Pharmacokinetics and effects of frusemide in patients with the nephrotic syndrome

Summary The renal handling and effects of an intravenous bolus of frusemide with and without plasma volume expansion with dextran or albumin, and with large variations in plasma albumin concentration, have been studied in five patients with the nephrotic syndrome.Decreased renal sensitivity to frusemide was found in only one patient, who also had hypovolaemia and an activated renin-angiotensin-aldosterone system. Plasma volume expansion increased the diuresis but not the saluresis, and slightly increased renal sensitivity to frusemide.An increase in albuminuria after albumin infusion did not reduce the sensitivity to frusemide. A decrease in plasma albumin concentration from 33 g·l^–1 after albumin infusion to 23 g·l^–1 after infusion of dextran caused a substantial increase in the renal clearance (from 84 to 123 ml·min^–1), non-renal clearance (from 72 to 138 ml·min^–1), and apparent volume of distribution (from 13 to 23 l) of frusemide, probably as a consequence of an increase in the unbound fraction. The rate of urinary excretion of frusemide was highest after albumin infusion, despite the fact that its renal clearance was lowest then.     

大剂量呋塞米持续静脉泵入对早期急性肾损伤伴急性肺水肿的临床疗效

目的 研究大剂量呋塞米持续静脉泵入对早期急性肾损伤伴急性肺水肿的临床疗效。方法 选择2012年2月~2015年12月在陕西省人民医院进行诊治的早期急性肾损伤伴急性肺水肿患者180例,所有患者均先持续静脉泵入1~2 mg/min呋塞米,再按照患者尿量的多少调整呋塞米的用药剂量。分别在治疗前和治疗后6、12、24、48、72 h,观察并记录患者的血肌酐、血尿素氮、氧合指数、血钾、机械通气时间、pH值、预后情况和不良反应发生情况。结果 呋塞米用药剂量开始减少的时间平均为（12.15±3.12）h;呋塞米的应用时间平均为（46.31±4.89）h;治疗后各时间点患者的血肌酐、血尿素氮、氧合指数、pH值和血钾均与治疗前有明显差异（P<0.05）,且治疗后各时间点上述观察指标均有明显差异（P<0.05）;180例患者中,治疗后有161例肾功能恢复,占89.44%,呼吸困难的症状得到明显减轻,X线胸片发现肺水肿有明显好转,成功停止机械通气,机械通气时间平均为（35.28±11.37）h;在治疗过程中,180例患者血流动力学稳定,均未出现低血压、耳聋和耳鸣等不良反应。结论 给予大剂量呋塞米治疗早期急性肾损伤伴急性肺水肿,能明显增加尿量,改善肾功能、内环境紊乱和预后,提高救治成功率。     

头孢呋辛对肾移植患者肾功能和环孢素血浓度的影响

采用FPIA法测定环孢素血药浓度,在32例肾移植术后患者中进行合用头孢呋辛对肾功能及环孢素血药浓度影响的研究.在合用头孢呋辛前、合用7d后、停药后d7测定患者的血清肌酐、尿素氮和环孢素全血谷值药物浓度.结果患者合并用药前、后的血清肌酐、尿素氮、环孢素浓度经统计学检验无显著性差异(P>0.05).表明头孢呋辛与环孢素合用对患者的肾功能无不良影响,且基本不改变环孢素的血药浓度.     

The pharmacokinetics of ceftazidime in patients with impaired renal function and concurrent frusemide therapy

Summary We have studied the pharmacokinetics of ceftazidime in 37 patients suffering from serious bacterial infections. All the patients had impairment of renal function and received moderate to high doses of frusemide concurrently. The doses of ceftazidime were given according to renal function as recommended by the manufacturer. Serum and urine samples were frequently collected, and drug concentrations measured by high performance liquid chromatography.The patients were grouped and evaluated according to renal function, mean (SD) creatinine clearances ranging from 70.1 (12.4) to 11.0 (3.2) ml·min^–1. The pharmacokinetics of ceftazidime depended on renal function. A statistically significant increase in ceftazidime elimination half-life and decreases in urinary recovery, total body clearance, and renal clearance in proportion to the decrease in renal function were observed (p<0.05). The apparent volume of distribution also increased, but not significantly (p>0.05). A linear correlation was found between the total body and renal clearances of ceftazidime and creatinine clearance. The extrarenal clearance increased from 3.9 to 14.0 ml·min^–1 with decreasing renal function.Concurrent treatment with ceftazidime and moderate to high doses of frusemide did not impair renal function and no evidence of nephrotoxicity was found.     

