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1.
AIDS Res Ther ; 21(1): 22, 2024 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627722

RESUMO

BACKGROUND: Initiation of ART among people living with HIV (PLWH) having a CD4 count ≤ 350cells/µl, produces poor immunological recovery, putting them at a high risk of opportunistic infections. To mitigate this, PLWH on ART in Uganda frequently use herbal remedies like Artemisia annua and Moringa oleifera, but their clinical benefits and potential antiretroviral (ARV) interactions remain unknown. This study examined the impact of A. annua and M. oleifera on CD4 count, viral load, and potential ARV interactions among PLWH on ART at an HIV clinic in Uganda. METHODS: 282 HIV-positive participants on antiretroviral therapy (ART) with a CD4 count ≤ 350cells/µl were randomized in a double-blind clinical trial to receive daily, in addition to their routine standard of care either; 1) A. annua leaf powder, 2) A. annua plus M. oleifera, and 3) routine standard of care only. Change in the CD4 count at 12 months was our primary outcome. Secondary outcomes included changes in viral load, complete blood count, and ARV plasma levels. Participants were followed up for a year and outcomes were measured at baseline, 6 and 12 months. RESULTS: At 12 months of patient follow-up, in addition to standard of care, administration of A. annua + M. oleifera resulted in an absolute mean CD4 increment of 105.06 cells/µl, (p < 0.001), while administration of A. annua plus routine standard of care registered an absolute mean CD4 increment of 60.84 cells/µl, (p = 0.001) compared to the control group. The A. annua plus M. oleifera treatment significantly reduced viral load (p = 0.022) and increased platelet count (p = 0.025) and white blood cell counts (p = 0.003) compared to standard care alone, with no significant difference in ARV plasma levels across the groups. CONCLUSION: A combination of A. annua and M. oleifera leaf powders taken once a day together with the routine standard of care produced a significant increase in CD4 count, WBCs, platelets, and viral load suppression among individuals on ART. A. annua and M. oleifera have potential to offer an affordable alternative remedy for managing HIV infection, particularly in low-resource communities lacking ART access. TRIAL REGISTRATION: ClinicalTrials.gov NCT03366922.


Assuntos
Fármacos Anti-HIV , Artemisia annua , Infecções por HIV , Moringa oleifera , Humanos , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Hospitais , Encaminhamento e Consulta , Uganda , Carga Viral , Método Duplo-Cego
2.
PLoS One ; 19(1): e0289851, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38241225

RESUMO

Although the roles of Medicines and therapeutic committees (MTCs) have been expanding, there is limited information on the role of their structure in optimal antibacterial use in hospitals, especially in low-and-middle-income countries. Our study explored the structure and role of MTC in supporting antibacterial use in regional referral, general hospitals and tertiary private not-for-profit (PNFP) hospitals in Uganda. We conducted an explanatory sequential mixed-method approach with triangulation to explore the structure and functional role of MTCs from August 2019 to February 2020 in hospitals in Uganda. Quantitative data was collected using an interviewer-administered questionnaire among chairpersons or secretaries of MTCs and was analysed using descriptive statistics. We conducted key informant interviews using an interview guide among long-term serving members of MTCs to collect qualitative data which triangulated the quantitative data. The study revealed that sixteen hospitals had successfully established MTCs with an average duration of the MTCs' existence of 5.6 (+2.7) years. The membership of the MTCs varied between 7 and 14, with a median value of 10, and the majority of members in MTCs were pharmacists (15 out of 16) and clinical specialists (13 out of 16). The most frequent subcommittees of the 16 hospitals MTC were supply chain (n = 14), antimicrobial stewardship (n = 13), and infection control (n = 12). Majority (14 out of 16) of the MTCs supported availability and access of antibacterial use by selecting and evaluating antibacterials agents for their formulary lists using established criteria. Additionally, 15 out 16 MTCs conducted antimicrobial stewardship activities to support optimal antimicrobial use. In our study, MTC membership and subcommittees were critical structural components that aided the selection and evaluation antibacterials on hospital formulary lists and they supported optimal antibacterial use through implementing various antimicrobial stewardship activities. There is a need for the Ministry of Health to conduct more training on operationalising MTCs structures in all hospitals.


