Comparative cardiac effects of antimalarial drug halofantrine with or without concomitant administration of kolanut or fluconazole in healthy volunteers.

Background: There is rekindled interest in the cardiotoxicity of antimalarial medicines. Halofantrine is associated with QT interval prolongation. Fluconazole and kolanut alter the pharmacokinetics of halofantrine. Objectives: The study assessed the electrocardiographic changes of concomitant administration of kolanut or fluconazole with halofantrine and the effects on the QTc interval. Methods: Eighteen healthy volunteers received a single oral dose of halofantrine, halofantrine with kolanut or halofantrine with fluconazole in a crossover study. Twelve lead electrocardiography (ECG) was performed to measure the PR and QT interval (QTc). Statistical analysis was with SPSS at 5% level of significance. Results: PR intervals were shortened by halofantrine alone and halofantrine with kolanut (169.29 28.67 to 165.29 28.007 and 172.73 29.843 to 163.00 18.336ms) but was prolonged by halofantrine with fluconazole (177.70 27.394 to 186.59 44.434ms). There was prolongation of QTc (384.76 21.727 to 394.12 21.525; 381.36 22.29 to 388.30 17.26 and 382.35 20.08 to 390.84 21.97) in all the three treatment groups at 6 hours, p>0.05. One subject on halofantrine and fluconazole had QTc >440ms. Pre-treatment PR interval (PR0) correlated well with post-treatment PR6, and with PR14 r= 0.519, p= 0.014; r=0.664, p=0.013. Conclusion: Concomitant intake of kolanut with halofantrine was significantly decrease cardiac effect of halofantrine.

Non-compartmental and population pharmacokinetic analysis of dapsone in healthy NIGERIANS: A pilot study.

Dapsone is employed for both non-dermatological and dermatological indications but with non-existent population pharmacokinetics (popPK) data in Nigerians. This study was therefore designed to develop a popPK model in Nigerians. Non-compartmental analysis and nonlinear mixed effects modelling were utilized for data analysis. Eleven participants administered 50 mg dapsone tablet were included in the analysis. Derived pharmacokinetic parameters were: Cmax = 1.16 ± 0.32 µg/mL, Tmax = 3.77 ± 2.40 h, and t1/2z = 30.23 ± 11.76 h. PopPK model parameter estimates with inter-individual variability were Tlag = 0.40 h (10.0%, fixed); ka = 1.78 h-1 (75.9%); V/F = 89.25 L (21.6%); and Cl/F = 1.32 Lh-1 (27.7%). Sex was significantly associated with Cl/F, and body weight with V/F. Best popPK model was one-compartment with lag time, and first-order absorption and elimination. Sex and body weight significantly influenced the clearance and distribution volume of dapsone respectively.

Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli.

BACKGROUND: Enteroaggregative Escherichia coli (EAEC) is a predominant but neglected enteric pathogen implicated in infantile diarrhoea and nutrient malabsorption. There are no non-antibiotic approaches to dealing with persistent infection by these exceptional colonizers, which form copious biofilms. We screened the Medicines for Malaria Venture Pathogen Box for chemical entities that inhibit EAEC biofilm formation. METHODOLOGY: We used EAEC strains, 042 and MND005E in a medium-throughput crystal violet-based antibiofilm screen. Hits were confirmed in concentration-dependence, growth kinetic and time course assays and activity spectra were determined against a panel of 25 other EAEC strains. Antibiofilm activity against isogenic EAEC mutants, molecular docking simulations and comparative genomic analysis were used to identify the mechanism of action of one hit. PRINCIPAL FINDINGS: In all, five compounds (1.25%) reproducibly inhibited biofilm accumulation by at least one strain by 30-85% while inhibiting growth by under 10%. Hits exhibited potent antibiofilm activity at concentrations at least 10-fold lower than those reported for nitazoxanide, the only known EAEC biofilm inhibitor. Reflective of known EAEC heterogeneity, only one hit was active against both screen isolates, but three hits showed broad antibiofilm activity against a larger panel of strains. Mechanism of action studies point to the EAEC anti-aggregation protein (Aap), dispersin, as the target of compound MMV687800. CONCLUSIONS: This study identified five compounds, not previously described as anti-adhesins or Gram-negative antibacterials, with significant EAEC antibiofilm activity. Molecule, MMV687800 targets the EAEC Aap. In vitro small-molecule inhibition of EAEC colonization opens a way to new therapeutic approaches against EAEC infection.

