chain, nor between locally manufactured and imported products was observed. CONCLUSION: There are sub-standard antimalarial products circulating within the drug distribution chains in the country, which will have serious implications on the reduced therapeutic effectiveness and on the development of drug resistance. This appears to be due to non-compliance with Good Manufacturing Practice guidelines by manufacturers in the production of the antimalarials.

Pyrimethamine-sulfadoxine efficacy and selection for mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase in Mali.

To assess pyrimethamine-sulfadoxine (PS) efficacy in Mali, and the role of mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) in in vivo PS resistance, 190 patients with uncomplicated P. falciparum malaria were treated with PS and monitored for 56 days. Mutation-specific polymerase chain reactions and digestion with restriction endonucleases were used to detect DHFR and DHPS mutations on filter paper blood samples from pretreatment and post-treatment infections. Only one case each of RI and RII level resistance and no cases of RIII resistance or therapeutic failure were observed. Post-PS treatment infections had significantly higher rates of DHFR mutations at codons 108 and 59. No significant selection for DHPS mutations was seen. Pyrimethamine-sulfadoxine is highly efficacious in Mali, and while the low level of resistance precludes assessing the utility of molecular assays for in vivo PS resistance, rapid selection of DHFR mutations supports their role in PS failure.

Efficacy and tolerability of a low-dose mefloquine-sulfadoxine-pyrimethamine combination compared with chloroquine in the treatment of acute malaria infection in a population with multiple drug-resistant Plasmodium falciparum.

The efficacy and tolerability of single, low-dose mefloquine, sulfadoxine-pyrimethamine (MSP) combination was compared with chloroquine (CQ) for malaria treatment in a malaria-endemic area of Nigeria with multiple drug-resistant Plasmodium falciparum. The two drug regimens (MSP and CQ) were tested in a 12-month prospective population study. The patients were divided into two groups. Group 1 patients were treated presumptively, based on malaria symptoms. Group 2 patients were treated based on a parasitologic diagnosis using the World Health Organization seven-day in vivo test and extended to a 28-day follow-up period. Tolerability was assessed by the incidence and intensity of adverse events. One thousand nine hundred thirty-five patients visiting 10 health facilities, including the University of Calabar Teaching Hospital, were enrolled. The study showed that the low-dose MSP was efficacious, with day 7 response rates of 95% and 91% for (presumptive) Group 1 and (in vivo) Group 2, respectively, while CQ had day 7 response rates of 82% and 66% in Groups 1 and 2, respectively. The low-dose MSP was significantly (P < 0.0001) more efficacious, with faster fever and parasite clearance times than CQ in this area of CQ-resistant P. falciparum malaria. Eight patients treated with CQ, including seven severe cases (RII-RIII) were successfully re-treated with MSP. Adverse events were generally more common among those treated with MSP (29%) than those treated with CQ (17%). However, the adverse events caused by both drugs were mild to moderate and self-limited. The MSP combination appears to be a good substitute for CQ, in view of multiple drug resistance, especially in areas with severe (RII-RIII) malaria.

Determination of the activity of pyrimethamine, trimethoprim, sulfonamides, and combinations of pyrimethamine and sulfonamides against Sarcocystis neurona in cell cultures.

Equine protozoal myeloencephalitis (EPM) is a neurologic syndrome in horses from the Americas and is usually caused by infection with the apicomplexan parasite, Sarcocystis neurona. The activities of pyrimethamine, trimethoprim, sulfachloropyridazine, sulfadiazine, sulfadimethoxine, sulfamethoxazole, sulfamethazine, and sulfathiazole were examined against developing S. neurona merozoites in bovine turbinate cell cultures. A microtiter plate host cell lesion based assay was used to determine the effects of agents on developing merozoites. A cell culture flask assay was used to determine if selective concentrations of the agents killed or only inhibited development of S. neurona. Pyrimethamine was coccidiocidal at 1.0 microg/ml and trimethoprim was coccidiocidal at 5.0 microg/ml. None of the sulfonamides had activity when used alone at 50.0 or 100.0 microg/ml. Combinations of sulfonamides (5.0 or 10.0 microg/ml) with 0.1 microg/ml pyrimethamine demonstrated improved activity.

Antimalarial drug quality in Africa.

BACKGROUND AND OBJECTIVE: There are several reports of sub-standard and counterfeit antimalarial drugs circulating in the markets of developing countries; we aimed to review the literature for the African continent. METHODS: A search was conducted in PubMed in English using the medical subject headings (MeSH) terms: 'Antimalarials/analysis'[MeSH] OR 'Antimalarials/standards'[MeSH] AND 'Africa'[MeSH]' to include articles published up to and including 26 February 2007. Data were augmented with reports on the quality of antimalarial drugs in Africa obtained from colleagues in the World Health Organization. We summarized the data under the following themes: content and dissolution; relative bioavailability of antimalarial products; antimalarial stability and shelf life; general tests on pharmaceutical dosage forms; and the presence of degradation or unidentifiable impurities in formulations. RESULTS AND DISCUSSION: The search yielded 21 relevant peer-reviewed articles and three reports on the quality of antimalarial drugs in Africa. The literature was varied in the quality and breadth of data presented, with most bioavailability studies poorly designed and executed. The review highlights the common finding in drug quality studies that (i) most antimalarial products pass the basic tests for pharmaceutical dosage forms, such as the uniformity of weight for tablets, (ii) most antimalarial drugs pass the content test and (iii) in vitro product dissolution is the main problem area where most drugs fail to meet required pharmacopoeial specifications, especially with regard to sulfadoxine-pyrimethamine products. In addition, there are worryingly high quality failure rates for artemisinin monotherapies such as dihydroartemisinin (DHA); for instance all five DHA sampled products in one study in Nairobi, Kenya, were reported to have failed the requisite tests. CONCLUSIONS: There is an urgent need to strengthen pharmaceutical management systems such as post-marketing surveillance and the broader health systems in Africa to ensure populations in the continent have access to antimalarial drugs that are safe, of the highest quality standards and that retain their integrity throughout the distribution chain through adequate enforcement of existing legislation and enactment of new ones if necessary, and provision of the necessary resources for drug quality assurance.