Assuntos
Hospitais , Comitê de Farmácia e Terapêutica , Humanos , Uganda , Antibacterianos/uso terapêutico , Farmacêuticos
3.
Clin Transl Sci ; 17(1): e13683, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37957894

RESUMO

Drug regulatory institutions, infrastructures, and systems are becoming increasingly interconnected across national boundaries and increasingly global in outlook. This process is reflected in the broadening and deepening application of the principles and practice of Regulatory Reliance, and parallel initiatives to strengthen the capacities of regulatory institutions in low- and middle-income countries (LMICs). Although these developments are important and constructive, they have tended to be framed in terms of the transfer of systems, knowledge, and skills from relatively "mature" regulatory agencies in high-income countries (HICs) to less-well-resourced regulatory agencies in LMICs. This framing recognizes and foregrounds the considerable practical challenges that many LMIC regulatory agencies face, but in doing so, also backgrounds and underestimates the significance of the different contextual insights that LMIC health researchers and regulators can bring to the regulatory deliberations of their HIC counterparts. This position paper argues that the systematic pursuit, identification, and sharing of these different contextual insights-a dimension of regulatory science that we term "Regulatory Complementarity"-can augment the current practice and goals of Regulatory Reliance, and further invigorate the emerging global regulatory ecosystem.


Assuntos
Países em Desenvolvimento , Controle de Medicamentos e Entorpecentes , Humanos
4.
In Silico Pharmacol ; 11(1): 31, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37899968

RESUMO

Combination pharmacotherapy is becoming increasingly necessary because most diseases are pathophysiologically controlled at the subcellular level by target proteins in a combinatorial manner. We demonstrate the application of the stimulus-response mechanistic model in characterising the drug and physiological properties of pharmacodynamic drug-drug interactions (PDDI) using previously published in vitro and in vivo drug combination experiments. The in vitro experiment tested the effect of a combination of SCH66336 and 4-HPR on the survival of in squamous cell carcinoma cell lines, while the in vivo experiment tested the effect of a combination of cetuximab and cisplatin on tumour growth inhibition in female xenograft mice. The model adequately described both experiments, quantified both system and drug properties and predicted the nature of the PDDI mechanism. Strong baseline signals of 7.35 and 610 units existed in the in vitro and in vivo experiments respectively. An overall synergistic relationship (interaction index = 1.03E-8) was detected in the in vitro experiment. In the in vivo model, the overall interaction index was 70,139.45 implying an antagonistic interaction between the cisplatin and the cetuximab signals.

6.
J Multidiscip Healthc ; 16: 635-651, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36919184

RESUMO

Purpose: The study aimed to document the existing knowledge and practices related to breast cancer recognition and treatment using medicinal plants by traditional health practitioners in Central Uganda. Methods: This cross-sectional exploratory survey, conducted between February and August 2020, applied a mixed methods research approach. A semi-structured questionnaire was administered to 119 traditional health practitioners (THPs) in Kampala, Wakiso and Mukono. Content analysis of qualitative data was done. Quantitative ethnobotanical survey indices, namely user reports (Nur), percentage of respondents with knowledge (PRK), informant consensus factor (Fic), fidelity level (FL), preference ranks (PR) and direct matrix ranking (DMR) were determined. Results: Most THPs recognized breast cancer by breast swelling (n=74, 62.2%) and breast pain (n=29, 24.4%). They cited 30 plants from 30 genera in 23 families (Fic 0.75 on breast cancer). Asteraceae, Apocynaceae, Euphorbiaceae, Fabaceae, Lamiaceae and Rutaceae were the predominant families. The ten most cited plants were Annona muricata L. (Nur=24), Rhoicissus tridentata (L.f.) Wild & R.B.Drumm (Nur =19), Erythrococca bongensis Pax (Nur=11), Ficus sp. (Nur=10), Cannabis sativa L. (Nur=8), Ipomoea wightii (Wall.) Choisy (Nur=7), Erythrina abyssinica DC. (Nur=5), Leucas martinicensis (Jacq.) R.Br. (Nur=4), Abelmoschus esculentus (L.) Moench (Nur=4) and Zanthoxylum chalybeum Engl. (Nur=3). Annona muricata L. was highly preferred by THPs (PR 1), Ficus sp. had highest fidelity level (FL=77%) and Zanthoxylum chalybeum Engl. ranked as the highest multipurpose plant (DMR 1). Herbs (n=14, 47%) were the most commonly used life forms besides trees (n=11, 37%) and shrubs (n=5, 16%). THPs mostly used leaves (46%), prepared decoctions (82%) and applied residues on the breast. Conclusion: THPs in Central Uganda recognized breast cancer by symptoms. Medicinal plants applied in its folk treatment have been documented and the claims of cure by THPs merit further investigation.

