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1.
Int J Clin Pharmacol Ther ; 58(1): 21-28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31657714

RESUMO

OBJECTIVE: Febuxostat, a novel non-purine selective xanthine oxidase inhibitor, is a recommended treatment option for patients with chronic kidney disease (CKD) and hyperuricemia. There are only a few trials on the long-term use of allopurinol and febuxostat for CKD. In this study, we compared the efficacy of allopurinol and febuxostat and their effects on renal function in patients with CKD and hyperuricemia. MATERIALS AND METHODS: This was a retrospective study of adult patients with hyperuricemia and CKD (estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73m2) treated with febuxostat or allopurinol. The proportion of patients who achieved the treatment goal and the difference in efficacy between different drug doses were evaluated. Further, the effects on cardiovascular and renal functions were assessed. Cardiovascular risk is defined as cardiovascular events occurring after treatment initiation. RESULTS: We enrolled 316 patients in the study, with 83 and 233 patients in the allopurinol and febuxostat groups, respectively. The application of linear mixed model for analysis revealed that febuxostat 40 mg was more effective than allopurinol 100 mg in reducing the serum uric acid level. The results indicated that the long-term eGFR slope of the febuxostat group was positive, whereas that of the allopurinol group was negative. CONCLUSION: The results showed that, in patients with CKD and hyperuricemia, febuxostat can be used to reduce the serum uric acid level. The long-term use of febuxostat may exert a protective effect on the kidneys. Moreover, there were no obvious adverse reactions and the patients tolerated the drug well.


Assuntos
Alopurinol/uso terapêutico , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Alopurinol/efeitos adversos , Febuxostat/efeitos adversos , Supressores da Gota/efeitos adversos , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Ácido Úrico/sangue
2.
Yakugaku Zasshi ; 139(12): 1557-1562, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31787645

RESUMO

Severe cutaneous adverse reactions (SCARs) are important in postmarketing drug safety because SCAR patients were highest in the adverse drug reaction relief system of Japan. The SCAR symptoms of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) include high fever, severe mucosal impairment, and epidermal necrosis-induced erosions and blisters. Approximately 600 cases of SJS and 300 cases of TEN are reported annually in Japan. Many suspected drugs such as acetaminophen, lamotrigine, allopurinol, and carbamazepine have been reported. Over the last 15 years, an association between human leukocyte antigen and SJS/TEN onset has been reported with several drugs. Pathophysiological examinations in those reports revealed marked CD8-positive T cell infiltration into epidermal lesions, and the presence of cytotoxic granulysin, soluble Fas ligand, and tumor necrosis factor (TNF)-α in blister fluid. Therefore, SJS and TEN are immunological disorders that lead to epidermal necrosis and are consequently treated with the systemic administration of corticosteroids and with high-dose intravenous immunoglobulin therapy and plasma exchange in severe cases. Additionally, because the epidermal necrosis has characteristics similar to those of organ rejection after transplantation, the administration of cyclosporine, an immunosuppressant that inhibits helper T cell activation, has been attempted. Further, the administration of the TNF-α inhibitor etanercept has also been reported. This review summarizes current knowledge on the mechanisms of onset of SJS/TEN and their treatments.


Assuntos
Acetaminofen/efeitos adversos , Alopurinol/efeitos adversos , Carbamazepina/efeitos adversos , Lamotrigina/efeitos adversos , Síndrome de Stevens-Johnson/etiologia , Corticosteroides/uso terapêutico , Antígenos de Diferenciação de Linfócitos T , Linfócitos T CD8-Positivos/imunologia , Ciclosporina/uso terapêutico , Epiderme/imunologia , Etanercepte/uso terapêutico , Proteína Ligante Fas , Antígenos HLA , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Japão/epidemiologia , Troca Plasmática , Síndrome de Stevens-Johnson/epidemiologia , Síndrome de Stevens-Johnson/terapia , Fator de Necrose Tumoral alfa
3.
Vasc Health Risk Manag ; 15: 539-550, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827327

RESUMO

Background: Left ventricular hypertrophy (LVH), as assessed by measurement of left ventricular mass (LVM), is one of the most important cardiovascular risk factors. It is commonly present in patients with ischemic heart disease (IHD), irrespective of the level of blood pressure; recently, oxidative stress has been shown to be an important factor in its development. The question then arises: can this risk factor be modified by antioxidant treatment (e.g., with allopurinol, a xanthine oxidase inhibitor)? Methods: This is an observational study with a cross-sectional design which explored the association between long-term (>12 months) allopurinol therapy and LV mass index (LVMI) as well as geometry in patients generally receiving standard treatments for IHD. The primary endpoint was LVMI measurement (by 2D-echocardiography) and secondary endpoints included the association of allopurinol use with LV function (ejection fraction), blood pressure, glycemic control, and lipid profile. Results: Ninety-six patients on standard anti-ischemic drug treatment (control group) and 96 patients who were additionally taking allopurinol (minimum dose 100 mg/day) were enrolled. Both groups were matched for age, sex, height, and co-morbidities, but poorer kidney function in the allopurinol group required further sub-group analysis based on renal function. Allopurinol treatment was associated with the lowest LVMI in the patients with normal serum creatinine (median LVMI; 70.5 g/m2): corresponding values were 76.0 and 87.0 in the control group with, respectively, normal and elevated serum creatinine, and 89.5 in the allopurinol group with elevated serum creatinine (P=0.027). In addition, allopurinol was associated with better glycemic control (HbA1c) with a difference of 0.8% (95% CI; 1.3, 0.2) (P=0.004) as compared with control patients. Conclusion: In our population, treatment with allopurinol (presumably because of its anti-oxidant properties) has shown a tendency to be associated with smaller LVM in IHD patients with normal serum creatinine, along with better glycemic control.


