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Objectives: To investigate the efficacy and safety of repurposed antiprotozoal and antiretroviral drugs, nitazoxanide and atazanavir/ritonavir, in shortening the time to clinical improvement and achievement of SARS-CoV-2 polymerase chain reaction (PCR) negativity in patients diagnosed with moderate to severe COVID-19.Trial Design: This is a pilot phase 2, multicentre 2-arm (1:1 ratio) open-label randomised controlled trial.Participants: Patients with confirmed COVID-19 diagnosis (defined as SARS-CoV-2 PCR positive nasopharyngeal swab) will be recruited from four participating isolation and treatment centres in Nigeria: two secondary care facilities (Infectious Diseases Hospital, Olodo, Ibadan, Oyo State and Specialist State Hospital, Asubiaro, Osogbo, Osun State) and two tertiary care facilities (Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State and Olabisi Onabanjo University Teaching Hospital, Sagamu, Ogun State). These facilities have a combined capacity of 146-bed COVID-19 isolation and treatment ward.Inclusion Criteria: Confirmation of SARS-CoV-2 infection by PCR test within two days before randomisation and initiation of treatment, age bracket of 18 and 75 years, symptomatic, able to understand study information and willingness to participate. Exclusion criteria include the inability to take orally administered medication or food, known hypersensitivity to any of the study drugs, pregnant or lactating, current or recent (within 24 hours of enrolment) treatment with agents with actual or likely antiviral activity against SARS-CoV-2, concurrent use of agents with known or suspected interaction with study drugs, and requiring mechanical ventilation at screening.Intervention and Comparator: Participants in the intervention group will receive 1000 mg of nitazoxanide twice daily orally and 300/100 mg of atazanvir/ritonavir once daily orally in addition to standard of care while participants in the control group will receive only standard of care. Standard of care will be determined by the physician at the treatment centre in line with the current guidelines for clinical management of COVID-19 in Nigeria.Main Outcome Measures: Main outcome measures are: (1) Time to clinical improvement (defined as time from randomisation to either an improvement of two points on a 10-category ordinal scale (developed by the WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection) or discharge from the hospital, whichever came first); (2) Proportion of participants with SARS-CoV-2 polymerase chain reaction (PCR) negative result at days 2, 4, 6, 7, 14 and 28; (3) Temporal patterns of SARS-CoV-2 viral load on days 2, 4, 6, 7, 14 and 28 quantified by RT-PCR from saliva of patients receiving standard of care alone versus standard of care plus study drugs.Randomisation: Allocation of participants to study arm is randomised within each site with a ratio 1:1 based on randomisation sequences generated centrally at Obafemi Awolowo University. The model was implemented in REDCap and includes stratification by age, gender, viral load at diagnosis and presence of relevant comorbidities.Blinding: None, this is an open-label trial.Number To Be Randomised (sample Size): 98 patients (49 per arm).Trial Status: Regulatory approval was issued by the National Agency for Food and Drug Administration and Control on 06 October 2020 (protocol version number is 2.1 dated 06 August 2020). Recruitment started on 9 October 2020 and is anticipated to end before April 2021.Trial Registration: The trial has been registered on ClinicalTrials.gov (July 7, 2020), with identifier number NCT04459286 and on Pan African Clinical Trials Registry (August 13, 2020), with identifier number PACTR202008855701534 .Full Protocol: The full protocol is attached as an additional file which will be made available on the trial website. In the interest of expediting dissemination of this material, the traditional formatting has been eliminated, and this letter serves as a summary of the key elements in the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2). [ABSTRACT FROM AUTHOR]

Imatinib, a tyrosine kinase inhibitor, is the drug of choice for the treatment of chronic myeloid leukemia in Nigeria. Several studies have established interindividual and interpopulation variations in imatinib disposition although no pharmacokinetic study have been conducted in an African population since the introduction of the drug. This study explored a population pharmacokinetic approach to investigate the disposition of imatinib in Nigerians and examined the involvement of some covariates including genetic factors in the variability of the drug disposition with a view to optimize the use of the drug in this population. A total of 250 plasma concentrations from 126 chronic myeloid leukemia patients were quantified using a validated method. A population pharmacokinetic model was fitted to the data using NONMEM VII software, and the influences of 12 covariates were investigated. The mean population-derived apparent steady-state clearance, elimination half-life, area under the concentration-time curve over 24 hours, and volume of distribution were 17.2 ± 1.8 L/h., 12.05 ± 2.1 hours, 23.26 ± 0.6 μg·h/mL, and 299 ± 20.4 L, respectively. Whole blood count, ethnicity, CYP3A5*3, and ABCB1 C3435T were found to have significant influence on the apparent clearance, while the interindividual variability in clearance and interoccasion variability in bioavailability were 17.4% and 20.4%, respectively. There was a wide variability in apparent clearance and area under the curve compared to those reported in other populations. Thus, treatment with a standard dose of imatinib in this population may not produce the desired effect in most of the patients, whereas continuous exposure to a low drug concentration could lead to pharmacokinetic-derived resistance. The authors suggest the need for therapeutic drug monitoring-guided dose individualization in this population. [ABSTRACT FROM AUTHOR]

