Chloroquine reduces urinary excretion of cloxacillin when it is administered concurrently with ampicillin-cloxacillin combination

Purpose: To investigate a possible effect of chloroquine on urinary excretion of cloxacillin when chloroquine is administered concurrently with ampicillin-cloxacillin combination. Methods: Eight healthy adult volunteers received single oral doses of Ampiclox® (ampicillin-cloxacillin combination) alone and in combination with chloroquine in a cross-over study design with one week washout period between the drug administrations. Total urine voided was collected from each volunteer at predetermined time intervals for a period of 9 hr. The urine was analyzed for cloxacillin by a reversed-phase HPLC method. Results: A significant reduction in the amount of cloxacillin excreted in urine was observed following the co-administration of chloroquine and the ampicillin-cloxacillin combination products. The mean total amount of cloxacillin (Du¥), maximum peak of excretion (Dumax) and % dose excreted after Ampliclox® was administered alone were 84.6 ± 57.0 mg, 49.5 ±41.6 mg and 33.9 ± 22.7% respectively. The corresponding values after co-administration with chloroquine were 30.2 ± 27.2 mg, 13.5 ± 10.4 mg and 12.1 ±10.9%. The respective times of maximum absorption (Tmax) and elimination half-life (t1/2) of cloxacillin were 2.7 ± 0.4 hr and 0.7 ± 0.4 hr after Ampiclox® alone and 1.5 ± 0.8 hr and 0.6 ± 0.5 hr after co-administration of the two drugs. The results showed a significant decrease (p < 0.0001) in the mean total amount as well as % dose of cloxacillin excreted in urine by 64% and a significant reduction (p < 0.05) in the Tmax of excretion by 45%. Conclusion: There is appreciable reduction in the urinary excretion of cloxacillin when given concurrently with chloroquine. The mode of this interaction and possible therapeutic implication is unknown. However, caution should be exercised when prescribing or administering these two drugs together. Key words: Drug-drug interaction, bioavailability, chloroquine, cloxacillin Tropical Journal of Pharmaceutical Research 2003; 2(1): 169-17

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

BackgroundStrategies 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.MethodsPaired 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.ResultsBased 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.ConclusionsEFV 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

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

From Springer Nature via Jisc Publications RouterHistory: received 2020-12-12, accepted 2021-11-02, registration 2021-11-04, pub-electronic 2021-11-26, online 2021-11-26, collection 2021-12Publication status: PublishedFunder: Postdoctoral Research Fellowship P2BSP3_178591Funder: Francis Crick Institute (Francis Crick Institute Limited); doi: https://doi.org/10.13039/100010438Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289; Grant(s): FC001202Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440; Grant(s): FC001202Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH); doi: https://doi.org/10.13039/100000002; Grant(s): U01 CA161032, U01 CA161032, R01 MD013452, R01 CA228198, U01 CA161032, R01 MD013452, P20-CA233307Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006; Grant(s): BCRF-20-071, BCRF-19-120Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272; Grant(s): 203141/Z/16/ZFunder: Susan G. Komen (Susan G. Komen Breast Cancer Foundation); doi: https://doi.org/10.13039/100009634; Grant(s): SAC110026, SAC210203Funder: American Cancer Society (American Cancer Society, Inc.); doi: https://doi.org/10.13039/100000048Abstract: Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies

Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women.

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants

Research Article - Chloroquine reduces urinary excretion of cloxacillin when it is administered concurrently with ampicillincloxacillin combination

