RESUMO
BACKGROUND: Leishmania infantum is an intracellular protozoan parasite which is endemic in countries of the Mediterranean Basin. Leishmaniosis is increasingly diagnosed in non-endemic areas due to the relocation of dogs from endemic areas and the travel of dogs to and from these areas. The prognosis of leishmaniosis in these dogs may differ from that of those in endemic areas. The aims of this study were (1) to determine the Kaplan-Meier estimated survival time for dogs with leishmaniosis in the Netherlands (a non-endemic country), (2) to determine if clinicopathological variables at the time of diagnosis predicted the survival of these dogs, and (3) to evaluate the effect of a two-phase therapy protocol of allopurinol monotherapy followed by meglumine antimoniate and/or miltefosine in the case of incomplete remission or relapse. METHODS: The database of the Department of Clinical Sciences of Companion Animals of the Faculty of Veterinary Medicine, Utrecht University was investigated for leishmaniosis patients. Patient records were reviewed for signalment and clinicopathological data at the time of diagnosis. Only treatment-naive patients were included. Follow-up was performed during the study by phone contact and included treatment received and date and cause of death. Univariate analysis was performed using the Cox proportional hazards regression model. RESULTS: The estimated median Kaplan-Meier survival time was 6.4 years. In the univariate analysis, increases in monocyte, plasma urea and creatinine concentrations, and urine protein to creatinine ratio were all significantly associated with decreased survival time. The majority of patients only received allopurinol monotherapy. CONCLUSIONS: Canine leishmaniosis patients in our study population in the Netherlands, which is non-endemic for the disease, had an estimated Kaplan-Meier median survival time of 6.4 years, which is comparable to the outcome of other reported therapy protocols. Increased plasma urea and creatinine concentrations and monocyte concentration were statistically associated with an increased risk of death. We conclude that initial allopurinol monotherapy for 3 months should be effective in more than half of canine leishmaniosis cases, provided there is adequate follow-up, and that meglumine antimoniate or miltefosine therapy should be started as the second phase of the protocol in cases where remission is incomplete or there is a relapse.
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Doenças do Cão , Leishmania infantum , Leishmaniose Visceral , Leishmaniose , Animais , Cães , Humanos , Antimoniato de Meglumina/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/veterinária , Leishmaniose Visceral/diagnóstico , Alopurinol/uso terapêutico , Prognóstico , Creatinina , Leishmaniose/veterinária , Doenças do Cão/tratamento farmacológico , Doenças do Cão/parasitologia , Recidiva , Ureia/uso terapêuticoRESUMO
OBJECTIVE: To identify prescription medications associated with a lower risk of three neurodegenerative diseases: Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. METHODS: We conducted a population-based, case-control study of U.S. Medicare beneficiaries in 2009 (42,885 incident neurodegenerative disease cases, 334,387 randomly selected controls). Using medication data from 2006-2007, we categorized all filled medications according to their biological targets and mechanisms of action on those targets. We used multinomial logistic regression models, while accounting for demographics, indicators of smoking, and health care utilization, to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 141 target-action pairs and each neurodegenerative disease. For target-action pairs inversely associated with all three diseases, we attempted replication in a cohort study that included an active comparator group. We constructed the cohort by following controls forward for incident neurodegenerative disease from the beginning of 2010 until death or end of 2014, i.e., up to five years after the two-year exposure lag. We used Cox proportional hazards regression while accounting for the same covariates. RESULTS: The most consistent inverse association across both studies and all three neurodegenerative diseases was for xanthine dehydrogenase/oxidase blockers, represented by the gout medication, allopurinol. Allopurinol was associated with a 13-34% lower risk for each neurodegenerative disease group in multinomial regression, and a mean reduction of 23% overall, as compared to individuals who did not use allopurinol. In the replication cohort we observed a significant 23% reduction for neurodegenerative disease in the fifth year of follow-up, when comparing allopurinol users to non-users, and more marked associations with an active comparator group. We observed parallel associations for a related target-action pair unique to carvedilol. DISCUSSION/CONCLUSION: Xanthine dehydrogenase/oxidase blockade might reduce risk of neurodegenerative disease. However, further research will be necessary to confirm that the associations related to this pathway are causal or to examine whether this mechanism slows progression.
