Combination Of Allopurinol Research Articles

Pallidifloside D from Smilax riparia enhanced allopurinol effects in hyperuricemia mice

Pallidifloside D, a saponin glycoside constituent from the total saponins of Smilax riparia, had been proved to be effective in hyperuricemic control. Allopurinol is a commonly used medication to treat hyperuricemia and its complications. In this study, we evaluated whether Pallidifloside D could enhance allopurinol's effects by decreasing the serum uric acid level in a hyperuricemic mouse model induced by potassium oxonate. We found that, compared with allopurinol alone, the combination of allopurinol and Pallidifloside D significantly decreased the serum uric acid level and increased the urine uric acid level (both P<0.05), leading to the normalized serum and urine uric acid concentrations. Data on serum, urine creatinine and BUN supported these observations. Our results showed that the synergistic effects of allopurinol combined with Pallidifloside D were linked to the inhibition of both serum and hepatic xanthine oxidase (XOD), the down-regulation of renal mURAT1 and mGLUT9, and the up-regulation of mOAT1. Our data may have a potential value in clinical practice in the treatment of gout and other hyperuricemic conditions.

Anti-hyperuricemia effects of allopurinol are improved by Smilax riparia, a traditional Chinese herbal medicine

Ethnopharmacological relevanceThe roots and rhizomes of Smilax riparia are called “Niu-Wei-Cai” in traditional Chinese medicine (TCM). This botanical has been used in treating the symptoms of gout and other hyperuricemic-related conditions in TCM. Allopurinol is a commonly used medication to treat hyperuricemia and its complications. In this study, we evaluated whether Smilax riparia could enhance allopurinol׳s effects by decreasing the serum uric acid level in a hyperuricemic mouse model induced by potassium oxonate. Materials and methodsWe examined the effects of allopurinol (5mg/kg) administration alone or in combination with Smilax riparia saponins (SRS, 500mg/kg) on the serum uric acid (SUA), serum creatinine (SCr) and blood urea nitrogen (BUN) levels in a hyperuricemic mouse model. The effects of allopurinol alone or those of allopurinol plus SRS on the XOD activities were measured. Western blot analysis was used to measure the levels of mURAT1, mGLUT9 and mOTA1 in the mice. ResultsCompared with allopurinol alone, the combination of allopurinol and SRS significantly decreased the serum uric acid level and increased the urine uric acid level (both P<0.05), leading to the normalized serum and urine uric acid concentrations. Data on serum and urine creatinine and BUN supported these observations. The attenuation of hyperuricemia-induced renal dysfunction was linked to the inhibition of both serum and hepatic xanthine oxidase (XOD), the down-regulation of renal mURAT1 and mGLUT9, and the up-regulation of mOAT1. ConclusionThe anti-hyperuricemia effects of allopurinol are improved by Smilax riparia co-administration. The results were supported by the measurement of uric acid, creatinine, BUN, XOD, mURAT1, mGLUT9 and mOAT1. Our data may have a potential value in clinical practice in the treatment of gout and other hyperuricemic conditions.

Treatment of gout patients with impairment of renal function: a systematic literature review.

To assess the efficacy and safety of gout-specific medications in gout patients with a comorbidity and/or comedication. A systematic literature search for gout, its medication, and the most common comorbidities and comedications, using serum uric acid (SUA) levels as the primary, and adverse events as the secondary outcomes. Eight trials met inclusion criteria. Trials covered treatment with allopurinol, benzbromarone, rasburicase, or febuxostat in a gout population with mild or moderate renal insufficiency. High risk of bias (5/8 trials) and heterogeneity precluded formal metaanalysis. The trials showed the following hierarchy in efficacy (lowering the SUA below 6.0 mg/dl): febuxostat 80 mg (44%-71%) > febuxostat 40 mg (43%-52%) > allopurinol 100 mg or 200 mg (0-46%) after 6 months of therapy; rasburicase (46%) > allopurinol 300 mg (16%) after 7 days of therapy; benzbromarone 100-200 mg (93%) > allopurinol 100-200 mg (63%) after 9-24 months of therapy. The combination of allopurinol and benzbromarone seemed to be effective, with a significant reduction in the SUA from 7.8 to 5.7 mg/dl (p < 0.05) after 1 month. One study showed that 89% achieved the target SUA using higher doses of allopurinol than usually recommended for patients with renal impairment without an apparent increase in adverse events. In addition, allopurinol and benzbromarone significantly improved renal function. In gout patients with renal insufficiency febuxostat, rasburicase, benzbromarone, and allopurinol + benzbromarone seemed to be effective and safe; allopurinol may be cautiously titrated until the target uric acid level has been reached, and may improve renal function.

