Preparation and characterisation of Dextran-70 hydrogel for controlled release of praziquantel

A hydrogel was developed from 70 kDa dextran (DEX-70) and praziquantel (PZQ) incorporated as a model drug. Biopharmaceutical properties, such as solubility and dissolution rate, were analysed in the design of the hydrogel. Furthermore, the hydrogel was also characterized by IR spectroscopy and DSC. Tests of the swelling rate showed that the hydrogel swelled slowly, albeit faster than the rate for the free polymer. In dissolution tests, the hydrogel released the drug slowly and continuously. This slow release was similar to that observed in the swelling tests and resulted in controlled release of the drug. Thus, this dextran is a suitable polymer for the development of hydrogels as vehicles for the controlled release of drugs.

Um hidrogel foi desenvolvido a partir de dextrano 70 kDa (DEX-70) e praziquantel incorporado (PZQ) como fármaco modelo. Propriedades biofarmacêuticas, como solubilidade e velocidade de dissolução, foram analisadas no desenvolvimento do hidrogel. Além disso, o hidrogel também foi caracterizado por espectroscopia na região do infravermelho e calorimetria diferencial exploratória (DSC). Testes da taxa de intumescimento mostraram que o hidrogel intumesce lentamente, embora tenha sido mais rápido do que a taxa do polímero livre. Nos testes de dissolução, o hidrogel liberou o fármaco lenta e continuamente. Esta liberação lenta foi semelhante a observada nos testes de intumescimento e resultou em uma liberação controlada do fármaco. Assim, o dextrano 70 kDa é um polímero adequado para o desenvolvimento de hidrogéis como veículos para a liberação controlada de fármacos.

Pharmacodynamics of mefloquine and praziquantel combination therapy in mice harbouring juvenile and adult Schistosoma mansoni

Praziquantel (PZQ) is currently the only drug widely used for the treatment of schistosomiasis, but the antimalarial drug mefloquine (Mef) possesses interesting antischistosomal properties. Combination therapy with these two drugs has been suggested as a strategy for transmission control, as PZQ is active against adult worms and Mef is active against schistosomula. To examine the efficacy of combination therapy, Schistosoma mansoni-reinfected mice were separated into seven groups: untreated (I), treated with PZQ in doses of 200 mg/kg (II) or 1,000 mg/kg (III), treated with Mef in doses of 200 mg/kg (IV) or 400 mg/kg (V); each dose was divided equally and given on two consecutive days. Group VI was treated with doses of PZQ + Mef as in groups II and IV, respectively, while group VII was treated with PZQ + Mef as in groups III and V, respectively. PZQ + Mef at the reduced doses of 200 mg/kg each enhanced the therapeutic efficacy over the reduced PZQ dose alone as shown by a very high reduction in the total numbers of mature worms (95 percent vs. 49 percent), immature worms (96 percent vs. 29 percent) and the complete eradication of immature females, mature females and immature eggs. The reduction in worm burden was associated with the healing of hepatic granulomatous lesions and the normalisation of all liver enzymes. Therefore, the use of Mef with PZQ is more effective than PZQ alone and should be considered for clinical trials in humans as a potential treatment regimen to prevent treatment failures in areas with high rates of schistosomiasis.

Modulation of expression and activity of cytochrome P450s and alteration of praziquantel kinetics during murine schistosomiasis

In this study, we investigated the expression and activity of liver cytochrome P450s (CYPs) and praziquantel (PZQ) kinetics in mice infected with Schistosoma mansoni. Swiss Webster (SW) mice of both genders were infected (100 cercariae) on postnatal day 10 and killed on post-infection days (PIDs) 30 or 55. Non-infected mice of the same age and sex served as controls. Regardless of mouse sex, infection depressed the activities of CYP1A [ethoxy/methoxy-resorufin-O-dealkylases (EROD/MROD)], 2B9/10 [pentoxy/benzyloxy-resorufin-O-dealkylases (PROD, BROD)], 2E1 [p-nitrophenol-hydroxylase (PNPH)] and 3A11 [erythromycin N-demethylase (END)] on PID 55 but not on PID 30. On PID 55, infection decreased liver CYP mRNA levels (real-time reverse transcription-polymerase chain reaction). On PID 30, whereas mRNA levels remained unaltered in males, they were depressed in females. Plasma PZQ (200 and 400 mg/kg body weight intraperitoneally) levels were measured (high-performance liquid chromatography) at different post-treatment intervals. In males and females, infection delayed the PZQ clearance on PID 55, but not on PID 30. Therefore, it can be concluded that schistosomiasis down-modulated CYP expression and activity and delayed PZQ clearance on PID 55, when a great number of parasite eggs were lodged in the liver. On PID 30, when egg-laying was initiated by the worms, no change of CYP expression and activity was found, except for a depression of CYP1A2 and 3A11 mRNAs in female mice.

short review of some pharmacological, therapeutic and toxicological properties of praziquantel in man and animals

Praziquantel is the current drug of choice against many trematodes and cestodes in both man and animals. This article summarizes the main pharmacological, therapeutic and toxicological properties of the drug, especially that have been reported during the last 10 years. In most cases, the effectiveness and safety of the drug have been confirmed, although there are currently concerns about the resistance/decreased effectiveness of the drug to certain Schistosome isolates, and also about the mutagenicity of the drug

