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1.
Clinics (Sao Paulo) ; 76: e3501, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34817047

RESUMO

OBJECTIVE: To assess the possible factors that influence sleep quality in adolescents with and without chronic immunosuppressive conditions quarantined during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This cross-sectional study included 305 adolescents with chronic immunocompromised conditions and 82 healthy adolescents. Online surveys were completed, which included questions on socio-demographic data and self-rated healthcare routine during COVID-19 quarantine and the following validated questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Pediatric Quality of Life Inventory 4.0 (PedsQL4.0), and Pediatric Outcome Data Collection Instrument (PODCI). RESULTS: The median current age [14 (10-18) vs. 15 (10-18) years, p=0.847] and frequency of female sex (62% vs. 58%, p=0.571) were similar in adolescents with chronic conditions compared with healthy adolescents. The frequency of poor sleep quality was similar in both groups (38% vs. 48%, p=0.118). Logistic regression analysis, including both healthy adolescents and adolescents with chronic conditions (n=387), demonstrated that self-reported increase in screen time (odds ratio [OR] 3.0; 95% confidence interval [CI] 1.3-6.8; p=0.008) and intrafamilial violence report (OR 2.1; 95% CI 1.2-3.5; p=0.008) were independently associated with poor sleep quality in these adolescents. However, the PODCI global function score was associated with a lower OR for poor sleep quality (OR 0.97; 95% CI 0.94-0.99; p=0.001). Further logistic regression, including only adolescents with chronic conditions (n=305), demonstrated that self-reported increase in screen time (OR 3.1; 95% CI 1.4-6.8; p=0.006) and intrafamilial violence report (OR 2.0; 95% CI 1.2-3.4; p=0.011) remained independently associated with poor quality of sleep, whereas a lower PODCI global function score was associated with a lower OR for sleep quality (OR 0.96; 95% CI 0.94-0.98; p<0.001). CONCLUSION: Self-reported increases in screen time and intrafamilial violence report impacted sleep quality in both healthy adolescents and those with chronic conditions. Decreased health-related quality of life was observed in adolescents with poor sleep quality.


Assuntos
COVID-19 , Qualidade de Vida , Adolescente , Criança , Doença Crônica , Estudos Transversais , Feminino , Humanos , Quarentena , SARS-CoV-2 , Sono , Inquéritos e Questionários
4.
Clinics ; Clinics;76: e3501, 2021. tab
Artigo em Inglês | LILACS | ID: biblio-1350624

RESUMO

OBJECTIVE: To assess the possible factors that influence sleep quality in adolescents with and without chronic immunosuppressive conditions quarantined during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This cross-sectional study included 305 adolescents with chronic immunocompromised conditions and 82 healthy adolescents. Online surveys were completed, which included questions on socio-demographic data and self-rated healthcare routine during COVID-19 quarantine and the following validated questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Pediatric Quality of Life Inventory 4.0 (PedsQL4.0), and Pediatric Outcome Data Collection Instrument (PODCI). RESULTS: The median current age [14 (10-18) vs. 15 (10-18) years, p=0.847] and frequency of female sex (62% vs. 58%, p=0.571) were similar in adolescents with chronic conditions compared with healthy adolescents. The frequency of poor sleep quality was similar in both groups (38% vs. 48%, p=0.118). Logistic regression analysis, including both healthy adolescents and adolescents with chronic conditions (n=387), demonstrated that self-reported increase in screen time (odds ratio [OR] 3.0; 95% confidence interval [CI] 1.3-6.8; p=0.008) and intrafamilial violence report (OR 2.1; 95% CI 1.2-3.5; p=0.008) were independently associated with poor sleep quality in these adolescents. However, the PODCI global function score was associated with a lower OR for poor sleep quality (OR 0.97; 95% CI 0.94-0.99; p=0.001). Further logistic regression, including only adolescents with chronic conditions (n=305), demonstrated that self-reported increase in screen time (OR 3.1; 95% CI 1.4-6.8; p=0.006) and intrafamilial violence report (OR 2.0; 95% CI 1.2-3.4; p=0.011) remained independently associated with poor quality of sleep, whereas a lower PODCI global function score was associated with a lower OR for sleep quality (OR 0.96; 95% CI 0.94-0.98; p<0.001). CONCLUSION: Self-reported increases in screen time and intrafamilial violence report impacted sleep quality in both healthy adolescents and those with chronic conditions. Decreased health-related quality of life was observed in adolescents with poor sleep quality.