Molecular mechanism of an adverse drug–drug interaction of allopurinol and furosemide in gout treatment

Gout patients receiving a combination of allopurinol and furosemide require higher allopurinol doses to achieve the target serum urate (SU) of <6mg/dl (Stamp et al., 2012) [1]. Our study aimed to identify the molecular basis for this observation. We used a fluorimetric assay to determine the impact of furosemide and oxypurinol (the active metabolite of allopurinol) on xanthine oxidase (XO) activity. Immunoblot analysis quantified expression of XO and AMP-kinase (AMPK) in drug-treated human liver (HepG2) and primary kidney (HRCE) cells. In silico analysis identified miR-448 as a potential XO-regulator, whose expression level in HepG2 cells was examined by qPCR.Fluorimetric experiments revealed no direct interactions between XO and furosemide, nor did the combination of oxypurinol/furosemide alter the XO inhibition profile of oxypurinol. In HepG2 cells, we found a significant decrease in XO protein expression following oxypurinol treatment, which was abolished after co-incubation with furosemide. Probenecid alone or in combination with furosemide reduced XO protein expression significantly. qPCR analysis of miR-448 in HepG2 cells mirrored the drug-dependent changes in XO protein expression. In addition, oxypurinol and the combination of oxypurinol/furosemide significantly down-regulated AMPK protein expression in HRCE cells.In conclusion, we show for the first time that besides the established effects of allopurinol on the purine synthetic pathway the efficiency of allopurinol treatment of gout patients is based on two further complementary mechanisms, the direct inhibition of XO activity by the allopurinol metabolite oxypurinol and a down-regulation of XO protein expression. The latter is compromised by addition of furosemide and might explain why patients receiving furosemide therapy require higher allopurinol doses. miR-448 was identified as a potential drug-dependent XO regulator. Finally, down-regulation of AMPK protein expression in HRCE cells by administration of oxypurinol/furosemide reveals a possible new mechanism of renal drug-induced hyperuricemia.

Allopurinol

Thiopurines are used as a maintenance therapy in patients with ulcerative colitis (UC). For some patients the metabolism of thiopurines is unfavorable, leading to increased adverse effects, including hepatotoxicity. There are many reports in the adult literature concerning the manipulation of thiopurine metabolism with allopurinol; however, there is only 1 publication in this respect for pediatric UC. We present 3 pediatric cases of UC wherein the combination of allopurinol and low-dose 6-mercaptopurine allowed for shunting of thiopurine metabolites to a more favorable pattern. This intervention supported clinical remission in all, including one case poorly responsive to infliximab.

Prospective evaluation of serum pancreatic lipase immunoreactivity and troponin I concentrations in Leishmania infantum-infected dogs treated with meglumine antimonate

Canine leishmaniosis (CanL) caused by Leishmania infantum is an important zoonotic disease. One of the most commonly used drugs for the treatment of CanL is meglumine antimonate. Drugs of this class have been associated with pancreatitis and cardiotoxicity in humans infected with Leishmania spp. The aim of this study was to measure serum canine pancreatic lipase immunoreactivity (Spec cPL) and cardiac troponin I (cTnI) concentrations in dogs with leishmaniosis during treatment with meglumine antimonate, and to compare them with those of dogs with leishmaniosis not treated with this drug. A total of 30 non-uremic dogs with leishmaniosis, living in Greece, were prospectively enrolled into the study. Of the 30 dogs, 20 (Group A) were treated with a combination of meglumine antimonate (100mg/kg, SC, q24h) and allopurinol (10mg/kg, PO, q12h) for 28 days, while 10 dogs (Group B) were treated with allopurinol alone (10mg/kg, PO, q12h) for 28 days. Blood samples were collected at timepoint 0 (before treatment) and at 14 and 28 days after the initiation of treatment. None of the dogs treated with meglumine antiomonate had a Spec cPL concentration suggestive of pancreatitis (≥400μg/L) or clinical signs suggestive of pancreatitis at any of the timepoints. Similarly, none of the dogs treated with meglumine antiomonate had a serum cTnI concentration above the upper limit of the reference range (>0.5ng/mL) or clinical evidence of cardiotoxicity at any of the 3 timepoints. In the present study, meglumine antimonate treatment in dogs with leishmaniosis did not result in clinical or laboratory evidence of either pancreatitis or cardiotoxicity.