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Produtos Biológicos , Doenças Neurodegenerativas , Medicamentos sob Prescrição , Humanos , Idoso , Estados Unidos/epidemiologia , Alopurinol/uso terapêutico , Estudos de Coortes , Medicare , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/epidemiologia , Estudos de Casos e Controles , Xantina Desidrogenase , Prescrições , Estudos RetrospectivosRESUMO
Many studies have been conducted confirming the effect of uric acid (UA) on kidney function. It is obvious that there is a relationship between the effect of UA not only on kidney function, but also on the cardiovascular system, increasing cardiovascular risk. The review article provides basic information about the pathogenesis, principles and features of prescribing therapy to patients with chronic kidney disease (CKD) and cardiovascular disease. A lot of data currently indicates that hyperuricemia, both with and without crystal deposition, is associated with high cardiovascular risk and decreased kidney function. A number of studies and meta-analyses indicate that urate-reducing therapy prevents and slows down the decline in kidney function in patients with CKD, many of whom suffer from cardiovascular diseases or at least have several risk factors. Despite the fact that currently the guidelines for the treatment of CKD do not include a recommendation for the start of urate-lowering therapy, a large amount of data has been accumulated on the potential benefits of such treatment even in the absence of a diagnosis of gout. The preferred group of drugs for this group of patients are xanthine oxidase inhibitors, and for patients with eGFR below 30 ml/min/1.73 m2, it seems that allopurinol currently has larger evidence base for the efficacy and safety of prescribing.
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Doenças Cardiovasculares , Hiperuricemia , Insuficiência Renal Crônica , Humanos , Hiperuricemia/complicações , Hiperuricemia/diagnóstico , Hiperuricemia/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/complicações , Supressores da Gota/uso terapêutico , Ácido Úrico/uso terapêutico , Febuxostat/efeitos adversos , Alopurinol/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , RimRESUMO
Pathophysiologic processes promoted by uric acid, including inflammation and oxidative stress, play a key role in the pathogenesis of several cardiovascular diseases. Furthermore, a number of epidemiological studies have shown an association between uric acid plasma levels and multiple cardiovascular risk factors. This ANMCO statement provides an update on available evidence regarding the association between elevated plasma uric acid levels and cardiovascular disease risk and the safety and efficacy of uric acid lowering agents (allopurinol and febuxostat) used in patients with urate crystal deposits. In addition, it summarizes practical indications for the use of these drugs in at-risk patients or in patients with cardiovascular disease.
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Doenças Cardiovasculares , Gota , Humanos , Ácido Úrico/uso terapêutico , Gota/tratamento farmacológico , Supressores da Gota/efeitos adversos , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/induzido quimicamente , Alopurinol/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Thoracic aortic aneurysm and dissection (TAAD) is a highly lethal vascular disease without effective drug therapy. Whether elevated serum concentrations of uric acid are involved in TAAD development remains unclear. METHODS: Serum uric acid levels were detected in different TAAD mouse models and patients. The urate-lowering drug allopurinol was administered in the drinking water of TAAD mice. Adenine diet-induced mice were established to investigate the role of hyperuricemia in TAAD formation and RNA-sequencing of thoracic aortas from these mice was performed. RESULTS: We found serum uric acid levels were elevated in various mouse TAAD models, including mice fed a ß-aminopropionitrile diet, Marfan mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+), and ApoE-/- mice infused with Ang II (angiotensin II), as well as in patients with TAAD. Administration of urate-lowering drug allopurinol in the drinking water significantly alleviated TAAD formation in ß-aminopropionitrile-treated mice, Fbn1C1041G/+ mice, and Ang II-infused ApoE-/- mice. Moreover, an adenine diet was used to induce hyperuricemia in mice. Intriguingly, a 4-week adenine diet feeding directly induced TAAD formation characterized by increased maximal thoracic aortic diameters and severe elastin degradation, which were ameliorated by allopurinol. Unbiased RNA-sequencing in mouse thoracic aortas suggested that FcγR (Fc gamma receptor) was upregulated upon adenine diet, but reciprocally repressed by allopurinol. Mechanistically, hyperuricemia activated FcγR-mediated ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation to induce macrophage inflammation and TAAD development, which was abrogated by allopurinol or FcγR deficiency. CONCLUSIONS: This study uncovered an important and previously unrecognized role of hyperuricemia in mediating the pathogenesis of TAAD, and uric acid-lowering drug may represent a promising therapeutic approach for TAAD.
