Trough plasma nevirapine levels, immunologic and virologic responses in composite CYP2B6*6/*18 HIV-infected adult Nigerian patients.

The influence of composite CYP2B6*6/*18 genotype on trough plasma nevirapine levels, HIV RNA levels (virologic response) and CD4+ T lymphocyte and absolute lymphocyte counts (immunologic response) of HIV-infected patients were evaluated. Patients with records of trough plasma nevirapine levels, CD4+ T lymphocyte, absolute lymphocyte and viral load counts at baseline and months 6 and 12 after initiation of nevirapine-based antiretroviral therapy combinations were retrospectively analysed. Participants were from a cohort of 150 patients previously genotyped and with measured plasma nevirapine levels. Relationship between genotype and nevirapine levels, absolute lymphocyte and CD4+ T lymphocyte counts and viral load were explored. Composite CYP2B6*6/*18 genotype was significantly associated with trough plasma nevirapine levels (geometric mean [standard deviation]: 4482 ng/ml [1349] of normal metabolizers vs. 4632 ng/ml [1793] of intermediate metabolizers vs. 6229 ng/ml [2549] of poor metabolizers; P < 0.001), but not the plasma HIV RNA levels, absolute lymphocyte and CD4+ T lymphocyte counts. Overall, immunologic response showed improvement with approximately 61.3% and 70.4% of patients with CD4+ T lymphocyte count >350 cells/mm3 at months 6 and 12 therapy duration respectively compared to 23.1% at baseline. Composite CYP2B6*6/*18 genotype correlated with plasma nevirapine levels but not immunologic and virologic responses.

Influence of selected polymorphisms in disposition genes on lumefantrine pharmacokinetics when coadministered with efavirenz.

BACKGROUND: Coadministration of artemether-lumefantrine and efavirenz has been shown to result in significant interactions. The influence of functional genetic polymorphisms in selected CYPs on the magnitude of this interaction was investigated in pregnant and nonpregnant adults. METHOD: A standard 3-day regimen of artemether-lumefantrine was administered to each patient on steady-state efavirenz-based antiretroviral therapy (ART). Pharmacokinetic parameters were obtained from intensive plasma concentration-time data. Genotyping data were tested for compliance with Hardy-Weinberg equilibrium by Chi-square test. Linear regressions, Mann-Whitney U-test or Kruskal-Wallis tests were conducted to examine the association of lumefantrine plasma level with CYP2B6 c.516G>T, NR1I3 152c-1089T>C, CYP2B6 c.983T>C, CYP3A5*3 and CYP3A4*22. RESULTS: Among a total of 69 malaria-HIV coinfected patients (34 nonpregnant and 35 pregnant), median (interquartile range) age was 33 (27-36.5) years and body weight was 59.5 (50-67.5) kg. In nonpregnant group, CYP2B6 c.516G>T was significantly associated with lower log Cday 7 of lumefantrine using multivariate linear regressions (ß = -0.239; P = 0.013). In 59% of women with CYP2B6 c.516T, Cday 7 of lumefantrine was below the target of 280 ng/mL compared to 47% in the noncarriers. CYP2B6 c.983T>C significantly associated with higher log Cday 7 of desbutyl lumefantrine in both pregnant (ß = 0.383; P = 0.033) and nonpregnant (ß = 0.395; P = 0.023) groups. Composite genotypes for both CYP2B6 Single-nucleotide polymorphisms strongly associated with lumefantrine plasma concentration. An associative trend between lumefantrine pharmacokinetics and NR1I3 152c-1089T>C genotypes indicated that 70% of the Cday 7 of lumefantrine in those with NR1I3 152c-1089TT genotype was below 280 ng/mL compared to 53% in those with NR1I3 152c-1089CC or CT genotype. CONCLUSION: The findings revealed that the efavirenz-lumefantrine interaction was accentuated in the group with CYP2B6 c.516T, c.983C and NR1I3 152c-1089T alleles. This warrants further investigations of other drug-drug interactions for optimising dosing in genetically defined subgroups, particularly during drug development.

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 CYP2B6*6 on the plasma pharmacokinetics of artemether, lumefantrine, and their metabolites in healthy volunteers. Thirty healthy and previously genotyped adult volunteers-15 noncarriers (CYP2B6*1/*1) and 15 homozygote carriers (CYP2B6*6/*6)-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-mass spectrometric methods. Pharmacokinetic parameters were evaluated using noncompartmental analysis. Artemether clearance of CYP2B6*6/*6 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-∞ ]) was greater by 35% (1.35 [0.95-1.93]) when compared with those of *1/*1 volunteers. Similarly, assuming complete bioconversion from artemether, the dihydroartemisinin AUC0-∞ was 22% lower. On the contrary, artemether-to-dihydroartemisinin AUC0-∞ ratio was 73% significantly higher (1.73 [1.27-2.37]). Comparison of lumefantrine exposure and lumefantrine-to-desbutyllumefantrine metabolic ratio of *6/*6 with corresponding data from *1/*1 volunteers showed no differences. The increased artemether-to-dihydroartemisinin metabolic ratio of *6/*6 volunteers is unlikely to result in differences in artemether-lumefantrine efficacy and treatment outcomes. This is the first study in humans to associate CYP2B6*6 genotype with artemether disposition.