7.
Afr Health Sci ; 23(4): 21-27, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38974262

RESUMO

Background: The current six months regimen for drug-susceptible tuberculosis (TB) is long, complex, and requires adherence monitoring. TB hair drug level assay is one innovative approach to monitor TB treatment adherence however, its acceptability in the context of African multi-cultural settings is not known. Objective: To determine the acceptability of hair harvest and testing as a TB therapeutic drug monitoring method. Methods: The study explored perceptions, and lived experiences among TB patients with regard to using hair harvest and testing as a method of tuberculosis therapeutic drug monitoring in the context of their cultural beliefs, and faith. We used a descriptive phenomenological approach. Results: Four main themes emerged namely: participants' perceptions about the cultural meaning of their body parts; perceptions about hair having any medical value or meaning; perceptions about hospitals starting to use hair harvest and testing for routine hospital TB treatment adherence monitoring; and perceived advantages and disadvantages of using hair for treatment adherence monitoring. Overall, we found that using hair to monitor adherence was acceptable to TB patients provided the hair was harvested and tested by a medical worker. Conclusion: Hair harvest for medical testing is acceptable to TB patients on the condition that it is conducted by a medical worker.


Assuntos
Antituberculosos , Monitoramento de Medicamentos , Cabelo , Pesquisa Qualitativa , Tuberculose Pulmonar , Humanos , Feminino , Adulto , Masculino , Antituberculosos/uso terapêutico , Monitoramento de Medicamentos/métodos , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/psicologia , Cabelo/química , Pessoa de Meia-Idade , Adesão à Medicação/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia
8.
Afr Health Sci ; 23(4): 35-41, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38974289

RESUMO

Background: Antiretroviral hair drug levels are currently being used to monitor adherence to HIV treatment. There is currently a dearth of literature on the preferred technique(s) of hair harvest for medical testing in the context of African multicultural settings. Objective: To explore the preferred techniques(s) of hair harvest for medical testing among TB patients. Methods: We used a descriptive phenomenological approach to conduct interviews for 15 TB patients from the 06th through the 24th of June 2022. Data was organized by N-VIVO version 10 and analysed step by step using a thematic analytical approach. Results: Participants aged <30 years were more knowledgeable, positively perceived, and experienced about the salon-based hair cutting technique compared to those aged≥30 years old. Participants aged ≥30 had experience, flexibility to use, and were knowledgeable in all three techniques, Overall, for all age categories (<30,30-40 and >40 years), majority of the respondents were knowledgeable, flexible and experienced in using all the three techniques. Conclusion: The majority of TB patients were knowledgeable, experienced and flexible about the hair cutting techniques however, efforts are needed to educate the youth that hair for medical testing can be cut by any of the three techniques without changing their cosmetic look.


Assuntos
Cabelo , Tuberculose Pulmonar , Humanos , Adulto , Masculino , Feminino , Cabelo/química , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Pessoa de Meia-Idade , Infecções por HIV/tratamento farmacológico , Conhecimentos, Atitudes e Prática em Saúde , Adulto Jovem , Remoção de Cabelo/métodos
9.
Afr Health Sci ; 23(4): 28-34, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38974301

RESUMO

Background: Accumulation of chemicals including drugs in hair has been used in forensic investigations. Studies have reported isoniazid drug levels in the hair of TB patients. Objective: To review literature for evidence on isoniazid hair drug levels as a tool to monitor adherence, exposure, and TB treatment outcomes and the acceptability of using human hair for medical testing. Methods: We reviewed literature through Pubmed, Embase, Medline, google scholar, and google grey literature. The search terms focused on isoniazid/TB hair drug levels, adherence, treatment outcomes, and acceptability of using hair for medical testing. We kept refining our search terms at each step of our search. Results: The initial search yielded 186859 articles, which dropped to 88 after removing duplicates and irrelevant articles and eventually to 14 on further refining our search terms. On full review,2 out of 14 and 1 out of 14 articles touched the area of Isoniazid hair drug levels; adherence, exposure, TB treatment outcomes, and acceptability respectively. Further scrutiny showed that none of the articles had addressed our research question. Conclusion: Literature on Isoniazid hair drug levels among TB patients as a tool to monitor adherence, exposure, and TB treatment outcomes, and its acceptability is limited and more research is needed.