Purpose: To investigate a possible effect of chloroquine on urinary excretion of cloxacillin when chloroquine is administered concurrently with ampicillin-cloxacillin combination. Methods: Eight healthy adult volunteers received single oral doses of Ampiclox® (ampicillincloxacillin combination) alone and in combination with chloroquine in a cross-over study design with one week washout period between the drug administrations. Total urine voided was collected from each volunteer at predetermined time intervals for a period of 9 hr. The urine was analyzed for cloxacillin by a reversed-phase HPLC method. Results: A significant reduction in the amount of cloxacillin excreted in urine was observed following the co-administration of chloroquine and the ampicillin-cloxacillin combination products. The mean total amount of cloxacillin (Du¥), maximum peak of excretion (dumax) and % dose excreted after Ampliclox® was administered alone were 84.6 ± 57.0 mg, 49.5 ±41.6 mg and 33.9 ± 22.7% respectively. The corresponding values after co-administration with chloroquine were 30.2 ± 27.2 mg, 13.5 ± 10.4 mg and 12.1 ±10.9%. The respective times of maximum absorption (Tmax) and elimination half-life (t1/2) of cloxacillin were 2.7 ± 0.4 hr and 0.7 ± 0.4 hr after Ampiclox® alone and 1.5 ± 0.8 hr and 0.6 ± 0.5 hr after co-administration of the two drugs. The results showed a significant decrease (p < 0.0001) in the mean total amount as well as % dose of cloxacillin excreted in urine by 64% and a significant reduction (p < 0.05) in the Tmax of excretion by 45%. Conclusion: There is appreciable reduction in the urinary excretion of cloxacillin when given concurrently with chloroquine. The mode of this interaction and possible therapeutic implication is unknown. However, caution should be exercised when prescribing or administering these two drugs together

Pharmacodynamic Profile of Ertapenem against Klebsiella pneumoniae and Escherichia coli in a Murine Thigh Model

The pharmacodynamic profile of ertapenem was evaluated in a neutropenic mouse thigh infection model. Extended-spectrum beta-lactamase (ESBL)-positive and ESBL-negative clinical strains of Escherichia coli and Klebsiella pneumoniae were studied. MICs ranged from 0.0078 to 0.06 μg/ml with standard inoculum tests. Ertapenem doses were administered once to five times daily to achieve various exposures, reported as the percentage of the dosing interval that the concentration of free ertapenem was in excess of the MIC (%T>MIC(free)). Mean values for the static exposure and 80% maximally effective exposure (ED(80)) were 19% (range, 2 to 38%) and 33% (range, 13 to 65%) T>MIC(free), respectively. Differences in exposure requirements based on the presence of an ESBL resistance mechanism or bacterial species were not evident. In addition, experiments using a 100-fold higher inoculum did not decrease the magnitude of the reduction in bacterial density from baseline achieved compared to lower-inoculum studies. The pharmacodynamic parameter of %T>MIC(free) correlated well with bactericidal activity for all isolates, and the static and ED(80) exposures are consistent with those reported previously for carbapenems

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

A Novel Derivatization Ultraviolet Spectrophotometric Method for the Determination of Dihydroartemisinin using p-Nitroaniline

Purpose: To develop a novel ultraviolet (UV)–spectrophotometric method for the determination of dihydroartemisinin (DHA) in tablets using p-nitroaniline (PNA) as a derivatizing agent. Methods: Derivatization was based on the reaction between methanol solutions of dihydroartemisinin (DHA) and p-nitroaniline (PNA) in acid medium (1M HCI) at elevated temperature and for a short reaction time. Optimal detector response was obtained within 15 min when the reaction was carried out at 90o C in a molar ratio of 2:1 (DHA:PNA). The method used for analysis was validated and a linear calibration curve constructed in the range of 30 – 100 µg/mL for the reaction mixture at an absorbance of 290 nm. Results: Separation of adduct from PNA was better achieved on reversed phase thin layer chromatography (TLC) using acetonitrile : water (60:50) or on high performance liquid chromatography (HPLC) with retention times of 2.8 min for PNA and 5.8 min for the adduct. The limit of detection was 6 µg/mL. The method was precise and accurate in the range 100.70 - 100.96 %, with intraday and interday precisions of less than 2 % at concentrations of 40 and 80 µg/mL, respectively. The new method was applied to the assay of two brands of dihydroartemisinin tablets with accuracy similar to that of the International Pharmacopoeia (IP) UV-spectrophotometric method (p > 0.05). Conclusion: The derivatization method is simple, direct, devoid of dilutions and inexpensive in terms of reagent requirements and analyte volume, and has a shorter reaction time, cpmpared with IP method. Based on the foregoing, the method can be adopted as an alternative to the official assay method for routine quality control of dihydroartemisinin tablets