Assuntos
Alopurinol/uso terapêutico , Antioxidantes/uso terapêutico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Alopurinol/efeitos adversos , Antioxidantes/efeitos adversos , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos de Casos e Controles , Creatinina/sangue , Estudos Transversais , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/sangue , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
4.
Exp Parasitol ; 206: 107768, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539540

RESUMO

Canine leishmaniosis due to Leishmania infantum is a widespread zoonotic disease. Although aminosidine can be an effective treatment, current therapeutic recommendations do not advocate its use, mainly due to concerns regarding the potential nephrotoxicity and ototoxicity of this drug. The aim of this randomized, blinded, controlled study was to evaluate the nephrotoxicity and ototoxicity of aminosidine-allopurinol combination and compare it with that of meglumine antimonate-allopurinol combination in non-azotemic dogs with leishmaniosis. Forty dogs with leishmaniosis were randomly assigned to be treated with either aminosidine at 15 mg/kg, subcutaneously, once daily for 28 days (group A) or with meglumine antimonate at 100 mg/kg, subcutaneously, once daily for 28 days (group B). In addition to either drug, dogs in both groups were administered allopurinol at 10 mg/kg per os twice daily for 2 months. Kidney function was evaluated through measurement of serum creatinine, urea nitrogen, inorganic phosphorus, and cystatin-c concentrations and complete urinalysis, including protein-to-creatinine ratio, at baseline and after 14, 28, and 60 days from the beginning of the treatment. At the same time points, vestibular and auditory functions were evaluated through neurological examination and brainstem auditory evoked response (BAER) recordings of wave I, wave V, inter-wave I-V latencies, and minimum hearing thresholds. None of the dogs developed clinicopathological evidence of kidney disease during the study. Serum creatinine concentration increased >0.3 mg/dl over baseline in 2 dogs in group A and in 5 dogs in group B. Parameters of kidney function were not significantly different or were improved compared to baseline and the only difference between the two groups was the lower concentration of serum creatinine in group A. None of the dogs developed peripheral vestibular syndrome or hearing impairment. At the end of the study, parameters of auditory function were not significantly different or were improved compared to baseline and there were no differences between the two groups. The results of this study show that the nephrotoxicity and ototoxicity of aminosidine, when administered to non-azotemic dogs with leishmaniosis at 15 mg/kg subcutaneously once daily for 28 days along with allopurinol, is minimal and does not differ from that of meglumine antimonate.


Assuntos
Alopurinol/efeitos adversos , Doenças do Cão/tratamento farmacológico , Audição/efeitos dos fármacos , Rim/efeitos dos fármacos , Leishmaniose Visceral/veterinária , Paromomicina/efeitos adversos , Alopurinol/administração & dosagem , Alopurinol/uso terapêutico , Animais , Cóclea/efeitos dos fármacos , Creatinina/sangue , Doenças do Cão/parasitologia , Cães , Método Duplo-Cego , Combinação de Medicamentos , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Perda Auditiva/induzido quimicamente , Perda Auditiva/veterinária , Injeções Subcutâneas/veterinária , Leishmania infantum , Leishmaniose Visceral/tratamento farmacológico , Masculino , Antimoniato de Meglumina/administração & dosagem , Antimoniato de Meglumina/efeitos adversos , Antimoniato de Meglumina/uso terapêutico , Exame Neurológico/veterinária , Paromomicina/administração & dosagem , Paromomicina/uso terapêutico , Distribuição Aleatória , Vestíbulo do Labirinto/efeitos dos fármacos
5.
Nutr Metab Cardiovasc Dis ; 29(10): 1011-1022, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31378626