Assuntos
Antituberculosos , Cabelo , Isoniazida , Tuberculose , Humanos , Isoniazida/uso terapêutico , Isoniazida/farmacocinética , Cabelo/química , Antituberculosos/uso terapêutico , Antituberculosos/farmacocinética , Tuberculose/tratamento farmacológico , Resultado do Tratamento , Adesão à Medicação/estatística & dados numéricos
10.
Afr. health sci. (Online) ; 23(4): 21-27, 2023. figures, tables
Artigo em Inglês | AIM (África) | ID: biblio-1532700

RESUMO

Background: The current six months regimen for drug-susceptible tuberculosis (TB) is long, complex, and requires adherence monitoring. TB hair drug level assay is one innovative approach to monitor TB treatment adherence however, its acceptability in the context of African multi-cultural settings is not known. Objective: To determine the acceptability of hair harvest and testing as a TB therapeutic drug monitoring method. Methods: The study explored perceptions, and lived experiences among TB patients with regard to using hair harvest and testing as a method of tuberculosis therapeutic drug monitoring in the context of their cultural beliefs, and faith. We used a descriptive phenomenological approach. Results: Four main themes emerged namely: participants' perceptions about the cultural meaning of their body parts; perceptions about hair having any medical value or meaning; perceptions about hospitals starting to use hair harvest and testing for routine hospital TB treatment adherence monitoring; and perceived advantages and disadvantages of using hair for treatment adherence monitoring. Overall, we found that using hair to monitor adherence was acceptable to TB patients provided the hair was harvested and tested by a medical worker. Conclusion: Hair harvest for medical testing is acceptable to TB patients on the condition that it is conducted by a medical worker


Assuntos
Tuberculose Pulmonar
11.
Afr. health sci. (Online) ; 23(4): 35-41, 2023. figures, tables
Artigo em Inglês | AIM (África) | ID: biblio-1532774

RESUMO

Background: Antiretroviral hair drug levels are currently being used to monitor adherence to HIV treatment. There is currently a dearth of literature on the preferred technique(s) of hair harvest for medical testing in the context of African multicultural settings. Objective: To explore the preferred techniques(s) of hair harvest for medical testing among TB patients. Methods: We used a descriptive phenomenological approach to conduct interviews for 15 TB patients from the 06th through the 24th of June 2022. Data was organized by N-VIVO version 10 and analysed step by step using a thematic analytical approach. Results: Participants aged <30 years were more knowledgeable, positively perceived, and experienced about the salon-based hair cutting technique compared to those aged≥30 years old. Participants aged ≥30 had experience, flexibility to use, and were knowledgeable in all three techniques, Overall, for all age categories (<30,30-40 and >40 years), majority of the respondents were knowledgeable, flexible and experienced in using all the three techniques. Conclusion: The majority of TB patients were knowledgeable, experienced and flexible about the hair cutting techniques however, efforts are needed to educate the youth that hair for medical testing can be cut by any of the three techniques without changing their cosmetic look.


Assuntos
Humanos , Masculino , Feminino , Tuberculose Pulmonar , Infecções por HIV , Cabelo , Técnicas de Laboratório Clínico , Diagnóstico
12.
J Multidiscip Healthc ; 15: 2249-2259, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36225858

RESUMO

Purpose: Antimicrobial resistance is now one of the leading five causes of death globally. This study evaluated the rationality of antibiotic prescriptions at lower primary care levels in three districts of Southwestern Uganda. Methods: This prospective cross-sectional study reviewed 9899 antibiotic prescriptions at 39 health centers following a drug delivery cycle by National Medical Stores in three phases (19 days each on average). Phase 1 started 3 days after delivery, mid-way (Phase 2) and towards the end (Phase 3). The proportion of rationally prescribed antibiotics was determined using a modified criterion by Badar and in reference to Uganda Clinical Guidelines (UCG). Using multivariate logistic regression, the factors associated with rational prescription were determined with 95% confidence intervals. Results: Seven of every 10 antibiotic prescriptions were irrational. Half the prescriptions were made by unauthorized personnel (nurses) and many of the pediatric prescriptions (916, 46.5%) did not bear body weight measurements to guide appropriate dosing. Also, the proportion of rational prescriptions in reference to UCG, 2016 was very low (3387, 34.2%). However, a high proportion of antibiotic prescriptions were legibly written (9462, 95.7%), prescribed by generic names (9083, 91.8%) and had a diagnosis (9677, 97.8%) indicated. Multivariate logistic analysis showed that; availability of medicines (phase 1) (phase 2 AOR=1.14, 95% CI:1.02-1.28, phase 3, AOR=1.23, 95% CI:1.1-1.38), legibly written prescription (AOR=0.61, 95% CI: 0.47-0.78), indication of a date on the prescription (AOR=0.56, 95% CI0.38-0.81) and being a medical officer were factors associated with rational antibiotic prescription. Conclusion: We observed a high rate of irrational prescription in the study sites and the majority of these were by unauthorized personnel. A review of antibiotic use policies and focused interventions is crucial in these settings.