Quality evaluation of chloroquine, quinine, sulfadoxine-pyrimethamine and proguanil formulations sold on the market in East Congo DR.

OBJECTIVE: Drug quality may be poor in many regions of the world. Our first aim was to verify whether the dose of the active compounds in various antimalarial medicines on the market in East Congo conforms to the quality requirements of the European Pharmacopoeia (Ph. Eur.). The second aim was to check the extent to which simple methods of analysis could be used to evaluate drug quality. METHODS: The formulations analysed included tablets, injections and syrups of chloroquine (CQ), quinine, sulfadoxine-pyrimethamine (SP) and proguanil. Ultraviolet (UV) spectrophotometry was used to quantify CQ and quinine in tablets and injections. Thin layer chromatography was used to identify the preservative(s) in the syrups. As the drug form (base or salt) in the tablets, is rarely declared, the estimated dose was calculated using both forms. High-performance liquid chromatography (HPLC) was used to check for assay interference and for measuring SP combinations. RESULTS AND DISCUSSION: When the dose declaration on the label was assumed to be of the salt form, 33% of CQ batches were underdosed and two of eight batches of quinine were underdosed by about 25% and 15% respectively. When the base form was assumed, only one batch of CQ tablets conformed. The underdosed batches contained about 50-66% of the claimed amount for CQ. The dose of quinine in the different batches of tablets was in the range 62-86%. For the CQ syrup, interference by the preservative Nipagin, confirmed by HPLC-UV, was observed with UV-spectrophotometry at 257 nm but not at 342 nm. The results for CQ syrup using UV-spectrophotometry at 342 nm and HPLC-UV at 257 nm were comparable and showed compliance with the European Pharmacopoeia limits of 95-105%. One of two batches of CQ injections and one of four batches of quinine injections were overdosed by about 14% and 8% respectively. The SP tablets were analysed by using HPLC-UV only. All five batches were underdosed in sulfadoxine (91-94%) but still met the United States Pharmacopeial (USP) limit of 90-110%. Two batches were slightly overdosed in pyrimethamine (106% and 108% respectively) while one batch contained neither active ingredient. The one batch of proguanil analysed, met the Ph. Eur. quality requirement (98.7%). CONCLUSION: Simple methods of analysis like UV-spectrophotometry can be used to check drug quality routinely. A substantial proportion of the antimalarial drugs sold on the Congo DR market is of poor quality. Some batches contain little or no drug. This is a serious threat to public health in the region of Congo DR.

The chemical and pharmaceutical equivalence of sulphadoxine/pyrimethamine tablets sold on the Tanzanian market.

This study investigated chemical and pharmaceutical equivalence of 11 brands of pyrimethamine-sulphadoxine combination tablets sold on the Tanzanian market. Physical and chemical tests were performed for all the 11 brands. These tests included hardness test, friability, disintegration, dissolution, weight uniformity and assay for the active components. All the brands passed all the quality specifications of the United States Pharmacopoeia (USP) and British Pharmacopoeia (BP) in terms of hardness, friability, disintegration, assay and dissolution test, except for three brands that failed the hardness, disintegration or friability tests. One brand failed both the hardness and disintegration test; one failed the hardness test, whereas another one failed the friability test. The percentage content of pyrimethamine in the brands was in the range of 91.04-100.20% whereas that of sulphadoxine ranged from 91.53% to 99.88%. There were no major differences between the different brands of tablets containing pyrimethamine and sulphadoxine and the innovator product (Fansidar), and all brands were physically and chemically equivalent. The results indicate that the post-market surveillance and registration process in Tanzania is having an impact on product quality as there was no brand which could be considered of very poor quality. Impurity profiling of all the locally produced brands indicated that they all contained the same sulphadoxine impurity, which was absent in the innovator product, suggesting a common source of generic raw material.

The quality of sulphadoxine-pyrimethamine and amodiaquine products in the Kenyan retail sector.

BACKGROUND AND OBJECTIVE: Malaria is a disease of major public health importance in Kenya killing 26,000 children under 5 years of age annually. This paper seeks to assess the quality of sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) products available over-the-counter to communities in Kenya as most malaria fevers are self-medicated using drugs from the informal retail sector. METHODS: A retail audit of 880 retail outlets was carried in 2002 in four districts in Kenya, in which antimalarial drug stocks and their primary wholesale sources were noted. In addition, the expiry dates on audited products and the basic storage conditions were recorded on a proforma. The most commonly stocked SP and AQ products were then sampled from the top 10 wholesalers in each district and samples subjected to standard United States Pharmacopoeia (USP) tests of content and dissolution. RESULTS AND DISCUSSION: SP and AQ were the most frequently stocked antimalarial drugs, accounting for approximately 75% of all the antimalarial drugs stocked in the four districts. Of 116 SP and AQ samples analysed, 47 (40.5%) did not meet the USP specifications for content and/or dissolution. Overall, approximately 45.3% of SP and 33.0% of AQ samples were found to be sub-standard. Of the sub-standard SP products, 55.2% were suspensions while 61.1% of the substandard AQ products were tablets. Most SP failures were because of the pyrimethamine component. CONCLUSION: There is a need to strengthen post-marketing surveillance systems to protect patients from being treated with sub-standard and counterfeit antimalarial drugs in Kenya.