RESUMO
Blood schizontocidal activity of 10 selected cis-fused cyclopenteno-1,2,4-trioxanes (namely Fenozan compound nos 6, 7, 11, 27, 32, 39, 44, 45, 48 and 51) have been re-investigated to establish their curative doses against the multidrug-resistant Plasmodium yoelii nigeriensis strain, which is lethal in Swiss mice. Freshly prepared formulations of these compounds prepared either in neutral groundnut (peanut) oil or in dimethyl sulfoxide (DMSO)-Tween-water, were compared for their antimalarial activity. Only 2 compounds, namely Fenozan derivatives 11 and 45, formulated in neutral groundnut oil for oral administration, showed highest activity with 100% cure rate in MDR P. yoelii nigeriensis-infected mice, while the DMSO-Tween-water formulations were inactive. Fenozan-48 produced 72.2% cure, when administered orally in groundnut oil (formulation) while its DMSO-Tween formulation was inactive. In the case of Fenozan 7, the oil and DMSO-Tween formulations produced 92.3 and 76.0% cures respectively. Fenozan derivatives nos 6, 27, 32, 39, 44 and 51 were not protective either in groundnut oil or DMSO-Tween oral formulations. The present study has applied more rigorous criteria for selection of active compounds, and has identified the 3,3-spirocyclopentane derivative Fenozan 11, and the 3,3-spirohydropyran derivative Fenozan 45, as potential blood schizontocides which can completely eliminate multidrug-resistant malaria infection in mice. Both these compounds are candidates for pre-clinical development. The present study advocates the preferred use of an oil vehicle for oral evaluation of potential antimalarial trioxanes/fenozans instead of the DMSO formulation, which gives inferior curative efficacy.
Assuntos
Antimaláricos/farmacologia , Resistência a Múltiplos Medicamentos , Malária/tratamento farmacológico , Fenilpropionatos/farmacologia , Plasmodium yoelii/efeitos dos fármacos , Administração Oral , Animais , Antimaláricos/uso terapêutico , Bioensaio , Humanos , Malária/parasitologia , Camundongos , Óleo de Amendoim , Fenilpropionatos/uso terapêutico , Óleos de Plantas/farmacologia , Distribuição Aleatória , Relação Estrutura-Atividade , Resultado do TratamentoRESUMO
Many different drug-resistant lines of rodent malaria are available as screening models. It is obligatory to screen new compounds for antimalarial activity against a series of resistant lines in order to identify a compound with potential for the treatment of multi-drug resistant (MDR) malaria infections. Instead of using a battery of resistant lines, a single MDR Plasmodium yoelii nigeriensis strain that shows a wide spectrum of drug resistance to high doses of chloroquine, mepacrine, amodiaquine, mefloquine, quinine, quinidine, halofantrine as well as tetracyclines, fluoroquinolines and erythromycin, was used to assess the blood schizontocidal efficacy of a new macrolide azithromycin and other antibiotics. The present study shows that only azithromycin has the potential to control an MDR P. y. nigeriensis infection in Swiss mice, provided the treatment with a dose of 50-100 mg/kg/day by oral route is continued for a period of 7 days. Tetracycline, oxytetracycline, doxycyline, erythromycin, ciprofloxacin and norfloxacin, although active in vitro, failed to protect the mice. Tetracycline, ciprofloxacin and norfloxacin combinations with chloroquine did not control the infection. Additionally, the antimalarial efficacy of azithromycin can be potentiated with the addition of arteether, which is an ethyl ether derivative of artemisinin. A total (100%) curative effect has been obtained with a shorter regimen of 4 days only.
Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Azitromicina/farmacologia , Plasmodium yoelii/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos , Quimioterapia Combinada , Camundongos , Parasitemia/sangueRESUMO
The gametocytocidal action of a new enamine analogue of primaquine, elubaquine (compound CDRI 80/53, bulaquine), has been evaluated against Plasmodium cynomolgi B in rhesus monkeys. Colony bred Anopheles stephensi mosquitoes were fed on gametocyte carrying rhesus monkeys prior to and at varying intervals after oral administration of a single dose of elubaquine at doses ranging between 0.63 and 5.00 mg/kg. Complete loss of oocyst development and mosquito infectivity was observed within 24 h after administering a single 1.25 mg/kg dose, while higher dose of 3.75 mg/kg inhibited oocyst development within 5 h, indicating gametocytocidal action of the compound. Elubaquine did not show any action against developing oocysts in the vector.
