Combination Of Allopurinol Research Articles

Inhibitiory mechanism of phloretin on xanthine oxidase and its synergistic effect with allopurinol and febuxostat

The development of natural xanthine oxidase (XO) inhibitors is an effective strategy for the treatment of hyperuricemia. In this study, the inhibition mechanism of phloretin on XO and its joint inhibition with clinical drugs (allopurinol and febuxostat) were investigated, using multispectroscopic and molecular simulation techniques. The results showed that phloretin reversibly inhibited XO in a mixed type with an IC50 value of 31.83 ± 0.32 μM. Phloretin quenched the fluorescence of XO with a static mechanism and hydrophobic interactions were the key binding force of phloretin binding to XO. Furthermore, the interaction between phloretin and XO resulted in a more relaxed structure and less stable of the enzyme with a reduction in the α-helix content from 21.5% to 11.3%. The heatmap analysis showed that a combination of phloretin (15 μM) and allopurinol (10 μM) or phloretin (30 μM) and febuxostat (0.01 μM) exhibited the strongest synergistic effect on XO inhibition in a mixed manner. The combination of phloretin and allopurinol/febuxostat enhanced the binding affinity with XO compared to the inhibitors individually. Molecular docking indicated that phloretin, allopurinol and febuxostat bound to different sites of XO to produce a synergistic inhibition by preventing substrate access to the Mo activity center and affecting electron transfer. This study may provide theoretical references for the development of phloretin and its formulation with clinical drugs as uric acid-lowering food functional factor or drug.

Comparison of Intralesional Meglumine Antimoniate Plus Oral Allopurinol with Intralesional Meglumine Antimoniate Alone for the Treatment of Cutaneous Leishmaniasis- A Prospective Study

Objective: To evaluate the efficacy of the combination of oral allopurinol plus intralesional meglumine for thetreatment of Cutaneous Leishmaniasis.Study Design: A prospective study.Place and Duration of Study: The study was carried out at the Department of Dermatology, Combined MilitaryHospital, Multan, Pakistan from 18th September 2021 to 18th March 2022.Methods: The study was conducted on a total of 60 patients (30 in each group) who fulfilled the inclusioncriteria. Patients in group A were given oral allopurinol (15mg/kg/day) and intralesional meglumineantimoniate (2-5 ml). Patients in group B were given intralesional meglumine antimoniate (2-5 ml). All patientswere given 2 injections each week and were followed up for 8 weeks. The efficacy of the treatment was noted bythe disappearance of induration of the lesion and complete reepithelization of the ulcer. Healing wascharacterized by scar formation and was recorded.Results: Results showed that the cure rate in Group B was 16.6% (5), while in Group A it was 56.6% (17) (P<0.03).There was no significant difference in efficacy between both groups when stratified based on age, number oflesions per patient, and lesion location. However, the cure rate of ulcers and papules was significantly higher ingroup A compared to group B.Conclusion: It was concluded that the combination of intralesional meglumine antimoniate and oral allopurinolhas higher efficacy than intralesional meglumine antimoniate alone in the treatment of patients withcutaneous leishmaniasis. How to cite this: Qayyum N, Gul P, Zainab A, Jawaid M, Azam M, Sattar S. Comparison of Intralesional Meglumine Antimoniate Plus Oral Allopurinol with Intralesional Meglumine Antimoniate Alone for the Treatment of Cutaneous Leishmaniasis- A Prospective Study. 2024; 5(2): 181-186. doi: http://doi.org/10.37185/LnS.1.1.511

Efectos de un extracto de hojas de Leucaena leucocephala en la actividad de xantina oxidasa y en los niveles séricos de oxipurinas en ratones

There is a need for novel alternatives to the medical use of allopurinol. In this sense, the present study obtained a leaf extract of L. leucocephala, and its chemical composition, inhibitory action against xanthine oxidase (XO) in vitro, inhibitory interaction between the extract and allopurinol, and the inhibitory action on XO in vivo using mice treated with potassium oxonate and hypoxanthine were determined. Polyphenol and flavonoid compounds were found in the leaf extract. For the leaf extract, the IC50 and maximal values were 334.60 µg/mL and 46.4 % for the inhibition of XO. The 3:1 ratio combination of allopurinol and extract showed IC50 and waDRI values of 1.35 µg/mL, 1.13 (allopurinol) and 1015.72 (extract) to inhibit XO, resulting in a synergistic interaction against XO in vitro. This combination also enhanced the therapeutic success in the mouse model compared with allopurinol administered alone. The present study presents the first evidence for the use of an allopurinol and L. leucocephala extract combination at a 3:1 ratio as a substitute for the administration of allopurinol alone.