Assuntos
Humanos , Feminino , Criança , Adolescente , Qualidade de Vida , COVID-19 , Sono , Quarentena , Doença Crônica , Estudos Transversais , Inquéritos e Questionários , SARS-CoV-2
5.
S Afr Med J ; 110(2): 159-166, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32657689

RESUMO

BACKGROUND: Tacrolimus forms the cornerstone for immunosuppression in solid-organ transplantation. It has a narrow therapeutic window with wide inter- and intra-patient variability (IPV). Cytochrome P-450 3A5 (CYP3A5) is the main enzyme involved in tacrolimus metabolism, and rs776746A>G is the most frequently studied polymorphism in the CYP3A5 gene. The rs776746A>G (i.e. CYP3A5*3) single-nucleotide polymorphism in CYP3A5 alters tacrolimus predose trough concentration (C0) and may also affect IPV, which may lead to immune- and/or drug-mediated allograft injury. CYP3A5*3 may result in absent (*3/*3), partial (*1/*3) or normal (*1/*1) CYP3A5 expression. The effect of CYP3A5*3 on tacrolimus exposure and variability has not been examined in South African (SA) transplant recipients. OBJECTIVES: To determine the frequencies and effect of CYP3A5 and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) polymorphisms on tacrolimus C0/dose ratios in different ethnic groups attending a tertiary renal transplant clinic in SA, and other factors that may explain inter- and IPV in tacrolimus C0. METHODS: All consenting stable renal transplant recipients on tacrolimus at the Livingstone Hospital Renal Unit in Port Elizabeth, SA, were included. Tacrolimus concentrations were obtained using a microparticle enzyme immunoassay method (ARCHITECT analyser, Abbott Laboratories). Polymerase chain reaction/restriction fragment length polymorphism was used to genotype for CYP3A5*3 and *6 allelic variants. RESULTS: There were 43 participants (35% black African, 44% mixed ancestry and 21% white), with a mean age of 44.5 years, median duration post-transplant of 47 months and median (interquartile range) creatinine and estimated glomerular filtration rate levels of 118 (92 - 140) µmol/L and 62 (49 - 76) mL/min at study inclusion. The mean tacrolimus C0 in the study was 6.7 ng/mL, with no difference across the different ethnic groups. However, the mean total daily dose of tacrolimus required was 9.1 mg (0.12 mg/kg), 7.2 mg (0.09 mg/kg) and 4.3 mg (0.06 mg/kg) in black, mixed-ancestry and white patients, respectively (p=0.017). The frequencies for CYP3A5 expressors (i.e. CYP3A5*1/*1 + CYP3A5*1/*3 genotypes) were 72%, 100%, 76% and 12% for all patients combined and black, mixed-ancestry and white patients, respectively. The frequencies for CYP3A5 non-expressors (i.e. CYP3A5*3/*3 genotypes) were 0%, 24% and 88% among the black, mixed-ancestry and white patients, respectively. None of the patients carried the CYP3A5*6 allele. CYP3A5*1/*1 and CYP3A5*1/*3 genotype carriers required a two-fold increase in dose compared with the non-expressor genotype carriers, CYP3A5*3/*3 (p<0.05). CYP3A5*3/*3 carriers also demonstrated higher IPV than CYP3A5*1/*1 and *1/*3 carriers (18.1% v. 14.2%; p=0.125). CONCLUSIONS: Compared with global transplant populations, SA renal transplant recipients demonstrated a very high rate of CYP3A5 expression, with a significant impact on tacrolimus pharmacokinetics. Genetic variation in CYP3A5 expression affects tacrolimus dosing requirements, and knowing the CYP3A5 genotype of transplant patients may allow better dose prediction compared with current standard dosing recommendations in a multi-ethnic population. Overall, black African patients required higher doses of tacrolimus than their white counterparts. While further prospective studies are needed to better evaluate dosing algorithms, it would appear that the starting dose of tacrolimus should be higher in black and mixed-race patients.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Tacrolimo/administração & dosagem , Adulto , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Variação Genética , Genótipo , Humanos , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Grupos Raciais/genética , Estudos Retrospectivos , África do Sul , Tacrolimo/farmacocinética
6.
S Afr Med J ; 110(1): 10-15, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31865936