Assuntos
Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Plasmodium cynomolgi/efeitos dos fármacos , Primaquina/análogos & derivados , Animais , Anopheles/parasitologia , Antimaláricos/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Insetos Vetores/parasitologia , Macaca mulatta , Masculino , Primaquina/farmacologia , Primaquina/uso terapêuticoRESUMO
Plasmodium knowlesi (W1) shows a high level of innate resistance to mefloquine as shown by recrudescence of blood-induced infection in rhesus monkeys, following oral mefloquine treatment with up to 80-160 mg/kg total dose over 3-4 days. Ketoconazole, at a dose of 75 mg/kg/day x 10 days given orally to P. knowlesi-infected rhesus monkeys, exerted a suppressive antimalarial effect in 1 of the 2 monkeys as evidenced by a delayed recrudescence (on day 30) and curative action in case of the other monkey, whereas a lower dose of ketoconazole (25 mg/kg/day x 10 days) failed to suppress infection effectively. When ketoconazole at a low dose (25 mg/kg/day x 10 days) treatment was combined with mefloquine (20 mg/kg/ day x 4), 1 of the 2 infected monkeys was cured, while the combination of a higher dose of ketoconazole (75 mg/kg/day x 10 days) with mefloquine (20 mg/kg/day x 4), had a complete curative effect on P. knowlesi infection in all the treated monkeys (7/7). Besides exerting direct antimalarial action against a mefloquine-resistant P. knowlesi, ketoconazole also acts as an inhibitor of hepatic microsomal CYP4503A, which regulates and slows down mefloquine biotransformation to carboxymefloquine, resulting in a possible elevation of the effective plasma drug level, which seems to be responsible for elimination of the resistant P. knowlesi. The study shows a resistance reversal effect of a ketoconazole - mefloquine combination that could be exploited for the control of mefloquine-resistant malaria infection. The study shows that ketoconazole can reverse mefloquine resistance of P. knowlesi. These findings can also be applied to reverse mefloquine resistance of P.falciparum in areas where mefloquine resistance is already established. The precise role of parasite CYP450 in mefloquine resistance and its possible role, if any, in expelling the intracellular mefloquine from the resistant plasmodia still remains to be elucidated.
Assuntos
Antimaláricos/uso terapêutico , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/uso terapêutico , Cetoconazol/uso terapêutico , Malária/tratamento farmacológico , Mefloquina/uso terapêutico , Animais , Antimaláricos/administração & dosagem , Relação Dose-Resposta a Droga , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Cetoconazol/administração & dosagem , Macaca mulatta , Mefloquina/administração & dosagem , Plasmodium knowlesiRESUMO
Ketoconazole at 200 mg/kg dose has been found to exert marginal antimalarial action against multidrug resistant (MDR) Plasmodium yoelii nigeriensis (P. yoelii nigeriensis) in Swiss mice with 25% protection (2/8 mice) while at lower Ketoconazole dose i.e., 75-100 mg/kg, 14.28% mice were protected. Mefloquine (MFQ) (at 8 and 16 mg/kg) exerted suppressive action against MDR P. yoelii nigeriensis resulting in 25 and 14.28% protection of mice respectively. Combined treatment with Ketoconazole and mefloquine resulted in protection of 5/6 mice (83.33%) at MFQ 4 mg/kg + Ketoconazole 100 mg/kg dose, 7/8 (87.5%) mice at MFQ 8 mg/kg + Ketoconazole 20 mg/kg dose and 5/7 (71.42%) mice at MFQ 16 mg/kg + Ketoconazole 25 mg/kg dose and 5/6 (83.33%) mice at MFQ 16 mg/kg + Ketoconazole 100 mg/kg dose. Ketoconazole has been found to enhance the protective effect of mefloquine against MFQ resistant P. yoelii nigeriensis resulting in 66-88% protection of the mice treated with the appropriate combinations. The combination also increased suppression of parasitaemia at different times. The Ketoconazole combination with MFQ significantly increased the mean survival time of the treated mice compared to individual drugs alone. The study shows that Ketoconazole when administered with MFQ exerts bio-enhancing action against mefloquine resistance of MDR P. yoelii nigeriensis.