Efficacy of optimised thiopurine therapy in patients with moderate-to-severe ulcerative colitis: retrospective long-term follow-up from two randomised trials

Objective The long-term outcome of thiopurine therapy in patients with ulcerative colitis (UC) enrolled in prospective trials have not been evaluated. We aimed to assess the effects of optimised thiopurine maintenance therapy for UC. Methods Long-term data were obtained from patients from our center enrolled in two randomised, prospective, open-label, controlled studies comprising 66 thiopurine-naïve moderate-to-severe patients with UC consisting of a low dose azathioprine (AZA)/allopurinol combination or AZA monotherapy. Following the randomised trials, treatment was adjusted according to adverse effects and metabolites. Patients requiring optimisation initially on AZA monotherapy treatment were switched to low dose AZA in combination with allopurinol, low dose 6-mercaptopurin in combination with allopurinol, or 6-mercaptopurin treatment alone, and those treated with low dose AZA in combination with allopurinol were switched to low dose 6-mercaptopurin in combination with allopurinol or 6-mercaptopurin alone. Results A total of 62 patients were included in the analysis; 31 were initially treated with AZA monotherapy and 31 with low dose AZA in combination with allopurinol. Initial treatment was tolerated by 67% patients (7 AZA monotherapy and 28 low dose AZA in combination with allopurinol), increasing to 94% (58 patients) post-adjustment. After a median 52-month follow-up period, 38 (93%) out of the 41 primary responding patients-maintained clinical remission without steroids, biologics or surgery. The four intolerant patients and the 17 not responding to optimisation were more likely to require colectomy (odds ratio 16.36; 95% confidence interval 3.08–87.03, p < 0.0001). Conclusion Optimised thiopurine therapy demonstrated effective long-term treatment for patients with ulcerative colitis.

Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial.

Key Points The SAPPHIRE trial was designed to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with allopurinol in patients with CKD.Verinurad 3, 7.5, and 12 mg in combination with allopurinol 300 mg did not reduce albuminuria during 34 weeks treatment compared with allopurinol alone or placebo.Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. Background Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine oxidase inhibitor allopurinol in patients with CKD and hyperuricemia. Methods In this randomized placebo and active controlled trial, we enrolled participants with serum urate concentrations ≥6.0 mg/dl, eGFR ≥25 ml/min per 1.73 m2, and a urinary albumin-creatinine ratio (UACR) 30–5000 mg/g to one of five treatment arms: placebo, placebo+allopurinol 300 mg/day, verinurad 3 mg+allopurinol 300 mg/day, verinurad 7.5 mg+allopurinol 300 mg/day, or verinurad 12 mg+allopurinol 300 mg/day in a 1:1:1:1:1 ratio. The primary end point was the change in UACR from baseline to 34 weeks. Secondary end points were changes from baseline in UACR at week 60 and changes in serum urate and eGFR at weeks 34 and 60. Results Between August 2019 and November 2021, 861 adults with CKD (mean age 65 years, 33.0% female, mean eGFR 48 ml/min per 1.73 m2, median UACR 217 mg/g) were enrolled. At 34 weeks, the geometric mean percentage change in UACR from baseline did not differ among treatment groups (16.7%, 95% confidence interval [CI], −0.6 to 37.1 in the 3 mg group, 15.0% [95% CI, −1.85 to 34.6] in the 7.5 mg group, 14.0% [95% CI, −3.4 to 34.4] in the 12 mg group versus 9.9% [95% CI, −6.6 to 29.4] in the allopurinol group, and 37.3% [95% CI, 16.6 to 61.8] in the placebo group). UACR and eGFR change from baseline did not differ among treatment groups after 60 weeks. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. The proportion of patients with adverse events and serious adverse events was balanced among treatment groups. Conclusions Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared with allopurinol alone or placebo. Clinical Trial registry name and registration number: SAPPHIRE Trial registration number, NCT03990363.

Combination of allopurinol with Dahuang Mudan Tang significantly improve kidney function and alleviate oxidative stress and inflammation of chronic kidney disease stage Ⅰ-Ⅲ patients with hyperuricemia.

