Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects

1   Eight healthy subjects received 50, 100, 300, 600 and 900  mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week.
2   The ratio of 1-methyluric acid (1MU) over 1-methylxanthine (1MX) in the urine, following a dose of 50  mg 1MX infused intravenously over 20  min, was used to measure the inhibition of xanthine oxidase.
3   The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50  mg to 600  mg day⁻¹, with a weak indication of saturation at the higher 900  mg day⁻¹ dose rate.
4   The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid E_max model and the C ₅₀ values for oxypurinol were 26.38±4.87, (mean±s.d.) 36.58±8.36 and 24.61±9.08  μm, respectively.
5   1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C ₅₀ for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar.
6   The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C ₅₀, was lower than those often observed in clinical practice.     

血压参数脉压对院内心血管病死率的相关分析

目的 :研究血压参数脉压对心血管病死率的相关作用。方法 :住院患者 14 4例入选 ,其中因心血管病死亡 2 4例 (病死组 ) ,选择连续病例 12 0例 (对照组 ) ,使用双变量相关分析判断年龄、糖尿病、收缩压、舒张压、平均动脉压和脉压与心血管病死率的相关性。结果 :两组间方差分析 :年龄、脉压差异有显著性 (P<0 .0 5 ) ,提示脉压增高可能是死亡的危险因素。其余参数差异没有显著性 (P>0 .0 5 )。相关分析结果表明死亡与年龄、脉压显著相关 ,而脉压有随着年龄增大而增大的相关趋势。结论 :与其他血压测值比较 ,脉压与心血管病死率呈明显相关性 ,更好地预测心血管病的死亡     

Kinetics of allopurinol and oxipurinol after chronic oral administration. Interaction with benzbromarone

Summary Previous studies have described a pharmacokinetic interaction between probenecid, a uricosuric drug, and oxipurinol, the major metabolite of allopurinol. In single dose studies, no interaction was found to occur between benzbromarone, another uricosuric agent, and oxipurinol.A cross over study was conducted in 12 volunteers to compare the kinetics of allopurinol and oxipurinol following treatment for 7 days with allopurinol alone or combined with benzbromarone 20 or 100 mg.The pharmacokinetic parameters of allopurinol were not modified by the uricosuric therapy, but those of oxipurinol were markedly altered by concurrent administration even of the lower dose of benzbromarone; the average plasma level fell by 30% and the renal elimination rate was increased by 50%.A parallel increase in the renal elimination rate of uric acid was observed (significant only with the higher dose of benzbromarone) and a positive linear correlation between the fractional excretion of uric acid and that of oxipurinol was established.     

Allopurinol prodrugs. III. Water-soluble N-acyloxymethyl allopurinol derivatives for rectal or parenteral use

Nine amino acid esters of 1-(hydroxymethyl)allopurinol were synthesized and evaluated as potential water-soluble prodrugs of allopurinol with the aim of developing preparations suitable for parenteral and/or rectal administration. Hydrochloride or hydrobromide salts of all the ₁-acyloxymethyl derivatives exhibited a water-solubility greater than 20%. The kinetics of hydrolysis of the compounds was studied in aqueous solution and in human plasma solutions at 37°C. Complete reversion to allopurinol was observed in all cases, the maximum stability of the derivatives occurring at pH < 4. The susceptibility of the derivatives to undergo enzymatic hydrolysis varied widely, the observed half-lives in 80% human plasma ranging from 3 to 140 min. It was concluded that N₁-acyloxymethyl derivatives of allopurinol containing an amino group in the acyl moiety are potentially useful as parenteral delivery forms of the parent drug. Furthermore, compounds containing a weakly basic amino group (pK_a 6–7.5) may be useful as prodrugs to enhance the rectal absorption of allopurinol as assessed on the basis of the water-solubility and lipophilicity of the derivatives.     