RESUMO

BACKGROUND: Effective combination antiretroviral therapy (cART) has tremendously reduced HIV-associated morbidity, mortality and mother-to-child transmission. However, the benefits of cART are threatened by comorbidities, adverse drug reactions and virus resistance to existing treatment regimens. One of the most occurring comorbidities is cytomegalovirus (CMV) infection. OBJECTIVES: To investigate the effects of cART on the occurrence of CMV infection among pregnant women. METHODS: Using a cross-sectional study design, 175 HIV-infected pregnant women were recruited, and data were obtained from their clinical records. Blood samples were collected for host DNA, CMV DNA and plasma efavirenz (EFV) measurement. CMV DNA was measured using real-time polymerase chain reaction (PCR). CYP2B6 c.516G>T and CYP2B6 c.983T>C single nucleotide polymorphisms were characterised using PCR/restriction fragment length polymorphism and TaqMan assays, respectively. Plasma EFV concentrations were determined using high-performance liquid chromatography. RESULTS: There was an inverse association between plasma EFV concentration and CMV DNA. Participants with lower plasma EFV concentrations were significantly (p<0.001) more likely to be CMV DNA positive than those with higher plasma concentrations. This result is also supported by the observation that carriers of CYP2B6 poor-metaboliser genotypes (CYP2B6 c.516T/T and CYP2B6 c.983T/C) were less likely to be positive for CMV DNA. Furthermore, poor metabolism as denoted by CYP2B6 c.516T/T and CYP2B6 c.983T/C genotypes was significantly associated with lower CMV viral load. CONCLUSIONS: HIV treatment disrupts the balance between host and co-infecting microbes. Reduced or subtherapeutic levels of antiretroviral drugs, which could be exacerbated by genetic polymorphisms in drug metabolism genes and non-adherence, predispose infected individuals to an increased risk of CMV infection in pregnancy.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/etiologia , Benzoxazinas/farmacocinética , Coinfecção/etiologia , Infecções por Citomegalovirus/etiologia , Complicações Infecciosas na Gravidez/etiologia , Inibidores da Transcriptase Reversa/farmacocinética , Infecções Oportunistas Relacionadas com a AIDS/sangue , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Adulto , Alcinos , Benzoxazinas/sangue , Benzoxazinas/uso terapêutico , Coinfecção/sangue , Coinfecção/diagnóstico , Coinfecção/prevenção & controle , Estudos Transversais , Ciclopropanos , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/prevenção & controle , Feminino , Humanos , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/prevenção & controle , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Fatores de Risco
7.
S Afr Med J ; 108(2): 79-81, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29429434