To evaluate the effect of Dahuang Mudan Tang (, DHMD) and allopurinol on the treatment of chronic kidney disease staged G1-G3b patients with hyperuricemia and to provide novel insights into the clinical management of chronic kidney disease complications. A total of 80 chronic kidney patients staged G1-G3b with hyperuricemia were randomly grouped to receive single allopurinol treatment (control) and combined treatment with DHMD (treated) for 8 weeks. The kidney function and proteinuria indicators of patients were compared between pre-and post-treatment. The oxidative stress and inflammation responses were evaluated by corresponding indicators and cytokines. The clinical efficiency rate and adverse reaction events were also summarized to assess the therapeutic efficiency and safety. The kidney function and proteinuria of enrolled patients were alleviated after their therapies, behaved as the increasing estimated glomerular filtration rate and decreasing serum creatinine, serum uric acid, urea nitrogen, 24 h urine protein levels. On the other hand, the malondialdehyde level and pro-inflammation cytokines were suppressed by the therapies, and the superoxide dismutase was found to be significantly enhanced. Patients in the treated groups showed a better recovery in kidney function, proteinuria, oxidative stress, and inflammation response. Moreover, patients in the treated group showed a higher efficiency rate (95%) and fewer adverse reaction events (5%). The combination of allopurinol with DHMD significantly promoted the recovery of chronic kidney disease stage G1-G3b patients with hyperuricemia, which can be considered a novel clinical therapeutic strategy.

Hypoxia-induced TMTC3 expression in esophageal squamous cell carcinoma potentiates tumor angiogenesis through Rho GTPase/STAT3/VEGFA pathway

BackgroundHypoxia is one of most typical features in the tumor microenvironment of solid tumor and an inducer of endoplasmic reticulum (ER) stress, and HIF-1α functions as a key transcription factor regulator to promote tumor angiogenesis in the adaptive response to hypoxia. Increasing evidence has suggested that hypoxia plays an important regulatory role of ER homeostasis. We previously identified TMTC3 as an ER stress mediator under nutrient-deficiency condition in esophageal squamous cell carcinoma (ESCC), but the molecular mechanism in hypoxia is still unclear.MethodsRNA sequencing data of TMTC3 knockdown cells and TCGA database were analyzed to determine the association of TMTC3 and hypoxia. Moreover, ChIP assay and dual-luciferase reporter assay were performed to detect the interaction of HIF-1α and TMTC3 promoter. In vitro and in vivo assays were used to investigate the function of TMTC3 in tumor angiogenesis. The molecular mechanism was determined using co-immunoprecipitation assays, immunofluorescence assays and western blot. The TMTC3 inhibitor was identified by high-throughput screening of FDA-approved drugs. The combination of TMTC3 inhibitor and cisplatin was conducted to confirm the efficiency in vitro and in vivo.ResultsThe expression of TMTC3 was remarkably increased under hypoxia and regulated by HIF-1α. Knockdown of TMTC3 inhibited the capability of tumor angiogenesis and ROS production in ESCC. Mechanistically, TMTC3 promoted the production of GTP through interacting with IMPDH2 Bateman domain. The activity of Rho GTPase/STAT3, regulated by cellular GTP levels, decreased in TMTC3 knockdown cells, whereas reversed by IMPDH2 overexpression. Additionally, TMTC3 regulated the expression of VEGFA through Rho GTPase/STAT3 pathway. Allopurinol inhibited the expression of TMTC3 and further reduced the phosphorylation and activation of STAT3 signaling pathway in a dose-dependent manner in ESCC. Additionally, the combination of allopurinol and cisplatin significantly inhibited the cell viability in vitro and tumor growth in vivo, comparing with single drug treatment, respectively.ConclusionsCollectively, our study clarified the molecular mechanism of TMTC3 in regulating tumor angiogenesis and highlighted the potential therapeutic combination of TMTC3 inhibitor and cisplatin, which proposed a promising strategy for the treatment of ESCC.

