常见可致药源性尿路结石的药物

本文通过检索国内外报道药源性肾结石的文献,对引起肾结石的药物进行分类归纳,总结可以引起肾结石的药物种类及发生机制,以帮助临床医师了解具有潜在引起肾结石风险的药物,规避药源性肾结石的发生率。引起肾结石的药物多由于长期大量用药所致,最常见的原型药物包括氨苯蝶啶、磺胺嘧啶、蛋白酶抑制剂等,药物代谢产物形成含钙或含嘌呤的结石。     

Drug-induced urinary retention: incidence, management and prevention.

Urinary retention is a condition in which impaired emptying of the bladder results in postvoidal residual urine. It is generally classified into 'acute' or 'chronic' urinary retention. Because of the complex mechanism of micturition, many drugs can interact with the micturition pathway, all via different modes of action. Although the incidence of urinary retention, in particular acute urinary retention, has been well studied in observational studies and randomized controlled trials, data on the incidence of drug-induced urinary retention are scarce. Data from observational studies suggest that up to 10% of episodes might be attributable to the use of concomitant medication. Urinary retention has been described with the use of drugs with anticholinergic activity (e.g. antipsychotic drugs, antidepressant agents and anticholinergic respiratory agents), opioids and anaesthetics, alpha-adrenoceptor agonists, benzodiazepines, NSAIDs, detrusor relaxants and calcium channel antagonists. Elderly patients are at higher risk for developing drug-induced urinary retention, because of existing co-morbidities such as benign prostatic hyperplasia and the use of other concomitant medication that could reinforce the impairing effect on micturition. Drug-induced urinary retention is generally treated by urinary catheterization, especially if acute, in combination with discontinuation or a reduction in dose of the causal drug. Studies have been carried out examining the effects of preventive measures for anaesthesia-related urinary retention, both during and after surgery, particularly into the effect of using opioids in combination with non-opioid analgesic drugs on the incidence of postoperative urinary retention. Although combination therapy reduces the opioid-related adverse events, the effect on urinary retention yields contradictory results. This article reviews the literature on drug-induced urinary retention and focuses on its incidence, the different classes of drugs that have been associated with it, and options for its management and prevention.     

Metabolic fate and solubility of triamterene--not an explanation for triamterene nephrolithiasis

In an attempt to explain the triamterene stone diathesis, we studied the excretion and solubility of triamterene, 1, and its metabolite, the sulfate ester of the hydroxy derivative of triamterene, 3. The urinary excretion pattern and metabolism in stone formers was the same as in other chronic users of triamterene or healthy volunteers. The solubility of triamterene in urine was approximately one-half of its solubility in buffer solution, whereas the sulfate ester, 3, was nearly twice as soluble in urine as in the buffer solution. In the majority of the subjects studied, we found concentrations of 3 which approached or exceeded apparent solubility limits in urine. This was not true for triamterene where most measured urine concentrations were less than the apparent solubility as determined by equilibration. Alteration in the metabolism of triamterene is probably not a causative factor for triamterene nephrolithiasis. The saturation of urine with triamterene and especially with the sulfate ester, 3, may be related to stone formation, but other physical factors play a role in determining the relative amounts of drug found in calculus material.     

高尿酸血症与缺血性卒中及其药物治疗

全球多项研究显示,高尿酸血症是缺血性脑卒中的独立危险因素之一,血尿酸水平升高可增加脑卒中的发生率和死亡率。高尿酸血症与缺血性卒中的危险因素(高血压、糖尿病、高血脂、动脉粥样硬化等)共同促进缺血性脑卒中的发生。对高尿酸血症的治疗已经从急性期治疗转变为强调长期控制血尿酸达标,预防各种合并症。高尿酸血症的治疗包括调整饮食结构、改变生活方式、积极控制与血尿酸升高相关的危险因素、避免应用血尿酸升高的药物、碱化尿液等。降低血尿酸的药物包括增加尿酸排泄的药物、抑制尿酸合成药物、辅助降尿酸药。如果引起血尿酸增高的原因不能去除,需要长期降尿酸治疗。     

Comparison of the diagnostic accuracy of di-22:6-bis(monoacylglycerol)phosphate and other urinary phospholipids for drug-induced phospholipidosis or tissue injury in the rat

