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1.
J Antimicrob Chemother ; 75(8): 2240-2248, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32361755

RESUMO

BACKGROUND: Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure. OBJECTIVES: To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks). METHODS: Plasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809). RESULTS: Statistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%-50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%-24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10-5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT. CONCLUSIONS: This modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.


Assuntos
Infecções por HIV , Inibidores de Integrase de HIV , HIV-1 , Glucuronosiltransferase/genética , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Humanos , Piridonas
2.
Genes (Basel) ; 11(5)2020 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-32370229

RESUMO

Introduction: Alzheimer's disease (AD) is a progressive and irreversible neurological disease. The genetics and molecular mechanisms underpinning differential cognitive decline in AD are not well understood; the genetics of AD risk have been studied far more assiduously. Materials and Methods: Two phase III clinical trials measuring cognitive decline over 48 weeks using Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog, n = 2060) and Clinical Dementia Rating-Sum of Boxes (CDR-SB, n = 1996) were retrospectively genotyped. A Genome-Wide Association Study (GWAS) was performed to identify and replicate genetic variants associated with cognitive decline. The relationship between polygenic risk score (PRS) and cognitive decline was tested to investigate the predictive power of aggregating many variants of individually small effect. Results: No loci met candidate gene or genome-wide significance. PRS explained a very small percentage of variance in rates of cognitive decline (ADAS-cog: 0.54%). Conclusions: These results suggest that incorporating genetic information in the prediction of cognitive decline in AD currently appears to have limited utility in clinical trials, consistent with small effect sizes estimated elsewhere. If AD progression is more heritable soon after disease onset, genetics may have more clinical utility.


Assuntos
Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Idoso , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Ensaios Clínicos como Assunto , Disfunção Cognitiva/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Herança Multifatorial/genética , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
3.
Pharmacogenet Genomics ; 29(6): 132-135, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31058715

RESUMO

GlaxoSmithKline (GSK) conducted pharmacogenetic (PGx) analyses to determine whether genetic variants influence response to belimumab treatment in patients with systemic lupus erythematosus (SLE). We conducted an exploratory genome-wide meta-analysis (GWAS) of 10.9 million genetic variants and the efficacy data from 816 belimumab-treated SLE patients in three phase 3 belimumab clinical studies. Two highly correlated variants, rs293983 and rs364370, in the ANO3 (anoctamin 3) gene region were significantly associated with efficacy as measured by the SLE Response Index (SRI4) with a per-T-allele odds ratio (OR) of 2.15 [95% confidence interval (CI): 1.66-2.79, P=8.0×10]. In contrast, there was no association with SRI4 response in 577 placebo-treated patients (per-T-allele OR: 0.98; 95% CI: 0.74-1.29, P=0.87). A post-hoc analysis by geographic region revealed a strong SRI4 response signal in 157 belimumab-treated patients from Asia (per-T-allele OR=2.85, 95% CI: 1.41-5.74, P=0.0021). On the basis of this encouraging finding in Asian patients, we conducted a confirmatory analysis of the SRI4 end point in an independent phase 3 study of SLE patients from northeast Asia. We found no evidence of an association between rs293983 and SRI4 response in 204 belimumab-treated patients (per-T-allele OR: 0.90, 95% CI: 0.52-1.57, P=0.64). The inability to replicate the observed GWAS effect suggests this was a false positive result; hence, we failed to identify any genetic variants significantly associated with belimumab efficacy.


Assuntos
Anoctaminas/genética , Anticorpos Monoclonais Humanizados/administração & dosagem , Imunossupressores/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Administração Intravenosa , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/genética , Masculino , Testes Farmacogenômicos , Variantes Farmacogenômicos , Resultado do Tratamento
4.
Nat Rev Genet ; 17(4): 197-206, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26972588

RESUMO

Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval. With the exception of oncology, systematic application of efficacy pharmacogenetics has not been integrated into drug discovery and development across the industry. Here, we argue for routine, early and cumulative screening for genetic predictors of efficacy, as an integrated component of clinical trial analysis. Such a strategy would identify clinically relevant predictors that may exist at the earliest possible opportunity, allow these predictors to be integrated into subsequent clinical development and provide mechanistic insights into drug disposition and patient-specific factors that influence response, therefore paving the way towards more personalized medicine.