Is the combination of linagliptin and allopurinol better prophylaxis against post-contrast acute kidney injury? A multicenter prospective randomized controlled study

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

Gout: A Case Report

Gout is a common clinical condition, usually seen with typical manifestations of swelling, erythema, tophi, and heat at joint(s). However, in rare circumstances, gout can present atypically, and it is important to recognize and manage it with appropriate medical therapy. This case study dives into a particularly atypical presentation of tophaceous gout in a patient with numerous comorbidities that complicate management. Visually appreciating the tophi, in this case, allows one to get an idea of their distribution on the digits, their unique chalky-white appearance, and how the presentation changed after therapy was initiated. Additionally, learning about the in-depth management and step-wise escalation of treatment is a crucial takeaway from this case, especially in the backdrop of the patient’s CKD3b and CHF - making selecting pharmacotherapy a challenge. After some trial and co-consultation with nephrology, the final effective treatment course for this patient involved using a combination of Allopurinol and Pegloticase (Krystexxa) together; this provided both a clinical improvement and a decrease in lab values of uric acid, dropping from 11.4mg/dL at peak to 4.4mg/dL.

Semi-mechanistic Modeling of Hypoxanthine, Xanthine, and Uric Acid Metabolism in Asphyxiated Neonates.

Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy. Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM®, version 7.5). In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33-0.77) and 0.2 1/h (95% confidence interval 0.09-0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48-0.92), suggesting full xanthine oxidoreductase inhibition during the period studied. This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status.

Possibility of Multiple Drug-Drug Interactions in Patients Treated with Statins: Analysis of Data from the Japanese Adverse Drug Event Report (JADER) Database and Verification by Animal Experiments.

Adverse drug events due to drug-drug interactions can be prevented by avoiding concomitant use of causative drugs; therefore, it is important to understand drug combinations that cause drug-drug interactions. Although many attempts to identify drug-drug interactions from real-world databases such as spontaneous reporting systems have been performed, little is known about drug-drug interactions caused by three or more drugs in polypharmacy, i.e., multiple drug-drug interactions. Therefore, we attempted to detect multiple drug-drug interactions using decision tree analysis using the Japanese Adverse Drug Event Report (JADER) database, a Japanese spontaneous reporting system. First, we used decision tree analysis to detect drug combinations that increase the risk of rhabdomyolysis in cases registered in the JADER database that used six statins. Next, the risk of three or more drug combinations that significantly increased the risk of rhabdomyolysis was validated with in vivo experiments in rats. The analysis identified a multiple drug-drug interaction signal only for pitavastatin. The reporting rate of rhabdomyolysis for pitavastatin in the JADER database was 0.09, and it increased to 0.16 in combination with allopurinol. Furthermore, the rate was even higher (0.40) in combination with valsartan. Additionally, necrosis of leg muscles was observed in some rats simultaneously treated with these three drugs, and their creatine kinase and myoglobin levels were elevated. The combination of pitavastatin, allopurinol, and valsartan should be treated with caution as a multiple drug-drug interaction. Since multiple drug-drug interactions were detected with decision tree analysis and the increased risk was verified in animal experiments, decision tree analysis is considered to be an effective method for detecting multiple drug-drug interactions.

Anti-hyperurisemic Activity of Combination of Beetroot Powder (Beta vulgaris L.) And Allopurinol in Potassium Oxonate-Induced White Rats

Introduction: Hyperuricemia is an abnormally high quantity of uric acid in the blood. Allopurinol is a type of xanthine oxidase inhibitor commonly used to lower uric acid levels in the general population. However, large doses of allopurinol can produce harmful effects, one of which being hepatotoxicity. The antioxidant activity of beetroot powder is high, and it has an antihyperuricemic effect. Giving beetroot powder and allopurinol together is intended to minimize allopurinol's adverse effects and give a positive increase in lowering uric acid levels. This study aims to evaluate the anti hyperuricemia effect of beetroot powder (Beta vulgaris L.) and allopurinol combination in white rats (Rattus novergicus strain Sprague Dawley) induced by potassium oxonate.Methods: This an experimental study with a randomized pre and post-test control group design. In this experiment, twenty rats were placed into four treatment groups; KP = Positive Control (hyperuricemic rats) + standard feed and drink; G1 = hyperuricemic rats + allopurinol 1,8 mg/Kg BW/day); G2 = Hyperuricemic rats + beet powder 1.56 g/Kg BW/day; G3 = hyperuricemic rats + allopurinol 1,8 mg/Kg BW/day and beetroot powder 1,56 g/Kg BW/day. On day 0 and day 28, the amounts of uric acid were measured. Data obtained were analyzed using SPSS version 23 for windows.Results: The mean pre-post changes in uric acid levels in each group were KP = 8.97 ± 0.48 mg/dl, G1 = 2.06 ± 0.15 mg/dl, G2 = 2.24 ± 0.10 mg/dl, and G3 = 2.11 ± 0.86 mg/dl. The mean pre-post changes in MDA levels in each group were KP = 8.14 ± 0.39 nmol/mL, G1 = 2.01 ± 0.38 nmol/mL, G2 = 3.13 ± 0.30 nmol/mL, and G3 = 2.35 ± 0.19 nmol/mL.Conclusion: Beetroot powder and allopurinol combination given for 28 days significantly reduced uric acid and MDA levels in potassium oxonate-induced white rats.