Arterial stiffness and cardiovascular outcome

1. Studies have reported an association between arterial function indices and cardiovascular risk factors, as well as the risk of incident cardiovascular events, including coronary heart disease and stroke. 2. The data are overwhelmingly in favour of an independent role for aortic pulse wave velocity in predicting fatal and non-fatal cardiovascular events in healthy and diseased populations and in the evaluation of cardiovascular risk. 3. Augmentation index may independently predict all-cause mortality and cardiovascular events in coronary and end-stage renal disease patients, but some outcome studies have questioned its usefulness in hypertensive subjects and dialysis patients. 4. Systemic arterial compliance, to this time, has not been shown to independently predict cardiovascular outcome. 5. Future cardiovascular risk is greatly modified by prior disease and risk factors; the greatest additional value in measuring arterial stiffness and compliance may be in those with little or no end-organ disease.     

反相高效液相色谱法测定注射用别嘌醇钠的含量

目的:建立测定反相高效液相色谱法测定注射用别嘌醇钠的含量。方法:采用C_(18)色谱柱(250mm×4．6 mm,5μm);0．125%磷酸二氢钾-甲醇(95:5)为流动相;柱温为30℃;流速为1．0mL·min~(-1);检测波长为230nm。结果:别嘌醇在21．3～149．1μg·mL~(-1)(进样量20μL)之间,样品浓度与峰面积呈良好的线性关系(r= 0．9999),平均回收率为100．7%,RSD为0．84%。结论:本法结果准确,精密度及重现性较好,可准确控制本品质量。     

SOD与别嘌呤醇对流感病毒感染致小鼠病损的保护作用

目的：探讨超氧化物歧化酶（ＳｕｐｅｒｏｘｉｄｅＤｉｓｍｕ－ｔａｓｅ，ＳＯＤ）、黄嘌呤氧化酶抑制剂别嘌呤醇在流感病毒感染小鼠致病中的保护作用。方法：流感病毒Ａ／ＦＭ１／１／４７（Ｈ１Ｎ１）鼠适应株，鼻腔内接种感染小鼠，分别于病毒感染后的不同时间对各用药组小鼠取肺进行检测。结果：ＳＯＤ和别嘌呤醇可显著降低小鼠支气管肺泡灌洗液中氧自由基水平和肺组织中黄嘌呤氧化酶活性，明显减轻小鼠肺组织损伤，从而使小鼠的生存率提高。ＳＯＤ与抗病毒药物三氮唑核苷联合应用，其保护作用优于单一用药。结论：ＳＯＤ、别嘌呤醇对小鼠的保护作用是通过对氧自由基的清除和产生的阻断，减轻了其组织损伤来实现的。     

别嘌醇缓释片人体药物动力学与生物等效性研究

目的　研究别嘌醇缓释片在健康受试者体内的药物动力学和生物等效性。方法　健康男性受试者单剂量或多剂量口服别嘌醇缓释片和普通片。用高效液相色谱法测定血浆中别嘌醇和氧别嘌醇浓度, 计算两药的药物动力学参数。结果　受试者口服单剂量别嘌醇缓释片和普通片后的别嘌醇 AUC0~12 分别为 (4. 58±1. 52) mg·h·L-1 和(4 43±1. 40) mg·h·L-1, tmax分别为 (2 .00±0. 41) h和 (1 .25±0 .41) h, cmax分别为 (1 .75±0 .49) mg·L-1和 (2. 06±0 .40) mg·h·L-1。氧别嘌醇 AUC0~72 分别为 (123. 94±23 .39) mg·h·L-1 和 (126. 52±27. 47)mg·h·L-1, tmax分别为 (6 .42±3. 47) h 和 (4. 18±1. 59) h, cmax 分别为 (3 .70±0 .52) mg·L-1 和 (3 99±0 61) mg·L-1。口服多剂量别嘌醇缓释片和普通片后的氧别嘌醇的稳态谷浓度 cmin分别为 (4. 41±0. 76) mg·L-1和 (4 07±0. 76) mg·L-1, 稳态峰浓度cmax分别为 (7. 33±1 .31) mg·L-1 和 (7 .31±1. 25) mg·L-1, tmax分别为 (2. 58±1. 44) h和 (5 .68±2 .03) h, 波动度 DF分别为 (0 .52±0 .18) 和 (0 .58±0 .13)。结论　每日 1次口服别嘌醇缓释片250 mg与每日2次口服普通片相同剂量在吸收程度上具有生物等效性。     