Introduction Thiopurine S-methyltransferase (TPMT) methylates clinically relevant thiopurine drugs most of which are noted for adverse reactions in certain users, largely due to polymorphisms in the TPMT gene. Aim This study investigated the prevalence of functionally relevant TPMT alleles in the Nigerian population. Material and methods One hundred eighty unrelated subjects consisting of 123 males and 57 females from the main Nigerian ethnicities (44 Igbo, 101 Yoruba, 23 Hausa and 12 from other minor ethnic groups) were genotyped for TPMT*2 , *3B , *3C and *4 alleles using the iPLEX genotyping assay technique. The genotype calls were validated with Sanger sequencing in a random set of samples and the acquired data were assessed for Hardy–Weinberg equilibrium using the Fisher's exact test. Results and discussion Defective TMPT alleles were found in individuals representing 10% of the study population. TPMT*3C constituted 9.4% (95% CI, 5.6–14.7) of all alleles detected, with one homozygote and 17 heterozygotes recorded. The prevalence of the TPMT*3C allele in the population conformed with Hardy–Weinberg equilibrium. TPMT*2 , 3B and *4 were, however, not detected in the population. Conclusions TPMT*3C was the only defective allele identified in Nigerians and may hence be the major underlying genetic contributor to adverse reactions due to thiopurine drugs in the population. [ABSTRACT FROM AUTHOR]

Background: In Nigeria, since 2002, Imatinib mesylate (glivec ® ) has been available freely to chronic myeloid leukaemia (CML) patients but only at a tertiary health care centre in the southwestern part of the country. Despite this, it is not readily accessible to many patients due to the distance and other challenges including low socioeconomic status and political problems, preventing timely access to specialist care. This study evaluated the effect of the baseline characteristics on the prognostic implication and treatment outcome of CML patients in Nigeria., Method: This study retrospectively evaluated the baseline characteristics, clinical presentations and treatment outcomes of 889 CML patients over 18 years (2002-2020). Of these, 576 (65%) patients had complete information with up-to-date BCR::ABL1 records. These 576 patients were categorized based on their responses to Imatinib therapy into three groups viz.; Optimal response (OR) defined as BCR::ABL1 ratio of < 0.1% or major molecular remission (≥ 3-log reduction of BCR::ABL1 mRNA or BCR::ABL1 ratio of < 0.1% on the International Scale), Suboptimal response (SR) with BCR::ABL ratio of 0.1-1%, and Treatment failure (TF) when MMR has not been achieved at 12 months. The variables were analyzed using descriptive and inferential statistics and a p-value < 0.05 was considered statistically significant., Results: The result revealed a median age of 37 years at diagnosis with a male-to-female ratio of 1.5:1. The majority (96.8%) of the patients presented with one or more symptoms at diagnosis with a mean symptom duration of 12 ± 10.6 months. The mean Sokal and EUTOS scores were 1.3 ± 0.8 and 73.90 ± 49.09 respectively. About half of the patients presented with high-risk Sokal (49%) and EUTOS (47%) scores. Interestingly, both the Sokal (r = 0.733, p = 0.011) and EUTOS (r = 0.102, p = 0.003) scores correlated positively and significantly with the duration of symptoms at presentation. Based on response categorization, 40.3% had OR while 27.1% and 32.6% had SR and TF respectively., Conclusion: This study observed a low optimal response rate of 40.3% and treatment failure rate of 32.6% in our CML cohort while on first-line Imatinib therapy. This treatment response is strongly attributable to the long duration of symptoms of 12 months or more and high Sokal and EUTOS scores at presentation. We advocate prompt and improved access to specialist care with optimization of tyrosine kinase inhibitor therapy in Nigeria., (© 2024. The Author(s).)

The Nigerian population exhibits huge ethnic and genetic diversity, typical of African populations, which can be harnessed for improved drug-response and disease management. Existing data on genes relevant to drug response, so far generated for the population, indeed confirm the prevalence of some clinically significant pharmacogenes. These reports detail prevailing genetic alleles and metabolic phenotypes of vital drug metabolizing monooxygenases, transferases and drug transporters. While the utilization of existing pharmacogenomic data for healthcare delivery remains unpopular, several past and on-going studies suggest that a future shift toward genotype-stratified dosing of drugs and disease management in the population is imminent. This review discusses the present state of pharmacogenomics in Nigeria and the potential benefits of sustained research in this field for the population.

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.