Antioxidative effects of allopurinol and sodium ascorbate increase posfatigue tension in avian skeletal muscle (LB809)

Muscle fatigue is conceived as a decrease in force development after periods of intense activity, and is considered a multifactorial process. Reactive oxygen species (ROS) could play an important role in the regulation of the signaling pathways involved in the proper functioning of muscles, particularly during fatigue. It has previously been reported that the use of antioxidants can reduce the development of fatigue and reverse the decline of force induced by ROS. Moreover, it has been reported that low concentrations of antioxidants are beneficial to the cells, while high concentrations may become detrimental. Although several studies indicate that mitochondria are the predominant site for ROS generation during activity, there has been considerable speculation concerning the role of xanthine oxidase in generation of ROS by skeletal muscle. The aim of this study was to determine the effect of Allopurinol (inhibitor of xanthine oxidase) and sodium ascorbate (ageneral antioxidant) during the muscle fatigue.Anterior Latissimus Dorsi (ALD) muscle of chicken was dissected and mounted on an experimental recording chamber by placing the proximal end to the bottom of the chamber and the distal end to the hook of a mechanic‐electric transducer (Grass FT03), which through an amplifier and a 320 CyberAmp analog‐digital interface (Digidata 1322A) allowed to acquire the muscle tension generated in a computer (Pentium 4) and a “software” of data acquisition (AXOTAPE, pCLAMP 9.2). We performed a fatigue protocol by twitches (pulses of 100 V, 300 ms duration, 0.5 Hz). The bundle was stimulated until the force decreased by 60 %, then was applied the study drug for 6 min to observe its effect. We used concentrations of Allopurinol (1uM, 10uM and 100 µM) and sodium ascorbate (10, 30 and 100 uM).In dose response curves the mayor effect for Allopurinol was 100 uM and 10 uM by sodium ascorbate. In combination of Allopurinol and sodium ascorbate the tension post‐fatigue increased to 27.24% ± 8.47% in peak tension, while in total tension was an increase by 53.38% ± 18.60% compared with fatigue. The post‐fatigue increase was similar in combination of both drugs that separately, this suggested us the necessity of certain amount of ROS for the normal behavior of the muscle, since both Allopurinol and sodium ascorbate might act as antioxidants.Grant Funding Source: Supported by CIC2014‐RMP

P573 A combination of low-dose thiopurine and allopurinol (ThioComp) is long-term efficacious and well-tolerated in IBD patients

performed. Non-responder imputation was used for missing data or that obtained after move to weekly dosing. Results: Mean BL CDAI, CDEIS, and SES-CD scores were 253.9, 8.9, and 11.0, for pts with moderately active CD, and 365.9, 11.4, and 13.6, for pts with severely active CD, respectively. A greater proportion of ADA-treated than induction ADA only/PBO-treated pts achieved MH at week 12 in both severity subgroups, although the differences were not statistically significant (Table, ADA vs PBO, p = 0.1 moderate CD, p = 0.3 severe CD). Statistically significant differences in MH rates were observed at week 12 in anti-TNF naive pts with moderate CD treated with ADA compared to induction ADA only/PBO-treated pts (37.5% vs 0, p < 0.05). Significantly more ADA-treated pts than induction ADA only/PBO pts had mucosal healing at week 52 in both severity groups (Table). None of the induction ADA only/PBO-treated pts had MH at week 52. Previous anti-TNF exposure did not show a consistent influence on MH outcomes.