Comparison of efavirenz levels in blood and hair with pharmacy refills as measures of adherence and predictors of viral suppression among people living with HIV in Nigeria.

BACKGROUND: Strategies to support adherence are constrained by the lack of tools to objectively monitor medication intake in low-resource settings. Pharmacologic measures are objective, but pharmacy refill data is more accessible and cost-efficient. This study compared short-term and long-term efavirenz (EFV) drug levels with pharmacy refill adherence data (PRA) and evaluated their ability to predict viral suppression among people living with HIV in Nigeria. METHODS: Paired hair and dried blood spot (DBS) samples were obtained from 91 adults living with HIV receiving 600 mg EFV-based antiretroviral therapy (ART) and EFV concentrations were measured via validated methods using liquid-chromatography-mass-spectrometry. PRA was estimated from pharmacy records, based on the number of days a patient collected medication before or after the scheduled pick-up date. PRA was categorized into ≤ 74%, 75-94% and ≥ 95%, defined as poor, medium and high adherence, respectively. HIV viral loads closest to the hair sampling time (within 6 months) were also abstracted. Receiver Operating Characteristics (ROC) curve analyses compared the ability of adherence metrics to predict viral suppression. RESULTS: Based on PRA, 81% of participants had high adherence while 11% and 8% had medium and poor adherence, respectively. The median (IQR) EFV concentrations were 6.85 ng/mg (4.56-10.93) for hair and 1495.6 ng/ml (1050.7-2365.8) for DBS. Of the three measures of adherence, hair EFV concentration had the highest Area Under Curve (AUC) to predict viral suppression. Correlations between EFV concentrations in DBS and hair with PRA were positive (r = 0.12, P = 0.27 and r = 0.21, P = 0.05, respectively) but not strong. CONCLUSIONS: EFV concentrations in hair were the strongest predictor of viral suppression and only weakly correlated with pharmacy refill adherence data in Nigeria. This study suggests that resource-limited settings may benefit from objective adherence metrics to monitor and support adherence.

Quinoline Antimalarials Increase the Antibacterial Activity of Ampicillin.

Bacterial and malaria co-infections are common in malaria endemic countries and thus necessitate co-administration of antibiotics and antimalarials. There have long been anecdotal clinical reports of interactions between penicillins and antimalarial agents, but the nature and mechanisms of these interactions remain to be investigated. In this study, we employed antimicrobial interaction testing methods to study the effect of two antimalarials on the antibacterial activity of ampicillin in vitro. Paper strip diffusion, a modified disc diffusion and checkerboard methods were used to determine the nature of interactions between ampicillin and quinoline antimalarials, chloroquine and quinine, against Gram-positive and Gram-negative bacteria. The impact of antimalarials and ampicillin-antimalarial drug combinations on cell integrity of test bacteria were determined by measuring potassium release. The tested antimalarials did not show substantial antibacterial activity but quinine was bactericidal at high concentrations. Chloroquine and quinine increased ampicillin activity, with increasing concentrations extending the antibacterial's inhibition zones by 2.7-4.4 mm and from 1.1 to over 60 mm, respectively. Observed interactions were largely additive with Fractional Inhibitory Concentration Indices of >0.5-1 for all ampicillin-antimalarial combinations. Quinine and, to a lesser extent, chloroquine increase the activity of ampicillin and potentially other ß-lactams, which has implications for combined clinical use.

Associations between efavirenz concentrations, pharmacogenetics and neurocognitive performance in people living with HIV in Nigeria.

