Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-group Prospective Cohort Study in two sub-Saharan Africa Populations.

We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations. ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done. Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART. We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations

Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso ( CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [ 95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa

Liver Enzyme Abnormalities and Associated Risk Factors in HIV Patients on Efavirenz-Based HAART with or without Tuberculosis Co-Infection in Tanzania.

To investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection. A total of 473 treatment naïve HIV patients (253 HIV only and 220 with HIV-TB co-infection) were enrolled prospectively. Plasma efavirenz concentration and CYP2B6*6, CYP3A5*3, *6 and *7, ABCB1 3435C/T and SLCO1B1 genotypes were determined. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of antiretroviral therapy. DILI case definition was according to Council for International Organizations of Medical Sciences (CIOMS). Incidence of DILI and identification of predictors was evaluated using Cox Proportional Hazards Model. The overall incidence of DILI was 7.8% (8.3 per 1000 person-week), being non-significantly higher among patients receiving concomitant anti-TB and HAART (10.0%, 10.7 per 1000 person-week) than those receiving HAART alone (5.9%, 6.3 per 1000 person-week). Frequency of CYP2B6*6 allele (p = 0.03) and CYP2B6*6/*6 genotype (p = 0.06) was significantly higher in patients with DILI than those without. Multivariate cox regression model indicated that CYP2B6*6/*6 genotype and anti-HCV IgG antibody positive as significant predictors of DILI. Median time to DILI was 2 weeks after HAART initiation and no DILI onset was observed after 12 weeks. No severe DILI was seen and the gain in CD4 was similar in patients with or without DILI. Antiretroviral and anti-tuberculosis DILI does occur in our setting, presenting early following HAART initiation. DILI seen is mild, transient and may not require treatment interruption. There is good tolerance to HAART and anti-TB with similar immunological outcomes. Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians

Policiklični aromatski ugljovodonici u sredstvima za zaštitu drveta na bazi uglja i nafte

Five commercial coal tar oils (DB, B, GX, PO, MA) and an oil sample derived from petroleum (RPO) were investigated in this work. The contents of benzo[a]pyrene (B[a]P) and 13 other polycyclic aromatic compounds (PACs) were determined. According to today's legislation RPO, DB, B, and GX containing less than 500 mg/Kg B[a]P may be used as wood preservatives for railway sleepers and wood poles. By law it is prohibited to apply PO and MA for wood treatments in EU countries at all. The B[a]P content of creosotes and other aromatic oils could be decreased through distillation, but in that case the concentration of other PACs with lower boiling points and similar or even higher relative cancerogenic potencies compared to B[a]P could remain unchanged. For instance, RPO contains more B[a]P than DB, B, and GX, but reveals the lowest value of total B[a]P equivalents compared to other coal tar oils. Therefore, determination of total B[a]P equivalents, i. e. cancerogenic PACs in a given oil sample is much safer than that of B[a]P solely, as it has been regulated by legislation so far.U ovom radu ispitivano je pet trgovačkih uzoraka ulja dobivenih iz katrana uglja (kreozotna ulja) (DB, B, GX, PO, MA) i jedan uzorak ulja dobiven iz nafte (RPO). Određeni su, pri tome, sadržaji benzo[a]pirena (B[a]P) i 13 drugih policikličnih aromatskih ugljovodonika (PACs). U skladu sa današnjim zakonima Evropske Unije uzorci RPO, DB, B i GX, koji su sadržali manje od 500 mg/Kg B[a]P smeju se koristiti kao sredstva za zaštitu drvenih željezničkih pragova i telegrafskih i električnih stubova. Zakon Evropske Unije zabranjuje upotrebu PO i MA za zaštitu drveta u svim slučajevima. Prema tome zakonu ukoliko sredstvo za zaštitu drveta sadrži manje od 50 mg/Kg B[a]P ono se srne koristiti u svim slučajevima kada se impregnisano drvo upotrebljava u industrijske svrhe van zatvorenih prostora, odnosno ne samo za pragove i stubove (B[a]P). Koncentracija B[a]P u kreozotnim i drugim aromatskim uljima može se smanjiti pomoću destilacije. U tom slučaju, međutim, koncentracija PACs koji imaju niže tačke ključanja, a slične ili čak veće relativne kancerogene potencije, mogu ostati nepromenjene. Na primer, RPO sadrži više B[a]P od DB, B i GX, ali ima najmanji zbir ukupnih B[a]P ekvivalenata. Zato današnje zakonsko ograničenje samo sadržaja B[a]P u kreozotnim i drugim aromatskim uljima može dovesti do pogrešnih procena njihove karcenogene potencije. Saglasno ovom radu mnogo je sigurnije koristiti zbir B[a]P ekvivalenata dobivenih množenjem sadržaja svakog kancerogenog PAG sa njegovom relativnom kancerogenom potencijom. Ovo tim pre, pošto posle jednom učinjene kalibracije sa smešom PACs poznatog sastava, praktično nema dodatnog eksperimentalnog rada u određivanju zbira B[a]P ekvivalenata u poređenju sa određivanjem sadržaja B[a]R Na osnovu rezultata ovoga rada RPO, tj. uzorak ulja dobiven iz nafte, može se smatrati uspešnom zamenom za ulja dobivena iz katrana uglja, tj. kreozotnih ulja