P311 Thiopurine metabolite monitoring and allopurinol combination therapy: current utilisation and influence on Australian gastroenterology IBD practice

the hospital and during their transition back to ambulatory care. Strategies to bridge this gap have not been formally evaluated. These data assess the outcome of inpatient to ambulatory care transition under our current standard of care. The McMaster University/Hamilton Health Sciences IBD Clinic is exploring a formal transition program led by a dedicated IBD nurse practitioner. Our outcomes will be reassessed following introduction of this pilot program.

Allopurinol, Benzbromarone, or a Combination in Treating Patients with Gout: Analysis of a Series of Outpatients

Objective. To profile a sample of gouty patients treated with allopurinol, benzbromarone, or a combination of these two drugs and to describe the impact of this therapy in reducing uric acid levels. Methods. An observational, transversal study was performed. We evaluated 48 patients diagnosed with gout who were seen at the Outpatient Rheumatology Clinic of the Federal University of Paraná between January 2009 and November 2010. Clinical data, creatinine serum levels, and basal and posttreatment levels of serum urates, transaminases, and bilirubins were recorded. Uric acid levels were measured in a 24-hour urine sample. Patients were divided into three groups: patients given only allopurinol (A), only benzbromarone (B), and both in combined therapy (A + B). Results. The average age of these patients was 56.6 ± 11.4 years, varying from 35 to 81 years. The entire patient group experienced a significant drop in serum urate levels, from 8.5 ± 1.8 mg/dL (0.472 ± 0.1 mmol/L) to 6.7 ± 2.1 mg/dL (0.372 ± 0.116 mmol/L) (P < 0.001), regardless of the prescribed medication. The number of patients taking both drugs whose serum uric acid values fell within normal range (men <7 mg/dL (0.38 mmol/L) and women <6 mg/dL (0.33 mmol/L)) was 85.7% (6/7) while this value for the group taking benzbromarone alone was 75% (3/4) and for the group taking allopurinol alone this number was 51.8% (14/27). Conclusions. The therapeutic combination of benzbromarone and allopurinol significantly decreased serum urate levels in patients with gout when compared to individual use of each of these agents. This finding is especially important in treating patients who cannot control hyperuricemia with monotherapy. Benzbromarone alone or in combination with allopurinol has an important clinical role in controlling hyperuricemia in patients with gout.

Allopurinol enhances the blood pressure lowering effect of enalapril in children with hyperuricemic essential hypertension

Essential hypertension is frequently associated with hyperuricemia in both adult and pediatric patients. Lowering serum uric acid level may provide greater benefit than simply treating hypertension. Forty-four adolescents, aged 12-19years, newly diagnosed as essential hypertension (secondary hypertension was excluded) and previously untreated were randomized (open label trial) to receive either enalapril or enalapril plus allopurinol in combination. All participants had baseline serum uric acid level ≥5.5mg/dl. Baseline mean blood pressure (BP), age and body mass index were similar between the two groups. After 8weeks' treatment, BP reduction was greater, percent of treatment group achieving target BP level was greater, and serum uric acid level was lower in the combination treatment group. There were no adverse effects during the course of therapy. Results suggest that uric acid reduction may be used as adjunctive antihypertensive therapy in hypertensive adolescents with hyperuricemia while closely monitoring for any adverse effect.

AB1064 No clinically meaningful drug interactions expected between lesinurad, a novel oral uricosuric agent, and drugs most commonly used by gout patients

BackgroundLesinurad is a novel URAT1 inhibitor that has been well tolerated in humans, with dose-dependent reductions of serum urate (sUA). In vitro experiments and in vivo human absorption, metabolism, and...

Atypical presentation of cutaneous leishmaniasis in a renal transplant recipient successfully treated with allopurinol and fluconazole

Leishmaniasis is a zoonotic infection acquired through the bite of a female sandfly, which introduces the amastigotes of Leishmania into the bloodstream. Cutaneous leishmaniasis is rare after solid organ transplantation. Its diagnosis is difficult in immunosuppressed patients. We report a case of isolated cutaneous leishmaniasis in a renal transplant patient resident in an endemic area. The patient was successfully treated with allopurinol and fluconazole and has remained relapse-free for 44 months. The diagnosis of cutaneous leishmaniasis must be considered in immunosuppressed patients living in endemic areas. Our report shows that cutaneous leishmaniasis may complicate the clinical course of kidney transplant recipients and its presentation can be atypical. Conventional treatment with pentavalent antimonial agents can cause many side effects; of particular concern in renal transplant patients are pancreatitis and nephrotoxicity. These latter may be avoided by using a combination of allopurinol and fluconazole.