RESUMO

BACKGROUND AND AIMS: Systemic reviews and meta-analyses suggest hyperuricemia is a cardiovascular risk factor. The effects of xanthine oxidase inhibitors on cardiac outcomes remain unclear. We assessed the effects of febuxostat and allopurinol on mortality and adverse reactions in adult patients with hyperuricemia. METHODS AND RESULTS: PubMed and EMBASE were searched to retrieve randomized controlled trials of febuxostat and allopurinol from January 2005 to July 2018. The meta-analysis consisted of 13 randomized controlled trials with a combined sample size of 13,539 patients. Febuxostat vs. allopurinol was not associated with an increased risk of cardiac-related mortality in the overall population (OR: 0.72, 95% CI: 0.24-2.13, P = 0.55). Regarding adverse skin reactions, the patients receiving febuxostat had significantly fewer adverse skin reactions than those receiving allopurinol treatment (OR: 0.50, 95% CI: 0.30-085, P = 0.01). Compared with allopurinol, febuxostat was associated with an improved safety outcome of cardiac-related mortality and adverse skin reactions (OR: 0.72, 95% CI: 0.55-0.96, P = 0.02). The net clinical outcome, composite of incident gout and the safety outcome, was not different significantly in the patients receiving febuxostat or allopurinol (OR: 1.04, 95% CI: 0.76-0.1.42, P = 0.79). In sensitivity analyses, a borderline significance was found in the patients randomized to febuxostat vs. allopurinol regarding cardiac-related mortality (OR: 1.29, 95% CI: 1.00-1.67, P = 0.05) after the CARES study was included. CONCLUSION: Febuxostat vs. allopurinol was associated with the improved safety outcome and have comparable mortality and net clinical outcome in patients with hyperuricemia. REGISTRATION NUMBER: PROSPERO(CRD42018091657).


Assuntos
Alopurinol/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Ácido Úrico/sangue , Idoso , Alopurinol/efeitos adversos , Doenças Assintomáticas , Biomarcadores/sangue , Inibidores Enzimáticos/efeitos adversos , Febuxostat/efeitos adversos , Feminino , Gota/sangue , Gota/enzimologia , Gota/mortalidade , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/sangue , Hiperuricemia/enzimologia , Hiperuricemia/mortalidade , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Xantina Oxidase/antagonistas & inibidores
6.
Am J Case Rep ; 20: 1245-1247, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31439827

RESUMO

BACKGROUND Pancytopenia is a hematological condition which is characterized by decreases in all three cellular elements: RBC, WBC, and platelets. As a result, patients with pancytopenia are more prone to anemia, infections, and excessive bleeding. Pancytopenia can be caused by medications or drug interactions that suppress the bone marrow. This case report highlights a drug interaction between allopurinol and mercaptopurine which led to pancytopenia and septic infection, resulting in the patient's death. This could easily have been avoided if a clinical pharmacist had been consulted. CASE REPORT A 55-year-old female patient with a past medical history of gout, depression, back pain, and type 2 diabetes was recently diagnosed with ulcerative colitis and was discharged with a new prescription of mercaptopurine. After 2 months of concurrent use of allopurinol and mercaptopurine, she developed infected foot ulcers, which progressed rabidly to sepsis. At the time, her laboratory findings confirmed pancytopenia. Despite treatment, the patient died. CONCLUSIONS This case illustrates the importance of consulting a clinical pharmacist in order to avoid such medical error. The dose of mercaptopurine should be reduced to 25% of the recommended dose when it is given concurrently with allopurinol to reduce the risk of pancytopenia. Health care providers should think about the significant role of clinical pharmacy services. In our case, there were no clinical pharmacist involved in the care of this patient, and as a result of such negligence, the patient lost her life.


Assuntos
Alopurinol/efeitos adversos , Mercaptopurina/efeitos adversos , Pancitopenia/induzido quimicamente , Sepse/etiologia , Colite Ulcerativa/tratamento farmacológico , Pé Diabético/complicações , Interações de Medicamentos , Evolução Fatal , Feminino , Gota/tratamento farmacológico , Supressores da Gota/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Pessoa de Meia-Idade , Farmacêuticos , Serviço de Farmácia Hospitalar , Encaminhamento e Consulta
7.
Ren Fail ; 41(1): 595-599, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31267805

RESUMO

The aim of this study was to evaluate the efficacy and tolerability of febuxostat in renal transplant recipients who were previously treated with allopurinol (the daily oral dose is 100 mg). A 6-month cohort study was conducted with 46 renal transplant recipients who had hyperuricemia. In 22 patients, treatment was changed from allopurinol to febuxostat (febuxostat was given at an oral dose of 20 mg once a day), and the other 24 patients continued the allopurinol treatment (the daily oral dose is 100 mg). The serum levels of uric acid (UA), creatinine, other biochemical parameters, estimated glomerular filtration rate (eGFR), and adverse events were measured at baseline as well as at 1, 3, and 6 months after the switch to febuxostat. Serum UA levels significantly decreased from 470.82 ± 34.37 to 378.77 ± 51.97 µmol/L in the febuxostat group, and decreased from 469.46 ± 33.47 to 428.21 ± 23.37 µmol/L in the allopurinol group. The eGFR increased from 75.55 to 85.23 mL/min in the febuxostat group, and decreased from 78.79 to 70.31 mL/min in the allopurinol group. In renal transplant recipients, febuxostat reduced the serum UA levels resulting in minor short-term improvement of renal function with no changes in the other biochemical parameters.