Assuntos
Antimaláricos/farmacologia , Cetoconazol/farmacologia , Malária/tratamento farmacológico , Mefloquina/farmacologia , Plasmodium yoelii/efeitos dos fármacos , Animais , Antimaláricos/uso terapêutico , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Cetoconazol/uso terapêutico , Malária/mortalidade , Malária/parasitologia , Mefloquina/uso terapêutico , Camundongos , Parasitemia/tratamento farmacológico , Parasitemia/mortalidade , Parasitemia/parasitologia , Taxa de SobrevidaRESUMO
A new 8-aminoquinoline antimalarial WR 238605 (Tafenoquine), developed initially as a primaquine alternative for prevention of Plasmodium vivax relapses was evaluated for blood schizontocidal activity against two simian malaria infections namely Plasmodium cynomolgi B and Plasmodium fragile in rhesus monkeys. Treatment with WR 238605 at a dose of 3.16 mg(base)/kg/day x 7 days cured established trophozoite induced infections in monkeys with both these parasites. The lower dose of 1.00 mg/kg/day cured 9 out of 12 monkeys infected with P. cynomolgi B and 10 out of 11 monkeys infected with P. fragile. Primaquine was only partially curative at 10.0 mg(base)/kg/day x 7 dose regimen against both these infections. The potent blood schizontocidal activity of tafenoquine adds to the armoury of antimalarial drugs.
Assuntos
Aminoquinolinas/sangue , Aminoquinolinas/farmacologia , Antimaláricos/sangue , Antimaláricos/farmacologia , Macaca mulatta , Malária/veterinária , Doenças dos Macacos/parasitologia , Plasmodium cynomolgi , Animais , Feminino , Malária/sangue , Malária/tratamento farmacológico , Malária/parasitologia , Masculino , Doenças dos Macacos/sangue , Doenças dos Macacos/tratamento farmacológico , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Parasitemia/veterinária , Primaquina/farmacologiaRESUMO
BACKGROUND: Plasmodium yoelii nigeriensis (P. y. nigeriensis) produces lethal malaria infection in Swiss albino mice. Tumor necrosis factor (TNF) has been implicated in the pathogenesis of malaria by production of reactive oxygen species. Chloroquine is a traditionally used antimalarial and has been postulated to inhibit TNF secretion during malaria infection. OBJECTIVE: The study the comparative effect of chloroquine and TNF treatment on hepatic oxidative stress and antioxidant defense indices in normal and P. y. nigeriensis-infected mice. MATERIALS AND METHODS: The mice were divided into six groups, each consisting of four to six animals. They were normal mice, normal mice treated with chloroquine, normal mice treated with TNF-alpha, P. y. nigeriensis-infected mice, P. y. nigeriensis-infected mice treated with chloroquine and P. y. nigeriensis-infected mice treated with TNF-alpha. RESULTS: Chloroquine treatment of the normal mice caused no significant alterations in hepatic oxidative stress and antioxidant defense indices while TNF treatment of normal mice caused a significant decrease in hepatic superoxide dismutase. Chloroquine treatment of P. y. nigeriensis-infected mice caused a decrease in blood parasitemia which was accompanied by restoration of altered indices to near normal levels. However, TNF treatment of P. y. nigeriensis-infected mice had no effect on blood parasitemia but caused a significant increase of hepatic xanthine oxidase and lipid peroxidation and a decrease in the activity of hepatic superoxide dismutase. CONCLUSION: Exogenous TNF acts synergistically with P. y. nigeriensis infection to generate oxidative stress in the host and also causes an impairment of the antioxidant defense enzyme SOD, while chloroquine treatment reduces the severity of malaria infection by decreasing the blood parasitemia and also perhaps by inhibiting the TNF release.