OBJECTIVE: Efavirenz (EFV) use is associated with neuropsychiatric side effects, which may include poor neurocognitive performance. We evaluated single nucleotide polymorphisms in genes that contribute to EFV pharmacokinetics and examined them in association with EFV concentrations in plasma and hair, as well as neurocognitive performance. DESIGN: Cross-sectional study in which adults with HIV receiving 600-mg EFV for at least 2 months were recruited and paired hair and dried blood spots (DBS) samples collected. METHODS: Participants (N = 93, 70.3% female) were genotyped for seven single nucleotide polymorphisms in CYP2B6, NRII3 and ABCB1 using DBS. EFV was quantified in DBS and hair using validated liquid-chromatography-tandem-mass-spectrometry methods, with plasma EFV concentrations derived from DBS levels. Participants were also administered a neurocognitive battery of 10 tests (seven domains) that assessed total neurocognitive functioning. RESULTS: Strong correlation (r = 0.66, P < 0.001) was observed between plasma and hair EFV concentrations. The median (interquartile range) hair EFV concentration was 6.85 ng/mg (4.56-10.93). CYP2B6 516G>T, (P < 0.001) and CYP2B6 983T>C (P = 0.001) were each associated with hair EFV concentrations. Similarly, 516G>T (P < 0.001) and 983T>C (P = 0.009) were significantly associated with plasma EFV concentration. No other genetic associations were observed. Contrary to other studies, total neurocognitive performance was significantly associated with plasma EFV concentrations (r = 0.23, P = 0.043) and 983T>C genotype (r = 0.38, P < 0.0005). CONCLUSION: This study demonstrated approximately three-fold and two-fold higher EFV plasma and hair concentrations, respectively, among CYP2B6 516TT compared with 516GG. Higher EFV concentrations were associated with better neurocognitive performance, requiring further study to elucidate the relationships between adherence, adverse effects and outcomes.

Haematological indices of sickle cell patients with chronic leg ulcers on compression therapy.

BACKGROUND: Recurrent chronic leg ulcers and its are morbidities associated with sickle cell anaemia (SCA). Compression therapy increases the rate of healing of these ulcers and also decreases the rate of recurrence. OBJECTIVE: This study evaluated the haematological parameters of patients with SCA and chronic leg ulcers placed on high compression bandaging to provide data for improved ulcer management and prevention. METHODS: Eighteen patients with SCA and chronic leg ulcers were recruited for treatment by compression therapy in Ibadan, Nigeria, from March to June 2015. Eighteen SCA patients with no history of chronic leg ulcers were age and sex matched and recruited as controls. Blood samples, wound biopsies and swabs were collected at different time points for full blood count, microbiology, culture and antimicrobial susceptibility tests. Haemoglobin variants were quantified by high performance liquid chromatography. Fasting blood sugar was tested for leg ulcer patients to determine diabetic status. RESULTS: Ulcers ranged from 0.5 cm2 to 416 cm2 (median: 38.4 cm2). Post-intervention ulcer size ranged from 0.0 cm2 to 272 cm2 (median: 18.6 cm2, p < 0.001); four ulcers completely healed. Compared to the control group, haematological indices at commencement of treatment were more severe in leg ulcer patients (p = 0.02). No patients with chronic leg ulcer was diabetic. Microorganisms isolated from the leg ulcers include Pseudomonas aeruginosa, Staphylococcus aureus, Proteus sp., Escherichia coli and Klebsiella oxytoca. CONCLUSION: Measures to improve haematological parameters during leg ulcer treatment in SCA patients should be taken to aid wound healing.

Pharmacokinetic Parameters of Quinine in Healthy Subjects and in Patients with Uncomplicated Malaria in Nigeria: Analysis of Data using a Population Approach.