RESUMO

Antiretroviral therapy (ART) has fundamentally altered the natural history of HIV/AIDS, sharply reducing HIV-related morbidity and prolonging longevity. However, there seems to be a resurgence in HIV infection rates in some parts of the world that has prompted consideration of pre-exposure prophylaxis (pre-EP) and vaccination. Despite their good viral suppression profiles, most drugs used as part of ART also have unwanted adverse drug reactions/effects (ADRs). In this article we acknowledge the utility of pre-EP in combating HIV transmission, but we also highlight the need to prepare for management of other unexpected outcomes such as ADRs and viral resistance, to ensure the success of the programme.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/administração & dosagem , Infecções por HIV/prevenção & controle , Profilaxia Pré-Exposição/métodos , Infecções por HIV/epidemiologia , Humanos , África do Sul/epidemiologia , Estudantes , Universidades
9.
Artigo em Inglês | MEDLINE | ID: mdl-29868213

RESUMO

BACKGROUND: The burden of communicable and non-communicable diseases in Sub-Saharan Africa poses a challenge in achieving quality healthcare. Although therapeutic drugs have generally improved health, their efficacy differs from individual to individual. Variability in treatment response is mainly because of genetic variants that affect the pharmacokinetics and pharmacodynamics of drugs. METHOD: The intersection of disease burden and therapeutic intervention is reviewed, and the status of pharmacogenomics knowledge in African populations is explored. RESULTS: The most commonly studied variants with pharmacogenomics relevance are discussed, especially in genes coding for enzymes that affect the response to drugs used for HIV, malaria, sickle cell disease and cardiovascular diseases. CONCLUSIONS: The genetically diverse African population is likely to benefit from a pharmacogenomics-based healthcare approach, especially with respect to reduction of drug side effects, and separation of responders and non-responders leading to optimized drug choices and doses for each patient.

10.
Artigo em Inglês | MEDLINE | ID: mdl-29868223

RESUMO

Partial carrier-resistance to Plasmodium falciparum malaria conferred by the sickle cell (HbS) mutation has resulted in the local amplification and positive selection of sickle cell disease (SCD) in malaria-endemic regions and particularly in sub-Saharan Africa (SSA). The present study investigated the ß-globin gene haplotypes, and selected malaria-associated variants among three cohorts of Bantu-speaking individuals from Malawi, Zimbabwe and South Africa compared with reports with data from others SSA populations. The data suggest a south-ward frequency decrease of malaria-associated variants in SSA linked to the evolutionary dynamics of various African populations' genomes through selective pressure of malaria. These selected genomics differences, positive selection of SCD in malaria-endemic regions among 'Bantus' from various part of Africa emphasise the evidence of the dissociation between genetics, anthropology and culture. The present study also showed a relatively prevalent Benin haplotype, which is mostly found in West Africa, among Southern African Blacks and very low Bantu haplotype, which could suggest a major migration route, of Southern Africa Bantu, along the African west coast, post-occurrence of the Sickle cell mutation, which date remain to be fully elucidated.

11.
S Afr Med J ; 106(6 Suppl 1): S119-23, 2016 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-27245545

RESUMO

BACKGROUND: Apolipoprotein B mRNA-editing catalytic polypeptide like-3G (APOBEC3G) is an antiviral enzyme that reduces viral fitness by introducing uracil to thymidine hypermutations in viral genomes. Thus, polymorphisms in the APOBEC3G gene have been implicated in differential outcomes of HIV infection and disease progression. However, there is insufficient evidence on the role of APOBEC3G gene variants on HIV infection, especially in African populations. This study therefore describes polymorphisms in the APOBEC3G gene in a Zimbabwean paediatric population and evaluates their effects on susceptibility to HIV infection among children born to HIV-infected mothers. Methods. A total of 104 children aged between 7 and 9 years, comprising 68 perinatally exposed to HIV (32 born infected (EI) and 36 born uninfected (EU)) and 36 unexposed and uninfected (UEUI) controls were recruited. Allelic variants (n=5) in the APOBEC3G gene were characterised. Results. Frequencies for minor APOBEC3G alleles in the HIV-uninfected groups (EU and UEUI) were c.557G (40%), g.-90C (32%), g.-571C (12%), c.467-85C (42%), and c.582-162G (6%). APOBEC3G c.467-85C frequency was statistically significantly different when compared to the Masai of Kinyawa, Kenya population (42% v. 18%). None of the single nucleotide polymorphisms individually or as part of haplotypes were significantly associated with HIV infection when comparing the EI and EU groups. Conclusions. Our findings suggest that APOBEC3G polymorphisms alone may not have significant predictive power for inferring genetic susceptibility to vertical transmission of HIV in children perinatally exposed to HIV.