Intima-media thickness of the common carotid arteries as a marker of retinopathy and nephropathy in sickle cell disease.

PURPOSE: This study was conducted to test the hypothesis that the carotid intima-media thickness (CIMT) is higher in patients with sickle cell disease (SCD) than in the normal population, and to determine the relationships of the CIMT with central retinal artery (CRA) and renal artery Doppler indices. METHODS: Forty-four confirmed steady-state SCD patients aged 16 years and above were recruited consecutively. The Doppler velocimetric indices of their right renal artery and both CRAs were obtained. The CIMT was also measured on each side via B-mode ultrasonography. The subjects were categorized by age and sex. Mean and median values for each group were determined. The Spearman correlation test was used to quantify the relationships between CIMT and the Doppler parameters. RESULTS: The participants had a median age of 24.50 years (interquartile range, 12.50 to 36.50 years). Twenty-three were men (52.3%) and 21 were women (47.7%). The median CIMT was 0.70 mm (IQR, 0.50 to 0.90 mm). Significant correlations with the CIMT were found for the CRA peak systolic velocity (r=0.312, P=0.003), the renal artery resistivity index (RI) (r=0.284, P=0.007), and the renal artery pulsatility index (PI) (r=0.273, P=0.010). There was no significant relationship between the CIMT and the CRA end-diastolic velocity, CRA RI, or CRA PI. CONCLUSION: CIMT in SCD patients was higher than in the previously reported age groups of the reference populations. In addition, the CIMT was significantly correlated with the CRA peak systolic velocity, the renal artery RI, and the renal artery PI.

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.

The Inflammatory Response to Surgery in Sickle Cell Disease Patients Undergoing Cholecystectomy.

BACKGROUND AND OBJECTIVES: Patients with sickle cell anemia (SCA) may have elevated inflammatory markers in health, and this may be heightened after open operations. The inflammatory response of patients with SCA after minimally invasive surgeries has not been fully explored. PATIENTS AND METHODS: Consecutive patients with SCA and with hemoglobin AA (HbAA) undergoing laparoscopic cholecystectomy for acute cholecystitis were recruited into the study. Blood samples were taken before induction of anesthesia (0-h); at 4, 12, 24, and 48 h; and on postoperative day 7. Samples were analyzed for serum C-reactive protein and interleukin (IL)-1 through IL-18. RESULTS: Twenty-three patients, including 9 with SCA and 14 with HbAA, were recruited with 4 cases performed by open laparotomy. At 0-h, proinflammatory IL-1 levels (6.1 versus 4.8) and C-reactive protein levels (32.5 versus 26.6) were higher in patients with hemoglobin SS (HbSS) than in patients with HbAA, respectively. Over time, inflammatory markers were generally higher at each time-point for patients with HbSS compared with patients with HbAA for both proinflammatory and anti-inflammatory cytokines, rising immediately after surgery and up to 48 hours, then returning to baseline by postoperative day 7. There was a higher mean IL-1 level across all time-points in the HbSS group than in the HbAA group (P = .04). CONCLUSION: This exploratory study found an enhanced inflammatory response to cholecystectomy in patients with SCA compared with patients with HbAA. Minimally invasive surgical strategies for this patient group may help to mediate this response.

Doppler ultrasonographic evaluation of celiac and mesenteric arteries in subjects with sickle cell disease.

Vasculopathy, as occurring in sickle cell disease (SCD), can affect celiac and mesenteric arteries and result in stenosis, with elevated peak systolic velocity (PSV) on Doppler ultrasonography. In six subjects with confirmed SCD in steady state, routine Doppler ultrasonographic examination discovered features of celiac artery (CA) or superior mesenteric artery (SMA) stenosis with CA PSV >200 cm/s (median = 222.8 cm/s; range = 201.5-427.1 cm/s) and/or SMA PSV >275 cm/s (median 183.2 cm/s; range = 87.8-289.3 cm/s). Among the six subjects, five had elevated soluble P-selectin values (median 72.55 ng/mL), while all six (100%) had elevated cystatin C levels (median 4.15 mg/L). Peripheral oxygen saturation was suboptimal in five subjects. All subjects had low hemoglobin concentration levels (median 8.5 g/dL) while four had elevated white blood cell count. Although vaso-occlusive crises result from microvessel occlusion, these findings at the macrovascular level suggest that SCD patients may also be vulnerable to mesenteric ischemic injury, especially in the setting of anemic heart failure from hemolysis.