The effect of chayote leaves (Sechium edule)’s flavonoid fraction on the reduction of the serum uric acid levels through the inhibition of xanthine oxidase activity

Uric acid is the final product of purine metabolism and is categorized as hyperuricemia when it reaches &gt;6.0 mg.dL-1 for women and &gt;7.0 mg.dL-1 for men. The chayote leaves (Sechium edule) contain a high amount of flavonoid and might be used as an alternative to reduce hyperuricemia. The purpose of this study is to analyze the effect of chayote leaves (Sechium edule)’s flavonoid fraction on the level of uric acid and the activity of xanthine oxidase (XO) in Sprague Dawley Rats. The flavonoid fraction (FF) was obtained by extracting the chayote leaves, fractionating with n-hexane, hydrolyzing with HCl, and finally re-fractionating with ethyl acetate. Thirty male Sprague Dawley rats were induced for hyperuricemia by potassium oxonate and broth block for 21 days, and the interventions were given orally for 14 days. The rats were divided randomly into five groups: normal control (K-), hyperuricemia control (K+), hyperuricemia with FF dose 50 mg.200g-1 body weight (P1), hyperuricemia with FF dose 100 mg.200g-1 body weight (P2) and hyperuricemia with allopurinol 1.8 mg.200g-1 body weight. Xanthine oxidase activity was measured by CheKineTM Xanthine Oxidase Assay Kit, with simple colorimetry methods. The statistical analysis for XO activity was done using Kruskal-Wallis followed by Mann Whitney. The results showed that chayote leaves (Sechium edule)’s flavonoid fraction contains apigenin, apigenin o-glucoside, and luteolin. It also has antioxidant activity with 98.45% inhibition. There was a significant reduction in xanthine oxidase activity in groups treated with FF (p &lt;0.005). The best dose of FF affecting XO activity was 100 mg.200g-1 body weight. The combination of FF and allopurinol can be more effective in decreasing uric acid levels by inhibiting XO activity.

Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates.

BackgroundAllopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates.ObjectiveThe aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated.MethodsForty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling.ResultsAllopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62–1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25–2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23–0.3) and 11 L (95% CI 9.9–12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31–0.42).ConclusionThe PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01068-0.

Serum cobalamin concentrations in dogs with leishmaniosis before and during treatment

Hypocobalaminemia in dogs is most commonly associated with gastrointestinal disorders leading to impaired absorption and utilization of cobalamin. The objectives of this study were to compare serum cobalamin concentrations between dogs with leishmaniosis and clinically healthy dogs, and to assess possible alterations of serum cobalamin concentrations in dogs with leishmaniosis at different timepoints during treatment. Fifty-five dogs with leishmaniosis and 129 clinically healthy dogs were prospectively enrolled. Diagnosis of leishmaniosis was based on clinical presentation, positive serology and microscopic detection of Leishmania amastigotes in lymph node aspiration smears. Twenty of the dogs with leishmaniosis were treated with a combination of meglumine antimonate and allopurinol for 28 days and serum cobalamin concentrations were measured in blood samples that were collected before initiation of treatment (timepoint 0) and on days 14 and 28. In order to estimate alterations of serum cobalamin concentrations during treatment, cobalamin concentrations were measured in blood samples from 20 out of 55 dogs with leishmaniosis at all timepoints. Serum cobalamin concentrations were significantly lower in dogs with leishmaniosis before treatment (median: 362 ng/L; IQR: 277−477 ng/L) compared to clinically healthy dogs (median: 470 ng/L; IQR: 367−632 ng/L; P = 0.0035). Serum cobalamin concentrations increased significantly in dogs with leishmaniosis on day 14 of treatment compared to timepoint 0 (P = 0.02).In the present study, serum cobalamin concentrations were significantly lower in dogs with leishmaniosis compared to clinically healthy dogs. In addition, there was an increase in serum cobalamin concentrations during treatment. The clinical significance of hypocobalaminemia in dogs with leishmaniosis remains to be determined.