Cationic amphiphilic drugs and aminoglycoside antibiotics can induce phospholipidosis (PLD), an abnormal accumulation of phospholipids in lysosome-derived vesicles, in preclinical studies. The incidence of PLD in patients and its clinical relevance are difficult to assess without noninvasive biomarkers. Di-docosahexaenoyl bis(monoacylglycerol)phosphate (di-22:6-BMP) is a phospholipid that is enriched in lysosomal membranes and a proposed urinary biomarker of drug-induced PLD. The specificity of di-22:6-BMP for PLD was compared to other phospholipid species that can increase in urine with nephrotoxicity. Using liquid chromatography coupled to mass spectrometry, 12 phospholipids were assayed in the urine of rats treated with drugs that induced PLD or caused renal or skeletal muscle injury. In receiver operating curve analyses, urinary di-22:6-BMP was a significantly better predictor of PLD and the least predictive of tissue injury of the phospholipids assayed. The data provide evidence supporting the use of di-22:6-BMP as a urinary biomarker of PLD in rats.     

药物性肝炎344例临床分析

目的:探讨药物性肝炎的病因、临床特点及治疗.方法:回顾性分析我院2004～2009年收治的药物性肝炎344例的临床资料,通过对基础病、用药种类、临床表现、实验室检查及临床转归等总结其发病规律及特点.结果:引起药物性肝炎的基础病主要为肺结核、糖尿病、甲亢、风湿性关节炎、精神性疾病等;引发药物性肝炎的药物种类较多,主要以中药、抗结核药、抗生素为主;临床表现乏力、纳差、尿黄、眼黄、身黄、恶心、皮肤瘙痒等;停药及保肝治疗后治愈率93.9%,肝衰竭发生率6.1%,死亡率0.9%,发生肝衰竭以抗结核药为主,其次为中药.人工肝支持治疗药物性肝炎,可明显降低病死率,缩短病程.结论:应高度重视药物性肝炎,注意了解药物的成分、适应证、禁忌证,影响药物性肝炎的因素主要有用药种类、用药时间及是否合并乙肝等.     

药源性睡行症的常见致病药物及防治

睡行症是一种在睡眠中出现的以行走或其他异常行为或活动为特征的睡眠障碍（sleep disorder），通常发生在非快速眼动睡眠的慢波期。由药物引起的睡行症称之为药源性睡行症。引起药源性睡行症的常见药物有镇静催眠药、抗精神病药物以及抗抑郁症药等。据称，药源性睡行症的发生由多因素所致，包括既往睡行症发作史，应用增加慢波睡眠的药物以及体内外刺激。药源性睡行症的发生机制尚不清楚，有人认为是某些神经递质如5-羟色胺、1-氨基丁酸增加慢波睡眠所致。药源性睡行症防治原则包括：减少致病药物的剂量或停药，排除危险因素，加强环境安全及给予苯二氮[艹卓]革类药物。     

喀什地区维吾尔族小儿上尿路结石3068例临床分析

目的 总结喀什地区维吾尔族小儿上尿路结石的临床特点及治疗效果.方法 收集喀什地区第一人民医院泌尿外科近十年共计3 068例维吾尔族小儿上尿路结石住院治疗患者的临床资料,男2 176例,女892例,年龄26天～ 14岁.2005至2012年初,主要采用输尿管切开取石或肾盂切开取石术治疗,2012年末至2014年主要采用输尿管镜或超声引导下微通道经皮肾镜碎石术治疗,双侧尿路结石致梗阻合并急性肾功能衰竭采用一期内引流,二期微创碎石取石术,术后3月、6月及1年分别进行随访.结果 本组3 068例患儿,肾结石占69.59％,输尿管结石占20.53％. 阳性结石占23.44％,阴性结石占76.56％,结石直径占0.5 ～ 4.8 cm.开放手术1 503例,微创手术1 243例,保守治疗292例;未能接受治疗30例;死亡26例.微创手术组在手术时间、出血量、术后进食时间、住院时间等指标优于开放手术.两种术式其一期结石清除率及预后不良发生率无明显差异(P＞ 0.05).随访时间6个月～2年,术后发生肾萎缩64例(6.08％),结石复发231例(21.96％),两种不同术式之间差异无统计学意义(P＞0.05).结论 喀什地区小儿上尿路结石以阴性结石为主.输尿管镜碎石术及MPCNL治疗小儿上尿路结石安全、可行、有效,对于双侧上尿路结石合并肾功能不全患儿可行分期手术.     