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Aneurisma da Aorta Torácica , Dissecção Aórtica , Água Potável , Hiperuricemia , Camundongos , Animais , Ácido Úrico , Aminopropionitrilo/efeitos adversos , Alopurinol/efeitos adversos , Água Potável/efeitos adversos , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Receptores de IgG , Transdução de Sinais , Aneurisma da Aorta Torácica/induzido quimicamente , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/prevenção & controle , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/genética , Dissecção Aórtica/prevenção & controle , RNA , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
An edible sea cucumber Holothuria atra has been hypothesized to have medicinal benefits against hyperuricemia owing to its bioactive compounds, including mono- and poly-unsaturated fatty acids. Herein, we aimed to investigate the fatty acids-rich extract produced from H. atra to treat hyperuricemic rats (Rattus novergicus). The extraction was carried out using n-hexane solvent and then administered to potassium oxonate-induced hyperuricemic rats, with allopurinol acting as a positive control. The extract (50, 100, 150 mg/kg body weight) and allopurinol (10 mg/kg) were administered QD through an oral route using a nasogastric tube. Serum uric acid, creatinine, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and blood urea nitrogen of the abdominal aortic blood were investigated. Our results suggested that the extract was rich in polyunsaturated (arachidonic acid) and monounsaturated fatty acids (oleic acid), in which its administration of 150 mg/kg could significantly reduce serum uric acid (p < 0.001), AST (p = 0.001), and ALT (p = 0.0302). The anti-hyperuricemic activity could be associated with the modulation of GLUT9 by the H. atra extract. In conclusion, the n-hexane extract from H. atra is a potential serum uric acid-lowering agent targeting GLUT9, where further investigations are crucially warranted.
Assuntos
Holothuria , Hiperuricemia , Ratos , Animais , Ácido Úrico , Alopurinol , Ácidos Graxos/metabolismo , Rim/metabolismoAssuntos
Síndrome de Hipersensibilidade a Medicamentos , Hipersensibilidade a Drogas , Humanos , Alopurinol/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Supressores da Gota/efeitos adversos , Progressão da Doença , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/etiologiaRESUMO
Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross-sectional studies. Participants were self-described "White" adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age- and dose-adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age-adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10-4 ). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype-inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose-adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex-specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.
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Alopurinol , Oxipurinol , Masculino , Feminino , Animais , Metoprolol , Estudos Prospectivos , Estudos Transversais , Relação Dose-Resposta a DrogaRESUMO
Introduction Gout in Aotearoa New Zealand (NZ) remains an equity issue. The prevalence in Pacific and Maori people is one of the highest internationally. Although Pacific and Maori experience earlier onset and higher burden of gout, which can severely impact their quality of life, their management of it is often sub-optimal. Aim To conduct a scoping review of the NZ literature for interventions to improve the uptake/management of allopurinol for gout and their evaluation. Methods Databases Medline, Scopus, Embase, and CINAHL Plus and the grey literature were searched systematically to identify all NZ intervention studies aiming to improve allopurinol uptake for gout treatment. Interventions included: if they were delivered in NZ, aimed to improve allopurinol uptake, and were provided in English. A narrative approach was used to extract and synthesise data. Results Eighteen peer-reviewed and grey literature publications met the search criteria. Interventions clustered into three domains: multifaceted or multi-practitioner; gout app; and online booklets or fact sheets. Serum urate levels improved in multi-faceted or multi-practitioner interventions only, whereas the gout app only improved patients' awareness and understanding of gout and medications. Online fact sheets and booklets need more active utilisation from health professionals to improve gout health literacy. Discussion Most gout interventions in NZ use multifaceted or multi-practitioner approaches. Although most interventions successfully controlled serum urate levels and improved equitable access for gout patients to urate-lowering therapy, these interventions did not sustain retention, completion, and engagement for certain population groups, particularly Pacific and Maori, who experience a higher burden of gout.