Assuntos
Alopurinol/administração & dosagem , Febuxostat/administração & dosagem , Supressores da Gota/administração & dosagem , Hiperuricemia/tratamento farmacológico , Transplante de Rim/efeitos adversos , Adulto , Aloenxertos/efeitos dos fármacos , Aloenxertos/fisiopatologia , Alopurinol/efeitos adversos , Substituição de Medicamentos , Febuxostat/efeitos adversos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/sangue , Hiperuricemia/etiologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transplantados , Resultado do Tratamento , Ácido Úrico/sangue
8.
Mayo Clin Proc ; 94(7): 1147-1157, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31272565

RESUMO

OBJECTIVE: To determine and compare the risk of cardiovascular events and mortality of febuxostat and allopurinol use. PATIENTS AND METHODS: We conducted a cohort study using the Taiwan National Health Insurance Research Database. New users of febuxostat and allopurinol between April 1, 2012 and December 31, 2015 were identified, and the two groups were 1:1 matched by propensity score, benzbromarone use history, renal impairment, and time of drug initiation. The risk of major adverse cardiovascular events (MACEs), venous thromboembolism (VTE), heart failure (HF) hospitalization, atrial fibrillation hospitalization, cardiovascular (CV) death, and all-cause mortality was assessed using Cox proportional hazards models. The dose-response relationship between xanthine oxidase inhibitor use and adverse CV outcomes were also determined. RESULTS: A total of 44,111 patients were included for each group, and all baseline covariates were well matched. Febuxostat users were at a significantly higher risk for HF hospitalization (hazard ratio [HR], 1.22; 95% CI, 1.13-1.33), atrial fibrillation hospitalization (HR, 1.19; 95% CI, 1.05-1.36), and CV death (HR, 1.19; 95% CI, 1.03-1.36) than allopurinol users, whereas no difference was found for the major adverse cardiac events composite endpoint, venous thromboembolism, myocardial infarction, ischemic stroke, and all-cause mortality. The elevated risk of HF hospitalization was consistent throughout the primary and sensitivity analyses. In addition, febuxostat increased the risk of adverse CV outcomes in a dose-dependent manner. CONCLUSION: The use of febuxostat, compared with allopurinol, was associated with a significantly increased risk of adverse CV events. Higher febuxostat doses had a greater impact. Further studies are needed to investigate the mechanisms linking febuxostat to adverse CV outcomes.


Assuntos
Alopurinol/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Gota/tratamento farmacológico , Idoso , Alopurinol/efeitos adversos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Bases de Dados Factuais , Febuxostat/efeitos adversos , Feminino , Gota/mortalidade , Hospitalização , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia
9.
J Surg Res ; 242: 157-165, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31078900

RESUMO

BACKGROUND: Limited data exist that compare the predominant cardiac preservation solutions (CPSs). MATERIALS AND METHODS: The United Network for Organ Sharing database was retrospectively reviewed from January 1, 2004 to March 31, 2018, for donor hearts. Of 34,614 potential donors, 21,908 remained after applying the exclusion criteria. The CPS analyzed included saline, the University of Wisconsin (UW), cardioplegia, Celsior, and Custodiol. The primary endpoints were recipient survival and posttransplant rejection. Logistic and Cox models were used to quantify survival endpoints. RESULTS: Saline was used as the CPS in 2549 patients (12%), UW in 10,549 (48%), cardioplegia in 1307 (6%), Celsior in 5081 (23%), and Custodiol in 2422 (11%). Donor age ranged from 15 to 68 y (mean = 32.0 y, median = 30.0 y), and 71% were male. Adjusted survival probabilities of recipients whose donor hearts were procured with saline was 96% 30 d, 90% 1 y, UW: 97% 30 d, 92% 1 y, cardioplegia: 95% 30 d, 87% 1 y, Celsior: 96% 30 d, 90% 1 y, and Custodiol: 97% 30 d, 92% 1 y. When these comparisons were adjusted for donor age, sex, ethnicity, ischemic time, recipient age, sex, ethnicity, creatinine, ventricular assist device (VAD), length of stay, region and days on waiting list, cardioplegia solution was demonstrated to have a higher risk of death (30 d, 1 y, overall) and posttransplant rejection versus UW (odds ratio 1.70, P = 0.001; odds ratio 1.63, P < 0.001; hazard ratio 1.22, P < 0.001; hazard ratio 1.21, P < 0.001, respectively). CONCLUSIONS: Cardioplegia solutions for cardiac preservation are associated with a higher mortality in heart transplant recipients.