Cefuroxime in the treatment of lower respiratory tract infection

Summary

Cefuroxime is a new parenteral antibiotic with a wider spectrum of activity than earlier cephalosporins and is particularly active against Haemophilus influenzae, including strains resistant to ampicillin due to β-lactamase production. From 18 centres, 274 patients suffering with 275 infections were treated with cefuroxime sodium using the standard regimen of 750?mg 8-hourly by intramuscular injection. The clinical results showed a 90% success rate in the patients with bronchopneumonia (105), 91% in patients with post-operative pneumonia (74), and 89% in the patients with acute exacerbations of chronic bronchitis (96). Renal function was closely monitored during therapy, and no adverse changes attributable to cefuroxime therapy were seen in any patient, including those who also received frusemide. Two patients (0.7%) developed a rash, although 8 penicillin-allergic patients were treated without incident. From these studies, it can be concluded that 750?mg cefuroxime 8-hourly is effective in the treatment of lower respiratory tract infections. It is suggested that the attributes of this antibiotic may offer several advantages over existing therapies.     

The urinary excretion of frusemide and its metabolites by kidney transplant patients

Summary Urine from 5 renal transplant recipients treated with frusemide was analyzed for unchanged frusemide (F), glucuronidated frusemide (G) and 4-chloro-5-sulfamoylanthranilic acid (CSA) by HPLC.In 3 recipients, whose renal function recovered steadily and whose hepatic function was normal throughout, the ratio of frusemide to its metabolites, F/(F+G+CSA), increased steadily in conjunction with the recovery of renal function. In one patient, who received frusemide 200–400 mg/day i.v., the urinary CSA concentration was 64–102 µg·ml^–1. In 2 patients who experienced shock and/or hepatic dysfunction after transplantation, the F/(F+G+CSA) ratio fluctuated.     

Effects of rhein on renal arachidonic acid metabolism and renal function in patients with congestive heart failure

Summary In a randomized double-blind cross-over study the effects of rhein (administered as diacetylrhein 50 mg b.d. for 5 days) and placebo on renal arachidonic acid metabolism and renal function have been compared in 12 elderly patients (mean age 75.2 years) with congestive heart failure, whose renal function was known to be dependent on the integrity of the renal prostaglandin system.Rhein like placebo, did not induce any change in the urinary excretion of prostaglandin (PG) E₂, 6-keto-PGF₁ and thromboxane (TX) B₂, nor did it affect creatinine clearance, blood urea, urine output, natriuresis, body weight, plasma renin activity or plasma aldosterone concentration. Separate analysis of the results obtained in the 5 patients receiving diuretic treatment did not show any significant effect of rhein as compared with placebo on the parameters investigated. Serum TXB₂ concentration during whole blood clotting, as an index of platelet arachidonic acid metabolism, also showed no significant difference when DAR and placebo were compared.It is concluded that in patients with congestive heart failure rhein does not inhibit renal or platelet eicosanoid metabolism, nor does it modify renal function, sodium excretion or the renal response to diuretics.     

3种 头孢菌素对肾功能及环孢素血浓度的影响

５１例肾移植术后患者中随机分组，考查３种新头孢菌素分别与环孢素合并使用时对肾功能及环孢素全血药浓浓度的影响，在合并用头孢菌素前，合并用药７ｄ，停药后７ｄ测定患者的血清肌酐、尿素氮和环孢素全血药物浓度。     

Nephrotoxicity: a comparison in humans of gentamicin and gentamicin C1 administration