Assuntos
Alopurinol , Gota , Humanos , Alopurinol/uso terapêutico , Supressores da Gota/uso terapêutico , Ácido Úrico , Nova Zelândia/epidemiologia , Qualidade de Vida , Gota/tratamento farmacológicoRESUMO
A 9-year-old domestic cat, positive for antibodies to feline immunodeficiency virus (FIV), was brought to a veterinary clinic with alopecia, ulcerative skin lesions, and upper respiratory tract (URT) signs. This was after being treated for suspected allergic dermatitis, without clinical improvement, for 2 y. Biopsy of the skin and fine-needle aspirates of the spleen and of the lymph nodes were taken which detected the presence of Leishmania amastigotes. Leishmania infection was further confirmed by detection of a high titer of anti-Leishmania antibodies (≥ 3200) with an indirect fluorescent antibody technique (IFAT) serology. After the diagnosis of feline leishmaniosis (FeL) was made, allopurinol and meglumine antimoniate were started and led to quick and complete clinical improvement. After 7 mo, allopurinol administration was briefly interrupted but was resumed following relapse of the skin lesions. One month later, the cat was treated for suspected acute kidney injury, which prompted reduction of the total daily dose of allopurinol by 50%. The cat remained clinically well, with complete resolution of the cutaneous and URT signs, for nearly 24 mo after the diagnosis of FeL; at which point it was euthanized for worsening cardiac disease. To our knowledge, this represents a rare case of successful treatment of FeL with a suspected nephrotoxic effect associated with long-term use of allopurinol. Further studies are required to clarify the relationship, if any, between leishmaniosis and congestive heart failure in cats.
Suivi à long terme d'un cas de leishmaniose féline traité par une association d'allopurinol et d'antimoniate de méglumine. Un chat domestique de 9 ans, positif pour les anticorps contre le virus de l'immunodéficience féline (FIV), a été présenté dans une clinique vétérinaire avec une alopécie, des lésions cutanées ulcéreuses et des signes des voies respiratoires supérieures (URT). Ceci après avoir été traité pour une suspicion de dermatite allergique sans amélioration clinique, pendant 2 ans. Une biopsie de la peau et des ponctions à l'aiguille fine de la rate et des ganglions lymphatiques ont été réalisées et ont détecté la présence d'amastigotes de Leishmania. L'infection à Leishmania a été confirmée par la détection d'un titre élevé d'anticorps sériques anti-Leishmania (≥ 3200) par une technique d'immunofluorescence indirecte (IFAT). Après le diagnostic de leishmaniose féline (FeL), un traitement à l'allopurinol et l'antimoniate de méglumine a été instauré et a entraîné une amélioration clinique rapide et complète. Après 7 mois, l'administration d'allopurinol a été brièvement interrompue mais a été reprise après la rechute des lésions cutanées. Un mois plus tard, le chat a été traité pour une lésion rénale aiguë suspectée, ce qui a entraîné une réduction de 50 % de la dose quotidienne totale d'allopurinol. Le chat est resté cliniquement en bonne santé, avec une résolution complète des signes cutanés et urinaires, pendant près de 24 mois après le diagnostic de FeL; à quel point il a été euthanasié pour aggravation de la maladie cardiaque.À notre connaissance, ceci représente un cas rare de traitement réussi de FeL avec un effet néphrotoxique suspecté associé à une utilisation à long terme d'allopurinol. D'autres études sont nécessaires pour clarifier la relation, le cas échéant, entre la leishmaniose et l'insuffisance cardiaque congestive chez les chats.(Traduit par Dr Serge Messier).
