RESUMEN
Malaria is among the tropical diseases that cause the most deaths in Africa. Around 500,000 malaria deaths are reported yearly among African children under the age of five. Chloroquine (CQ) is a low-cost antimalarial used worldwide for the treatment of Plasmodium vivax malaria. Due to resistance mechanisms, CQ is no longer effective against most malaria cases caused by P. falciparum. The World Health Organization recommends artemisinin combination therapies for P. falciparum malaria, but resistance is emerging in Southeast Asia and some parts of Africa. Therefore, new medicines for treating malaria are urgently needed. Previously, our group identified the 4-aminoquinoline DAQ, a CQ analog containing an acetylenic bond in its side chain, which overcomes CQ resistance in K1 P. falciparum strains. In this work, the antiplasmodial profile, drug-like properties, and pharmacokinetics of DAQ were further investigated. DAQ showed no cross-resistance against standard CQ-resistant strains (e.g., Dd2, IPC 4912, RF12) nor against P. falciparum and P. vivax isolates from patients in the Brazilian Amazon. Using drug pressure assays, DAQ showed a low propensity to generate resistance. DAQ showed considerable solubility but low metabolic stability. The main metabolite was identified as a mono N-deethylated derivative (DAQM), which also showed significant inhibitory activity against CQ-resistant P. falciparum strains. Our findings indicated that the presence of a triple bond in CQ-analogues may represent a low-cost opportunity to overcome known mechanisms of resistance in the malaria parasite.
Asunto(s)
Antimaláricos , Malaria Falciparum , Malaria Vivax , Malaria , Plasmodium , Niño , Humanos , Cloroquina/farmacología , Cloroquina/uso terapéutico , Plasmodium falciparum , Acetileno/farmacología , Acetileno/uso terapéutico , Alquinos/farmacología , Alquinos/uso terapéutico , Resistencia a Medicamentos , Antimaláricos/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Malaria Vivax/tratamiento farmacológico , Malaria/tratamiento farmacológicoRESUMEN
Schistosomiasis, one of 17 diseases deemed to be neglected by the World Health Organization, has received little attention from the biopharmaceutical industry. Due to this, only a handful of drugs have been developed to treat schistosomiasis, with only one, praziquantel, used in most endemic regions. Growing concern over resistance coupled with praziquantel's incomplete efficacy across all stages of the Schistosoma platyhelminth life cycle highlights the urgent need for new drugs. The WIPO Re:Search consortium is a platform whereupon biopharmaceutical company compounds are being repurposed to efficiently and cost-effectively develop new drugs for neglected diseases such as schistosomiasis. This article summarizes recent clinical-stage efforts to identify new antischistosomals and highlights biopharmaceutical company compounds with potential for repurposing to treat schistosomiasis.
Asunto(s)
Antihelmínticos/farmacología , Reposicionamiento de Medicamentos , Enfermedades Desatendidas/tratamiento farmacológico , Schistosoma/efectos de los fármacos , Esquistosomiasis/tratamiento farmacológico , Animales , Antihelmínticos/economía , Análisis Costo-Beneficio , Reposicionamiento de Medicamentos/economía , Reposicionamiento de Medicamentos/métodos , Humanos , Enfermedades Desatendidas/economía , Esquistosomiasis/economíaRESUMEN
Neglected tropical diseases (NTDs), malaria, and tuberculosis have a devastating effect on an estimated 1.6 billion people worldwide. The World Intellectual Property Organization (WIPO) Re:Search consortium accelerates the development of new drugs, vaccines, and diagnostics for these diseases by connecting the assets and resources of pharmaceutical companies, such as compound libraries and expertise, to academic or nonprofit researchers with novel product discovery or development ideas. As the WIPO Re:Search Partnership Hub Administrator, BIO Ventures for Global Health (BVGH) fields requests from researchers, identifies Member organizations able to fulfill these requests, and helps forge mutually beneficial collaborations. Since its inception in October 2011, WIPO Re:Search membership has expanded to more than 90 institutions, including leading pharmaceutical companies, universities, nonprofit research institutions, and product development partnerships from around the world. To date, WIPO Re:Search has facilitated over 70 research agreements between Consortium Members, including 11 collaborations focused on anthelmintic drug discovery.
Asunto(s)
Enfermedades Desatendidas/terapia , Medicina Tropical/tendencias , Animales , Conducta Cooperativa , Diarrea/tratamiento farmacológico , Industria Farmacéutica , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Agencias Internacionales , Cooperación Internacional , Malaria/tratamiento farmacológico , Asociación entre el Sector Público-Privado , Investigación , Esquistosomiasis/tratamiento farmacológico , Naciones UnidasRESUMEN
Liver fibrosis is characterized by increased synthesis, and decreased degradation, of extracellular matrix (ECM) within the injured tissue. Decreased ECM degradation results, in part, from increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), which blocks matrix metalloproteinase (MMP) activity. TIMP-1 is also involved in promoting survival of activated hepatic stellate cells (HSCs), a major source of ECM. This study examined the effects of blocking TIMP-1 activity in a clinically relevant model of established liver fibrosis. Rats were treated with carbon tetrachloride (CCl(4)), or olive oil control, for 6 weeks; 24 days into the treatment, the rats were administered a neutralizing anti-TIMP-1 antibody derived from a fully human combinatorial antibody library (HuCAL), PBS, or an isotype control antibody. Livers from CCl(4)-treated rats exhibited substantial damage, including bridging fibrosis, inflammation, and extensive expression of smooth muscle alpha-actin (alpha-SMA). Compared to controls, rats administered anti-TIMP-1 showed a reduction in collagen accumulation by histological examination and hydroxyproline content. Administration of anti-TIMP-1 resulted in a marked decrease in alpha-SMA staining. Zymography analysis showed antibody treatment decreased the activity of MMP-2. In conclusion, administration of a TIMP-1 antibody attenuated CCl(4)-induced liver fibrosis and decreased HSC activation and MMP-2 activity.