Assuntos
Desaminase APOBEC-3G/genética , Predisposição Genética para Doença , Infecções por HIV/epidemiologia , Transmissão Vertical de Doenças Infecciosas , Alelos , População Negra , Criança , Estudos Transversais , Feminino , Infecções por HIV/genética , Infecções por HIV/transmissão , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Gravidez , Complicações Infecciosas na Gravidez/virologia , Zimbábue/epidemiologia
12.
Clin Genet ; 90(3): 288-90, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27246798

RESUMO

In sub-Saharan Africa GJB2-related nonsyndromic hearing impairment (NSHI) is rare. Ten Cameroonian families was studied using a platform (OtoSCOPE®) with 116 genes. In seven of 10 families (70%), 12 pathogenic variants were identified in six genes. Five of the 12 (41.6%) variants are novel. These results confirm the efficiency of comprehensive genetic testing in defining the causes of NSHI in sub-Saharan Africa.


Assuntos
Conexinas/genética , Surdez/genética , Sequenciamento de Nucleotídeos em Larga Escala , Camarões , Surdez/fisiopatologia , Feminino , Genômica , Genótipo , Humanos , Masculino , Mutação , Linhagem
13.
Artigo em Inglês | MEDLINE | ID: mdl-29868201

RESUMO

Pharmacogenomics has the potential of transforming clinical research and improving healthcare in sub-Saharan Africa (SSA). The role of African genome diversity and the opportunities for pharmacogenomics research are highlighted and will enable discovery of novel genetic mechanisms and validation of established markers. African genomics and biobank consortia will play an important role in building capacity for pharmacogenomics in SSA.

14.
S Afr Med J ; 105(1): 23-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26046157

RESUMO

BACKGROUND: Deafness is the most common sensory disability in the world. Globally, mutations in GJB2 (connexin 26) have been shown to play a major role in non-syndromic deafness. Two other connexin genes, GJB6 (connexin 30) and GJA1 (connexin 43), have been implicated in hearing loss, but these genes have seldom been investigated in black Africans. We aimed to validate the utility of testing for GJB2, GJB6 and GJA1 in an African context. METHODS: Two hundred and five patients with non-syndromic deafness from Cameroon and South Africa had the full coding regions of GJB2 sequenced. Subsequently, a carefully selected subset of 100 patients was further sequenced for GJB6 and GJA1 using Sanger cycle sequencing. In addition, the large-scale GJB6-D3S1830 deletion was investigated. RESULTS: No pathogenic mutations that could explain the hearing loss were detected in GJB2, GJB6 or GJA1, and the GJB6-D3S1830 deletion was not detected. There were no statistically significant differences in genomic variations in these genes between patients and controls. A comprehensive literature review supported these findings. CONCLUSION: Mutations in GJB2, GJB6 and GJA1 are not a major cause of non-syndromic deafness in black Africans and should not be investigated routinely in clinical practice.