BACKGROUND: The varied disposition of the antimalarial quinine partly explains its poor tolerance and toxicity in humans. OBJECTIVE: Using a population approach, the disposition of quinine in healthy subjects and patients with acute uncomplicated symptomatic malaria from Nigeria was re-examined with a view to providing population-specific attributes. METHODS: Concentration versus time profiles of quinine over 48 hours in healthy individuals, and over 7 days in malaria-infected patients, were stratified to reflect: concentration versus time data during the first 48 hours of quinine administration for healthy subjects and infected patients, concentration versus time data after 48 hours in infected patients, and all concentration versus time data available for healthy subjects and infected patients. Pharmacokinetic parameters were then estimated with a stochastic approximation expectation maximization algorithm. RESULTS: All datasets were fitted by a 1-compartment model with covariate contributions from body weight and infection status. The absorption rate constant, and volume of distribution and clearance were 1.72 h-1, 86.8 to 157.4 L, and 6.6 to 9.6 L/h, respectively. Infected patients experienced a 38% decrease in volume of distribution and a 31% decrease in clearance in the first 48 hours relative to healthy individuals. The contraction in volume of distribution and clearance diminished significantly after 48 hours of chronic quinine dosing in infected patients. CONCLUSIONS: The study findings suggest that clinical interventions aimed at enhancing the safety and tolerance of quinine might be achieved by a rational decrease in dose size and/or dosing interval, post-48 hours of chronic quinine administration, in malaria-infected patients.

Willingness to Donate Hair Samples for Research Among People Living with HIV/AIDS Attending a Tertiary Health Facility in Ibadan, Nigeria.

The use of hair samples in biomedical research is a rapidly growing field. High acceptability rates for hair collection have been demonstrated in multiple settings. Each setting may have unique issues and, to our knowledge, no previous study has assessed the acceptability of hair sampling for HIV-related research in Nigeria. This study aimed to assess the willingness to donate hair for research among people living with HIV (PLWH). A cross-sectional study was conducted among 381 PLWH in a tertiary institution in Southwest Nigeria, using convenience sampling. An interviewer-administered questionnaire was used to collect data from consenting participants, including a question on willingness to donate hair for research. The mean age of respondents was 42.1 ± 10.5 years and more than three-quarters of the respondents were females. Two hundred and eighty-eight (75.8%) respondents had at least a tertiary education. Only 51.4% of the respondents were willing to donate their hair for research. Possible sample diversion for rituals was the major (60.5%) reason cited for unwillingness to donate hair. In multivariate analysis, respondents with primary education or less exhibited a trend toward being more willing to donate hair than those with secondary education or more (p = .091). Muslims were 1.7 times more willing to donate hair than Christians even after adjusting for other demographic covariates (95% confidence interval: 1.11-2.72); p = .016. There is a moderate willingness to donate hair for research among our population of PLWH in Nigeria. These results underscore the importance of cultural sensitivity and community education when introducing innovative HIV research techniques to new settings.

N-acetyltransferase 2 enzyme genotype-phenotype discordances in both HIV-negative and HIV-positive Nigerians.

BACKGROUND: The N-acetyltransferase 2 (NAT2) enzyme has been understudied in Nigerians including genotype-phenotype association studies. OBJECTIVE: The aim of this study was NAT2 haplotype identification and genotype-phenotype investigations in HIV-positive and HIV-negative Nigerians. PATIENTS AND METHODS: Phenotypes included self-reported sulphonamide hypersensitivity survey, experimental and computational NAT2 phenotyping. The NAT2 gene was amplified by PCR. Gene sequencing used ABI 3730 and Haploview 4.2 for haplotype reconstruction. Genotype-phenotype analyses used the χ P-value and odds ratio with a 95% confidence interval. RESULTS: Self-reported sulphonamide hypersensitivity showed a prevalence of 3.1 and 12.4% in HIV-positive and HIV-negative Nigerians, respectively. NAT2 genetic variants 191G>A, 282C>T, 341T>C, 481C>T, 590G>A, 803A>G and 857G>A were not significantly different between both groups (odds ratio=0.87; 95% confidence interval: 0.54-1.38, P=0.55). Nine haplotypes: NAT2*4, NAT2*12A, NAT2*13A, NAT2*5B, NAT2*6A, NAT2*7B, NAT2*5C, NAT2*14B and NAT2*14A had frequencies more than 1%, whereas NAT2*12B had 1.1% in the HIV-positive and 0.4% in the HIV-negative group. Overall, slow acetylator haplotypes made up 68%. The NAT2*12 signature single-nucleotide polymorphism was in high linkage disequilibrium with signature single-nucleotide polymorphism for NAT2*13 (D'=0.97, r=0.61) and NAT2*5 (D'=0.98, r=0.64). Genotype-phenotype association analysis showed haplotypes NAT2*13A, NAT2*5C, NAT2*7B and NAT2*14A to be associated strongly with the slow metabolic phenotype (P=0.002, 0.029, 0.032 and 0.050, respectively). Computational phenotypes were similar, with 30.9, 66 and 3.1% for slow, intermediate and rapid acetylators, respectively, among HIV-positive Nigerians and 31.2, 66.3 and 2.5% among the HIV-negative group. Overall, slow phenotypes made up 31%. CONCLUSION: NAT2 haplotype frequencies are similar in Nigerians, irrespective of HIV status, but genotype-phenotype discordances exist.

