Pharmacokinetics of quinine in patients with chronic renal failure

Methods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (t_max 4.5 vs 1.6 h, C_max 6.17 vs 3.45 g·ml^–1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min^–1·kg^–1, whereas V_z/f remained unchanged (1.82 vs 2.78 1·kg^–1). This resulted in the increased values of AUC and prolongation of the t_1/2z and MRT in the patients (AUC 181.5 vs 61.8 g·min^–1·ml^–1, t_1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.     

Acute renal failure alters the kinetics of pralidoxime in rats

There is a trend towards increasing doses of pralidoxime to treat human organophosphate poisonings that may have relevance in subpopulations. Indeed, pralidoxime is eliminated unchanged by the renal route. This study assesses the effect of renal failure on the kinetics of pralidoxime in a rat model of acute renal failure induced by potassium dichromate administration. On the first day, Sprague–Dawley rats received subcutaneously potassium dichromate (study) or saline (control). Forty-eight hours post-injection, animals received pralidoxime methylsulfate (50 mg/kg of pralidoxime base) intramuscularly. Blood specimens were sampled during 180 min after the injection. Urine was collected daily during the 3 days of the study. Plasma pralidoxime concentrations were measured by liquid chromatography with electrochemical detection. There was a 2-fold increase in mean elimination half-life and a 2.5-fold increase in mean area under the curve in the study compared to the control group. The mean total body clearance was halved in the study compared to the control group. Our study showed acute renal failure does not modify the distribution of pralidoxime but significantly alters its elimination from plasma. These results suggest that dosages of pralidoxime should be adjusted in organophosphate-poisoned humans with renal failure when using high dosage regimen of pralidoxime.     

Disposition of oral quinine in acute falciparum malaria

Summary Plasma quinine concentrations following oral quinine sulphate 10 mg salt/kg have been measured by HPLC in 15 adult Thai patients with uncomplicated falciparum malaria. In 10 of the same patients the study was repeated in convalescence. In acute malaria plasma concentrations were approximately 50% higher than in convalescence; the mean acute peak plasma quinine concentration was 8.4 mg·l^–1 compared to 5.7 mg·l^–1 in convalescence.There was considerable variation in the rate of drug absorption, particularly in acute malaria. The mean time to peak plasma concentration was 5.9 h in acute malaria and 3.2 h in convalescence. The apparent clearance of oral quinine (CL/f) during the illness was 1.51 ml·kg^–1·min^–1, which was significantly lower than in convalescence — 2.67 ml·kg^–·min^–1. Estimated free quinine clearance was also lower in the acute phase: 30.6 compared to 49.0 ml·kg^–1·min^–1 in convalescence. Mean (SD) plasma protein binding of quinine was 94.7% in acute malaria and 92.8% in convalescence. Binding was significantly correlated with the plasma concentration of ₁ acid glycoprotein (r=0.5), which was significantly higher in the acute phase; 1.48 g·l^–1 compared to 1.05 g·l^–1 during convalescence.Oral quinine sulphate was well absorbed in uncomplicated falciparum malaria. High blood concentrations following the administration of oral quinine in acute malaria are probably related to increased plasma protein binding, lower apparent volume of distribution, and a reduction in its systemic clearance.     

Pharmacokinetics of quinine in African patients with acute falciparum malaria.

The pharmacokinetics of quinine were studied in six Nigerian patients during acute uncomplicated falciparum malaria and convalescent periods. An oral dose of 10 mg/kg quinine dihydrochloride administered 8hourly for 7 days gave parasite and fever clearance times of 36.0 ± 16.6 h and 18.0 ± 6.4 h, respectively. From the individual quinine plasma profiles the mean plasma concentration of quinine at the time of parasite clearance was estimated as 4.5 ± 1.1 g/ml. Plasma quinine levels during malaria rose rapidly reaching a peak around the second and third days and declining thereafter as patients improved clinically. In acute malaria plasma quinine levels were more than two-fold higher than in convalescence; the mean AUC(0-12) in malaria was 37.9 ± 14.7 g.h/ml compared to 17.9 ± 8.5g.h/ml in convalescence. The apparent oral clearance (CL/F) and volume of distribution (Vd/F) duri ng the acute phase of the malaria (1.9 ± 0.7 ml/min/kg and 1.8 ± 0.9 l/kg, respectively) were significantly lower than in convalescence (4.5 ± 2.1 ml/min/kg and 4.2 ± 3.2 l/kg). The present data suggest that malaria parasites in African patients are still very sensitive to quinine and that the current dosage of quinine is effective for the treatment of acute falciparum malaria in African patients without augmenting therapy with any other drug such as tetracycline or sulphadoxine-pyrimethamine. It also confirms that malaria significantly alters the pharmacokinetics of quinine in humans.     