别嘌醇缓释片的制备及释药机理的初步探讨

目的制备别嘌醇缓释片并探讨其释药机理。方法采用正交试验法进行处方优化,用数学模型拟合释放曲线。结果羟丙基甲基纤维素(HPMC)和乳糖的用量对释药有显著性影响,别嘌醇缓释骨架片的体外释药行为符合零级释放模型。结论制备出体外释放度符合要求的别嘌醇缓释片。     

别嘌醇致药源性肝病1例

别嘌醇(allopurinol)是通过抑制次黄嘌呤氧化酶,使尿酸合成减少,从而降低血中尿酸浓度,减少尿酸盐在骨、关节及肾脏的沉着.临床上常作口服,用于治疗慢性痛风.常见的不良反应有服药后可出现皮疹、瘙痒等皮肤反应,偶有低热和出现暂时性转氨酶增高等.多是短暂性的,停药后很快消失,但如再次用药,上述症状会复发.曾有报道[1]因服用别嘌醇引起剥脱性皮炎,伴肝、肾功能异常,最终肾功能衰竭致死.但致全身性和中毒性反应不常见.现将因服用别嘌醇致严重的药源性肝病1例报道如下.     

别嘌呤醇对老年高尿酸血症患者血压的影响

目的观察别嘌呤醇对老年高尿酸血症患者血压的影响并探讨其可能机制。方法选择原发性高尿酸血症伴高血压的老年患者105例,分为别嘌呤醇组(低嘌呤饮食+别嘌呤醇100 mg,bid)56例和对照组(低嘌呤饮食)49例,观察周期12周。观察前后测诊室血压(BP),并采血测空腹血糖(FBG)、三酰甘油(TG)、胆固醇(I℃)、肌酐(Cr)、尿素氮(BUN)、高敏C-反应蛋白(hsCRP)、尿素(UA)、肾素(Renin)、血管紧张素Ⅱ(AngⅡ)和肝功能,观察各项指标的变化并监测药物的不良反应。结果别嘌呤醇组患者12周后与治疗前比较,在UA、BP、hsCRP、Renin、AngⅡ水平等方面均显著下降(P<0.01);对照组除UA水平降低外(P<0.05),在其他方面无变化。在别嘌呤醇应用中,有1例患者出现轻度肝功能损害,另1例患者出现皮疹。结论别嘌呤醇可以降低原发性高尿酸血症伴高血压老年患者的血UA;在降低UA的同时,可以引起血压下降。     

别嘌醇致重症药疹和迟发型过敏性休克

1例74岁男性因尿酸增高口服别嘌醇0．1g,2次／d。用药第16天出现全身瘙瘁,第21天胸部及背部皮肤出现针尖样红色皮疹,停药并给予对症处理2d无效,皮疹加重,且出现头昏、胸闷,遂入院。入院后检查心率73次／min,血压70／46mmHg（1mm Hg=0．133kPa）,血清丙氨酸转氨酶124U／L,天冬氨酸转氨酶80U／L,尿素氮22．6mmol／L,肌酐151μmol／L,尿酸738tzmol／L。入院后心率一度降至42次／min。给予对症、支持治疗21d后,患者皮疹基本消退,血压、心率及肾功能正常,肝功能仍异常。     

The impact of pharmaceuticals on the decline of cardiovascular mortality in Germany