Inter-individual variation in imatinib disposition: any role for prevalent variants of CYP1A2, CYP2C8, CYP2C9, and CYP3A5 in Nigerian CML patients?

Imatinib has been successful in the management of chronic myeloid leukemia (CML) but some patients experience adverse reactions or develop resistance to its use. The roles of some polymorphisms in genes encoding enzymes critical for the biotransformation of imatinib have been previously examined. This study, hence, evaluated some other unstudied functionally significant polymorphisms in CYP1A2, CYP2C8, CYP2C9, and CYP3A5. Trough imatinib blood levels and genotypes were determined in 42 CML patients by an HPLC-UV technique and a Sequenom iPLEX assay, respectively. Statistical analysis of the influence of genetic polymorphisms on standardized trough level detected no significant relationship. However, higher trough levels were observed in two homozygous carriers of CYP2C8*2 while diminished imatinib levels were seen in two homozygous carriers of CYP3A5*7. The study findings suggest that polymorphisms in drug metabolizing enzymes may be significant for imatinib therapy only in instances where all copies of the relevant studied genes are functionally impaired.

Pharmacogenetics of artemether-lumefantrine influence on nevirapine disposition: Clinically significant drug-drug interaction?

AIMS: In this study the influence of first-line antimalarial drug artemether-lumefantrine on the pharmacokinetics of the antiretroviral drug nevirapine was investigated in the context of selected single nucleotide polymorphisms (SNPs) in a cohort of adult HIV-infected Nigerian patients. METHODS: This was a two-period, single sequence crossover study. In stage 1, 150 HIV-infected patients receiving nevirapine-based antiretroviral regimens were enrolled and genotyped for seven SNPs. Sparse pharmacokinetic sampling was conducted to identify SNPs independently associated with nevirapine plasma concentration. Patients were categorized as poor, intermediate and extensive metabolizers based on the numbers of alleles of significantly associated SNPs. Intensive sampling was conducted in selected patients from each group. In stage 2, patients received standard artemether-lumefantrine treatment with nevirapine, and intensive pharmacokinetic sampling was conducted on day 3. RESULTS: No clinically significant changes were observed in key nevirapine pharmacokinetic parameters, the 90% confidence interval for the measured changes falling completely within the 0.80-1.25 no-effect boundaries. However, the number of patients with trough plasma nevirapine concentration below the 3400 ng ml-1 minimum effective concentration increased from 10% without artemether-lumefantrine (all extensive metabolizers) to 21% with artemether-lumefantrine (14% extensive, 4% intermediate, and 3% poor metabolizers). CONCLUSIONS: This approach highlights additional increase in the already existing risk of suboptimal trough plasma concentration, especially in extensive metabolizers when nevirapine is co-administered with artemether-lumefantrine.

Intima-media thickness of the common femoral artery as a marker of leg ulceration in sickle cell disease patients.

Leg ulceration is a debilitating chronic complication of sickle cell disease (SCD) the pathogenesis of which is yet to be fully elucidated. We hypothesized that SCD patients with histories of previous leg ulcers would have intima hyperplasia of the common femoral artery (CFA). We enrolled 44 SCD patients and 33 age-matched and sex-matched controls with hemoglobin AA. Anthropometric measurements, biochemical parameters, and sonographic intima-media thickness (IMT) of the CFA were determined. The median CFA IMT in SCD limbs with history of leg ulcers (SWLU) was 1.0 mm, whereas it was 0.7 mm in SCD limbs with no history of leg ulcer (SNLU) and 0.60 mm in controls (P < .001). Among the SNLU, 70.3% had CFA IMT <0.9 mm, whereas only 29.7% had CFA IMT ≥0.9 mm. Conversely, only 20.8% of SWLU had CFA IMT <0.9 mm, whereas the remaining 79.2% had CFA IMT ≥0.9 mm. All the controls had CFA IMT <0.9 mm. Binary logistic regression to determine the odds of having leg ulcer among SCD limbs with CFA IMT of ≥0.9 mm yielded an odds ratio of 9, indicating that SCD limbs with CFA IMT ≥0.9 mm had a 9 times greater risk of having leg ulcer compared with those with CFA IMT <0.9 mm. There is a significant increase in the CFA IMT of SCD limbs with ulcer compared with controls and SCD limbs without ulcer, suggesting that arterial vasculopathy plays a major role in the formation of these ulcers.