Assuntos
Soluções Cardioplégicas/efeitos adversos , Rejeição de Enxerto/epidemiologia , Insuficiência Cardíaca/cirurgia , Soluções para Preservação de Órgãos/efeitos adversos , Preservação de Órgãos/efeitos adversos , Adenosina/efeitos adversos , Adolescente , Adulto , Idoso , Aloenxertos/efeitos dos fármacos , Alopurinol/efeitos adversos , Dissacarídeos/efeitos adversos , Eletrólitos/efeitos adversos , Feminino , Seguimentos , Glucose/efeitos adversos , Glutamatos/efeitos adversos , Glutationa/efeitos adversos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Coração/efeitos dos fármacos , Insuficiência Cardíaca/mortalidade , Transplante de Coração/efeitos adversos , Histidina/efeitos adversos , Humanos , Insulina/efeitos adversos , Masculino , Manitol/efeitos adversos , Pessoa de Meia-Idade , Preservação de Órgãos/métodos , Cloreto de Potássio/efeitos adversos , Procaína/efeitos adversos , Rafinose/efeitos adversos , Estudos Retrospectivos , Solução Salina/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
10.
J Clin Pharm Ther ; 44(4): 525-533, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30972811

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Tumour lysis syndrome is an oncological emergency, characterized by rapid cytolysis leading to an abrupt rise of serum uric acid levels. The aim of the present meta-analysis is to evaluate the efficacy and safety of febuxostat as a preventive measure in patients at risk of tumour lysis syndrome development, by comparing it with allopurinol administration. METHODS: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov and Google Scholar databases were searched from inception to 15 December 2018. All studies evaluating the effectiveness of febuxostat in preventing tumour lysis syndrome were held eligible. RESULTS AND DISCUSSION: Six studies were included with a total of 658 patients. Compared to allopurinol, febuxostat achieved a similar response rate (OR: 1.39, 95% CI: [0.55, 3.51]) and tumour lysis syndrome incidence (OR: 1.01, 95% CI: [0.56, 1.81]). Serum uric acid levels did not differ between the investigated groups at the second (MD: -0.21 mg/dL, 95% CI: [-1.30, 0.88]) and seventh (MD: -0.43 mg/dL, 95% CI: [-1.38, 0.51]) day of treatment. Elevation of liver function tests was the most common adverse effect, although its incidence was similar among patients treated with allopurinol and febuxostat. WHAT IS NEW AND CONCLUSIONS: The present meta-analysis suggests that febuxostat may serve as an effective alternative to allopurinol in the prevention of tumour lysis syndrome. Future large-scale studies should define the optimal febuxostat dosage, explore the most appropriate population for its administration and better define its safety profile.


Assuntos
Febuxostat/administração & dosagem , Febuxostat/efeitos adversos , Síndrome de Lise Tumoral/prevenção & controle , Alopurinol/administração & dosagem , Alopurinol/efeitos adversos , Animais , Supressores da Gota/administração & dosagem , Supressores da Gota/efeitos adversos , Humanos , Síndrome de Lise Tumoral/sangue , Ácido Úrico/sangue
11.
Joint Bone Spine ; 86(4): 419-427, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30910706

RESUMO

OBJECTIVE: A systematic review and meta-analysis were conducted to investigate the associations of hyperuricemia, gout, and uric acid (UA)-lowering therapy with the risk of fractures. METHODS: Electronic searches on PubMed, the Cochrane Library, and Embase were conducted from inception to January 2, 2019. Observational studies assessing the effects of hyperuricemia, gout, and UA-lowering therapy on fractures were included in the meta-analysis. Summary risk estimates with 95% confidence intervals (CI) were calculated by a random-effects model. RESULTS: A total of 14 eligible studies with 909 803 participants and 64 047 incident fractures were included. The results suggested that hyperuricemia and gout are not associated with any type of fracture (relative risk [RR], 0.98, 95% CI 0.85-1.11; P = 0.71) or osteoporotic fractures (RR, 1.02, 95% CI 0.90-1.14; P = 0.79). Further analysis indicated that hyperuricemia is associated with a lower risk of fractures (RR, 0.80, 95% CI 0.66-0.96; P = 0.02) but not with osteoporotic fractures (RR, 0.84, 95% CI 0.68-1.03; P = 0.10). However, gout is associated with an increased risk of fractures (RR, 1.17, 95% CI 1.04-1.31; P = 0.007) as well as osteoporotic fractures (RR, 1.13, 95% CI 1.00-1.26; P = 0.045). Furthermore, no significant association of UA-lowering therapy with the risk of fractures was found compared with the placebo (RR, 0.88, 95% CI 0.76-1.03; P = 0.11). Evidence supporting a non-linear association between serum UA levels and fractures was found (P < 0.001 for non-linearity), which revealed a U-shaped curve. CONCLUSION: Our meta-analysis revealed that hyperuricemia was associated with lower risk for any type fracture but not associated with osteoporotic fractures; however, gout was associated with an increased risk of any type fracture as well as osteoporotic fractures. Notably, a U-shaped relationship may exist between the serum UA level and fractures. The associations observed in our study may be due to reasons other than causality.