PURPOSE: The effect of innovative medicines and surgical interventions on the decline of (cardiovascular) mortality is often called into question. The increase in general economic prosperity is often seen as the main reason for the continuous increase in life expectancy. The purpose of this study is to investigate the extent to which mortality from cardiovascular diseases has been affected by pharmaceuticals and other medical interventions over the last 30 years in Germany. METHODS: Main outcome measures were the time series of direct method death rates (DMDR) of cardiovascular and non-cardiovascular mortalities. To control for socioeconomic and secular trends the difference between both time series was calculated. The impact of interventions on mortality was analysed by developing two linear regression models: The onset model analyses whether the introduction of interventions influences mortality or not. The consumption model estimates the quantitative impact of interventions in two phases. RESULTS: Cardiovascular mortality as a percentage of total mortality fell from 40 to 38% over the study period. All investigated interventions had statistically significant effects on the decline of cardiovascular diseases, which is expressed by the standardised regression coefficient: onset model: preventive behaviour index (PBI) -8.3, angioplasty/CABG -0.6, antithrombotic agents -1.5, diuretics -0.9, beta-blockers -1.0, calcium channel blockers -0.8 and ACE inhibitors -1.1 (all interventions p < 0.01); consumption model: innovative drugs phase I -7.5 (p = 0.017), innovative drugs phase II -6.9 (p < 0.01), PBI -13.1 (p < 0.01) and angioplasty/CABG -9.9 (p < 0.01). CONCLUSIONS: All innovative drug classes and surgical interventions had a positive effect on the decline of cardiovascular mortality.     

巨大膀胱尿酸性结石1例报告并文献复习

膀胱结石是临床常见病、多发病,但本例患者膀胱结石长到如此巨大且为纯尿酸性极为罕见,经治疗后好转出院.现将病例及巨大膀胱尿酸性结石的形成、特点、危害、防治总结如下,以提高临床医生的重视程度.     

硒和别嘌呤醇对镧损伤小鼠肝的保护作用

小鼠iv LaCl_3 7.5 mg/kg使肝发生明显损伤,ALT显著升高;光镜下见肝细胞变性,PAS染色显示糖原减少或消失;电镜下见胞浆中含许多脂滴,线粒体凝缩,内质网扩张、断裂,粗面内质网上的核糖小体脱落;血清脂质过氧化物水平显著升高。iv LaCl_3前预先给APL或Se保护的动物,ALT的升高程度显著地受到阻抑,光镜和电镜下均见肝细胞的损伤明显减轻,血清脂质过氧化物水平显著降低。结果表明APL和Se对镧引起的肝损伤均有保护作用,可能与它们能降低血清脂质过氧化物的作用有关。     

Microencapsulation of allopurinol by solvent evaporation and controlled release investigation of drugs

Abstract

The microencapsulation of drugs is gaining importance in many research activities. A common technique for preparing microcapsules is the solvent evaporation method which is simple but has a large number of reaction control parameters. This study reports the microcapsulation of allopurinol by the solvent evaporation method and the release of the drug from the microcapsules. The effect of concentration of poly(vinyl alcohol) (as a surfactant), molecular weight of ethyl cellulose and stirrer speed in the preparative method were studied. The effect of molecular weight of ethyl cellulose and particle size on drug release were also investigated. It has been found that the drug release is decreased with increasing molecalar weight of polymer and increasing particle size.     

非布司他对比别嘌醇治疗痛风患者心血管不良事件及死亡风险的Meta分析

目的:对非布司他相比别嘌醇用于治疗痛风患者的心血管不良事件及死亡风险做Meta分析.方法:计算机检索PubMed、EMbase、Cochrane Library(2020年第1期)、CNKI、CBM、VIP、Wanfang数据库,搜集非布司他对比别嘌醇用于治疗痛风患者的随机对照试验(RCT),检索时限均从建库至2020...     