14.
Front Pediatr ; 10: 880355, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35813373

RESUMO

Background: Children living with HIV (CLHIV) and children who are exposed to HIV but uninfected (CHEU) are at increased risk of developing malnutrition. Severely malnourished children have high mortality rates, but mortality is higher in CLHIV/CHEU. This study aims to investigate whether empiric use of an antibiotic with greater antimicrobial sensitivity (ceftriaxone) than standard-of-care (ampicillin plus gentamicin) will reduce mortality among CLHIV/CHEU admitted with severe acute malnutrition. Methods: This is an open label randomized controlled trial involving 300 children; 76 CLHIV and 224 CHEU. The participants are being randomized to receive 1 week of ceftriaxone (n = 150) or standard-of-care (ampicillin/gentamicin) (n = 150), in addition to other routine care. The trial's primary outcome is in-hospital mortality. Secondary outcomes are: length of hospitalization; weight-for-height, weight-for-age and height-for-age z-scores; and pattern/antimicrobial sensitivity of pathogens. In addition, 280 severely malnourished children of unknown serostatus will be tested for HIV at admission to determine the prevalence and factors associated with HIV-infection. Furthermore, all the CLHIV on LPV/r will each provide sparse pharmacokinetic (PK) samples to evaluate the PK of LPV/r among malnourished children. In this PK sub-study, geometric means of steady-state LPV PK parameters [Area Under the Curve (AUC) 0-12h , maximum concentration (Cmax) and concentration at 12 h after dose (C12h)] will be determined. They will then be put in pharmacokinetic-pharmacodynamic (PK-PD) models to determine optimal doses for the study population. Discussion: This study will ascertain whether antibiotics with higher sensitivity patterns to common organisms in Uganda and similar settings, will produce better treatment outcomes. The study will also provide insights into the current pattern of organisms isolated from blood cultures and their antimicrobial sensitivities, in this population. In addition, the study will ascertain whether there has been a significant change in the prevalence of HIV-infection among children presenting with severe malnutrition in the WHO recommended option B plus era, while determining the social/structural factors associated with HIV-infection. There will also be an opportunity to study PK parameters of antiretroviral drugs among severely malnourished children which is rarely done, and yet it is very important to understand the dosing requirements of this population. Trial Registration: ClinicalTrials.gov, identifier: NCT05051163.

15.
PLoS One ; 17(3): e0264339, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35271592

RESUMO

BACKGROUND: Sub-Saharan Africa has the highest burden of malaria in the world. Artemisinin-based combination therapies (ACTs) have been the cornerstone in the efforts to reduce the global burden of malaria. In the effort to facilitate early detection of resistance for artemisinin derivatives and partner drugs, WHO recommends monitoring of ACT's efficacy in the malaria endemic countries. The present systematic meta-analysis study summarises the evidence of therapeutic efficacy of the commonly used artemisinin-based combinations for the treatment of uncomplicated P. falciparum malaria in Sub-Saharan Africa after more than a decade since the introduction of the drugs. METHODS: Fifty two studies carried out from 2010 to 2020 on the efficacy of artemether-lumefantrine or dihydro-artemisinin piperaquine or artesunate amodiaquine in patients with uncomplicated P. falciparum malaria in Sub-Saharan Africa were searched for using the Google Scholar, Cochrane Central Register of controlled trials (CENTRAL), PubMed, Medline, LILACS, and EMBASE online data bases. Data was extracted by two independent reviewers. Random analysis effect was performed in STATA 13. Heterogeneity was established using I2 statistics. RESULTS: Based on per protocol analysis, unadjusted cure rates in malaria infected patients treated with artemether-lumefantrine (ALU), artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DHP) were 89%, 94% and 91% respectively. However, the cure rates after PCR correction were 98% for ALU, 99% for ASAQ and 99% for DHP. CONCLUSION: The present meta-analysis reports the overall high malaria treatment success for artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine above the WHO threshold value in Sub-Saharan Africa.