Inherited Breast Cancer in Nigerian Women.

PURPOSE: Among Nigerian women, breast cancer is diagnosed at later stages, is more frequently triple-negative disease, and is far more frequently fatal than in Europe or the United States. We evaluated the contribution of an inherited predisposition to breast cancer in this population. PATIENTS AND METHODS: Cases were 1,136 women with invasive breast cancer (mean age at diagnosis, 47.5 ± 11.5 years) ascertained in Ibadan, Nigeria. Patients were selected regardless of age at diagnosis, family history, or prior genetic testing. Controls were 997 women without cancer (mean age at interview, 47.0 ± 12.4 years) from the same communities. BROCA panel sequencing was used to identify loss-of-function mutations in known and candidate breast cancer genes. RESULTS: Of 577 patients with information on tumor stage, 86.1% (497) were diagnosed at stage III (241) or IV (256). Of 290 patients with information on tumor hormone receptor status and human epidermal growth factor receptor 2, 45.9% (133) had triple-negative breast cancer. Among all cases, 14.7% (167 of 1,136) carried a loss-of-function mutation in a breast cancer gene: 7.0% in BRCA1, 4.1% in BRCA2, 1.0% in PALB2, 0.4% in TP53, and 2.1% in any of 10 other genes. Odds ratios were 23.4 (95% CI, 7.4 to 73.9) for BRCA1 and 10.3 (95% CI, 3.7 to 28.5) for BRCA2. Risks were also significantly associated with PALB2 (11 cases, zero controls; P = .002) and TP53 (five cases, zero controls; P = .036). Compared with other patients, BRCA1 mutation carriers were younger ( P < .001) and more likely to have triple-negative breast cancer ( P = .028). CONCLUSION: Among Nigerian women, one in eight cases of invasive breast cancer is a result of inherited mutations in BRCA1, BRCA2, PALB2, or TP53, and breast cancer risks associated with these genes are extremely high. Given limited resources, prevention and early detection services should be especially focused on these highest-risk women.

Broadening Participation in the Sciences within and from Africa: Purpose, Challenges, and Prospects.

Many of Africa's challenges have scientific solutions, but there are fewer individuals engaged in scientific activity per capita on this continent than on any other. Only a handful of African scientists use their skills to capacity or are leaders in their disciplines. Underrepresentation of Africans in scientific practice, discourse, and decision making reduces the richness of intellectual contributions toward hard problems worldwide. This essay outlines challenges faced by teacher-scholars from sub-Saharan Africa as we build scientific expertise. Access to tertiary-level science is difficult and uneven across Africa, and the quality of training available varies from top-range to inadequate. Access to science higher education needs to increase, particularly for female students, first-generation literates, and rural populations. We make suggestions for collaborative initiatives involving stakeholders outside Africa and/or outside academia that could extend educational opportunities available to African students and increase the chance that Africa-based expertise is globally available.

Phenotyping and genotyping of CYP2C19 using comparative metabolism of proguanil in sickle-cell disease patients and healthy controls in Nigeria.