Assuntos
População Negra/genética , Conexina 43/genética , Conexinas/genética , Camarões , Conexina 26 , Conexina 30 , Surdez/genética , Deleção de Genes , Testes Genéticos/métodos , Perda Auditiva , Humanos , Mutação , África do Sul
15.
Eur J Endocrinol ; 168(3): 403-12, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23239757

RESUMO

BACKGROUND: Uncertainty exists whether glucocorticoid receptor (GCR) polymorphisms play a role in steroid-related side effects in Addison's disease (AD) patients on hydrocortisone. The polymorphisms Bcll and N363S appear to increase sensitivity to cortisol, while the ER22/23EK polymorphism has been associated with resistance to cortisol. METHOD: One hundred and forty seven AD patients, and gender, and ethnicity-matched controls were recruited in South Africa. Three polymorphisms in the GCR were studied, using PCR followed by restriction fragment length analysis. Associations with BMI, lipids, glucose and inflammatory markers were investigated. RESULTS: In both patients and controls, the Bcll polymorphism occurred more frequently in whites than in other ethnic groups studied but was not associated with any of the metabolic parameters tested. The ER22/23EK polymorphism was associated with an increased BMI in both patients (29.4 vs 24.7  kg/m²) and control subjects (26.3 vs 24.2  kg/m²). The ER22/23EK polymorphism was also associated with lower LDL cholesterol in control subjects (3.46 vs 3.93  mmol/l) and in patients (3.52 vs 4.10  mmol/l). N363S was associated with increased BMI in controls 29.9  kg/m² vs wild type 24.8  kg/m². Median hydrocortisone doses were greater in patients heterozygous for either ER22/23EK 30.0  mg or N363S 25.0  mg polymorphisms than in wild type patients 20.0  mg (both comparisons). CONCLUSION: Alterations in lipids, BMI and hydrocortisone dose were associated with two polymorphisms. Further larger studies are warranted to corroborate these findings.


Assuntos
Doença de Addison/genética , Doença de Addison/fisiopatologia , Resistência a Medicamentos , Hiperlipidemias/etiologia , Sobrepeso/complicações , Polimorfismo Genético , Receptores de Glucocorticoides/genética , Doença de Addison/complicações , Doença de Addison/tratamento farmacológico , Adulto , Índice de Massa Corporal , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Estudos de Associação Genética , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Hidrocortisona/administração & dosagem , Hidrocortisona/efeitos adversos , Hidrocortisona/uso terapêutico , Hiperlipidemias/epidemiologia , Masculino , Pessoa de Meia-Idade , Receptores de Glucocorticoides/metabolismo , Fatores de Risco , África do Sul/epidemiologia
16.
J Neuroimmunol ; 246(1-2): 96-9, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22458981

RESUMO

We investigated the association of an ophthalmoplegic complication developing in African myasthenia gravis (MG) subjects with polymorphisms in the regulatory region of TGFB1. We found significant associations with several putative functional single nucleotide polymorphisms (SNPs) (including two novel SNPs) that potentially alter transcription factor binding. Our data support a hypothesis that altered TGFB1 regulation may predispose individuals who harbour these SNPs to developing ophthalmoplegia as a result of increased TGF-ß1 driven myofibrosis as a consequence to complement-mediated damage.


Assuntos
Miastenia Gravis/imunologia , Miastenia Gravis/patologia , Oftalmoplegia/imunologia , Oftalmoplegia/patologia , Polimorfismo de Nucleotídeo Único/imunologia , Fator de Crescimento Transformador beta1/genética , Fibrose , Humanos , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Miastenia Gravis/genética , Oftalmoplegia/genética , África do Sul , Fator de Crescimento Transformador beta1/biossíntese , Fator de Crescimento Transformador beta1/fisiologia , Regulação para Cima/genética , Regulação para Cima/imunologia
17.
Eur J Clin Pharmacol ; 68(4): 339-47, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22057858