Pharmacokinetics of intravenously administered ciprofloxacin in intensive care patients with acute renal failure

The pharmacokinetics of ciprofloxacin after a single intravenous administration of 100 mg were studied in intensive care patients with an acute renal impairment. There was no correlation found between the creatinine clearance and the renal clearance of ciprofloxacin. This applies to the entire group of patients. The decrease in renal clearance of ciprofloxacin was, however, more pronounced than the change in the elimination half-life, suggesting an important extra-renal elimination of the drug.     

脑钠肽对慢性肾衰竭合并心力衰竭的诊断价值

目的观察肾小球滤过率（eGFR）与脑钠肽（BNP）之间的关系,比较慢性肾衰竭合并心力衰竭（心衰）患者不同eGFR水平BNP的诊断界值（cut—off值）,研究肾功能对BNP应用于心衰诊断的影响。方法对老年eCRF合并心衰未透析患者52例及无心衰29例和老年健康体检者30例（健康对照组）采用酶联免疫吸附法测定血清BNP浓度,根据eGFR分组进行对比。结果eGFR小于30ml、30～60ml心衰组BNP水平均高于eGFR小于30ml、30—60ml无心衰对照组和eGFR大于60ml健康对照组（P〈0．05）,eGFR小于30ml、30—60ml无心衰对照组BNP水平较eGFR大于60柚健康对照组显著升高（P〈0．05）。eGFR小于30ml心衰组与eGFR30—60ml心衰组BNP相比较,差异无统计学意义（t=0．62,P〉0．05）。eGFR与BNP心衰组无相关,无心衰对照组呈负相关（心衰组γ=-0．081,P〉0．05,对照组γ=-0．581,P〈0．01）。eGFR30～60ml心衰组ROC曲线下面积（AUC）为0．951,1500ng／L作为临界值的敏感度为96．4％,特异度为86．7％;eGFR小于30ml心衰组AUC为0．860,1850ng/L作为临界值的敏感度为66．7％,特异度为92．9％。结论CRF合并心衰时心衰是导致BNP升高的主要原因,BNP可作为判断CRF患者是否合并心衰的诊断指标。     

Disposition of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) and its metabolite 4-bromo-2-hydroxy-5-methoxyphenethylamine in rats after subcutaneous administration

The psychedelic compound 4-bromo-2,5-dimethoxyphenethylamine (2C-B) has appeared as an agent in drug abuse or overdose cases in humans. The human pharmacokinetics of this drug is unknown and only partial information is available on its metabolites. Our experimental study was focused on the disposition and kinetic profile of 2C-B in rats after subcutaneous administration using a GC-MS validated method. One of the major metabolites 4-bromo-2-hydroxy-5-methoxyphenethylamine (2H5M-BPEA) was confirmed in rat tissues of lung, brain, liver and was quantitatively evaluated as well. The disposition of 2C-B was characterized by its estimated half-life 1.1h and estimated volume of distribution 16L/kg. The lung susceptibility for drug retention and gradual temporal release parallel to the brain were ascertained. The drug penetrating the blood/brain barrier was without significant delay. 2C-B brain to serum ratio attained a maximum value of 13.9 and remained over the value of 6.5 to the end of our observation (6h after the dose). The distribution of the hydroxylated metabolite 2H5M-BPEA into the lipophilic brain tissue was less efficient in relation to the parent compound. The kinetics of the drug partitioning between blood to brain may be important for the subsequent assessment of its psychotropic or toxic effects.     