他汀类与核苷类药物所致横纹肌溶解症及其防治

本文列举了他汀类和核苷类药物中可诱发药源性横纹肌溶解症的相关药物,介绍药源性横纹肌溶解症的防治措施.通过对横纹肌溶解症的发生机制及诱发该不良反应的药物应用进行分析,并结合临床诊断及治疗进行阐述.认为临床上应该慎用可能诱发药源性横纹肌溶解症的药物,观察到横纹肌溶解症出现的初始症状及时停用相关药物,避免横纹肌溶解症的发生,促进临床合理用药.     

Pharmacological studies on experimental nephritic rats (6). Antinephritic effects of sodium chondroitin sulfate and other drugs on modified type of Masugi's nephritis]

Using the modified model of Masugi's nephritis in rats, the antinephritic effects of sodium chondroitin sulfate (CS) and other drugs were evaluated by determining the biochemical parameters in urine, serum and renal cortex as well as light microscopic observation in kidneys by preventive and curative tests. In the preventive test where drug treatment was initiated at the same time as the injection of anti-kidney serum, CS (200 mg/kg p.o.) was effective in reducing serum triglyceride level, but was ineffective against other parameters. In the curative test where drug treatment was given from the 10th day after the induction of nephritis, CS (200 mg/kg p.o.) resulted in reductions of urinary excretions of protein and enzymes such as alkaline phosphatase and N-acetyl-beta-glucosaminidase, the inhibition of urinary fibrinolytic activity and reduction in levels of serum cholesterol and triglyceride. Moreover, histological examination indicated a significant reduction of the index of glomerular lesions by the treatment of this drug. Of other drugs, dexamethasone (0.1 mg/kg p.o.) was effective in both tests, while warfarin potassium (0.05 or 0.1 mg/kg p.o.) exerted a beneficial effect only in the preventive test. From these results, the effectiveness of CS in the curative test is probably due to promotion of healing of damaged tissue in the kidneys.     

药源性肾损害的诊断与治疗探讨

目的:探讨药源性肾损害的治疗,促进合理使用药物.方法:总结我院对药源性肾损害的临床诊断及治疗,停用对肾损害的可疑药物,对症治疗.结果:药源性肾损害的患者基本痊愈或好转.结论:临床应严格掌握用药指征,密切观察用药后反应,尽可能避免或减少药源性肾损害的发生.     

Lack of effects of sodium 2-mercaptoethane sulfonate (mesna) on Ochratoxin A induced renal tumorigenicity following life-time oral administration of Ochratoxin A in DA and Lewis rats

Sodium 2-mercaptoethane sulfonate (Mesna) reacts with urotoxic metabolites of oxazaphosphorine drugs (e.g. cyclophosphamide or ifosfamide) and has been used clinically to protect against damage induced by these aggressive anti-neoplastic drugs in the kidney and lower urinary and genital tracts. Ochratoxin A (OTA) is a potent nephrotoxin in several species. In order to elucidate whether mesna has curative or preventive effects on OTA-induced renal damage or renal tumor development, we administered OTA and/or mesna to both DA and Lewis rats for their life-time and examined kidney, urethra and urinary bladder histologically. OTA induced sex- and strain-specific renal tumors. However, there was no evidence of any effect of mesna on the incidence and distribution of any type of tumor or non-neoplastic finding in the kidney in either strain or treated group. In this study, we have confirmed that mesna treatment did not show any curative or preventive effects on either OTA-induced kidney damage or renal tumor development in two different strains that have distinct metabolic characteristics.     

Drug-induced diabetes insipidus: incidence, prevention and management.

Drug-induced diabetes insipidus is always of the nephrogenic type, i.e. unresponsiveness of the kidneys to the action of antidiuretic hormone. This condition is easily diagnosed by measuring urinary concentrating capacity during a thirst test (e.g. 12 hours of water deprivation) or by administration of a modified antidiuretic hormone, desmopressin, to demonstrate the renal unresponsiveness. Drug-induced nephrogenic diabetes insipidus is not a common disorder except in patients receiving treatment with lithium salts for affective disorders where it may affect about 10% of patients treated long term (15 years). Drug-induced nephrogenic diabetes insipidus caused by other drugs usually occurs in critically ill patients in intensive care units receiving a multitude of drugs dominated by antimicrobials and cytostatics. A search of the World Health Organization's adverse effect database revealed 359 reports of drug-induced diabetes insipidus. Lithium was the most common cause (159 reports) followed by foscarnet (15) and clozapine (10). Treatment is symptomatic in most patients and the offending drug should be stopped. If urine volumes exceed 4 L/day, treatment with thiazides and amiloride has been advocated, and nonsteroidal anti-inflammatory drugs, such as indomethacin, may be tried in severe cases. Prevention of lithium-induced nephrogenic diabetes insipidus is an important aspect of the treatment of affective disorders. In patients treated long term it appears to be only partly reversible upon lithium discontinuation. Close monitoring of the treatment aiming at 12-hour trough value of 0.4 to 0.6 mmol/L is recommended. Yearly measurement of the urinary volume/day is effective in making both the patient and the physician aware of the development of the drug-induced nephrogenic diabetes insipidus. The condition is a serious adverse effect because of the risk of developing dehydration and aggravation of drug intoxications.     