RESUMO

OBJECTIVE: To investigate the influence of CYP2B6 516G>T polymorphism, as a covariate, and of interoccasion variability (IOV) on the oral clearance (CL/F) of efavirenz (EFV) in treatment-naïve black South African children over a period of 24 months post-antiretroviral therapy (ART) initiation. METHODS: HIV-infected black children (n = 60, aged 3-16 years), with no prior exposure to ART, eligible to commence ART and attending an outpatient clinic were enrolled into this study. Blood samples were taken at mid-dose interval at 1, 3, 6, 12, 18 and 24 months post-ART initiation. EFV plasma samples were determined with an adapted and validated LC/MS/MS method. Genotyping of the CYP2B6 G516T single nucleotide polymorphism (SNP) was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). NONMEM was used for the population pharmacokinetic modelling. RESULTS: EFV concentrations below 1 µg/mL accounted for 18% (116/649), EFV concentrations >4 µg/mL accounted for 29.5% (192/649) and concentrations within the therapeutic range (1-4 µg/mL) represented 52.5% (341/649) of all the samples determined. The covariates age, weight and CYP2B6 G516Tgenotype were included in the final model with population estimates for CL/F determined as 2.46, 4.60 and 7.33 L/h for the T/T, G/T and G/G genotype groups respectively. CONCLUSIONS: The inclusion of both age and weight to predict accurate EFV CL values for the respective genotype groups within this paediatric population was required, whereas the addition of gender and body surface area did not improve the predictions. The importance of introducing IOV in a PK model for a longitudinal study with sparsely collected data was again highlighted by this investigation.


Assuntos
Fármacos Anti-HIV/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Benzoxazinas/farmacocinética , Infecções por HIV/genética , Oxirredutases N-Desmetilantes/genética , Inibidores da Transcriptase Reversa/farmacocinética , Adolescente , Alcinos , Fármacos Anti-HIV/sangue , Hidrocarboneto de Aril Hidroxilases/metabolismo , Benzoxazinas/sangue , Criança , Pré-Escolar , Ciclopropanos , Citocromo P-450 CYP2B6 , Feminino , Genótipo , Infecções por HIV/metabolismo , Humanos , Masculino , Modelos Biológicos , Oxirredutases N-Desmetilantes/metabolismo , Polimorfismo Genético , Inibidores da Transcriptase Reversa/sangue , África do Sul
18.
Eur J Clin Pharmacol ; 57(1): 11-7, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11372584

RESUMO

OBJECTIVES: The study was carried out to investigate the distribution of cytochrome P450 2D6 (CYP2D6) and CYP2C19 genotype frequencies in three African populations and to compare these frequencies between healthy individuals and psychiatric patients. METHODS: Three hundred and eighty-four subjects from South Africa (Venda), Tanzania, and Zimbabwe who consented to the study were genotyped for CYP2D6 (CYP2D6*1, *2, *3, *4, *5, and *17) and CYP2C19 (CYP2C19*1, *2, and *3) by PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) techniques. RESULTS: The genotypes for CYP2D6 predicted a poor metabolizer frequency of 2.3% (2/88) in Tanzanian psychiatric patients, 1.9% (2/106) in Tanzanian healthy controls and 2.6% (2/76) in the South African Venda. The low-activity CYP2D6*17 allele frequency was higher in psychiatric patients (30%, 53/176) than in healthy individuals (20%, 43/212) in Tanzanians. The frequencies for CYP2C19*2 genotypes were predictive of a low prevalence of poor metabolizers (PMs). The CYP2C19*3 allele was absent in the three populations studied. There was no difference in CYP2D6 or CYP2C19 PM genotype frequencies between psychiatric patients and healthy subjects. CONCLUSION: The genotype results predict a low prevalence of people with deficient CYP2D6 and CYP2C19 activity among linguistically (Bantu) related populations of East and Southern Africa. The high frequency of the low-activity CYP2D6*17 allele predicts that the Bantu people have a reduced capacity to metabolise drugs that are CYP2D6 substrates.


Assuntos
Hidrocarboneto de Aril Hidroxilases , Citocromo P-450 CYP2D6/genética , Sistema Enzimático do Citocromo P-450/genética , Transtornos Mentais/enzimologia , Transtornos Mentais/genética , Oxigenases de Função Mista/genética , Polimorfismo Genético/genética , Adolescente , Adulto , África Oriental , África Austral , Citocromo P-450 CYP2C19 , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
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