Allopurinol to Prevent Mercaptopurine Adverse Effects in Children and Young Adults With Acute Lymphoblastic Leukemia.

Mercaptopurine (6MP) is used to treat acute lymphoblastic leukemia (ALL) and is metabolized by hypoxanthine guanine phosphoribosal transferase to form 6-thioguanine nucleotide (6TGN). It is also metabolized by thiopurine methyl-transferase to produce 6-methylmercaptopurine (6MMP). Elevated levels of 6MMP have been associated with toxic effects that may interfere with therapy. Allopurinol is known to inhibit thiopurine methyl-transferase which reduces red cell 6MMP and increases 6TGN. Allopurinol has been utilized successfully in adult and pediatric patients with inflammatory bowel disease who have experienced 6MMP related gastrointestinal toxicity. Between August 2015 and August 2018 we started 25 patients with ALL in maintenance on allopurinol in combination with a reduced dose of 6MP. They all had unacceptable side-effects from elevated 6MMP, including abdominal pain, nausea, vomiting, decreased appetite, hypoglycemia, fatigue, and liver toxicity. In addition many had a facial rash. All patients showed resolution of symptoms within a few weeks after starting allopurinol. The red cell levels of 6MMP rapidly declined in the first month. The red cell levels of 6TGN transiently increased in spite of the lower 6MP dose. There was no decrease in absolute neutrophil count or hemoglobin. Platelets decreased slightly not requiring therapy modification. Elevated bilirubin normalized, and alanine aminotransferase decreased significantly with most normalizing. All patients continued on allopurinol with reduced dose 6MP until completing therapy. Allopurinol, in conjunction with a reduced dose of 6MP, effectively resolves 6MMP related side-effects in ALL patients on maintenance chemotherapy. This approach may lead to increased adherence to oral 6MP during ALL maintenance in patients with 6MMP induced side-effects.

Developing, optimizing, and assessing a green electrophoretic method for determination of benzbromarone and allopurinol with its active metabolite in biological and pharmaceutical matrices.

A combination of allopurinol and benzbromarone is a common gout treatment protocol. A suboptimal response to allopurinol in patients is very common due to its pharmacokinetics variability. Moreover, the safe doses of benzbromarone is very crucial in patients with hepatic diseases. This raised the inquisitiveness to develop and optimize a capillary zone electrophoresis method for the determination of allopurinol and benzbromarone in their coformulation and in the presence of oxypurinol, the active metabolite of allopurinol, in biological and pharmaceutical matrices. The method greenness profile was assessed using green metric tools the "National Environmental Method Index," the "Analytical Eco-Scale," and the "Green Analytical Procedure Index" by which the method proved to be ecofriendly. The method was successfully applied for the analysis of the pharmaceutical preparation and urine samples spiked with both drugs and the active metabolite. The linearity range was 25.0-250.0 μg/mL for benzbromarone, 50.0-350.0 μg/mL for allopurinol, and 100.0-500.0 μg/mL for oxypurinol. The recoveries were 99.60 ± 0.67, 99.89 ± 0.98, and 98.71 ± 1.18% for benzbromarone, allopurinol, and oxypurinol, respectively. The analysis results indicate potential usefulness of capillary zone electrophoresis as a competitive and greener method of analysis in biological and quality control labs.

Beyond Good’s syndrome: A case of multifactorial thymoma-related immunodeficiency with cytomegalovirus reactivation

Introduction: Thymomas, by virtue of T-cell maturation derangement, are frequently accompanied by parathymic syndromes. Classically, Good’s syndrome characterizes immunodeficiency in patients with thymoma, comprising of hypogammaglobulinemia and various degrees of T-cell impairment; however, these patients frequently suffer from additional iatrogenic effects of chemotherapy or immunosuppressors used to control autoimmune phenomena. As a result, they often exhibit signs of decreased bone marrow response and cytopenias, leading to opportunistic infections such as cytomegalovirus (CMV) reactivation, whose role in perpetuating the state of immunodeficiency may be under-explored. Case Report: We describe the case of a 62-year-old man with a thymoma who exhibited several paraneoplastic syndromes, including Good’s syndrome. The patient had also been diagnosed with sigmoidal adenocarcinoma, previously medicated with capecitabine and was currently medicated with corticosteroids and azathioprine, placing an additional strain on his already compromised immune system. After being inadvertently exposed to the combination of azathioprine and allopurinol, he developed pancytopenia with little response to granulocyte-colony stimulating factor (G-CSF) after withdrawal of the offending agents. A high CMV viral load was suspected as a cause for perpetuating leukopenia. Treatment with ganciclovir resulted in bone marrow recovery, and immunoglobulin replacement together with antibiotic and antiviral prophylaxis prevented other serious infections until thymectomy and completion of chemotherapy. Conclusion: This case exemplifies many of the complexities in managing patients with thymomas, particularly when balancing autoimmunity and immune suppression. Cytomegalovirus reactivation is not unusual in this context and cytopenias may be the only manifestation. Although treatment of symptomatic disease is beneficial, the role of prophylaxis is not yet consensual due to its potentially myelosuppressive effects.