Assuntos
Injúria Renal Aguda , Doenças do Gato , Leishmaniose , Gatos , Animais , Antimoniato de Meglumina , Alopurinol , Seguimentos , Leishmaniose/veterinária , Injúria Renal Aguda/veterináriaRESUMO
BACKGROUND: Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3-5 chronic kidney disease (CKD) patients with underlying DKD. METHODS: Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2 days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2nd received allopurinol, the 3rd group received linagliptin, and the 4th received both allopurinol and linagliptin. Post-procedure follow-up for kidney functions was conducted for 2 weeks in all patients. RESULTS: 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (p < 0.02 and <0.03, respectively). None of the post-contrast AKI cases required dialysis. CONCLUSION: Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03470454.
Assuntos
Injúria Renal Aguda , Alopurinol , Meios de Contraste , Nefropatias Diabéticas , Linagliptina , Substâncias Protetoras , Humanos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Alopurinol/administração & dosagem , Alopurinol/uso terapêutico , Nefropatias Diabéticas/classificação , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/diagnóstico , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Linagliptina/administração & dosagem , Linagliptina/uso terapêutico , Estudos Prospectivos , Insuficiência Renal Crônica/classificação , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Meios de Contraste/efeitos adversos , Quimioprevenção/métodos , Quimioterapia Combinada , Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/efeitos adversos , Substâncias Protetoras/uso terapêutico , Solução Salina/administração & dosagem , Solução Salina/uso terapêuticoRESUMO
Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but severe cutaneous adverse drug reactions. Certain human leukocyte antigen (HLA) types have been associated with SJS/TEN onset, e.g., HLA-B∗58:01 with allopurinol-induced SJS/TEN, but HLA typing is time-consuming and expensive; thus, it is not commonly used in clinical situations. In the previous work, we demonstrated that the single-nucleotide polymorphisms (SNP) rs9263726 was in absolute linkage disequilibrium with HLA-B∗58:01 in the Japanese population, and can be used as a surrogate marker for the HLA. Here, we developed a new genotyping method for the surrogate SNP using the single-stranded tag hybridization chromatographic printed-array strip (STH-PAS) technique and performed an analytical validation. The results of genotyping rs9263726 using STH-PAS correlated well with those obtained using the TaqMan SNP Genotyping Assay for 15 HLA-B∗58:01-positive and 13 HLA-B∗58:01-negative patients (analytical sensitivity and specificity were both 100%). Additionally, at least 1.11 ng of genomic DNA was sufficient to digitally and manually detect positive signals on the strip. Robustness studies showed that the annealing temperature (66 °C) was the most important condition related to reliable results. Collectively, we developed an STH-PAS method that can rapidly and easily detect rs9263726 for predicting SJS/TEN onset.
Assuntos
Alopurinol , Síndrome de Stevens-Johnson , Humanos , Síndrome de Stevens-Johnson/genética , Técnicas de Genotipagem , Genótipo , População do Leste Asiático , Antígenos HLA-B/genética , BiomarcadoresRESUMO
Calcium stones are common and recurrent in nature, yet few therapeutic tools are available for secondary prevention. Personalized approaches for stone prevention have been informed by 24-hour urine testing to guide dietary and medical interventions. However, current evidence is conflicting about whether an approach guided by 24-hour urine testing is more effective than a generic one. The available medications for stone prevention, namely thiazide diuretics, alkali, and allopurinol, are not always prescribed consistently, dosed correctly, or tolerated well by patients. New treatments on the horizon hold the promise of preventing calcium oxalate stones by degrading oxalate in the gut, reprogramming the gut microbiome to reduce oxalate absorption, or knocking down expression of enzymes involved in hepatic oxalate production. New treatments are also needed to target Randall's plaque, the root cause of calcium stone formation.