Polymorphic expression of metabolic enzymes have been identified as one of the key factors responsible for the interindividual/ethnic/racial variability in drug metabolism and effect. In Nigeria, there is a disproportionately high incidence of sickle-cell disease (SCD), a condition characterized by painful crisis frequently triggered by malaria. Proguanil, a substrate of the polymorphic CYP2C19, is a chemoprophylactic antimalarial drug widely used among SCD patients in Nigeria. This study aimed to conduct a comparative CYP2C19 phenotyping among SCD patients and healthy controls and to compare the results with those previously reported. One hundred seventy-seven unrelated subjects comprising 131 SCD patients and 46 non-SCD volunteers were phenotyped. This was carried out by collecting pooled urine samples over 8 h following PG administration. Proguanil and its major CYP2C19-dependent metabolites were measured by high-performance liquid chromatography. Metabolic ratios (MRs) were computed and employed in classifying subjects into poor or extensive metabolizers. Among SCD group, 130 (99.2%) were extensive metabolizers (EMs) and 1 (0.8%) was poor metabolizer (PM) of PG, while 95.7 and 4.3% non-SCDs were EMs and PMs, respectively. MRs ranged from 0.02 to 8.70 for SCD EMs and from 0.22 to 8.33 for non-SCD EMs . Two non-SCDs with MRs of 18.18 and 25.76 and the SCD with MR of 16.77 regarded as PMs had earlier been genotyped as CYP2C19*2/*2. Poor metabolizers of proguanil in SCD patients are reported for the first time. Regardless of clinical significance, a difference in metabolic disposition of proguanil and CYP2C19 by SCDs and non-SCDs was established.

Significant Pharmacokinetic Interactions Between Quinine and Ampicillin-Cloxacillin Combination.

INTRODUCTION: The co-existence of malaria with bacterial infections is common in the tropics, hence the concurrent use of antimalarials and antibiotics. OBJECTIVE: This study aimed to investigate the effect on pharmacokinetics and antimicrobial activity of co-administration of quinine and combined ampicillin-cloxacillin. METHODS: In total, 14 healthy adults received single oral doses of ampicillin-cloxacillin combination alone and with quinine in a randomized crossover manner. Urine samples collected at predetermined intervals over 48 h were analysed. The effect of quinine on minimum inhibitory concentrations (MICs) of ampicillin and cloxacillin were determined against Staphylococcus aureus by agar diffusion, agar dilution, and broth dilution. RESULTS: Quinine significantly reduced the rate and extent of excretion of ampicillin and cloxacillin (p < 0.0002). The total amounts of ampicillin and cloxacillin excreted unchanged (Du(∞)) alone were 217.10 ± 53.82 and 199.0 ± 64.29 mg versus 126.40 ± 50.63 and 135.20 ± 52.24 mg, respectively, with quinine. Respective maximum excretion rates (dDu/dt max) for ampicillin and cloxacillin were 43.55 ± 19.41 and 77.64 ± 29.65 mg/h alone versus 18.01 ± 8.52 and 53.16 ± 20.72 mg/h with quinine. This indicates a significant reduction in Du(∞)and dDu/dt max by 41.78 and 58.65 % for ampicillin and 32.06 and 31.53 % for cloxacillin. Conversely, the disposition of quinine was unaffected by ampicillin-cloxacillin (p > 0.1). The MIC of antibiotics alone versus with quinine, respectively, were 0.11 ± 0.04 and 0.78 ± 0.1 µg/ml for ampicillin, and 0.18 ± 0.1 and 0.92 ± 0.4 µg/ml for cloxacillin, with a five- to sevenfold increase (p > 0.01); indicating a decrease in antimicrobial activity by quinine. CONCLUSIONS: Quinine therefore, reduced the bioavailability and the antimicrobial activity of ampicillin-cloxacillin upon co-administration, which may have therapeutic implications. Caution is required with the co-administration of these medicines.

Neo-adjuvant capecitabine chemotherapy in women with newly diagnosed locally advanced breast cancer in a resource-poor setting (Nigeria): efficacy and safety in a phase II feasibility study.