Allopurinol y domperidona en el tratamiento de leishmaniosis visceral canina

&lt;p&gt;El tratamiento de la leishmaniosis humana en Argentina está normatizado con el esquema&lt;br /&gt;terapéutico sugerido por la OMS y es suministrado por el estado nacional en forma&lt;br /&gt;gratuita. La mayoría de las drogas utilizadas son desaconsejadas en el tratamiento farmacológico de perros afectados por leishmaniosis visceral por la dificultad de acceder al elevado costo y al riesgo de aumentar la generación de cepas resistentes. El presente trabajo tuvo como objetivo evaluar la progresión de los signos clínicos, valores de laboratorio y carga parasitaria, al inicio y durante la administración combinada de allopurinol y domperidona por&lt;br /&gt;vía oral, en la Facultad de Veterinaria de Corrientes (Argentina). Se estudiaron 10 pacientes&lt;br /&gt;caninos en los cuales se evaluaron los signos clínicos, se efectuó el análisis serológico y se&lt;br /&gt;obtuvieron muestras de médula ósea. Se inició un protocolo terapéutico mediante la combinación de ambos fármacos y se efectuó un seguimiento con controles de los parámetros&lt;br /&gt;clínicos, laboratoriales y parasitológicos. Todos los pacientes mostraron mejoría clínica al&lt;br /&gt;inicio, pero la evolución fue irregular y particular para cada caso, con reclasificaciones de&lt;br /&gt;acuerdo a lo sugerido por el grupo Leishvet. Al realizar ajustes de acuerdo a los signos clínicos,&lt;br /&gt;perfiles bioquímicos y estimación de la carga parasitaria, la combinación de allopurinol&lt;br /&gt;y domperidona mostró resultados favorables a la dosis recomendada. Si bien es necesario una&lt;br /&gt;mayor casuística y tiempo de ensayo, los resultados permiten inferir que este protocolo podría&lt;br /&gt;constituir una alternativa en el tratamiento farmacológico y en el control epidemiológico&lt;br /&gt;de la leishmaniosis visceral canina.&lt;/p&gt;

Comparison of Two Dosing Regimens of Miltefosine, Both in Combination With Allopurinol, on Clinical and Parasitological Findings of Dogs With Leishmaniosis: A Pilot Study.

Miltefosine (MIL)–allopurinol combination therapy administered at standard dosage is effective to treat canine leishmaniosis, nevertheless for some dogs the digestive tolerance of MIL is not acceptable. This study evaluates an alternative therapeutic protocol by using a modified dosage of MIL to increase its effectiveness and improve the digestive tolerance. Thirty-four Leishmania infantum owned naturally infected dogs were included and monitored for 180 days. The dogs were allocated in two randomized groups: Group X−18 dogs treated with MIL registered dose of 2 mg/kg, oral administration, once daily, for 28 days; Group Y−16 dogs treated with 1.2 mg/kg for 5 days followed by 2.5 mg/kg for 25 days. Both groups were also treated with allopurinol. Digestive tolerance was monitored by adverse events observation. Treatments effectiveness was evaluated by monitoring the reduction of clinical score, the improvement of clinicopathological abnormalities, the reduction of parasitological load by PCR and the number of relapses. 16.6% dogs of group X and 12.5% dogs of group Y showed treatment associated adverse events. The reduction of clinical score was 61.7% for group X and 71.6% for group Y. All dogs showed an improvement of laboratory parameters after treatment. Quantitative PCR showed better results in group Y compared to group X; relapses were only registered in four dogs of group X. The modified protocol demonstrates a better trend of results in term of tolerance, clinical effectiveness, parasitological load reduction and relapses control, suggesting it could be considered for new large-scale studies.