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Líquidos Corporais , Cálcio , Humanos , Alopurinol , Álcalis , Doença Crônica , OxalatosAssuntos
Alopurinol , COVID-19 , Humanos , Alopurinol/efeitos adversos , Selectina E , Regulação para Baixo , HospitalizaçãoRESUMO
OBJECTIVE: The purpose of this study was to explore the effects of nanoparticles on gouty arthritis, and to provide evidence for the preclinical application of nanoparticles in gouty arthritis and ideas for nanomedicine improvement for nanoparticle researchers. METHODS: Five databases including the Cochrane Library, PubMed, Scopus, Web of Science, and Embase were searched for eligible studies until April 2022. The quality of the selected studies was assessed by SYRCLE's risk of bias (RoB) tool, and the random-effects model was used to calculate the overall effect sizes of weighted mean differences (WMD). RESULTS: Ten studies met the inclusion criteria. Results showed that nanoparticles were effective in reducing uric acid levels (WMD: -4.91; 95% confidence interval (CI): - 5.41 to - 4.41; p < 0.001), but were not better than allopurinol (WMD: -0.20; 95% CI: - 0.42 to 0.02; p = 0.099). It was worth noting that the nanoparticles were safer than allopurinol. Subgroup analyses indicated that nanoparticle encapsulated substance, animal species, nanoparticle dosage, animal quantity, and animal gender were all sources of heterogeneity. CONCLUSION: The nanoparticles are safe medications for gouty arthritis which can effectively reduce uric acid levels in rodents. Although the results are still uncertain, it is expected to have certain clinical application value. The nanoparticles may be the preclinical medications for gouty arthritis in the future.
Assuntos
Artrite Gotosa , Nanopartículas , Animais , Artrite Gotosa/tratamento farmacológico , Ácido Úrico , Alopurinol/uso terapêuticoRESUMO
BACKGROUNDS: HLA-B*58:01 allele was strongly associated with allopurinol induced severe cutaneous adverse drug reaction (SCAR). However, HLA-B genotype is not sufficient to predict the occurrence of allopurinol-induced SCAR. OBJECTIVE: To discover DNA methylation markers for allopurinol-induced SCAR which may improve the prediction accuracy of genetic testing. STUDY DESIGN: The study was designed as a retrospective case-control clinical study in multicenter hospitals across Taiwan, Mainland China, Malaysia and Canada. 125 cases of allopurinol-induced SCAR patients and 139 cases of allopurinol tolerant controls were enrolled in this study during 2005 to 2021. RESULTS: The results of genome-wide DNA methylation assay of 62 patients revealed that ITGB2 showed strong discriminative ability of allopurinol-induced SCAR in both HLA-B*58:01 positive and negative patients with AUC value of 0.9364 (95% CI 0.8682-1.000). In validation study, significant hypermethylation of ITGB2 were further validated in allopurinol-induced SCAR patients compared to tolerant controls, especially in those without HLA-B*58:01(AUC value of 0.8814 (95% CI 0.7121-1.000)). Additionally, the methylation levels of 2 sites on ITGB2 were associated with SCAR phenotypes. Combination of HLA-B*58:01 genotyping and ITGB2 methylation status could improve the prediction accuracy of allopurinol-induced SCAR with the AUC value up to 0.9387 (95% CI 0.9089-0.9684), while the AUC value of HLA-B*58:01 genotyping alone was 0.8557 (95% CI 0.8030-0.9083). CONCLUSIONS: Our study uncovers differentially methylated genes between allopurinol-induced SCAR patients and tolerant controls with positive or negative HLA-B*58:01 allele and provides the novel epigenetic marker that improves the prediction accuracy of genetic testing for prevention of allopurinol-induced SCAR.