The majority of clinical trials of neo-adjuvant therapy for breast cancer have been conducted in resource-rich countries. We chose Nigeria, a resource-poor country, as the major site for a phase II feasibility open-label multicenter clinical trial designed to evaluate the efficacy, safety, and tolerability of neo-adjuvant capecitabine in locally advanced breast cancer (LABC). Planned treatment consisted of 24 weeks of capecitabine at a dose of 1,000 mg/m(2) twice daily (2,000 mg/m(2) total per day). The primary endpoints were overall, partial, complete clinical response rate (OCR, PCR, CCR) and complete pathologic response (cPR). A total of 16 patients were recruited from August 2007 to April 2010. The study was terminated early as a result of slow accrual. After the first three cycles of therapy, PCR were seen in five of 16 patients (31%; 95% CI 11-59%). Of the remaining 11 patients, eight had no response (NR) or stable disease (SD), and three had progressive disease (PD). Seven patients proceeded with further therapy of which had SD. OCR at the end of eight cycles was 44% (95% CI 20-70%). Clinical response and radiologic response by ultrasonomammography were highly concordant (spearman correlation 0.70). The most common adverse effect was Grade 1 hand-foot syndrome, which was seen in 75% of patients. Despite several limitations, we successfully carried out this phase II feasibility study of neo-adjuvant capecitabine for LABC in Nigeria. Capecitabine monotherapy showed good overall response rates with minimal toxicity and further studies are warranted.

Effect of kolanut on the pharmacokinetics of the antimalarial drug halofantrine.

OBJECTIVE: To study the effect of the concomitant consumption of kolanut, a caffeine-containing nut, on the pharmacokinetics of halofantrine. METHODS: A single dose of 500 mg halofantrine hydrochloride was orally administered either alone or concomitant with 12.5 g kolanut to 15 healthy male volunteers in a Latin-square randomized crossover design with a wash-out period of 6 weeks between treatments. Blood samples were collected and analyzed by HPLC for halofantrine and the active metabolite N-desbutylhalofantrine. RESULTS: Concomitant intake of kolanut with halofantrine significantly decreased C(max) and AUC of both halofantrine and the metabolite desbutylhalofantrine, while no significant effect was observed for t (max) and t(1/2) of the compounds. In the case of halofantrine, C(max) decreased from 179 +/- 119 to 98 +/- 32 ng/ml, and the AUC was reduced from 17,450 +/- 4,611 to 11,821 +/- 4,069 ng x h/ml. C(max) of desbutylhalofantrine decreased from 124 +/- 41 to 62 +/- 23 ng/ml and the AUC from 13,341 +/- 4,749 to 7,359 +/- 3,018 ng x h/ml when kolanut was co-administered. CONCLUSIONS: Co-administration of halofantrine and kolanut caused a significant decrease in the plasma concentrations of halofantrine and the active metabolite desbutylhalofantrine probably during adsorption of the drug due to complex formation. This indicates that caution should be exerted when the drug is taken together with caffeine-containing nutrients.

Determination of the physicochemical properties of pyronaridine - a new antimalarial drug.

The physicochemical properties of pyronaridine, a new antimalarial drug, have been determined for the first time in this study, since these parameters are comprehensively not available in literature. UV-Vis spectral analysis of both pyronaridine and its tetraphosphate salt were carried out in various solvents, in addition to solubility of the two drugs in these solvents. Partition coefficient was done in n-octanol-water mixture using the Leo-Hansch method as well hydrophobicity index determination. pKa determination was carried out on the tetraphosphate. UV-Vis spectral characteristics showed that both the base and the tetraphosphate salt have significant light absorption in the range 190-380 nm. Solubility in different solvents revealed that pyronaridine base is sparingly soluble in chloroform (1.34%) while it is slightly soluble in methanol (0.29%) and ethanol (0.42%) and very slightly soluble in octanol and distilled water. The tetraphosphate salt was sparingly soluble in water (1.46%) while it is only very slightly soluble in other solvents. The higher aqueous solubility of the salt was further revealed by a greater Rm value on extrapolation to 100% water concentration in hydrophobicity index determination. Log P value determination showed that the base {log P of 0.26+/-0.02} is more liposoluble than the salt {log P of - (1.240.21)}. Four prominent pKa values were obtained for the tetraphosphate titrated which when extrapolated to the base gave values of 7.08+/-0.05, 7.39+/-0.05, 9.88+/-0.05 and 10.30+/-0.10. The results should guide in formulation of appropriate dosage forms to improve bioavailability of the drug especially from oral routes.