Assuntos
Antimaláricos/farmacologia , Cloroquina/farmacologia , Sequestradores de Radicais Livres/metabolismo , Fígado/metabolismo , Malária/metabolismo , Estresse Oxidativo/fisiologia , Plasmodium yoelii/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Antimaláricos/uso terapêutico , Cloroquina/uso terapêutico , Antagonismo de Drogas , Fígado/efeitos dos fármacos , Malária/tratamento farmacológico , Camundongos , Camundongos Endogâmicos , Parasitemia/tratamento farmacológico , Parasitemia/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
Pyronaridine, administered intramuscularly (im) to Swiss mice infected with the lethal multidrug-resistant Plasmodium yoelii nigeriensis, was found to exert high blood schizontocidal activity. The efficacy of doses of pyronaridine ranging from 0.625 to 30 mg (base/kg) was evaluated using a 4 day treatment schedule (drug was administered at 0, 24, 48 and 72 hrs). It was found that doses of 2.5mg/ kg and higher protected animals completely from the lethal effects of the parasite. The same degree of protection was found when the treatment duration was reduced to 3 days. This study shows that pyronaridine is a potentially useful antimalarial drug that could be exploited for the control of multidrug-resistant malaria infection.
Assuntos
Antimaláricos/farmacologia , Malária/tratamento farmacológico , Naftiridinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistência a Múltiplos Medicamentos , Malária/sangue , Camundongos , Naftiridinas/sangue , Plasmodium yoeliiRESUMO
A multidrug-resistant strain of Plasmodium yoelii nigeriensis (MDR) showing a wide spectrum of resistance to chloroquine, amodiaquine, mepacrine, mefloquine, halofantrine, quinine, and quinidine was used in this study for in vivo evaluation of the blood schizontocidal activity of pyronaridine, a topoisomerase II inhibitor, in Swiss mice. The parasite produces 100% lethal infection in mice. The drug was administered orally once a day from day 0 onward. The initial studies showed that low doses of pyronaridine (0.625 to 5.0 mg base/kg x9 days) did not completely control blood-induced P. yoelii nigeriensis infection. Finally a series of doses of pyronaridine ranging from 1.25 to 30.0 mg/kg administered orally for 7 consecutive days were evaluated and in spite of high level of resistance to standard antimalarials, the parasite P. yoelii nigeriensis has shown complete susceptibility to pyronaridine (15 mg/kg dose x7 days). The present paper also compares the merits of a single MDR strain vs a battery of different resistant lines for quick antimalarials screening.
Assuntos
Antimaláricos/farmacologia , Resistência a Múltiplos Medicamentos , Malária/tratamento farmacológico , Naftiridinas/farmacologia , Plasmodium yoelii/efeitos dos fármacos , Animais , Antimaláricos/uso terapêutico , Malária/parasitologia , Camundongos , Naftiridinas/uso terapêutico , Inibidores da Topoisomerase IIRESUMO
The present communication deals with drug-resistant Plasmodium falciparum malaria complicating hematologic malignancies (leukemias, n = 24, and lymphomas, n = 7) in children. Of 50 cases of hematologic malignancies, 31 patients were microscopically diagnosed as having P. falciparum infection (MP +). Initially, all the patients were treated with chloroquine. The results of primary treatment showed chloroquine resistance in 16 (51. 62%) cases. Of these 16 chloroquine-resistant cases, 13 were secondarily treated with a combination of pyrimethamine plus sulfamethopyrazine. The results of secondary treatment also revealed resistance to pyrimethamine plus sulfamethopyrazine in 6 of 13 (46. 10%) cases. The 6 pyrimethamine plus sulfamethopyrazine-resistant P. falciparum cases were finally cured by quinine therapy, against which no resistance was encountered. Conversely, in the control group comprising 38 cases of P. falciparum without malignancy, the incidence of chloroquine resistance was found in only 9 cases, which is rather low (23.70%). Of these 7 chloroquine-resistant cases, 5 were found to be sensitive to pyrimethamine plus sulfamethopyrazine treatment, while the 2 nonresponders were finally cured with quinine. The overall results of this study show a high prevalence of chloroquine resistance among clinical cases of falciparum malaria (25/69; 30.6%). Among the nonresponders (n = 20) 40% of cases were also resistant to the pyrimethamine plus sulfamethopyrazine combination. There was no resistance to quinine.