Assuntos
Supressores da Gota/efeitos adversos , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Fraturas por Osteoporose/etiologia , Alopurinol/efeitos adversos , Alopurinol/uso terapêutico , Feminino , Gota/complicações , Gota/diagnóstico , Supressores da Gota/uso terapêutico , Humanos , Hiperuricemia/complicações , Hiperuricemia/diagnóstico , Masculino , Estudos Observacionais como Assunto , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/fisiopatologia , Segurança do Paciente , Medição de Risco
12.
Drugs ; 79(5): 531-541, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30868398

RESUMO

Cardiovascular disease affects more than 90 million Americans. Recent studies support an increased cardiovascular disease risk in inflammatory conditions, such as gout. Increased serum urate levels, or hyperuricemia, are a precursor to gout. Data from meta-analyses have shown hyperuricemia to be linked to hypertension and coronary heart disease. Similarly, gout has been associated with an increased risk of myocardial infarction, cerebrovascular accidents, and death from cardiovascular disease in randomized clinical trials. Urate-lowering therapy reduces serum urate and may decrease systemic inflammation, generation of oxidative species, and reverses endothelial dysfunction through hyperuricemia-dependent or hyperuricemia-independent pathways. Cardioprotective benefits of allopurinol, a first-line agent for the treatment of gout, have been demonstrated to potentially prevent myocardial infarction, stroke, atrial fibrillation, and other cardiovascular diseases in observational studies in select populations. Randomized controlled trials (RCTs) have also examined the role of newer urate-lowering therapies, such as febuxostat and lesinurad, and their risk of cardiovascular-specific mortality in comparison to allopurinol. A large post-marketing study of febuxostat vs. allopurinol showed higher all-cause and cardiovascular-specific mortality in the febuxostat group than in the allopurinol group; a major study limitation was that large numbers of patients were lost to follow-up or discontinued treatment. RCTs are required to assess the comparative effectiveness of urate-lowering therapies, validate findings of observational studies, and to determine which subgroup populations of gout are most likely to benefit from appropriate long-term urate-lowering therapy. This review examines the data for increased cardiovascular disease in gout and potential underlying mechanisms (including hyperuricemia, inflammation, endothelial dysfunction, oxidative stress) and the effect of urate-lowering therapy on cardiovascular disease.


Assuntos
Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Gota/complicações , Gota/tratamento farmacológico , Ácido Úrico/antagonistas & inibidores , Alopurinol/efeitos adversos , Alopurinol/uso terapêutico , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Febuxostat/efeitos adversos , Febuxostat/uso terapêutico , Feminino , Supressores da Gota/uso terapêutico , Humanos , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Masculino , Tioglicolatos/efeitos adversos , Tioglicolatos/uso terapêutico , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/uso terapêutico
14.
Am J Med Sci ; 357(4): 348-351, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30638600

RESUMO

Allopurinol is a first line agent in treating gout, but it also carries the risk of severe side effects. Stevens-Johnson syndrome (SJS) is one of the life threatening severe cutaneous adverse reactions caused by allopurinol. The severity of the severe cutaneous adverse reactions can be categorized based upon the area of skin involvement: (1) erythema multiforme major limited to 1-2 % of the body surface area (BSA); (2) SJS involving <10% of the BSA, (3) SJS and toxic epidermal necrolysis overlap involving 10-30% of the BSA and (4) toxic epidermal necrolysis syndrome involving >30% of the BSA. SJS can be caused by drugs and viruses, the former being more frequent. We report a case of an 85-year-old Han-Chinese female who developed SJS after ingestion of allopurinol 8 days prior to the hospitalization. The patient also had concomitant acute viral illness, which complicated the clinical scenario causing acute renal failure and hemodynamic compromise.


Assuntos
Alopurinol/efeitos adversos , Supressores da Gota/efeitos adversos , Síndrome de Stevens-Johnson/terapia , Lesão Renal Aguda/fisiopatologia , Lesão Renal Aguda/terapia , Lesão Renal Aguda/virologia , Idoso de 80 Anos ou mais , China , Feminino , Humanos , Síndrome de Stevens-Johnson/etiologia , Resultado do Tratamento , Viroses/complicações , Viroses/fisiopatologia , Viroses/terapia
15.
Int J Clin Pract ; 73(5): e13316, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30681751

RESUMO

AIMS: Allopurinol carries a well-known risk of cutaneous adverse reactions (CARs). Although febuxostat, a xanthine-oxidase inhibitor with different chemical structure, has been considered an alternative to allopurinol, post-marketing case reports of life-threatening febuxostat-related CARs have been reported. We aimed to compare the risk of CARs between allopurinol and febuxostat in real-world settings and to assess the impact of the market entry of febuxostat on allopurinol use and associated CARs. METHODS: A nationwide study was conducted using Taiwan's National Health Insurance Research Database. In the new-user cohort study, patients who received their first prescriptions of allopurinol or febuxostat were included, and Poisson regression was used to estimate the incidence rate ratios (IRRs) of CARs. In the interrupted time series analysis, time series data on new users and incidence rate of CARs were divided into three periods based on the reimbursement scheme of febuxostat in Taiwan, and segmented regression models were used to estimate changes in both the level and trend in each period. RESULTS: We identified 526 cases of CARs with 487 among new users of allopurinol and 39 among new users of febuxostat (incidence rate: 15.37 vs 3.48 per 1000 person-years). Allopurinol was associated with higher risk of CARs (adjusted IRR 5.55, 95% CI [3.97-7.76]), mild CARs (1.86, [1.24-2.81]), severe CARs (16.75, [8.87-31.62]) and fatal CARs (16.18, [5.05-51.83]) than febuxostat. The overall incidence rates of xanthine-oxidase inhibitor-related CARs decreased from 15.28 to 14.28 per 1000 person-years after the initial reimbursement of febuxostat and further decreased to 9.46 after the reimbursement coverage of febuxostat expanded; however, the changes were not statistically significant. CONCLUSION: Febuxostat can be considered an alternative for patients carrying risk factors for allopurinol-related CARs. However, since there were fatal cases of febuxostat-related CARs, the closely monitoring of symptoms of CARs during the initiation of febuxostat is still warranted.


