Mefloquine loaded niosomes as a promising approach for the treatment of acute and chronic toxoplasmosis.

Toxoplasmosis is a disease with a worldwide distribution and significant morbidity and mortality. In search of effective treatment, mefloquine (MQ) was repurposed and loaded with niosomes to treat acute and chronic phases of toxoplasmosis in experimental mice. Mice were orally inoculated with 20 cysts of Toxoplasma gondii (ME 49 strain) for the acute model of infection and 10 cysts for the chronic model of infection. Infected mice were dosed with MQ solution or MQ-niosomes at 50 mg/kg/day, starting from the second day post-infection (PI) (acute model) or the fifth week PI (chronic model), and this was continued for six consecutive days. The effects of MQ solution and MQ-niosomes were compared with a pyrimethamine/sulfadiazine (PYR/SDZ) dosing combination as mortality rates, brain cyst number, inflammatory score, and immunohistochemical studies that included an estimation of apoptotic cells (TUNEL assays). In the acute infection model, MQ solution and MQ-niosomes significantly reduced the mortality rate from 45% to 25 and 10%, respectively, compared with infected untreated controls, and decreased the number of brain cysts by 51.5% and 66.9%, respectively. In the chronic infection model, cyst reduction reached 80.9% and 12.3% for MQ solution and MQ-niosomes treatments, respectively. MQ-niosomes significantly decreased inflammation induced by acute or chronic T. gondii infection. Additionally, immunohistochemical analysis revealed that MQ solution and MQ-niosomes significantly increased the number of TUNEL-positive cells in brain tissue, indicative of induction of apoptosis. Collectively, these results indicate that MQ-niosomes may provide a useful delivery strategy to treat both acute and chronic toxoplasmosis.

A new effective antiplasmodial compound: Nanoformulated pyrimethamine.

OBJECTIVES: The aim of this study was to evaluate the efficacy of pyrimethamine-loaded poloxamer 407 nanomicelles on Plasmodium berghei strain NICD in vivo. METHODS: Pyrimethamine-loaded nanomicelles were prepared and their zeta potential, particle size and polydispersity index were measured. For antiplasmodial assessment, 54 mice were randomly divided into six groups. Four groups were infected intraperitoneally with P. berghei, whereas the two remaining groups did not receive the parasite (negative controls). Three of the P. berghei-infected groups received treatment with either pyrimethamine-loaded nanomicelles (2 mg/kg), pyrimethamine (2 mg/kg) or empty nanomicelles (2 mg/kg); the fourth group remained untreated (positive control). The parasitaemia rate, survival rate and histopathological changes in the liver, spleen and kidneys were examined and were compared with the negative and positive control groups. RESULTS: The mean parasitaemia rate differed significantly between the nanoformulated pyrimethamine group and each of the other groups (P<0.05). Moreover, the survival rate of mice in the nanoformulated pyrimethamine group (7/9; 78%) was significantly higher compared with each of the other groups (P<0.01). The main histopathological changes, including hepatic necrosis in the liver, lymphoid hypoplasia in the spleen, and tubular nephrosis and perivascular and interstitial lymphocytic infiltration in the kidneys, were considerably lower in the nanoformulated pyrimethamine group than in the pyrimethamine and positive control groups. CONCLUSION: Pyrimethamine-loaded nanomicelles showed potent antimalarial activity and can be considered as a potential candidate for further examination of their suitability as an antimalarial drug.

Antimalarial drugs and reduced incidence of dental plaque.

Known antimalarial compunds from several chemical classes were tested for their ability to inhibit in vitro growth of microorganisms causing dental plaque and to prevent the development of plaque in a hamster model. Approximately a third of the compounds tested inhibited in vitro growth; however, none prevented development of plaque.

Synergism of cimetidine with anti-malarial agents.

The histamine type-2 receptor antagonist and cytochrome P450 inhibitor cimetidine was examined for its antimalarial properties in the presence or absence of chloroquine or pyrimethamine. When used alone, cimetidine displayed little activity against a number of Plasmodium falciparum clones in vitro, with an IC50 of 300-700 microM. The compound was found to be highly synergistic in combination with chloroquine and also displayed a degree of synergism when used in combination with pyrimethamine. These synergistic effects were independent of the chloroquine- or pyrimethamine-resistance status of the clones. The cytochrome P450 inhibitor proadifen displayed weak synergism or antagonism with chloroquine, depending on the clone tested, and clear antagonism with pyrimethamine. The results with proadifen indicate that cimetidine was exerting its synergistic activity via a mechanism distinct from inhibition of cytochrome P450. Additional experiments have demonstrated that cimetidine interferes with neither plasmodial sterol metabolism nor heme polymerization.