Assuntos
Descoberta de Drogas , Farmacogenética , Biomarcadores Farmacológicos/análise , Descoberta de Drogas/tendências , Genótipo , Humanos , Farmacogenética/tendências , Medicina de Precisão/tendências , Resultado do Tratamento
5.
Br J Clin Pharmacol ; 76(6): 858-67, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23701202

RESUMO

AIMS: The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. METHODS: Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. RESULTS: The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. CONCLUSIONS: No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects.


Assuntos
Aminoquinolinas , Antimaláricos , Cloroquina , Administração Oral , Adolescente , Adulto , Aminoquinolinas/administração & dosagem , Aminoquinolinas/efeitos adversos , Aminoquinolinas/farmacocinética , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Área Sob a Curva , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Cloroquina/farmacocinética , Método Duplo-Cego , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
6.
Trop Med Int Health ; 16(2): 200-4, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21091860

RESUMO

OBJECTIVES: To determine the frequencies of HLA-B alleles in Ugandan patients in the NORA substudy of the DART trial and to compare HLA-B allele frequencies in those with and without clinically diagnosed hypersensitivity reaction (HSR). METHODS: DNA-based HLA-B genotyping was used to determine HLA alleles in 247 participants who received abacavir, including all six participants ('cases') with clinically diagnosed abacavir HSR. RESULTS: The incidence of clinical abacavir HSR in this double-blinded study was 2.0% (6/300) in the abacavir group. As HLA-B*5701 was absent throughout the entire cohort, including the six HSR 'cases', an association could not be established between HLA-B*5701 and clinically diagnosed abacavir HSR. No other HLA-B*57 alleles were present among the six 'cases'. HLA-B*5703 was the most frequent HLA-B*57 allele among the abacavir-tolerant participants. CONCLUSION: The rate of clinical HSR was low, which may reflect the expected 2-3% clinical false-positive rate seen in previous double-blind randomized studies. The presumption that these cases may be false-positive abacavir HSR is supported by the fact that no HLA-B*5701 alleles were found in the abacavir group. Implementation of prospective HLA-B*5701 screening must be based on benefit/risk considerations within local practice. Clinical risk management remains paramount.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/genética , Infecções por HIV/genética , Antígenos HLA-B/genética , Adulto , Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Método Duplo-Cego , Hipersensibilidade a Drogas/etiologia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Infecções por HIV/tratamento farmacológico , Humanos , Nevirapina/efeitos adversos , Nevirapina/uso terapêutico , Uganda
7.
Pharmacogenomics ; 11(12): 1637-47, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21142906

RESUMO

The 2010 US FDA-Drug Industry Association (DIA) Pharmacogenomics (PGx) Workshop follows a series that began in 2002 bringing together multidisciplinary experts spanning regulatory authorities, medical research, healthcare and industry. This report summarizes the 'Building PGx into Labels' sessions from the workshop, which discussed the critical elements in developing PGx outcomes leading to product labels that inform efficacy and/or safety. Examples were drawn from US prescribing information, which integrated PGx knowledge into medical decisions (e.g., panitumumab, warfarin and clopidogrel). Attendees indicated the need for broader dialog and for guidelines on evidentiary considerations for PGx to be included into product labels. Also discussed was the understanding of appropriate PGx placement on labels; how to encourage adoption by medical communities of label recommendations on PGx tests; and, given the global nature of drug development, worldwide considerations including European Summary of Product Characteristics.