Use of thiopurines in inflammatory bowel disease

The use of thiopurines as immunosuppression for the treatment of refractory or chronic active inflammatory bowel disease is established for both Crohn's disease and ulcerative colitis. Nevertheless, many questions remain concerning the optimal treatment regimens of azathioprine, 6-mercaptopurine and thioguanine. We will briefly summarize dose recommendations, indications for thiopurine therapy and side effects which are relevant in clinical practice. We discuss some currently debated topics, including the combination of azathioprine and allopurinol, switching of thiopurine therapy in case of side effects, the use of azathioprine in pregnancy, the infection risk using thiopurines and the evidence when to stop thiopurines. Excellent reviews have been published on the thiopurine metabolic pathway which will not be discussed here in detail.

Both combined oral azithromycin plus allopurinol and intramuscular Glucantime yield low efficacy in the treatment of Old World cutaneous leishmaniasis: a randomized controlled clinical trial

Old World cutaneous leishmaniasis (OWCL) is an endemic and major health problem in Iran. The optimal treatment of OWCL is unknown, and current treatments are not ideally effective and have many adverse effects. To compare the efficacy and tolerability of combined oral azithromycin and allopurinol with intramuscular Glucantime in the treatment of OWCL, we conducted a prospective randomized clinical trial. A total of 86 patients with OWCL were assigned and divided randomly into two groups; they received a combination of azithromycin capsule 10 mg/kg/d and allopurinol tablet 10 mg/kg/d for two months or IM injection of Glucantime 20 mg/kg of antimony daily for 20 days. All patients were followed for two months after termination of treatment. Although immediately at the end of the treatment period, complete response was seen in 27.8% of patients on combination therapy vs. 0% in the Glucantime group. The combination of azithromycin and allopurinol had a better outcome; two months after the end of the treatment period, complete, partial, and no responses were seen in 38.9%, 22.2%, and 38.9% in combination therapy and 40%, 31.4%, and 28.6% in the Glucantime group. There was no significant difference between the response rate in both groups after two months (P = 0.5). No severe adverse effect occurred. This study demonstrated that the efficacy of combined oral azithromycin and allopurinol at the above doses and duration was similar to that of IM Glucantime in the treatment of OWCL.

A skewed thiopurine metabolism is a common clinical phenomenon that can be successfully managed with a combination of low-dose azathioprine and allopurinol

Background and aimsA skewed thiopurine metabolism is a phenomenon associated with both poor treatment response and toxicity. Our aim was to evaluate the frequency of this phenomenon and the relationship to thiopurine methyltransferase (TPMT) function. MethodsAll thiopurine metabolite measurements in adult patients (n=4033) between January 2006 and April 2012 were assessed to evaluate the occurrence of a skewed metabolism and the relationship to TPMT genotype and activity. ResultsA skewed metabolism was observed in 14% of all patients. It only developed in patients with a normal TPMT genotype, but was observed at all TPMT activity levels within the normal range (9.1–24.2U/ml RBC). Two cases that illustrate typical clinical scenarios of a skewed metabolism and the effect of combination treatment with low-dose azathioprine and allopurinol are presented. ConclusionsA skewed metabolism is a common clinical phenomenon in patients with a normal TPMT function, which can develop at all TPMT activity levels within the normal range. We suggest that metabolite measurements should be considered in patients not responding to treatment and in those with hepatotoxicity or myelotoxicity in order to detect a skewed metabolism, since this phenomenon can be successfully managed by a combination of low-dose azathioprine and allopurinol.