Assuntos
Alopurinol/efeitos adversos , Erupção por Droga/etiologia , Febuxostat/efeitos adversos , Supressores da Gota/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Gota/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Análise de Séries Temporais Interrompida , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taiwan , Adulto Jovem
16.
Yonsei Med J ; 60(2): 208-215, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30666843

RESUMO

PURPOSE: Despite morbidities and fatalities, nationwide epidemiologic data for severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), are not widely available. We aimed to investigate SCAR epidemiology over the last two decades in Korea. MATERIALS AND METHODS: We analyzed individual case safety reports (ICSRs) of SCARs in the Korea Adverse Event Reporting System from 1988 to 2013. Administered drugs, demographic profiles, and causality assessment according to the World Health Organization-Uppsala Monitoring Center system were analyzed. RESULTS: A total of 755 SCAR cases (508 SJS/TEN, 247 DRESS) were reported. The number of SCAR ICSRs has been increasing with increasing ICSRs for overall adverse drug events. Since 2010, the number of SCAR ICSRs has increased up to 100 cases/year. Allopurinol was the most common causative drug (SJS/TEN: 10.2%; DRESS: 11.3%; SCAR ICSRs: 10.6%), followed by carbamazepine (SJS/TEN: 8.7%; DRESS: 9.7%; SCAR ICSRs: 8.6%). Regarding drug groups, antiepileptics (19.5%) and antibiotics for systemic use (12.7%) were common causative drug groups. Twenty SCAR-related deaths were recorded. Antibacterials were the most common causes of deaths (8 cases), followed by antiepileptics (5 cases). The potential risk of SCARs was not specified in the drug information leaflet for 40.2% of drugs causing SJS/TEN and 82.5% causing DRESS syndrome in Korea. CONCLUSION: The number of SCAR ICSRs has increased rapidly with recent active pharmacovigilance programs in Korea. Allopurinol and antiepileptics are the most common individual and categorical causative agents, respectively.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Dermatopatias/induzido quimicamente , Alopurinol/efeitos adversos , Antibacterianos/efeitos adversos , Anticonvulsivantes/efeitos adversos , Carbamazepina/efeitos adversos , Rotulagem de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Dermatopatias/mortalidade , Síndrome de Stevens-Johnson/etiologia
17.
Mol Immunol ; 106: 170-177, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30623817

RESUMO

Stevens-Johnson syndrome (SJS) /toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions characterized by widespread epidermal necrosis. Recent studies have indicated that SJS/TEN is a specific immune reaction regulated by T cells. Certain drug serves as foreign antigens that are presented by major histocompatibility complex (MHC) and recognized by T cell receptors (TCRs), inducing adaptive immune responses. However, few studies have performed detailed characterization of TCR repertoire in SJS/TEN, and it remains unclear whether the particular types of TCRs expanded clonally are drug-specific, which would provide a potential underlying mechanism of SJS/TEN. In this study, using high-throughput sequencing, we comprehensively assessed the diversity, composition and molecular characteristics of the TCRß repertoires in 17 SJS/TEN patients associated with three different causative drugs including methazolamide (MZ), carbamazepine (CBZ) and allopurinol (ALP). Systematic analysis of the TCRß sequences revealed that SJS/TEN patients had more highly expanded clones and less TCR repertoire diversity, and the TCR repertoire diversity of these patients showed certain associations with the clinical severity of disease. Similar predominant clonotypes, shared-usage TRBV/TRBJ subtypes and combinations thereof were observed among different subjects with the same causative agent. Our observations provide enhanced understanding of the role of T lymphocytes in the pathogenesis of SJS/TEN and enumerate potential therapeutic targets.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Síndrome de Stevens-Johnson/genética , Alopurinol/administração & dosagem , Alopurinol/efeitos adversos , Carbamazepina/administração & dosagem , Carbamazepina/efeitos adversos , Feminino , Humanos , Masculino , Metazolamida/administração & dosagem , Metazolamida/efeitos adversos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Síndrome de Stevens-Johnson/imunologia , Síndrome de Stevens-Johnson/patologia
18.
Clin Pharmacol Ther ; 105(1): 112-120, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29569740