Assuntos
Biomarcadores Farmacológicos/análise , Desenho de Fármacos , Indústria Farmacêutica , Rotulagem de Medicamentos/métodos , Programas Governamentais , Farmacogenética/normas , Indústria Farmacêutica/normas , Rotulagem de Medicamentos/legislação & jurisprudência , Rotulagem de Medicamentos/tendências , Farmacogenética/tendências , Estados Unidos , United States Food and Drug Administration
8.
Pharmacogenomics ; 11(12): 1657-67, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21142908

RESUMO

The 2010 US FDA-Drug Industry Association (DIA) Pharmacogenomics Workshop, the fifth in a series of meetings that begun in 2002, brought together multidisciplinary experts from regulatory authorities, medical research, healthcare and drug development. This article summarizes the 'Designing Pharmacogenomic Studies to be Fit for Purpose' track in which considerations regarding the use of retrospective and prospective studies were examined in relation to their ability to influence treatment decisions and labeling for drugs. The aim of the session, using real-world examples (KRAS/panitumumab and HLA-B*5701/abacavir), was to identify good scientific principles that would guide the design of studies to identify subgroups of responders during development programs (including marketed drugs), which could subsequently be used to guide treatment decisions.


Assuntos
Biomarcadores Farmacológicos , Desenho de Fármacos , Indústria Farmacêutica , Farmacogenética , Projetos de Pesquisa , Biomarcadores Farmacológicos/análise , Indústria Farmacêutica/normas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Farmacogenética/normas , Estados Unidos , United States Food and Drug Administration
9.
Pharmacogenomics ; 10(2): 225-33, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19207023

RESUMO

Abacavir hypersensitivity (ABC HSR) is a treatment-limiting adverse event associated with the use of the antiretroviral medicine, abacavir. The objective of the ABC HSR pharmacogenetics program was to identify clinically useful genetic risk factors to predict an individual patient's risk for ABC HSR. The major histocompatibility complex allele, HLA-B*5701, was identified retrospectively and confirmed with independent sample sets. The clinical utility of prospective HLA-B*5701 screening was demonstrated in a blinded randomized clinical trial and in open-label cohorts. Screening has been incorporated into clinical practice and the ABC HSR pharmacogenetics program has been highlighted as a success by pharmacogenetics researchers. Important lessons from this pharmacogenetics program will be discussed in this paper.


Assuntos
Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/genética , Inibidores da Transcriptase Reversa/efeitos adversos , Hipersensibilidade a Drogas/mortalidade , Antígenos HLA-B/genética , Humanos , Fenótipo , Estudos Prospectivos , Projetos de Pesquisa , Estudos Retrospectivos
10.
Clin Infect Dis ; 46(7): 1111-8, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18444831

RESUMO

BACKGROUND: Although the human leukocyte antigen (HLA)-B*5701 is highly associated with a hypersensitivity reaction (HSR) to abacavir (ABC), variable sensitivities have been reported when clinical data alone have been used to define an ABC HSR. This study evaluated the sensitivity of detection of the HLA-B*5701 allele as a marker of ABC HSRs in both white and black patients, using skin patch testing to supplement clinical diagnosis. METHODS: White and black patients, identified through chart review, were classified as having received a diagnosis of an ABC HSR based on clinical findings only (a clinically suspected ABC HSR) or based on clinical findings and a positive skin patch test result (an immunologically confirmed [IC] ABC HSR). Control subjects were racially matched subjects who tolerated ABC for >/=12 weeks without experiencing an ABC HSR. Patients and control subjects were tested for the presence of HLA-B*5701. Sensitivity, specificity, and odds ratios for the detection of HLA-B*5701 as a marker for an ABC HSR were calculated for white and black participants. RESULTS: Forty-two (32.3%) of 130 white patients and 5 (7.2%) of 69 black patients who met the criteria for clinically suspected HSRs had IC HSRs. All 42 white patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 1945; 95% confidence interval, 110-34,352). Among all white patients with clinically suspected HSRs, sensitivity was 44% (57 of 130 patients tested positive for HLA-B*5701); specificity among white control subjects was 96%. Five of 5 black patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 900; 95% confidence interval, 38-21,045). Among black patients with clinically suspected HSRs, the sensitivity was 14% (10 of 69 tested positive for HLA-B*5701); specificity among black control subjects was 99%. CONCLUSIONS: Although IC ABC HSRs are uncommon in black persons, the 100% sensitivity of HLA-B*5701 as a marker for IC ABC HSRs in both US white and black patients suggests similar implications of the association between HLA-B*5701 positivity and risk of ABC HSRs in both races.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/genética , Antígenos HLA-B/genética , Farmacogenética/métodos , Adolescente , Adulto , Idoso , População Negra , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Testes Cutâneos , Estados Unidos , População Branca
11.
N Engl J Med ; 358(6): 568-79, 2008 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-18256392

