Physicochemical characterization and dissolution properties of binary systems of pyrimethamine and 2- hydroxypropyl-&#946-cyclodextrin

Pyrimethamine (PYR), a drug effective against protozoan parasites, such as Toxoplasma gondii and Plasmodium falciparum, is poorly water soluble and exhibits marked variation in oral bioavailability. Thisstudy was aimed at investigating the possibility and extent of enhancement of the dissolution properties of PYR via complexation with 2-hydroxypropyl--cyclodextrin (HP--CD) as well ascharacterization of the complex formation of the drug with the cyclodextrin. The interaction between PYR and HP--CD in solution was studied by phase solubility analysis while binary systems of thecompounds at 1:1 molar ratios were prepared by using the physical mixture, kneading, co-evaporation and freeze-drying methods. The binary systems were characterized using differential scanningcalorimetry (DSC), powder x-ray diffractometry (PXRD) and Fourier transform infrared (FT-IR) spectroscopy. Phase solubility studies revealed an AL-type diagram indicating a 1:1 stoichiometricinclusion complex and a stability constant value of 914 M-1. Solubility and dissolution rates of PYR and the binary systems were determined and found to be markedly enhanced by cyclodextrin complexation.The extent of enhancement of dissolution properties was dependent on the preparation method of the complex, and the product prepared by the freeze-drying method was shown to have the most superiordissolution efficiency than the other binary systems. The PXRD patterns and DSC curves especially for the co-evaporated and freeze-dried systems indicated strong drug amorphization and/or inclusion of PYR in the CD cavities. The results of this study suggest that the complexation of PYR with HP--CD could reduce variability in the drug absorption and improve therapeutic efficacy of the drug throughincreased drug dissolution efficiency

Imported Plasmodium falciparum malaria in HIV-infected patients: a report of two cases

As HIV becomes a chronic infection, an increasing number of HIV-infected patients are travelling to malaria-endemic areas. Association of malaria with HIV/AIDS can be clinically severe. Severe falciparum malaria is a medical emergency that is associated with a high mortality, even when treated in an Intensive Care Unit. This article describes two cases of HIV-positive patients, who returned from malaria-endemic areas and presented a parasitaemia > 5% of erythrocytes and clinical signs of severe falciparum malaria, both with > 350 CD4 cell count/μl, absence of chemoprophylaxis and successful response. Factors like drug interactions and the possible implication of anti-malarial therapy bioavailability are all especially interesting in HIV-malaria co-infections

The Frequency of Malaria Is Similar among Women Receiving either Lopinavir/Ritonavir or Nevirapine-based Antiretroviral Treatment

HIV protease inhibitors (PIs) show antimalarial activity in vitro and in animals. Whether this translates into a clinical benefit in HIV-infected patients residing in malaria-endemic regions is unknown. We studied the incidence of malaria, as defined by blood smear positivity or a positive Plasmodium falciparum histidine-rich protein 2 antigen test, among 444 HIV-infected women initiating antiretroviral treatment (ART) in the OCTANE trial (A5208; ClinicalTrials.gov: NCT00089505). Participants were randomized to treatment with PI-containing vs. PI-sparing ART, and were followed prospectively for ≥48 weeks; 73% also received cotrimoxazole prophylaxis. PI-containing treatment was not associated with protection against malaria in this study population

Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria

Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance

CYP2B6*6 genotype specific differences in artemether‐lumefantrine disposition in healthy volunteers

Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of the antimalarial drugs artemether and lumefantrine. Here we investigated the effect of&nbsp;CYP2B6*6 on the plasma pharmacokinetics of artemether, lumefantrine, and their metabolites in healthy volunteers. Thirty healthy and previously genotyped adult volunteers&mdash;15 noncarriers (CYP2B6*1/*1) and 15 homozygote carriers (CYP2B6*6/*6)&mdash;selected from a cohort of 150 subjects from the Ilorin metropolitan area were administered the complete 3‐day course of artemether and lumefantrine (80 and 480 mg twice daily, respectively). Intensive pharmacokinetic sampling was conducted at different time points before and after the last dose. Plasma concentrations of artemether, lumefantrine, dihydroartemisinin, and desbutyllumefantrine were quantified using validated liquid chromatography&ndash;mass spectrometric methods. Pharmacokinetic parameters were evaluated using noncompartmental analysis. Artemether clearance of&nbsp;CYP2B6*6/*6&nbsp;volunteers was nonsignificantly lower by 26% (ratios of geometric mean [90% CI]; 0.74 [0.52‐1.05]), and total exposure (the area under the plasma concentration‐time curve from time 0 to infinity [AUC0‐&infin;]) was greater by 35% (1.35 [0.95‐1.93]) when compared with those of&nbsp;*1/*1&nbsp;volunteers. Similarly, assuming complete bioconversion from artemether, the dihydroartemisinin AUC0‐&infin;&nbsp;was 22% lower. On the contrary, artemether‐to‐dihydroartemisinin AUC0‐&infin;&nbsp;ratio was 73% significantly higher (1.73 [1.27‐2.37]). Comparison of lumefantrine exposure and lumefantrine‐to‐desbutyllumefantrine metabolic ratio of&nbsp;*6/*6&nbsp;with corresponding data from&nbsp;*1/*1&nbsp;volunteers showed no differences. The increased artemether‐to‐dihydroartemisinin metabolic ratio of&nbsp;*6/*6&nbsp;volunteers is unlikely to result in differences in artemether‐lumefantrine efficacy and treatment outcomes. This is the first study in humans to associate&nbsp;CYP2B6*6&nbsp;genotype with artemether disposition.</p

Differential impact of nevirapine on artemether-lumefantrine pharmacokinetics in individuals stratified by CYP2B6 c.516G>T genotypes

There is an increased recognition of the need to identify and quantify the impact of genetic polymorphisms on drug-drug interactions. This study investigated the pharmacogenetics of the pharmacokinetic drug-drug interaction between nevirapine and artemether-lumefantrine in HIV-positive and HIV-negative adult Nigerian subjects. Thirty each of HIV-infected patients on nevirapine-based antiretroviral therapy and HIV-negative volunteers without clinical malaria, but with predetermined CYP2B6 c.516GG and TT genotypes, were administered a complete treatment dose of 3 days of artemether-lumefantrine. Rich pharmacokinetic sampling prior to and following the last dose was conducted, and the plasma concentrations of artemether/dihydroartemisinin and lumefantrine/desbutyl-lumefantrine were quantified using tandem mass spectrometry. Pharmacokinetic parameters of artemether-lumefantrine and its metabolites in HIV-infected patients on nevirapine were compared to those in the absence of nevirapine in HIV-negative volunteers. Overall, nevirapine reduced exposure to artemether and desbutyl-lumefantrine by 39 and 34%, respectively. These reductions were significantly greater in GG versus TT subjects for artemether (ratio of geometric mean [90% confidence interval]: 0.42 [0.29 to 0.61] versus 0.81 [0.51 to 1.28]) and for desbutyl-lumefantrine (0.56 [0.43 to 0.74] versus 0.75 [0.56 to 1.00]). On the contrary, it increased exposure to dihydroartemisinin and lumefantrine by 47 and 30%, respectively. These increases were significantly higher in TT versus GG subjects for dihydroartemisinin (1.67 [1.20 to 2.34] versus 1.25 [0.88 to 1.78]) and for lumefantrine (1.51 [1.20 to 1.90] versus 1.08 [0.82 to 1.42]). This study underscores the importance of incorporating pharmacogenetics into all drug-drug interaction studies with potential for genetic polymorphisms to influence drug disposition