Disposition kinetics of disopyramide in patients with renal insufficiency

The pharmacokinetics of an intravenous injection of disopyramide was studied in five normal subjects and six patients with varying degrees of renal impairment. The elimination rate constant (β) was related to the endogenous creatinine clearance (Cl_cr). However, a decrease in β was not observed until the Cl_cr was reduced below 40 ml min^?1. Below 40 ml min^?1 a linear relationship existed between β and Cl_cr. Similarly, the plasma elimination half-life (t_½β) showed a significant increase when the Cl_cr was less than 30 ml min^?1. Hence, dosage modification for disopyramide is necessary only when renal function is severely impaired. Overall, the apparent volume of distribution in patients with renal insufficiency was reduced to two-thirds of that in normal subjects. Therefore, in patients with Cl_cr less than 40 ml min^?1 both the loading and maintenance dose of disopyramide should be reduced.     

老年肾功能衰竭患者血液透析疗效分析

目的 评估老年肾功能衰竭患者血液透析的临床疗效,以减少透析并发症,提高其存活率.方法 观察总结36例老年肾功能衰竭患者维持性血液透析治疗后的生存率,死亡原因和常见的并发症.结果 老年维持性血液透析患者死亡原因主要为心血管疾病,感染及严重营养不良,常见并发症为心力衰竭,感染.结论 施行个体化,充分的透析和治疗,积极改善营养状况和贫血,减少感染,有助于减少老年透析患者的并发症发生和提高生存率.     

Pharmacokinetics of mirtazapine and its main metabolites after single intravenous and oral administrations in rats at two dose rates

Background

Mirtazapine (MRZ) is a human antidepressant drug metabolized to 8-OH mirtazapine (8-OH) and dimethylmirtazapine (DMR) metabolites. Recently, this drug has been proposed as a potential analgesic for use in a multidrug analgesic regime in the context of veterinary medicine. The aim of this study was to assess the pharmacokinetics of MRZ and its metabolites DMR and 8-OH in rats.

Findings

Eighteen fasted, healthy male rats were randomly divided into 3 groups (n = 6). Animals in these groups were respectively administered MRZ at 2 and 10 mg/kg orally and 2 mg/kg intravenously. Plasma MRZ and metabolite concentrations were evaluated by HPLC-FL detection method. After intravenous administration, MRZ was detected in all subjects, while DMR was only detected in three. 8-OH was not detected. After oral administration, MRZ was detected in 3 out of 6 rats treated with 2 mg/kg, it was detected in 6 out of 6 animals in the 10 mg/kg group. DMR was only detectable in the latter group, while 8-OH was not detected in either group. The oral bioavailability was about 7% in both groups.

Conclusions

The plasma concentration of the MRZ metabolite 8-OH was undetectable, and the oral bioavailability of the parental drug was very low.     

连续性血液净化治疗烧伤并发急性肾功能衰竭

目的探讨连续性血液净化（CBP）治疗重度烧伤并发急性肾功能衰竭的疗效及安全性。方法对12例严重烧伤并发急性肾功能衰竭患者早期接受CBP治疗,观察患者治疗前后生命体征、肾功能、血电解质及白细胞介素-6（IL-6）水平的变化。结果12例患者治疗后,肌酐、血钠、血钾浓度明显下降[（376．2±24．5）与（145．2±57．1）μmol／L、（5．3±1．6）与（4．0±0．7）mmol／L、（153．4±13．0）与（140．1±8．6）mmol／L]（t=2．79、3．06、3．01,均P〈0．05）,临床症状明显改善（均P〈0．05）;治疗前APACHEII评分及IL-6水平分别为：（15．2±5．8）分、（264．31±122．42）ng／L,治疗后分别为：（5．4±3．6）分、（94．18±63．82）ng／L,治疗前后差异均有统计学意义（t=4．17、3．67,均P〈0．05）;治愈8例,死亡4例。结论CBP能清除烧伤并发急性肾功能衰竭患者血循环中的炎性介质,维持内环境的稳定,是一种有效的辅助治疗方法。     

Clearance of indometacin occurs predominantly by renal glucuronidation

In this report we describe the conditions of collection, storage and handling of urine samples, collected after oral dosing with indometacin in man, in order to maintain the integrity of the labile glucuronide formed. We found that the body clearance occurs predominantly by renal metabolism, due to glucuronidation in the human kidney. These glucuronides may be converted to isomeric glucuronides and/or the parent compound indometacin during the residence time in the bladder.     