RESUMO

Specific ethnic genetic backgrounds are associated with the risk of Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) especially in Asians. However, there have been no large cohort, multiple-country epidemiological studies of medication risk related to SJS/TEN in Asian populations. Thus, we analyzed the registration databases from multiple Asian countries who were treated during 1998-2017. A total 1,028 SJS/TEN cases were identified with the algorithm of drug causality for epidermal necrolysis. Furthermore, those medications labeled by the US Food and Drug Administration (FDA) as carrying a risk of SJS/TEN were also compared with the common causes of SJS/TEN in Asian countries. Oxcarbazepine, sulfasalazine, COX-II inhibitors, and strontium ranelate were identified as new potential causes. In addition to sulfa drugs and beta-lactam antibiotics, quinolones were also a common cause. Only one acetaminophen-induced SJS was identified, while several medications (e.g., oseltamivir, terbinafine, isotretinoin, and sorafenib) labeled as carrying a risk of SJS/TEN by the FDA were not found to have caused any of the cases in the Asian countries investigated in this study.


Assuntos
Grupo com Ancestrais do Continente Asiático , Rotulagem de Medicamentos/normas , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/epidemiologia , United States Food and Drug Administration/normas , Alopurinol/efeitos adversos , Anti-Infecciosos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticonvulsivantes/efeitos adversos , Antipsicóticos/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Depuradores de Radicais Livres/efeitos adversos , Humanos , Sistema de Registros , Fatores de Risco , Síndrome de Stevens-Johnson/genética , Estados Unidos/epidemiologia
19.
J Investig Med ; 67(1): 48-51, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30042112

RESUMO

Few studies focus on the relationship between allopurinol and ischemic cerebrovascular disease. The goal of the study was to investigate the association of long-term therapy of allopurinol with the first-time attack of ischemic cerebrovascular disease in Taiwan. We performed a case-control study using the database of the Taiwan National Health Insurance Program. The case group included 14,937 subjects aged 20-84 years with the first-time attack of ischemic cerebrovascular disease from 2000 to 2013. The control group included 14,937 sex-matched and age-matched subjects aged 20-84 years without any type of cerebrovascular disease. Ever use of allopurinol was defined as subjects who had at least a prescription for allopurinol before the index date. The OR and the 95% CI for ischemic cerebrovascular disease associated with allopurinol use were measured by the multivariable logistic regression model. The adjusted OR of ischemic cerebrovascular disease was 0.992 (95% CI 0.989 to 0.996) for subjects with increasing cumulative duration of allopurinol use for every 1 month, compared with never use. In a further analysis, the adjusted OR of ischemic cerebrovascular disease was 0.74 (95% CI 0.57 to 0.96) for cumulative duration of allopurinol use >3 years, compared with never use. Our findings suggest that lone-term therapy of allopurinol >3 years is associated with decreased risk of the first-time attack of ischemic cerebrovascular disease, compared with no allopurinol therapy.


Assuntos
Alopurinol/efeitos adversos , Transtornos Cerebrovasculares/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
20.
J Formos Med Assoc ; 118(1 Pt 2): 371-377, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29941331

RESUMO

BACKGROUND/PURPOSE: Previous studies have reported that the indication and starting dose of allopurinol may be associated with the incidence of hypersensitive reactions. As allopurinol-related severe cutaneous adverse reactions (SCARs) constitute a significant proportion of drug injury relief applications in Taiwan, this study sought to examine allopurinol use and related adverse reactions through an analysis of recent drug injury relief applications. METHODS: Allopurinol-related drug injury relief applications from 1999 to 2016 were collected, and descriptive statistical methods were used to analyze recent applications dating from 2011 to 2016. RESULTS: A total of 174 allopurinol-related drug injury relief applications were submitted between 2011 and 2016, with the majority involving cases over the age of 65 (75.3%; mean age of all cases was 69.2). Most allopurinol-related drug injuries concerned the skin (173 out of 174 cases, 99.4%). The majority of cases had other co-morbidities such as cardiovascular disease/hypertension (86.2%), chronic kidney disease (58.6%), or diabetes (46.6%). Over 70% of cases initiated allopurinol at a dose of 100 mg/day or less. Analysis revealed that the greatest number of cases (44.6%) occurred in those with an estimated glomerular filtration rate (eGFR) between 15 and 60 mL/min/1.73 m2 and who initiated allopurinol at a dose of 100 mg/day. CONCLUSION: Old age and renal dysfunction are key risk factors for allopurinol hypersensitivity. When considering allopurinol for elderly patients with impaired kidney function, a full risk-benefit assessment, dosage adjustments, and careful monitoring may be warranted.


Assuntos
Alopurinol/efeitos adversos , Supressores da Gota/efeitos adversos , Síndrome de Stevens-Johnson/epidemiologia , Síndrome de Stevens-Johnson/etiologia , Adulto , Fatores Etários , Idoso , Alopurinol/administração & dosagem , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Taxa de Filtração Glomerular , Supressores da Gota/administração & dosagem , Humanos , Hipertensão/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/epidemiologia , Medição de Risco , Fatores de Risco , Taiwan/epidemiologia
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