RESUMO

BACKGROUND: Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir. METHODS: This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir. RESULTS: The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001). CONCLUSIONS: HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)


Assuntos
Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/diagnóstico , Testes Genéticos , Antígenos HLA-B/genética , Testes do Emplastro , Inibidores da Transcriptase Reversa/efeitos adversos , Adolescente , Adulto , Idoso , Didesoxinucleosídeos/uso terapêutico , Método Duplo-Cego , Hipersensibilidade a Drogas/genética , Hipersensibilidade a Drogas/prevenção & controle , Feminino , Marcadores Genéticos , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/uso terapêutico
12.
Pharm Stat ; 7(2): 121-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17534855

RESUMO

Pharmacogenetics (PGx) - the study of DNA variation in the human genome and the way this impacts the efficacy and safety of medicines - is becoming an increasingly important research tool as physicians, patients, regulatory authorities and payers look for innovative ways to improve the risk:benefit ratio of medicines. While scientific knowledge about PGx is rapidly increasing, implementation of PGx findings to patient care has yet to be fully achieved. One area where significant progress has been made is in the identification of PGx markers associated with variable response to antiretroviral medicines. For example, the major histocompatibility complex HLA-B*5701 allele has been associated with hypersensitivity to abacavir (ABC) by several independent researchers. While PGx associations have been identified largely through retrospective examination, the clinical utility of these PGx markers in patient care has not been prospectively determined in a randomized study. This paper outlines the design of a study to evaluate the utility of prospective screening for HLA-B*5701 to reduce the incidence of ABC hypersensitivity in an ABC-naïve population of HIV-infected subjects. This represents the first fully powered, randomized, blinded, prospective study to determine the clinical utility of PGx screening to reduce drug-associated adverse events in any patient population. This type of trial design may have utility for other important medicines which have treatment-limiting side effects.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Ensaios Clínicos como Assunto/métodos , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/genética , Infecções por HIV/tratamento farmacológico , Antígenos HLA-B/genética , Interpretação Estatística de Dados , Humanos , Farmacogenética , Estudos Prospectivos , Projetos de Pesquisa , Tamanho da Amostra
13.
Pharmacogenet Genomics ; 17(12): 1065-76, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18004211