氨转运蛋白RhBG在大鼠肾脏集合管的表达

目的观察氨转运蛋白Rhbg在低蛋白饮食大鼠肾脏集合管的表达。方法利用定量免疫组织化学法分别检测低蛋白饮食组和正常对照组氨转运蛋白Rhbg在大鼠肾脏皮质、内髓、外髓集合管的表达。结果低蛋白饮食可以明显增加Rhbg在大鼠肾脏皮质部集合管的表达(P<0.05),但不改变Rhbg在大鼠肾脏内髓和外髓集合管的表达。结论饮食中蛋白的限制可能会增加Rhbg在大鼠肾脏皮质部集合管的表达。     

氯沙坦对慢性心力衰竭大鼠心室重塑和心功能保护作用的实验研究

目的研究氯沙坦(Los)对腹主动脉缩窄致慢性心力衰竭大鼠心室重塑和心功能的保护作用。方法SD大鼠40只,随机分为腹主动脉缩窄(COA)+Vehicle组,COA+Los组,假手术(Sham)+Vehicle组,Sham+Los组。药物干预8周后采用超声心动图和心室插管法评估心功能,计算左、右心室质量指数(LVMI、RVMI),比色法检测心肌羟脯氨酸(HYP)含量,酶联免疫吸附试验(ELISA)检测心肌Ⅰ型和Ⅲ型胶原含量和比值,放射免疫法(RIA)检测心肌血管紧张素Ⅱ(Ang Ⅱ)和醛固酮(ALD)水平。常规苏木素-伊红(HE)、Masson三色染色和透射电镜观察心肌组织形态学改变。结果与COA组相比,COA+Los组大鼠心功能和LVMI等指标明显好转,心肌HYP和Ⅰ型胶原含量降低,Ⅰ/Ⅲ型胶原比值降低;心肌Ang Ⅱ和ALD水平降低;心肌组织形态改变明显好转。结论Los通过阻断Ang Ⅱ与AT1-R结合,抑制心肌Ang Ⅱ和ALD生成,从而改善心肌肥厚和胶原重构所致心室重塑,提高心功能,延缓心力衰竭进展。     

急性肾功能衰竭患者炎性反应与心钠素的关系

目的 探讨急性肾功能衰竭患者慢性炎性反应与心钠素的关系.方法 测定75例急性肾功能衰竭患者慢性炎性指标血C-反应蛋白(CRP)、IL-6、TNF-α及心钠素,分析它们之间的关系.结果 有62.7%急性肾功能衰竭患者心钠素超过正常参考值,心钠素升高组血清CBP、IL-6显著高于心钠素降低组(均P<0.05);血心钠素与CRP(P<0.01)、IL-6及TNF-α呈正相关(P<0.05).结论 急性肾功能衰竭患者存在炎性反应,可能引起心钠素等代谢异常.     

血液透析联合血液灌流治疗慢性肾衰竭并发继发性甲状旁腺功能亢进临床观察

目的探讨终末期肾衰竭患者运用维持性血液透析和血液透析联合血液灌流治疗慢性肾衰竭并发继发性甲状旁腺功能亢进（简称甲旁亢）的临床效果及对患者营养状况、肾功能、血压、C-反应蛋白（CRP）等的影响。方法将44例慢性肾衰竭并发继发性甲旁亢维持性血液透析患者随机分为常规血液透析组和血液透析联合血液灌流组,记录入组前两组患者透前收缩压、舒张压,透后收缩压、舒张压,透前血红蛋白、清蛋白、肌酐、尿素氮,血清钙、磷、甲状旁腺激素、β2-微球蛋白（β2-MG）、CRP水平,6个月后重复检查,记录结果。结果两组患者透析6个月后,透前收缩压、舒张压,透后收缩压、舒张压、清蛋白、血清钙、CRP基线情况相似,差异无统计学意义（P〉0．05）。血液透析联合血液灌流组血红蛋白水平较治疗前升高,血清磷、甲状旁腺激素、β2-MG水平较血液透析组升高,差异有统计学意义（P〈0．05）。结论血液透析联合血液灌流能更好地降低血清磷、甲状旁腺激素、β2-MG水平,改善慢性肾衰竭并发继发性甲旁亢症状,同时还能改善患者贫血状态。     

