Preparation and in vitro evaluation of suppositories of halofantrine hydrochloride

Halofantrine (HF) hydrochloride is commercially available only as oral dosage forms. Limitations of oral dosing of the drug coupled with non-availability of the safe parenteral preparations prompted the needto develop and evaluate suppository HF formulations, which may serve as a practical alternative. The effects of type of suppository base and incorporation of non ionic surfactants on in vitro release characteristics of HF from suppositories were investigated. The release rates were determined using a modification of the continuous flow bead-bed dissolution apparatus for suppositories. The resultsshowed that the drug release from water-soluble base (polyethylene glycol) was significantly greater than that from lipophilic bases (Shea butter and Witepsol H15) (

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

Chemotherapeutic action between Khaya grandifoliola (WELW) CDC steam bark extract and two anti-malarial drugs in mice

In malarial endemic countries especially in the tropics, conventional antimalarial drugs are used with herbal remedies either concurrently or successively. Khaya grandifoliola is one of such popular herbs used in the treatment of malaria. Various doses of ethanol extract of K. grandifoliola stem bark (50-400 mg/kg/day) were administered orally to Swiss albino mice infected with Plasmodium yoelii nigerense. A dose of 100 mg/kg/day of the extract was also combined with 2.5 mg/kg/day of chloroquine or 6.25 mg/kg/day of halofantrine in both early and established malaria infection test models. The results showed that in the early malaria infection test, K. grandifoliola in combination with chloroquine or halofantrine elicited enhanced antiplasmodial effect in the established infection, there was significantly greater parasite clearance following administration of the combination when compared to the effects of K. grandifoliola or the conventional drugs alone. The mean survival period of parasitized animals was also enhanced by the extract/halofantrine combination. Lower therapeutic doses of halofantrine may be required to potentiate parasite clearance when used in combination with K. grandifoliola. This may constitute great advantage to halofantrine which is associated with cardiotoxicity at high doses.Key words: Khaya grandifoliola, Antimalarial, Chemotherapeutic interaction, Chloroquine, Halofantrin

Pharmacokinetic changes of halofantrine in experimentally-induced diabetes mellitus following oral drug administration

It was hypothesized in this study that alterations in plasma lipoprotein profile and disturbed gastrointestinal motility as observed in diabetes mellitus may influence the disposition of halofantrine (HF), a highly lipophilic antimalarial drug. Therefore, using a rat model of diabetes mellitus induced by administration of alloxan monohydrate, the effects of the disease on the pharmacokinetics of HF was investigated. Also, the drug binding to normal and diabetic plasma components was determined. Results showed that the mean Cmax values of HF and its major metabolite, desbutylhalofantrine (DHF), were markedly higher (up to 2.5 times) in the control than in diabetic rats (p 0.05). The binding of HF and DHF in diabetic plasma was significantly higher when compared to control (p < 0.05) and correlated well with increased triglycerides concentrations. Elevated plasma drug levels expected in diabetes due to observed marked increase in drug binding to plasma components appear to be counterbalanced by otherpharmacokinetic-modulating processes induced by the disease. It is suggested that the significantly reduced Cmax of the drug and its metabolite in diabetes may have clinical implications since the clinicalefficacy of HF is influenced by its peak plasma concentrations

Optimizing the programmatic deployment of the anti-malarials artemether-lumefantrine and dihydroartemisinin-piperaquine using pharmacological modelling

Background: Successful programmatic use of anti-malarials faces challenges that are not covered by standard drug development processes. The development of appropriate pragmatic dosing regimens for low-resource settings or community-based use is not formally regulated, even though these may alter factors which can substantially affect individual patient and population level outcome, such as drug exposure, patient adherence and the spread of drug resistance and can affect a drug’s reputation and its eventual therapeutic lifespan. Methods: An in silico pharmacological model of anti-malarial drug treatment with the pharmacokinetic/ pharmacodynamic profiles of artemether-lumefantrine (AM-LF, Coartem®) and dihydroartemisinin-piperaquine (DHA-PPQ, Eurartesim®) was constructed to assess the potential impact of programmatic factors, including regionally optimized, age-based dosing regimens, poor patient adherence, food effects and drug resistance on treatment outcome at population level, and compared both drugs’ susceptibility to these factors. Results: Compared with DHA-PPQ, therapeutic effectiveness of AM-LF seems more robust to factors affecting drug exposure, such as age- instead of weight-based dosing or poor adherence. The model highlights the sub-optimally low ratio of DHA:PPQ which, in combination with the narrow therapeutic dose range of PPQ compared to DHA that drives the weight or age cut-offs, leaves DHA at a high risk of under-dosing. Conclusion: Pharmacological modelling of real-life scenarios can provide valuable supportive data and highlight modifiable determinants of therapeutic effectiveness that can help optimize the deployment of anti-malarials in control programmes

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data

Background Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. Methods and findings We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (−61.77 milliseconds; 95% credible interval [CI]: −80.71 to −42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (−110.89 milliseconds; 95% CI: −140.38 to −81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: −3.17 to −2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. Conclusions Adjustment for malaria and fever-recovery–related QT lengthening is necessary to avoid misattributing malaria-disease–related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval–prolonging medications are important therapeutic options