The role of electrocardiogram in sex verification in a young adult with primary amenorrhea: a case report.

BACKGROUND: The use of electrocardiogram for sex verification in adults is an emerging concept in medicine. It is feasible through the utilization of Ogunlade Sex Determination Electrocardiographic Score. The aim of this study was to use an electrocardiogram to verify the sex of a woman with primary amenorrhea. CASE PRESENTATION: We report a case of a 36-year-old woman of Yoruba ethnicity who presented with primary amenorrhea. A physical examination revealed a woman with a feminine appearance characterized by long plaited hair and well-developed breasts. As part of the investigations to unravel the sex status, she had a resting standard 12-lead electrocardiogram which revealed a masculine electrocardiogram pattern with Ogunlade Sex Determination Electrocardiographic Score of 9 (T-wave pattern in lead V1, 3; ST segment in lead V2 or V3, 3; QRS rotation, 2; heart rate of 79, 1). An abdominopelvic ultrasonography done by a radiologist showed absence of uterus, fallopian tubes, and ovaries. When our patient was considered for transvaginal scan, she declined but embraced translabial ultrasound as she claimed to be a virgin. Translabial ultrasonography revealed the presence of undescended hypoplastic testes with associated testicular microlithiasis at the external inguinal rings bilaterally. Karyotyping using a blood sample revealed 46,XY and a sex-determining region Y report showed that the blood sample was positive for the SRY gene confirming the status as male. This synchronized with the initial electrocardiogram evaluation. The testes were later removed. CONCLUSION: This report concluded that an electrocardiogram as a cheap, readily available and non-invasive test has a role in sex verification in young adults with primary amenorrhea.

Hepatobiliary Ultrasonographic Abnormalities in Adult Patients with Sickle Cell Anaemia in Steady State in Ile-Ife, Nigeria.

BACKGROUND: Sickle cell anaemia (SCA) is associated with structural manifestations in the hepatobiliary axis. This study aimed to investigate the hepatobiliary ultrasonographic abnormalities in adult patients with sickle cell anaemia in steady state attending the Haematology clinic of a federal tertiary health institution in Ile-Ife, Nigeria. MATERIAL/METHODS: Basic demographic data as well as right upper abdominal quadrant ultrasonography of 50 consecutive sickle cell anaemia patients were compared with those of 50 age- and sex-matched subjects with HbAA as controls. RESULTS: Each of the study groups (patients and controls) comprised of 21 (42%) males and 29 (58%) females. The age range of the patients was 18-45 years with a mean (±SD) of 27.6±7.607 years, while that of the controls was 21-43 years with a mean (±SD) of 28.0±5.079 years (p=0.746). Amongst the patients, 32 (64%) had hepatomegaly, 15 (30%) cholelithiasis and 3 (6%) biliary sludge. Fourteen (28%) of the patients had normal hepatobiliary ultrasound findings. In the control group, one (2%) person had cholelithiasis, one (2%) biliary sludge, one (2%) fatty liver and none hepatomegaly. Forty-seven (94%) of the controls had normal hepatobiliary ultrasound findings. There was a statistically significant difference in the prevalence of hepatomegaly and cholelithiasis between the patients and controls (p value <0.001 for both comparisons). CONCLUSIONS: In this study, hepatomegaly, cholelithiasis and biliary sludge were the most common hepatobiliary ultrasound findings in patients with sickle cell anaemia. Ultrasonography is a useful tool for assessing hepatobiliary abnormalities in patients with sickle cell anaemia.

Determinants of Overall and Progression-Free Survival of Nigerian Patients with Philadelphia-Positive Chronic Myeloid Leukemia.

Objective. The tyrosine kinase inhibitors have markedly changed the disease course for patients with Ph(+) and/or BCR-ABL1 (+) chronic myeloid leukemia (CML). This study was embarked upon to assess the long-term effects of imatinib therapy on survival in adult Nigerian patients with CML. Methods. All adult patients on imatinib (400-600 mg) seen from July 2003 to December 2010 were assessed. Male/female distribution was 171/101, with a median age of 38 (range, 20-75) years. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier techniques. Results. Of all the 272 patients, 205 were in chronic phase, 54 in accelerated phase, and five in blastic phase, at commencement of imatinib. As at December 2010, 222 were alive. OS at 1 and 5 years was 94% and 63%, while PFS was 89% and 54%, respectively. Similarly, amongst the 205 patients in chronic phase, OS at 1 and 5 years was 97% and 68%, while PFS was 92% and 57%. Conclusion. Imatinib's place as first-line therapy in the treatment of CML has further been reinforced in our patients, with improved survival and reduced morbidity, comparable with outcomes in other populations.