Subchronic urinary bladder effects of muraglitazar in male rats.

Muraglitazar, a PPARalpha/gamma dual agonist, was dosed orally to rats once daily for 13 weeks to evaluate urinary and urothelial changes of potential relevance to urinary bladder tumorigenesis. Groups of 17 young or aged rats per sex were fed a normal or 1% NH4Cl-supplemented diet and were dosed with 0, 1, or 50 mg/kg muraglitazar. Lithogenic ions and sediment were profiled from freshly voided urine samples collected 24 h after dosing, and drug exposures were measured. Urinary citrate, oxalate, and epidermal growth factor (EGF) were assayed from 18-h urine collections. Urothelium was assessed by light microscopy, scanning electron microscopy, and BrdU and TUNEL immunohistochemistry. When fed a normal diet, urine pH was higher in males (above 6.5). Urine volume/body weight was greater in females. Urine soluble/total calcium and magnesium and phosphorus/creatinine ratios were lower in male rats fed a normal diet. Urine citrate levels were decreased and oxalate was increased in young male rats treated with 50 mg/kg muraglitazar compared to age/sex/diet-matched controls. No changes in urine sediment were detected 24 h after dosing. In young male rats treated with 50 mg/kg on normal diet, multifocal urothelial necrosis and proliferation were observed, whereas urothelial apoptosis and urine EGF levels were unchanged compared to age/sex/diet-matched controls. Urothelial necrosis and proliferation were not correlated to systemic or urinary drug exposures and were prevented by dietary acidification. These data suggest that muraglitazar-associated changes in urine composition predispose to urothelial cytotoxicity and proliferation in the urinary bladder of young male rats and that urine sediment must be profiled at multiple daily timepoints to fully qualify drug-induced changes in urine composition.     

Drug-induced hypomagnesaemia : scope and management.

Nearly 50 medications have been implicated as inducing hypomagnesaemia, sometimes based on insufficient data regarding clinical significance and frequency of occurrence. In fact, clinical effects attributed to hypomagnaesemia have been reported in only 17 of these drugs. A considerable amount of literature relating to individual drugs has been published, yet a comprehensive overview of this issue is not available and the hypomagnesaemic effect of a drug could be either overemphasised or under-rated. In addition, there are neither guidelines regarding treatment, prevention and monitoring of drug-induced hypomagnesaemia nor agreement as to what serum level of magnesium may actually be defined as 'hypomagnesaemia'. By compiling data from published papers, electronic databases, textbooks and product information leaflets, we attempted to assess the clinical significance of hypomagnesaemia induced by each drug. A practical approach for managing drug-induced hypomagnesaemia, incorporating both published literature and personal experience of the physician, is proposed. When drugs classified as inducing 'significant' hypomagnesaemia (cisplatin, amphotericin B, ciclosporin) are administered, routine magnesium monitoring is warranted, preventive treatment should be considered and treatment of hypomagnesaemia should be initiated with or without overt clinical manifestations. In drugs belonging to the 'potentially significant' category, among which are amikacin, gentamicin, laxatives, pentamidine, tobramycin, tacrolimus and carboplatin, magnesium monitoring is justified when either of the following occurs: clinical manifestations are apparent; persistent hypokalaemia, hypocalcaemia or alkalosis are present; other precipitating factors for hypomagnesaemia coexist; or treatment is with more than one potentially hypomagnesaemic drug. No preventive treatment is required and treatment should be initiated only if hypomagnesaemia is accompanied by symptoms or clinically significant relevant laboratory findings. In those drugs whose hypomagnesaemic effect is labelled as 'questionable', including furosemide and hydrochlorothiazide, routine monitoring and treatment are not required.     