Omi/HtrA2抑制剂对肾脏缺血再灌注损伤诱导的肾小管上皮细胞凋亡的影响

目的研究Omi/HtrA2抑制剂(UCF-101)对大鼠肾脏缺血/再灌注(I/R)损伤诱导的肾小管上皮细胞凋亡的影响。方法雄性Wistar大鼠随机分为5组:假手术组(DMSO)、模型1组(I/R+R前DMSO)、模型2组(I/R+R后DMSO)、治疗1组(I/R+R前UCF-101)和治疗2组(I/R+R后UCF-101)。双侧肾动脉夹闭45min再灌注24h制作动物模型;比色法测定血清肌酐和尿素氮浓度;Western blot法检测肾组织中天冬氨酸特异性半胱氨酸蛋白酶(caspase)-3、caspase-9的蛋白质表达;原位末端标记TUNEL法检测肾小管上皮细胞凋亡。结果肾脏缺血45min再灌注24h后,大鼠肾功能明显减退(P<0.05);肾组织中caspase-3、caspase-9蛋白质表达显著增加(P<0.05),大量肾小管上皮细胞凋亡(P<0.05)。再灌注前给予UCF-101能显著改善肾功能(P<0.05),并显著下调caspase-3、caspase-9蛋白质表达(P<0.05),减轻肾小管上皮细胞凋亡(P<0.05),而再灌注后给药不能改善肾功能及caspase-3、caspase-9蛋白质的表达(P>0.05)。结论再灌注前给予UCF-101能抑制肾脏I/R损伤诱导的肾小管上皮细胞凋亡,对肾脏I/R损伤具有保护作用。     

肾康注射液治疗慢性肾功能衰竭的临床观察

目的 观察肾康注射液对慢性肾功能衰竭（CRF）的疗效.方法 将100例CRF患者按随机数字表法分为2组.在常规治疗基础上,观察组50例：肾康注射液60ml加入0.9％氯化钠注射液250 ml中静脉滴注,1次/d,疗程为14 d;对照组50例：丹红注射液20ml加入0.9％氯化钠注射液250 ml中静脉滴注,疗程14 d.分别对治疗前后临床疗效和血尿素氮、肌酐、内生肌酐清除率、血红蛋白进行评价.结果 观察组治疗后总有效率高于对照组,血尿素氮、肌酐较对照组低,内生肌酐清除率、血红蛋白较对照组高,差异均有统计学意义[90.0％（45/50）比74.0％（37/50）,（14±8）mmol/L比（25±11） mmol/L,（422±112） μmol/L比（573±126） μmol/L,（19±8） ml/min比（14±8）ml/min,（77±18） g/L比（66±14） g/L]（均P＜0.05）.结论 肾康注射液治疗CRF疗效确切,可延缓CRF的疾病进展,不良反应少,患者依从性好.     

Effects of Korean red ginseng extract on acute renal failure induced by gentamicin and pharmacokinetic changes by metformin in rats

Aim of the studyKorean red ginseng is one of the best selling dietary supplements and its individual constituents enhance renal function. Acute renal failure (ARF) is a predisposing complication of diabetes mellitus as a result of combination drug therapy. The combination of antibiotic–antidiabetic drugs can entail toxicities and drug interactions because of the antibiotic resistance in patients with severe bacterial infection. Currently, gentamicin–metformin combination therapy is commonly prescribed for treating bacterial infections and diabetes, even though both drugs are mainly excreted via the kidney. Thus, this study was designed to investigate whether a Korean red ginseng extract (KRG) prevents renal impairment and pharmacokinetic changes by metformin in rats with renal failure induced by gentamicin.Materials and methodsThe in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of metformin were assessed using control (CON), control with Korean red ginseng extract (KRG-CON), acute renal failure induced by gentamicin (ARF), and ARF with Korean red ginseng (KRG-ARF) rats.Results and conclusionsPharmacokinetic changes of metformin did not occur in KRG-ARF rats because KRG reduce the renal accumulation of gentamicin compared to ARF rats. Thus, KRG seemed to prevent acute renal failure induced by gentamicin treatment.