Assuntos
Antimaláricos/farmacologia , Doença de Hodgkin/complicações , Leucemia Mieloide Aguda/complicações , Linfoma não Hodgkin/complicações , Malária Falciparum/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Animais , Antimaláricos/uso terapêutico , Criança , Pré-Escolar , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Lactente , Malária Falciparum/tratamento farmacológico , Masculino , Plasmodium falciparum/efeitos dos fármacos , Pirimetamina/farmacologia , Pirimetamina/uso terapêutico , Quinina/uso terapêutico , Sulfaleno/farmacologia , Sulfaleno/uso terapêuticoRESUMO
Reactive oxygen species are important mediators of tissue injury during malaria infection. The status of hepatic oxidative stress and antioxidant defence indices were studied during Plasmodium yoelii nigeriensis (P. y. nigeriensis) infection and chloroquine/ polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly ICLC) treatment of infected mice. P. y. nigeriensis infection resulted in a significant increase in oxidative stress indices viz., xanthine oxidase and rate of lipid peroxidation (LPO). This was accompanied by a highly significant increase in antioxidant defence indices viz., reduced glutathione (GSH) and glutathione reductase while superoxide dismutase (SOD) and catalase showed a highly significant decrease with respect to normal mice. Chloroquine treatment of infected mice caused a decrease in parasitaemia which was associated with restoration of indices altered during infection towards normalization. Poly ICLC treatment of infected mice caused no change in blood parasitaemia but resulted in a significant increase in GSH, glutathione reductase, SOD and catalase with respect to infected mice. Combination therapy of chloroquine and poly ICLC resulted in clearance of parasitaemia and restoration of all oxidative stress and antioxidant defence indices to normal levels.
Assuntos
Antioxidantes/metabolismo , Carboximetilcelulose Sódica/análogos & derivados , Cloroquina/uso terapêutico , Fígado/efeitos dos fármacos , Malária/tratamento farmacológico , Estresse Oxidativo , Poli I-C/uso terapêutico , Polilisina/análogos & derivados , Animais , Antimaláricos/uso terapêutico , Carboximetilcelulose Sódica/uso terapêutico , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Malária/enzimologia , Malária/metabolismo , Masculino , Camundongos , Plasmodium yoelii/isolamento & purificação , Polilisina/uso terapêutico , Superóxido Dismutase/metabolismoRESUMO
Artemisinin and its derivative alpha, beta-arteether have been evaluated for activity against experimental primary amoebic meningoencephalitis. In vivo experiments have shown that amphotericin B at dose of 2.5 mg/kg for 5 days produced 100% protection. Artemisinin and alpha, beta-arteether, even when tested at a high doses (60-120 mg/kg x 5 days and 90-180 mg/x 5 days) respectively, were not curative and showed only slight protection as indicated by extension of mean survival time.
Assuntos
Amebíase/tratamento farmacológico , Amebicidas/uso terapêutico , Artemisininas , Meningoencefalite/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Amebíase/parasitologia , Amebicidas/administração & dosagem , Anfotericina B/administração & dosagem , Anfotericina B/uso terapêutico , Animais , Meningoencefalite/parasitologia , Camundongos , Naegleria fowleri/isolamento & purificação , Sesquiterpenos/administração & dosagemRESUMO
Swiss mice infected with multidrug-resistant Plasmodium yoelii nigeriensis were treated with polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethyl cellulose (Poly ICLC), a potent interferon (IFN) inducer and immune enhancer, in combination with chloroquine (CQ), which completely eliminated the malaria parasite from these animals. The enhancement of the antimalarial activity of poly ICLC was found to be completely reversed by the cytochrome P-450 inducer, phenobarbitone. No effect of Nw nitro-L-arginine (NLA), an inhibitor of nitric oxide, was seen on the enhancement of the antimalarial activity of CQ by Poly ICLC. These results suggest the possible involvement of cytochrome P-450 enzyme-mediated mechanism in the enhancement of the antimalarial activity of CQ by Poly ICLC.