The influence of allopurinol and size of dose on the metabolism of phenylbutazone in patients with gout

Summary Administration of allopurinol 300 mg/day produced minimal changes in the disappearance of phenylbutazone in each of five subjects following single doses (6 mg/kg) in clinical range and caused some prolongation (21%, 52%) of drug half-lives in two of six subjects after single small doses (0.5 mg/kg); mean half-life was not significantly altered by allopurinol at either dose level (means of 52 versus 48 at 0.5 mg/kg and 68 versus 70 h at 6 mg/kg). Size of dose altered half-life when phenylbutazone was used alone; three subjects showed considerably longer half-lives at the higher dose (86 versus 47, 91 versus 41, 65 versus 38 h). Allopurinol caused a greater than 50% prolongation of half-lives in two of five subjects who received single 0.5 g doses of probenecid. These preliminary data do not indicate a need to change the dose of phenylbutazone when subjects are receiving allopurinol.     

Pharmacokinetics and pharmacodynamics of allopurinol in elderly and young subjects

AIMS: The prevalence of hyperuricaemia and gout increases with age as does the incidence of adverse effects to allopurinol, the major uric acid lowering drug. The present study was performed to compare the disposition and effects of allopurinol and its active metabolite oxipurinol in elderly and young subjects without major health problems. METHODS: Ten elderly (age range 71-93 years) and nine young subjects (24-35 years) received an oral dose of 200 mg allopurinol in an open, single dose, cross sectional design. Four of these individuals were additionally dosed with 200 mg allopurinol intravenously. Plasma and urine concentrations of allopurinol, oxipurinol, hypoxanthine, xanthine, and uric acid were measured by h. p.l.c. RESULTS: Total clearance of allopurinol was not different in elderly (15.7+/-3.8 ml min-1 kg-1, mean+/-s.e. mean) and young subjects (15.7+/-2.1), whereas total clearance of oxipurinol was significantly reduced in the aged (0.24+/-0.03) compared with young controls (0.37+/-0.05) as was the distribution volume of oxipurinol (0.60+/-0.09 and 0.84+/-0.07 l kg-1, respectively). Oxipurinol was eliminated primarily by the kidneys, allopurinol by metabolism. Fractional peroral bioavailability of allopurinol was 0.81+/-0.16 (n=4, two elderly and two young subjects). Although maximal plasma concentrations of oxipurinol were significantly higher in elderly (5. 63+/-0.83 microgram ml-1 ) than in young persons (3.75+/-0.25) as was the area under the oxipurinol plasma concentration-time curve, AUC (260+/-46 and 166+/-23 microgram ml-1 h, respectively), the pharmacodynamic effect of oxipurinol was smaller in elderly than young subjects (time-dependent decrease of plasma uric acid 83+/-30 microgram ml-1 h in elderly compared with 176+/-21 in young controls). Oxipurinol increased the renal clearance of xanthine, suggesting inhibition of tubular xanthine reabsorption by oxipurinol. CONCLUSIONS: Although allopurinol elimination is not reduced in the aged, that of its active metabolite oxipurinol is because of an age-dependent decline in renal function. Xanthine oxidase inhibition by oxipurinol appears to be reduced in old age. In addition to its uricostatic action, oxipurinol has a xanthinuric effect which is also diminished in the elderly.     

Dosage prescribing and plasma oxipurinol levels in patients receiving allopurinol therapy

Summary This study examined dosage prescribing patterns and steady-state oxipurinol plasma concentrations in 66 patients receiving chronic allopurinol therapy. Most patients (65%) were taking 300 mg allopurinol daily, although renal impairment was common.Using published guidelines, it was estimated that 35% of patients were receiving excessive dosages of allopurinol. Consequently, the plasma oxipurinol concentrations were often very high (mean (SD) was 156 (109) mol·1^–1). Accumulation of oxipurinol was inversely related to renal function. Plasma concentrations of oxipurinol and urate were not significantly related. However, most patients with oxipurinol concentrations of up to 100 mol·1^–1 had urate concentrations within the normal reference range.