Assuntos
Hipersensibilidade a Drogas , Síndrome de Stevens-Johnson , Humanos , Alopurinol/efeitos adversos , Estudos Retrospectivos , Metilação de DNA , Hipersensibilidade a Drogas/epidemiologia , Antígenos HLA-B/genética , Síndrome de Stevens-Johnson/tratamento farmacológico , Síndrome de Stevens-Johnson/genéticaRESUMO
OBJECTIVE: To evaluate Chinese long-term economic impact of universal human leukocyte antigen B (HLA-B)*58:01 genotyping-guided urate-lowering therapy or febuxostat initiation therapy for gout patients with mild to moderate chronic kidney disease (CKD) from perspective of healthcare system. METHODS: A Markov model embedded in a decision tree was structured including four mutually exclusive health states (uncontrolled-on-therapy, controlled-on-therapy, uncontrolled-off-therapy, and death). Mainly based on Chinese real-world data, the incremental costs per quality-adjusted life years (QALYs) gained were evaluated from three groups (universal HLA-B*58:01 testing strategy, and no genotyping prior to allopurinol or febuxostat initiation therapy) at 25-year time horizon. All costs were adjusted to 2021 levels based on Chinese Consumer Price Index and were discounted by 5% annually. One-way and probability sensitivity analysis were performed. RESULTS: Among these three groups, universal HLA-B*58:01 genotyping was the most cost-effective strategy in base-case analysis according to Chinese average willingness-to-pay threshold of $37 654.50 per QALY. The based incremental cost-effectiveness ratio was $31784.55 per QALY, associated with 0.046 additional QALYs and $1463.81 increment costs per patient at a 25-year time horizon compared with no genotyping prior to allopurinol initiation strategy. Sensitivity analysis showed 64.3% robustness of these results. CONCLUSION: From Chinese perspective of healthcare system, HLA-B*58:01 genotyping strategy was cost-effective for gout patients with mild to moderate CKD in mainland China, especially in the most developed area, such as Beijing and Shanghai. Therefore, we suggest China's health authorities choose the genotyping strategy and make different recommendations according to the differences of local conditions.
Assuntos
Gota , Antígenos HLA-B , Insuficiência Renal Crônica , Humanos , Alopurinol/uso terapêutico , China , Análise Custo-Benefício , População do Leste Asiático , Febuxostat/uso terapêutico , Gota/tratamento farmacológico , Gota/genética , Supressores da Gota/uso terapêutico , Antígenos HLA-B/genética , Anos de Vida Ajustados por Qualidade de Vida , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/genéticaRESUMO
BACKGROUND: During status epilepticus, severe seizures can occur, generating recurrent cycles of excitotoxicity and oxidative stress that cause neuronal damage and cell death. The administration of agents with antioxidant properties represents a therapeutic alternative aimed at reducing the severity of status epilepticus and mitigating the neurobiological consequences that precede them. OBJECTIVE: The objective of this work was to evaluate the antiseizure effect of the antioxidants allopurinol (ALL) and ellagic acid during status epilepticus induced by pilocarpine (PILO). METHODS: Male Wistar rats (200-250 g) were injected with ALL (50 mg/kg) or ellagic acid (50 mg/kg), 30 min before PILO administration (pretreatment) or 60 min after the beginning of status epilepticus, to evaluate the antiseizure effect of these drugs on epileptiform activity and convulsive behavior. RESULTS: ALL or ellagic acid administration before or after PILO significantly decreased the epileptiform activity and the severity of convulsive behavior. Better efficacy was observed when the drugs were administered as a pretreatment, increasing the latency time of the appearance of status epilepticus from 27.2 ± 2.6 to 45.8 ± 3.31 min, and significantly reducing the amplitude of epileptiform discharges by 53.5% with ALL and 68.9% with ellagic acid. CONCLUSION: The antioxidants ALL and ellagic acid showed an antiseizure effect, representing an alternative to reduce epileptiform activity and severity of convulsive behavior during status epilepticus, an effect that may be used as adjuvants to mitigate or reduce oxidative damage processes.