Analysis of the antimalarial drug halofantrine and its major metabolite N-desbutylhalofantrine in human plasma by high performance liquid chromatography.

The determination of halofantrine and its major metabolite N-desbutylhalofantrine in human plasma by reversed phase high-pressure liquid chromatography is described. The method involves protein precipitation of plasma samples by acetonitrile followed by basification with sodium hydroxide and subsequent liquid-liquid extraction using hexane-diethyl ether (1:1, v/v). The chromatographic separation was carried out on a C-18 column with a mobile phase consisting of methanol/0.05 M KH2PO4 (78:22, v/v) containing 55 mM perchloric acid. Chlorprothixen was used as internal standard. The relative standard deviations of intraday and interday precision for both compounds were less than 7%, the relative standard deviation of the accuracy did not exceed 7.1% at concentrations of 50 and 300 ng/ml. This method is simple, rapid, sensitive and cost effective and was applied to the determination of the pharmacokinetics of halofantrine and N-desbutylhalofantrine in two healthy male volunteers after an oral administration of 500 mg halofantrine. Moreover, the influence of the frequently consumed kolanut on the pharmacokinetics of halofantrine was investigated.

Penetration, efflux and intracellular activity of tigecycline in human polymorphonuclear neutrophils (PMNs).

OBJECTIVES: To evaluate the penetration, efflux and intracellular activity of tigecycline in human polymorphonuclear neutrophils (PMNs). METHODS: PMNs were isolated from fresh whole blood and tested for viability and purity prior to use. Tigecycline drug uptake was evaluated by incubating 5 x 10(6) cells/mL at 37 degrees C up to 3 h at tigecycline concentrations of 1, 2, 5 and 10 mg/L. Drug efflux from PMNs was determined following a 2 h incubation with tigecycline at 10 mg/L. Its intracellular activity against Staphylococcus aureus was evaluated following tigecycline extracellular exposures of 1 mg/L. RESULTS: Tigecycline uptake was rapid and achieved high concentrations within PMNs with maximal penetration noted at 1 h of incubation. At 1 h, dose-dependent intracellular concentrations ranged from 15.83 +/- 11.09 mg/L to 264 +/- 54.60 mg/L at tigecycline 1 and 10 mg/L, respectively. At these exposures, intracellular drug concentrations were approximately 20 and 30 times higher at 1 h than extracellular concentrations. By 3 h, tigecycline displayed sustained high intracellular exposures. Tigecycline cell efflux followed first order kinetics with a half-life of 1.39 h. Tigecycline was bacteriostatic against intracellular S. aureus. CONCLUSIONS: Tigecycline rapidly achieved high intracellular concentrations in PMNs and exhibited static activity against S. aureus supporting its potential clinical utilization.

Effect of adjunctive treatment with gamma interferon against Pseudomonas aeruginosa pneumonia in neutropenic and non-neutropenic hosts.

To evaluate the adjunctive effect of interferon-gamma (IFN-gamma) in treatment of Pseudomonas aeruginosa pneumonia, neutropenic and non-neutropenic mice received LD(100) of the organism intratracheally, followed by subcutaneous administration of IFN-gamma, ceftazidime (TAZ) or a combination of both agents 2 h post-inoculation. Treatment with IFN-gamma alone showed no significant increase in survival when compared with control. Addition of IFN-gamma to TAZ resulted in no significant change in survival compared with TAZ alone. Survival in TAZ and TAZ + IFN-gamma groups, was significantly higher than in control and IFN-gamma groups. This suggests that adjunctive treatment with IFN-gamma in combination with ceftazidime may not be more beneficial than the antibiotic alone when managing acute P. aeruginosa pneumonia in both immunocompromised and immunocompetent hosts.