RESUMEN
Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca's 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-Wolbachia consortium (AâWOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-Wolbachia activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs.
Asunto(s)
Descubrimiento de Drogas , Filaricidas/análisis , Ensayos Analíticos de Alto Rendimiento , Aedes , Animales , Línea Celular , WolbachiaRESUMEN
In 1997, the World Health Organization (WHO) made a commitment to eliminate lymphatic filariasis. The WHO Global Program to Eliminate Lymphatic Filariasis (WHO-FIL) needed a reliable supply of diethylcarbamazine citrate (DEC) of known acceptable quality at an affordable price, so in August 1999, it started the DEC Project. Today's standards required development of a modern stability-indicating assay method for DEC and for DEC tablet dissolution. ADD Advanced Drug Delivery Technologies (Switzerland) developed a high-pressure liquid chromatography assay, which was independently validated and is in the United States Pharmacopoeia 25 (2002). After a global search, the project found that almost all existing and potential DEC active pharmaceutical ingredient (API) and tablet manufacturers are in low-income countries. The project constructed an audit team to conduct on-site audits to assess good manufacturing practices according to European Union standards. National/state inspectors accompany the audit team. The team prequalified one DEC API manufacturer and three DEC tablet manufacturers. The project plans to increase the number of prequalified DEC manufacturers. Now, WHO-FIL only purchases from prequalified manufacturers. Consolidation of several national program DEC requirements into a limited international competitive bid reduced the price for DEC tablets between 30% and 45%, compared to previous small-scale WHO purchases.
Asunto(s)
Dietilcarbamazina/normas , Filaricidas/normas , Cromatografía Líquida de Alta Presión , Dietilcarbamazina/análisis , Industria Farmacéutica/normas , Estabilidad de Medicamentos , Filariasis Linfática/tratamiento farmacológico , Filariasis Linfática/epidemiología , Filaricidas/análisis , Control de Infecciones , Farmacopeas como Asunto , Control de Calidad , Comprimidos , Organización Mundial de la SaludRESUMEN
A simple and reproducible method for the estimation of diethylcarbamazine citrate (DEC) by high performance liquid chromatography (HPLC) in DEC-medicated salt was developed. HPLC analysis was conducted with a mobile phase containing acetonitrile/phosphate buffer (20 mM KH(2)PO(4,) adjusted to pH 3.2 with 10% ortho-phosphoric acid) in the ratio of 1:9 and at a flow rate of 1.5 ml/min. A Phenomenex C8 column (15 cmx4.6 mm) of 5 microm particle size was used for the analysis. Analysis was done at UV 210 nm, 0.02 a.u.f. and 40 degrees C. The coefficient of variation was <10% in the range of 1-25 microg/ml and the minimum detectable level was 0.5 microg/ml. The quality of DEC-medicated salt prepared by two methods was analyzed by using the HPLC method. In spray drying method, 29 and 71% of the samples and in rotating drum method, 9 and 12% of samples were found to contain DEC at 0.15-0.25% and >0.25%, respectively. Thus, this quick and simple HPLC method for the estimation of DEC could play a vital role in checking the quality of the DEC medicated salt used for the control of filariasis.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Dietilcarbamazina/análisis , Filaricidas/análisis , Cloruro de Sodio Dietético , Animales , Dietilcarbamazina/normas , Dietilcarbamazina/uso terapéutico , Filariasis Linfática/tratamiento farmacológico , Filaricidas/uso terapéutico , Humanos , Reproducibilidad de los Resultados , Cloruro de Sodio Dietético/uso terapéuticoRESUMEN
The World Health Organization has called for an effort to eliminate Lymphatic Filariasis (LF) around the world. In regions where the disease is endemic, local production and distribution of medicated salt dosed with diethylcarbamazine (DEC) has been an effective method for eradicating LF. A partner of the Notre Dame Haiti program, Group SPES in Port-au-Prince, Haiti, produces a medicated salt called Bon Sel. Coarse salt is pre-washed and sprayed with a solution of DEC citrate and potassium iodate. Iodine levels are routinely monitored on site by a titrimetric method. However, the factory had no method for monitoring DEC. Critical analytical issues include 1) determining whether the amount of DEC in each lot of Bon Sel is within safe and therapeutically useful limits, 2) monitoring variability within and between production runs, and 3) determining the effect of a common local practice (washing salt before use) on the availability of DEC. This paper describes a novel titrimetric method for analysis of DEC citrate in medicated salt. The analysis needs no electrical power and requires only a balance, volumetric glassware, and burets that most salt production programs have on hand for monitoring iodine levels. The staff of the factory used this analysis method on site to detect underloading of DEC on the salt by their sprayer and to test a process change that fixed the problem.