Effects of Surface Characteristics of Polymeric Nanocapsules on the Pharmacokinetics and Efficacy of Antimalarial Quinine.

INTRODUCTION: The surface charge of nanoparticles, such as nanospheres (NS) and nanocapsules (NC), has been studied with the purpose of improving the in vivo performance of drugs. The aim of this study was to develop, characterize, and evaluate the in vitro antimalarial efficacy of NCP80 and NSP80 (polysorbate coated) or NCEUD and NSEUD (prepared with Eudragit RS 100) loading quinine (QN). METHODS: Formulations were prepared by the nanoprecipitation method, followed by wide physicochemical characterization. Antimalarial activity in Plasmodium berghei-infected mice and populational pharmacokinetics (PopPK) in rats were evaluated. RESULTS: The formulations showed a nanometric range (between 138 ± 3.8 to 201 ± 23.0 nm), zeta potential (mV) of -33.1 ± 0.7 (NCP80), -30.5 ± 1 (UNCP80), -25.5 ± 1 (NSP80), -20 ± 0.3 (UNSP80), 4.61 ± 1 (NCEUD), 14.1 ± 0.9 (UNCEUD), 2.86 ± 0.3 (NSEUD) and 2.84 ± 0.6 (UNSEUD), content close to 100%, and good QN protection against UVA light. There was a twofold increase in the penetration of QN into infected erythrocytes with NC compared to that with NS. There was a significant increase in t1/2 for all NC evaluated compared to that of Free-QN, due to changes in Vdss. PopPK analysis showed that NCP80 acted as a covariate to Q (intercompartmental clearance) and V2 (volume of distribution in the peripheral compartment). For NCEUD, V1 and Q were modified after QN nanoencapsulation. Regarding in vivo efficacy, NCEUD increased the survival of mice unlike Free-QN. CONCLUSION: Cationic nanocapsules modified the pharmacology of QN, presenting a potential alternative for malaria treatment.

Nanoencapsulation increases quinine antimalarial efficacy against Plasmodium berghei in vivo.

The aims of this work were to develop quinine (QN)-loaded nanocapsules, to evaluate their efficacy in vivo and to determine their pharmacokinetics and erythrocyte partition coefficient. Plasmodium berghei-infected Wistar rats were used to evaluate the efficacy of QN-loaded nanocapsules using different dosing regimens. Pharmacokinetics was evaluated after intravenous administration of free or nanoencapsulated QN (25 mg/kg) to infected rats. The QN partition coefficient into P. berghei-infected erythrocytes was evaluated. QN-loaded nanocapsules presented an adequate particle size (176 nm), narrow particle distribution (0.19), negative zeta potential (-18 mV) and high drug content and encapsulation efficiency. Intravenous administration of QN-loaded nanocapsules at 75 mg/kg/day to infected rats resulted in 100% survival, representing an almost 30% reduction compared with the free QN effective dose (105 mg/kg/day). The pharmacokinetic parameters of nanoencapsulated QN were not significantly different from those determined for free drug (alpha=0.05). The QN partition coefficient into infected erythrocytes doubled (6.25+/-0.25) when the drug was nanoencapsulated compared with the free drug (3.03+/-0.07). Therefore, nanoencapsulation increased the interaction between QN and the erythrocyte and this mechanism is responsible for the drug's increased efficacy when nanoencapsulated.

Plasmodium falciparum in vivo resistance to quinine: description of two RIII responses in French Guiana.

The resistance of Plasmodium falciparum to antimalarial drugs is one of the most worrisome problems in tropical medicine, but few clinical studies or observations have described confirmed cases of therapeutic failure. We report two cases of in vivo P. falciparum resistance (RIII response) to quinine in French Guiana, an Amazonian focal zone in which multi-resistant malaria is endemic. Both patients presented with uncomplicated malaria and were initially treated with intravenous quinine. Although absorption was normal, the treatment was not effective and the patients still had fever and significant parasitemia three days after the onset of treatment (day 3). The addition of intravenous tetracycline completely resolved the parasitemia within approximately 96 hours. These clinical reports confirm the necessity to combine quinine with tetracycline in this area, as recommended by the recent French regional antimalarial policy.

Tratamento da malária por Plasmodium falciparum com cloroquina e quinina: estudo da cardiotoxidade e resposta terapêutica / Treatment of malaria by Plasmodium falciparum wuth chloroquine or quinine: study of yours cardiotoxicity

Em 109 pacientes com malária por Plasmodium falciparum, 63 tratados com cloroquina (50 a 90 mg/kg peso, em 3 a 6 dias) e 46 com quinina (1,5 g/dia, durante 7 dias), foram estudadas a cardiotoxicidade e resposta terapêutica dessas drogas. A avaliaçåo da cardiotoxicidade baseou-se em achados clínicos, evoluçåo eletrocardiográfica e determinaçåo dos níveis enzimáticos (transaminase glutâmico-oxalacética e creatinafosfotransferase) antes, durante e após o tratamento. Quanto à cloroquina, a cardiotoxicidade manifestou-se principalmente sobre os mecanismos da repolarizaçåo ventricular (42,8 pôr cento), embora tenha ocorrido, com muito menor freqüencia, depressåo da excitabilidade (4,7 pôr cento), retardo na conduçåo do estímulo elétrico (14,2 pôr cento), arritmia supraventricular (1,6 pôr cento) e queda da pressåo arterial (3,2 pôr cento. Em relaçåo à quinina a depressåo da excitabilidade (bradicardia) foi a manifestaçåo mais significativa (34,7 pôr cento); foram também detectadas alteraçöes da repolarizaçåo ventricular (15,2 pôr cento), retardo na conduçåo do estímulo elétrico (19,5 pôr cento) e queda da pressåo arterial (21,7 pôr cento). No tocante à resposta terapêutica, nåo houve resistência a nível de RII e RIII, segundo os padröes da Organizaçåo Mundial da Saúde, com quaisquer das drogas. A cloroquina apresentou 15,0 pôr cento de resistência (RI) e a quinina 2,4 pôr cento. Ambas as drogas mostraram-se eficazes para o tratamento da doença, sobretudo nas formas graves, nåo tendo havido diferença importante em relaçåo à resposta clínica, apesar da açåo esquizonticida da cloroquina ter se mostrado discretamente mais rápida que a da quinina