Sequential combined treatment with allopurinol and benznidazole in the chronic phase of Trypanosoma cruzi infection: a pilot study

Even though the use of combined drugs has been proved to be effective in other chronic infections, assessment of combined treatment of antiparasitic drugs in human Chagas' disease has not been performed. Herein, a pilot study was conducted to evaluate the tolerance and side effects of a sequential combined treatment of two antiparasitic drugs, allopurinol and benznidazole, in the chronic phase of Trypanosoma cruzi infection. Changes in total and T. cruzi-specific T and B cells were monitored during a median follow-up of 36 months. Allopurinol was administered for 3 months (600 mg/day) followed by 30 days of benznidazole (5 mg/kg/day) in 11 T. cruzi-infected subjects. The combined sequential treatment of allopurinol and benznidazole was well tolerated. The levels of T. cruzi-specific antibodies significantly decreased after sequential combined treatment, as determined by conventional serology and by a multiplex assay using recombinant proteins. The frequency of T. cruzi-specific interferon-γ-producing T cells significantly increased after allopurinol treatment and decreased to background levels following benznidazole administration in a substantial proportion of subjects evaluated. The levels of total naive (CD45RA + CCR7 + CD62L+) CD4 + and CD8 + T cells were restored after allopurinol administration and maintained after completion of the combined drug protocol, along with a decrease in T cell activation in total peripheral CD4 + and CD8 + T cells. This pilot study shows that the combination of allopurinol and benznidazole induces significant modifications in T and B cell responses indicative of a reduction in parasite burden, and sustains the feasibility of administration of two antiparasitic drugs in the chronic phase of Chagas' disease.

PWE-234 Optimising the response to thiopurine therapy: a search for novel explanations for thiopurine hypermethylation

IntroductionThiopurines are not effective in up to 1/3 of patients with inflammatory bowel disease (IBD) and 1/5 have to discontinue therapy due to side effects. An important cause of these...

OC-167 Calculating the “missed opportunity” of thiopurine monotherapy overcome with thiopurine and allopurinol combination therapy

IntroductionA proportion of patients preferentially methylate thiopurines, resulting in high levels of methylated metabolites and low levels of thioguanine nucleotides. This can result in hepatotoxicity and treatment non-response. Co-prescription of...

567 Optimizing the Response to Thiopurine Therapy: A Search for Novel Explanations for Thiopurine Hypermethylation

Introduction Thiopurines are not effective in up to 1/3 of patients with inflammatory bowel disease (IBD) and 1/5 have to discontinue therapy due to side effects. An important cause of these problems is thiopurine hypermethylation. This is a catabolic process leading to an unfavourable thiopurine metabolite profile (high methyl-mercaptopurine (MeMP) to low thioguanine nucleotide (TGN) ratio; >11:1), which cannot be predicted by measurement of thiopurine- S -methyltransferase (TPMT) activity. Importantly thiopurine hypermethylation can be circumvented with the use allopurinol in combination with a low dose thiopurine. The aim of this study is to establish the mechanism of thiopurine hypermethylation and identify predictive genetic markers to allow early combination therapy. We hypothesised that thiopurine hypermethylation occurs as a result of genetic factors that affect methylation flux and the cellular transport of methylated metabolites. Methods 168 age and dose-matched patients prescribed AZA/6-MP were identified. Genomic DNA was extracted from EDTA blood samples of 76 patients demonstrating thiopurine hypermethylation and 92 patients with normal methylation profiles. Polymorphic sequence variants in genes predicted to affect thiopurine methylation flux and cellular metabolite transport were identified from single nucleotide polymorphism (SNP) databases and genotyped by Taqman assay. Associations were tested using Fisher9s Exact test. Results We found a significant association between the haplotype of rs9332377 T and rs4646316 C, which encodes a low-activity synonymous Catechol-O-methyltransferase (COMT) variant, and protection from thiopurine hypermethylation (rs9332377 T, p=0.0178, rs4646316 C, p=0.03). A polymorphism in the nucleo-base transporter, ABCB5, was significantly associated with thiopurine hypermethylation (rs2031641 G/G, p=0.0098). The association was strengthened when patients with MeMP levels >5000 pmol/l vs MeMP Conclusion Changes in methylation flux due to the activity of methyltransferases other than TPMT affect the formation of thiopurine methylated metabolites, likely through direct competition for the essential co-factor S-adenosylmethionine. Furthermore, polymorphism in the ABCB5 gene, which affects the nucleotide-binding domain of this transporter, is associated with thiopurine hypermethylation, suggesting reduced cellular efflux of methylated metabolites. Further studies are now indicated to establish the role of these genetic markers in clinical practice. Competing interests None declared.