Efecto in vitro de prazicuantel sobre la actividad de Giardia intestinalis / In vitro effects of praziquantel over the trophozoites of Giardia intestinalis

Se realizó un estudio in vitro para conocer el efecto farmacológico de prazicuantel sobre los trofozoítos de Giardia intestinalis cepa P-1. Después de cultivarlos axénicamente, con cinco diferentes concentraciones de prazicuantel (de 0.32 hasta 1.62 nM/mL) durante 24 h a 37ºC, la viabilidad y la CI50 evaluada por la captación de colorante fluorogénico con citometría de flujo mostró un desplazamiento logarítmico de 10º a 10 a la tercera lo que correspondió a una concentración de 1.28 nM/mL. La incorporación de H3 metil-timidina como parámetro de crecimiento celular a 50 por ciento alcanzó 1.20 nM/mL de prazicuantel y el efecto citotóxico calculado por la capacidad de lisar células CHO (células de ovario de hámster chino) marcados con Cr51 se observó para la CI50 en una concentración de 1.05 nM/mL. Con estos tres parámetros se puede inferir qué viabilidad a 50 por ciento se observó a concentraciones más altas de prazicuantel comparadas con la capacidad para dividirse, así como el efecto citolítico, en donde la concentraciones más altas de prazicuantel comparadas con la capacidad para dividirse, así como el efecto citolítico, en donde la concentración de prazicuantel fue la más baja a lo que se atribuye la cualidad de apagar radicales libres, sin embargo, esto no fue proporcional al incrementar la concentración suponiéndose una importante capacidad detoxificante en Giardia. Se concluye que prazicuantel desarrolló actividad farmacológica en protozoarios, lo que le hace susceptible de emplearse contra la giardiasis

Plasma concentrations of praziquantel during the therapy of neurocysticerosis with praziquantel, in the presence of antiepileptics and dexamethasone.

Plasma praziquantel concentrations were measured in 11 Thai patients with active neurocysticercosis (8 males and 3 females). Praziquantel (Biltricide 600 mg per tablet) was given at a daily dose of 45 mg/kg given in 3 divided doses for 15 consecutive days. All patients had significant improvement with resolution of symptoms and signs, and reduction of active lesions of cysticercosis shown by the brain computed tomographic scanning. After oral administration, the drug was rapidly absorbed from the gastrointestinal tract. There was substantial inter-individual variability in plasma concentrations of praziquantel. After the first dose, maximum plasma concentrations in the range of 42-540 ng/ml was attained at 30 minutes to 5 hours. In all cases, the drug almost totally disappeared from plasma within 8 hours; drug levels measured prior to the first doses on the following days showed undetectable levels. The area under the plasma concentration-time curves of praziquantel following the first dose were between 125 and 990 ng hour/ml. The results suggested that the unusual low plasma availability of the drug observed in this group of patients could be a consequence of pharmacokinetic drug interactions of the concomitant therapy with antiepileptic drugs and dexamethasone. Active metabolite(s), rather than praziquantel itself, may play a significant part in the therapy of neurocysticerosis.

Pharmacokinetics of praziquantel in patients with opisthorchiasis.

The pharmacokinetics of praziquantel was investigated in 9 Thai male patients with asymptomatic opisthorchiasis (stool positive) and 9 patients (6 males, 3 females) with moderately advanced infection (hepatomegaly). The geometric means of the pretreatment Opisthorchis viverrini egg count in these patients were 2,950 vs 4,468 eggs per gram of stool. The results indicate the impairment of metabolism of praziquantel in the moderately advanced stage opisthorchiasis. The pharmacokinetics of the drug in these patients during the acute infection was markedly altered when compared with that after recovery and in patients with early stage of the infection. The clearance rate (Cl/f) was significantly reduced [medians and ranges of 106 (43-242) vs 192 (112-692) and 171 (133-427) ml/min/kg] and the t1/2z and MRT were prolonged [t1/2z: 3.8 (2.0-6.2) vs 2.7 (1.7-4.3) and 2.3 (1.7-2.8) hours; MRT: 6.2 (3.2-11.0) vs 4.6 (2.7-6.2) and 4.5 (2.9-5.1) hours]. In addition, AUCo-alpha was significantly greater [6.0 (2.5-15.6) vs 3.5 (0.6-6.0) and 3.9 (1.6-5.0) micrograms hour/ml].

Farmacología de praziquantel / Pharmacology of the praziquantel

Praziquantel es un nuevo fármaco, eficaz contra un amplio espectro de cestodes y trematodes parásitos del hombre. Es una droga con una biodisponibilidad oral elevada, se distribuye ampliamente, es intensamente metabolizado en el hígado (metabolismo de primer paso) y se excreta fundamentalmente por el riñon (metabolitos). Su T1/2 es corta y no se acumula. No produce efectos farmacodinámicos en el hombre. Los estudios para mutagenecidad, carcinogénesis y teratogenicidad han sido negativos. La baja incidencia de efectos secundarios menores no limitan su uso terapéutico