Assuntos
Antimaláricos , Malária Falciparum , Malária , África Subsaariana/epidemiologia , Amodiaquina/farmacologia , Amodiaquina/uso terapêutico , Antimaláricos/farmacologia , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas , Artesunato/uso terapêutico , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Humanos , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Piperazinas , Plasmodium falciparum , Quinolinas
16.
J Clin Pharm Ther ; 47(2): 135-138, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34254326

RESUMO

WHAT IS KNOWN AND OBJECTIVE: The Anatomical Therapeutic Chemical Classification/Defined Daily Doses (ATC/DDD) methodology is a WHO gold standard for ensuring systematic Drug Utilization Research (DUR) and has been mainly used in the developed world. This article examines the challenges and way forward for using this methodology in resource-limited countries. CONTENT: The ATC/DDD is superior over other methods employed in DUR as it offers a unified medicines regulation and management system at all care levels. The ATC/DDD allows access to standardized and validated information on DUR by: assessing patterns of utilization, defining optimal use levels, identification of gaps, aggregating and analysing statistics for reporting adverse drug reactions, as well as assisting in developing rational medicines use interventions and monitoring their outcomes. WHAT IS NEW AND CONCLUSION: Application of the ATC/DDD methodology is crucial for improved patient management, optimal consumption of national pharmaceutical budgets and policy formulation in resource-limited countries.


Assuntos
Uso de Medicamentos/normas , Países em Desenvolvimento , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Humanos , Uso Excessivo dos Serviços de Saúde/prevenção & controle , Assistência Centrada no Paciente , Organização Mundial da Saúde
17.
J Pers Med ; 11(12)2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34945777

RESUMO

(1) Background: Efavirenz plasma concentration displays wide between-patient variability partly due to pharmacogenetic variation and autoinduction. Pediatric data on efavirenz pharmacokinetics and the relevance of pharmacogenetic variation are scarce, particularly from sub-Saharan Africa, where >90% of HIV-infected children live and population genetic diversity is extensive. We prospectively investigated the short- and long-term effects of efavirenz auto-induction on plasma drug exposure and the influence of pharmacogenetics among HIV-infected Ethiopian children. (2) Method: Treatment-naïve HIV-infected children aged 3-16 years old (n = 111) were enrolled prospectively to initiate efavirenz-based combination antiretroviral therapy (cART). Plasma efavirenz concentrations were quantified at 4, 8, 12, 24, and 48 weeks of cART. Genotyping for CYP2B6, CYP3A5, UGT2B7, ABCB1, and SLCO1B1 common functional variant alleles was performed. (3) Results: The efavirenz plasma concentration reached a peak at two months, declined by the 3rd month, and stabilized thereafter, with no significant difference in geometric mean over time. On average, one-fourth of the children had plasma efavirenz concentrations ≥4 µg/mL. On multivariate analysis, CYP2B6*6 and ABCB1c.3435 C > T genotypes and low pre-treatment low-density lipoprotein (LDL) were significantly associated with higher plasma efavirenz concentration regardless of treatment duration. Duration of cART, sex, age, nutritional status, weight, and SLCO1B, CYP3A5, UGT2B7, and ABCB1 rs3842 genotypes were not significant predictors of efavirenz plasma exposure. (4) Conclusion: Pre-treatment LDL cholesterol and CYP2B6*6 and ABCB1c.3435 C > T genotypes predict efavirenz plasma exposure among HIV-infected children, but treatment-duration-dependent changes in plasma efavirenz exposure due to auto-induction are not statistically significant.