Assuntos
Antimaláricos/uso terapêutico , Carboximetilcelulose Sódica/análogos & derivados , Cloroquina/uso terapêutico , Indutores de Interferon/uso terapêutico , Plasmodium yoelii/efeitos dos fármacos , Poli I-C/uso terapêutico , Polilisina/análogos & derivados , Animais , Carboximetilcelulose Sódica/uso terapêutico , Sistema Enzimático do Citocromo P-450/biossíntese , Resistência a Múltiplos Medicamentos , Quimioterapia Combinada , Indução Enzimática , Camundongos , Fenobarbital/uso terapêutico , Polilisina/uso terapêuticoAssuntos
Atenção à Saúde , Saúde Global , Educação Médica , Humanos , Medicina Tradicional , Predomínio SocialRESUMO
An estimated 300-500 million new infections and 1.5-2.7 million deaths attributed to malaria occur annually in the developing world, and every year tens of millions of travelers from countries where malaria is not transmitted visit countries with malaria. Because the parasites that cause malaria have developed resistance to many antimalarial drugs, new methods for prevention are required. Intraperitoneal injection into mice of one dose of 150 ng (approximately 7.5 micrograms per kg body weight) recombinant mouse interleukin-12 (rmIL-12) 2 days before challenge with Plasmodium yoelii sporozoites protects 100% of mice against malaria. We report that one subcutaneous injection of 10 micrograms/kg recombinant human IL-12 (rhIL-12) 2 days before challenge with P. cynomolgi sporozoites protected seven of seven rhesus monkeys. Protection was associated with marked increases in plasma levels of interferon-gamma (IFN-gamma), and relative increases of lymphoid cell messenger RNA coding for IFN-gamma and several other cytokines. We speculate that rIL-12 protects monkeys through IFN-gamma-dependent elimination of P. cynomolgi-infected hepatocytes. This first report of rIL-12-induced protection of primates against an infectious agent supports assessment of rhIL-12 for immunoprophylaxis of human malaria.
Assuntos
Interleucina-12/farmacologia , Malária/prevenção & controle , Plasmodium cynomolgi , Plasmodium yoelii , Animais , Relação Dose-Resposta a Droga , Interferon gama/sangue , Interferon gama/efeitos dos fármacos , Interferon gama/genética , Interleucina-12/sangue , Interleucinas/genética , Interleucinas/metabolismo , Leucócitos Mononucleares/metabolismo , Macaca mulatta/imunologia , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Proteínas Recombinantes/farmacologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Hepatocytes from bonet monkey (Macaca radiata) obtained by perfusion of a liver biopsy were infected in-vitro with Plasmodium cynomolgi bastianellii sporozoites raised in Anopheles stephensi. The development of exoerythrocytic (EE) stages was seen under phase contrast microscope and by Giemsa staining. Multinucleated EE-stages were seen in the cultured hepatocytes on day 7-8 post-sporozoite inoculation.
Assuntos
Malária/parasitologia , Plasmodium cynomolgi/crescimento & desenvolvimento , Animais , Biópsia , Células Cultivadas , Fígado/citologia , Fígado/parasitologia , Macaca radiata , Microscopia de Contraste de Fase , Esporos/isolamento & purificaçãoRESUMO
Arteether (alpha/beta) (a mixture of alpha and beta enantioners) has been reported to possess gametocytocidal activity against Plasmodium cynomolgi B when the drug is given by the intramuscular route, but it would be preferable to use oral route therapy for gametocyte carriers. This is a report of a study of the gametocytocidal action of arteether administered by the oral route. The results indicate high levels of activity at 10 mg/kg in a single dose or in two divided doses when given orally.
Assuntos
Antimaláricos/administração & dosagem , Artemisininas , Malária/tratamento farmacológico , Plasmodium cynomolgi/efeitos dos fármacos , Sesquiterpenos/administração & dosagem , Administração Oral , Animais , Anopheles , Modelos Animais de Doenças , Macaca mulatta , Malária/parasitologia , Plasmodium cynomolgi/crescimento & desenvolvimentoRESUMO
In vitro as well as in vivo studies suggest that cytokine-induced synthesis of nitric oxide (NO) from L-arginine is a major effector mechanism against intracellular pathogens. In this study, we demonstrate that golden hamsters infected with Leishmania donovani amastigotes upon treatment with polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly ICLC), a potent interferon inducer and immune enhancer, in combination with L-arginine, develop the capacity to eliminate intracellular pathogens. This antileishmanial activity of poly ICLC was suppressed by N w nitro-L-arginine (N w NLA), an inhibitor of inducible NO synthase. Furthermore, prolonged treatment of infected animals with L-arginine alone for 5 days more after 5 day treatment with poly ICLC plus L-arginine increased the antileishmanial activity compared with 5 day treatment with poly ICLC plus L-arginine, suggesting that inducible NO synthase, once activated, produces NO for 5 days more. Our results suggest that an L-arginine-dependent, NO-mediated mechanism is probably responsible for the antileishmanial action of poly ICLC.