Cellular Uptake Mechanism of Paclitaxel Nanocrystals Determined by Confocal Imaging and Kinetic Measurement

Nanocrystal formulation has become a viable solution for delivering poorly soluble drugs including chemotherapeutic agents. The purpose of this study was to examine cellular uptake of paclitaxel nanocrystals by confocal imaging and concentration measurement. It was found that drug nanocrystals could be internalized by KB cells at much higher concentrations than a conventional, solubilized formulation. The imaging and quantitative results suggest that nanocrystals could be directly taken up by cells as solid particles, likely via endocytosis. Moreover, it was found that polymer treatment to drug nanocrystals, such as surface coating and lattice entrapment, significantly influenced the cellular uptake. While drug molecules are in the most stable physical state, nanocrystals of a poorly soluble drug are capable of achieving concentrated intracellular presence enabling needed therapeutic effects.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9774-0) contains supplementary material, which is available to authorized users.KEY WORDS: cellular uptake, confocal microscopy, nanocrystals, paclitaxel, pharmacokinetics     

PEG–lipid micelles as drug carriers: physiochemical attributes,formulation principles and biological implication

PEG–lipid micelles, primarily conjugates of polyethylene glycol (PEG) and distearyl phosphatidylethanolamine (DSPE) or PEG–DSPE, have emerged as promising drug-delivery carriers to address the shortcomings associated with new molecular entities with suboptimal biopharmaceutical attributes. The flexibility in PEG–DSPE design coupled with the simplicity of physical drug entrapment have distinguished PEG–lipid micelles as versatile and effective drug carriers for cancer therapy. They were shown to overcome several limitations of poorly soluble drugs such as non-specific biodistribution and targeting, lack of water solubility and poor oral bioavailability. Therefore, considerable efforts have been made to exploit the full potential of these delivery systems; to entrap poorly soluble drugs and target pathological sites both passively through the enhanced permeability and retention (EPR) effect and actively by linking the terminal PEG groups with targeting ligands, which were shown to increase delivery efficiency and tissue specificity. This article reviews the current state of PEG–lipid micelles as delivery carriers for poorly soluble drugs, their biological implications and recent developments in exploring their active targeting potential. In addition, this review sheds light on the physical properties of PEG–lipid micelles and their relevance to the inherent advantages and applications of PEG–lipid micelles for drug delivery.     

Preparation of polymeric nanoparticles containing corticosteroid by a novel aerosol flow reactor method

Polymeric drug-containing nanoparticles were prepared using a novel aerosol flow reactor method. The polymeric drug-containing nanoparticles prepared consist of a poorly water soluble corticosteroid, beclomethasone dipropionate, and polymeric materials Eudragit E 100 or Eudragit L 100. The novel method used in this study allows synthesis of nanoparticles directly as dry powders. The nanoparticles can contain various ratios of drug and polymer, and the use of any additional stabilisation materials is avoided. In this study, nanoparticles with different drug-to-polymer ratios were prepared. Particle size and morphology, crystallinity, and thermal behaviour were determined as a function of particle composition. It was found that all the nanoparticles produced, regardless of particle composition, had geometric number mean diameters of approximately 90 nm, and were spherical showing smooth surfaces. The drug was molecularly dispersed in the amorphous polymeric matrix of the nanoparticles, and drug crystallisation was not observed when the ambient temperature was below the glass transition temperature of the polymer.     

上尿路结石的诊断和治疗

近年来,我国上尿路结石的发病率有逐年上升的趋势,随着检查方法以及各种腔镜碎石器械的改进,上尿路结石的诊断与治疗方法发生了巨大的改变,大部分上尿路结石患者已由传统开放手术转为微创手术治疗。本文对上尿路结石的诊断与治疗进行阐述。     

儿童药物性血尿1056例临床分析

目的:探讨儿童药物性血尿的原因和机制,提出预防措施,促进临床合理用药。方法:对2005-2010年国内公开发表的医药期刊报道的1056例儿童(≤16岁)药物性血尿进行统计、分析。结果:本研究中药物性血尿共涉及5类药物41个品种,以抗微生物药、解热镇痛抗炎药和抗感冒药为主,且与年龄、给药剂量、给药途径等有关。结论:充分认识药物性血尿产生的原因,安全、合理地使用药品,积极采取预防措施,对避免或减少儿童药物性血尿的发生有重要的临床意义。