18.
Malar J ; 19(1): 389, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33143714

RESUMO

BACKGROUND: Therapeutic ineffectiveness of artemisinin-based combination therapy (ACT) increases the risk of malaria-related morbidity and mortality, and raises healthcare costs. Yet, little has been done to promote the pharmacovigilance (PV) of ACT ineffectiveness in sub-Saharan Africa, particularly in Uganda. This study aimed to determine the extent and associated factors of the past 6 months reporting of suspected or confirmed ACT therapeutic ineffectiveness by healthcare professionals (HCPs), and difficulties and potential solutions to the PV of ACT therapeutic ineffectiveness. METHODS: Survey of 685 HCPs conducted using a self-administered questionnaire from June to July 2018 in a nationally representative sample of public and private health facilities in Uganda. HCPs disclosed if they had spontaneously reported ACT therapeutic ineffectiveness to appropriate authorities in the previous 6 months. Multivariable logistic regression models were used to identify determinants of past 6-months, HCP-reported ACT therapeutic ineffectiveness. RESULTS: One in five (20%, 137/685; 95% CI 17-23%) HCPs reported ACT therapeutic ineffectiveness to an appropriate authority in the previous 6 months. HCPs commonly reported ACT therapeutic ineffectiveness to immediate supervisors (72%, 106/147), mostly verbally only (80%, 109/137); none had ever submitted a written report of ACT therapeutic ineffectiveness to Uganda's National Pharmacovigilance Centre. Common difficulties of reporting ACT therapeutic ineffectiveness were: unavailability of reporting procedures (31%, 129/421), poor follow-up of treated patients (22%, 93/421) and absence of reporting tools (16%, 68/421). Factors associated with reporting ACT therapeutic ineffectiveness in the past 6 months were: hospital-status (vs other; OR = 2.4, 95% CI 1.41-4.21), HCPs aged under 25 years (OR = 2.2, 95% CI 1.29-3.76), suspicion of ACT therapeutic ineffectiveness in the past 4 weeks (OR = 2.3, 95% CI 1.29-3.92), receipt of patient-complaint(s) of ACT therapeutic ineffectiveness in the past 4 weeks (OR = 2.9, 95% CI 1.62-5.12) and HCPs from northern (vs central; OR = 0.5, 95% CI 0.28-0.93) and western (vs central; OR = 0.4, 95% CI 0.17-0.77) parts of Uganda. CONCLUSION: One in five HCPs reported ACT therapeutic ineffectiveness, mostly verbally to supervisors. The existing adverse drug reaction (ADR)-reporting infrastructure could be leveraged to promote the PV of ACT therapeutic ineffectiveness.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária/prevenção & controle , Farmacovigilância , Resultado do Tratamento , Combinação de Medicamentos , Quimioterapia Combinada/estatística & dados numéricos , Humanos , Uganda
19.
Front Pharmacol ; 11: 406, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32390827

RESUMO

Cyclophosphamide (CPA) containing chemotherapy regimen is the standard of care for breast cancer treatment in sub-Saharan Africa. Wide inter-individual variations in pharmacokinetics (PK) of cyclophosphamide (CPA) influence the efficacy and toxicity of CPA containing chemotherapy. Data on the pharmacokinetics (PK) profile of CPA and its covariates among black African patients is lacking. We investigated population pharmacokinetic/pharmacogenetic/pharmacodynamic (PK-PG-PD) of CPA in Ethiopian breast cancer patients. During the first cycle of CPA-based chemotherapy, the population PK parameters for CPA were determined in 267 breast cancer patients. Absolute neutrophil count was recorded at baseline and day 20 post-CPA administration. A population PK and covariate model analysis was performed using non-linear mixed effects modeling. Semi-mechanistic and empiric drug response models were explored to describe the relationship between the area under concentration-time curve (AUC), and neutrophil toxicity. One compartment model better described CPA PK with population clearance and apparent volume of distribution (VD) of 5.41 L/h and 46.5 L, respectively. Inter-patient variability in CPA clearance was 54.5%. Patients carrying CYP3A5*3 or *6 alleles had lower elimination rate constant and longer half-life compared to wild type carriers. CYP2C9 *2 or *3 carriers were associated with increased clearance of CPA. Patients who received 500 mg/m2 based CPA regimen were associated with a 32.3% lower than average clearance and 37.1% lower than average VD compared to patients who received 600 mg/m2. A 0.1 m2 unit increase in body surface area (BSA) was associated with a 5.6% increment in VD. The mean VD (33.5 L) in underweight group (BMI < 18.5 kg/m2) was significantly lower compared to those of overweight (48.1 L) or obese patients (51.9 L) (p < 0.001). AUC of CPA was positively correlated with neutropenic toxicity. In conclusion, we report large between-patient variability in clearance of CPA. CYP3A5 and CYP2C9 genotypes, BSA, BMI, and CPA dosage regimen influence PK of CPA. Plasma CPA exposure positively predicts chemotherapy-associated neutropenic toxicity.

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