Comparative bioavailability of the microemulsion formulation of cyclosporine (Neoral) with a generic dispersion formulation (Cicloral) in young healthy male volunteers

The aim of this study was to compare the bioavailability of cyclosporine (CyA) from the generic dispersion formulation Cicloral (CIC) with the microemulsion formulation Neoral (NEO) and the original Sandimmune (SIM) capsules after single doses of 100, 300, or 600 mg of drug, respectively. The study was performed according to an open 3-period cross-over design with 12 young healthy male volunteers for each dosage. The concentrations of CyA and its main metabolites were determined by high performance liquid chromatography in whole blood and urine up to 48 hours postdosing. Peak concentrations and area under the time-concentration curve were greater for the NEO and CIC formulations compared with SIM, and the mean bioavailability of CIC was significantly (P<0.05) lower compared with NEO. The bioavailability of SIM compared with NEO was 54% to 71%, in agreement with previous results. Bioequivalence was not demonstrated between CIC (test) and NEO (reference) as the 90% confidence intervals were outside the 80% to 125% guidelines based on log-transformed AUCs, and were 75.2% to 87.7% at 100 mg, 79.2% to 91.8% at 300 mg, and 76.6% to 94.5% at 600 mg doses. The respective values for Cmax were 78.9% to 94.6%, 80.7% to 95.0%, and 71.4% to 84.1%. A good correlation was demonstrated between the urinary recovery of CyA and the AUC4. Therefore, the urinary recovery of CyA may be helpful as a surrogate parameter for the systemic exposure of patients to CyA. Whereas the relative amount of hydroxylated metabolites (AM1, AM9, AM1c) was similar for all formulations and doses, the urinary recovery of the N-demethylated metabolite AM4N decreased with increasing dose indicating saturable metabolism. No relationship could be demonstrated between CYP3A activity using dextromethorphan as a probe for the metabolic clearance of CyA

Description of demographic and baseline laboratory characteristics of patients with and without DILI.

<p>Description of demographic and baseline laboratory characteristics of patients with and without DILI.</p

Univariate and Multivariate Cox proportional regression analysis to show the risk factors for developing DILI.

<p>Univariate and Multivariate Cox proportional regression analysis to show the risk factors for developing DILI.</p

Kaplan-Meier curves indicating estimate cumulative hazard for the development of drug induced liver injury between the different CYP2B6*6 genotypes in patients receiving efavirenz based HAART with or without rifampicin based anti-TB therapy during the first three months of follow up period.

<p>Kaplan-Meier curves indicating estimate cumulative hazard for the development of drug induced liver injury between the different CYP2B6*6 genotypes in patients receiving efavirenz based HAART with or without rifampicin based anti-TB therapy during the first three months of follow up period.</p