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are highly effective in the treatment of type 2 diabetes. In some patients, PPARgamma ligands are associated with fluid retention/oedema, for which the mechanism is not fully understood. A pharmacogenetic study was undertaken to investigate effects of variations in 21 candidate genes related to epithelial sodium channel (ENaC) pathways on oedema. This study used DNA samples collected from type 2 diabetes phase III clinical trials of the PPARgamma agonist farglitazar (administered alone or in combination with insulin or glyburide) and investigated oedema reported as an adverse event as phenotype. Initial case-control analysis of oedema identified candidate gene single nucleotide polymorphisms with significant associations. These included three polymorphisms in ENaCbeta subunit (SCNN1B) that showed significant associations (P<0.05) with the two combination treatments in discrete regions of the gene, but not farglitazar treatment alone. Sequencing of SCNN1B in 207 Caucasian participants receiving farglitazar plus insulin or glyburide combination therapies, identified additional polymorphisms that were also significantly associated with oedema (P<0.0005) and maintained the treatment-regional associations. Further covariate analysis accounting for clinical factors influencing oedema supported these observations. One of the SCNN1B polymorphisms, at position -405 of the 5' flanking region (rs34241435), was predicted to modify transcriptional interactions and in a transfected COS cell luciferase reporter gene assay exhibited higher promoter activity. These exploratory studies provide clinical pharmacogenetic and functional genomic evidence to support a pivotal role for ENaC regulation in PPARgamma-induced oedema and provide insight into mechanisms and possible management of this side effect.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Edema/etiologia , Canais Epiteliais de Sódio/genética , Oxazóis/efeitos adversos , Tirosina/análogos & derivados , Adulto , Idoso , Sequência de Bases , Primers do DNA/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Edema/metabolismo , Feminino , Genes Reporter , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , PPAR gama/agonistas , Farmacogenética , Fenótipo , Regiões Promotoras Genéticas , Fatores de Risco , Fatores de Tempo , Tirosina/efeitos adversos
14.
Pharmacogenomics ; 5(2): 203-11, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15016610

RESUMO

Abacavir is an effective antiretroviral drug used to treat HIV-1 infection. Approximately 5% of patients treated with abacavir develop a hypersensitivity reaction that requires discontinuation of the drug. In an initial pharmacogenetic study conducted in a predominantly White male population, multiple markers in the human leukocyte antigen (HLA)-B chromosomal region were associated with hypersensitivity to abacavir. The HLA-B*5701 association has now been confirmed in White males in a subsequent, larger study (n=293, p=4.7 x 10(-18)) and is also observed in White females (n=56, p=6.8 x 10(-6)) and Hispanics (n=104, p=2.1 x 10(-4)). HLA-B*5701 was not associated with hypersensitivity in Blacks (n=78, p=0.27). HLA-B*5701 alone lacks sufficient predictive value to identify patients at risk for hypersensitivity to abacavir across diverse patient populations. Efforts are ongoing to identify markers with sufficient sensitivity and specificity to be clinically useful. Even after a marker set is identified, appropriate clinical identification and management of hypersensitivity to abacavir must remain the cornerstone of clinical practice.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Variação Genética , Antígenos HLA-B/genética , População Negra/genética , Estudos de Casos e Controles , Hipersensibilidade a Drogas/metabolismo , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Fator de Necrose Tumoral alfa/genética , População Branca/genética
16.
Lancet ; 359(9312): 1121-2, 2002 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-11943262

RESUMO

Hypersensitivity to abacavir affects about 4% of patients who receive the drug for HIV-1 infection. We did a retrospective, case-control study to identify multiple markers in the vicinity of HLA-B associated with hypersensitivity reactions. HLA-B57 was present in 39 (46%) of 84 patients versus four (4%) of 113 controls (p<0 small middle dot0001). However, because of low numbers of women and other ethnic groups enrolled, these findings relate largely to white men. The lower sensitivity of HLA-B57 for predicting hypersensitivity to abacavir identified in this study compared with a previous report highlights that predictive values for markers will vary across populations. Clinical monitoring and management of hypersensitivity reactions among patients receiving abacavir must remain unchanged.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/diagnóstico , Variação Genética , Antígenos HLA-B/genética , Polimorfismo Genético , Inibidores da Transcriptase Reversa/efeitos adversos , Adulto , Idoso , Estudos de Casos e Controles , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/genética , Feminino , Marcadores Genéticos , Infecções por HIV/tratamento farmacológico , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Grupos Raciais/genética , Estudos Retrospectivos , Sensibilidade e Especificidade , Fator de Necrose Tumoral alfa/genética
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