The relative nephrotoxicities of the gentamicin complex (Garamycin) and gentamicin C₁ were studied using “acute” (intravenous infusion, five normal renal function subjects) and 3-day (multiple injections for 3 days, five normal renal function subjects) administration of the drug. Inulin, creatinine, and para-aminohippurate (PAH) clearances, renal concentrating capacity, urinary alkaline phosphatase, N-acetyl-β-d-glucosaminidase and β-glucuronidase enzyme excretions, and quantitative urinary sediment counts were measured before and during treatment. Although transient elevations of urinary enzymes occurred with both drugs, these were judged neither excessive nor abnormal. Renal function indicators showed no change after drug administration and there were no significant differences between drugs. Also, urinary sediment showed no changes from normal, and the gentamicin C₁ administration was not significantly different from results after gentamicin complex administration. By the presently rather imprecise criteria defining the lower limits of nephrotoxicity, neither drug when administered by the present recommendations for the upper dose limits for therapy with gentamicin complex was shown to be toxic. The 3-day multiple-dosing schemes for both drugs results in a total dose comparable to chronic dosing for 7–10 days at more usual doses and were judged to be comparable.     

202例次万古霉素血药浓度监测与临床应用分析

目的 分析万古霉素血药浓度监测结果及临床应用情况,为临床合理用药提供参考。方法 采用反相-高效液相色谱法测定万古霉素血药浓度,对万古霉素血药浓度监测结果及相关用药信息进行比较分析。结果 万古霉素谷浓度监测202次,平均血药谷浓度（14.36±8.12）mg/L,浓度小于10 mg/L的有68例次（33.66%）,在10～20 mg/L的有100例次（49.51%）,大于20 mg/L的有34例次（16.83%）;肾功能正常与异常组间,血药谷浓度有显著性差异;用药前后,各项肾功能指标无显著性差异。结论 万古霉素个体差异大,需加强血药浓度监测;针对肾功能异常患者,临床医生和药师需审慎评估给药剂量;临床医生应根据血药浓度及时调整用药方案,实现个体化给药。     

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.     

Increased severity of gentamicin nephrotoxicity in aging rats is mediated by a reduced glomerular nitric oxide production

The present experiments have been performed to assess whether the increased severity of gentamicin-induced nephrotoxicity in old animals could be mediated by a decreased production of nitric oxide. Aging rats (12 months) treated with gentamicin showed higher plasma creatinine and a higher reduction in creatinine clearance. After gentamicin treatment, glomerular nitrite production was higher in young than in old animals, whereas no differences in cortical gentamicin concentration were observed between young and aging animals. The increased severity of gentamicin-induced acute renal failure in old animals could be based on a decreased glomerular NO production after gentamicin treatment.     

Gentamicin and sisomicin — Induced renal tubular damage

Summary Early signs of aminoglycoside — induced renal tubular damage were detected in 26 patients given gentamicin and 23 given sisomicin. The urinary elimination of 3 low molecular weight proteins (LMWP) — beta 2 microglobulin, retinol binding protein and lysozyme (LZM), and the urinary activity of 2 enzymes — alanine aminopeptidase and N-acetylbeta-glucosaminidase — was measured before, during and after treatment. In gentamicin — treated patients LMWP elimination increased, especially LZM which rose markedly during treatment and returned to normal values after its end. Enzyme activities also rose while gentamicin was being given. Sisomicin produced smaller changes. As neither the mean serum creatinine nor the mean urinary elimination of transferrin were increased, glomerular function was probably not affected. However, tubular damage was detected, as shown by the LMWP output (especially LZM) and increased enzyme activity. Urinary LMWP and enzyme measurements are presented as sensitive and reliable methods to monitor early aminoglycoside — induced tubular impairment. It is suggested that the different renal toxicities of gentamicin and sisomicin are related to differences in their accumulation in the renal cortex.     

Dosing of gentamicin in patients with end-stage renal disease receiving hemodialysis

The aim of this study was to evaluate dosing schedules of gentamicin in patients with end-stage renal disease and receiving hemodialysis. Forty-six patients were recruited who received gentamicin while on hemodialysis. Each patient provided approximately 4 blood samples at various times before and after dialysis for analysis of plasma gentamicin concentrations. A population pharmacokinetic model was constructed using NONMEM (version 5). The clearance of gentamicin during dialysis was 4.69 L/h and between dialysis was 0.453 L/h. The clearance between dialysis was best described by residual creatinine clearance (as calculated using the Cockcroft and Gault equation), which probably reflects both lean mass and residual clearance mechanisms. Simulation from the final population model showed that predialysis dosing has a higher probability of achieving target maximum concentration (Cmax) concentrations (> 8 mg/L) within acceptable exposure limits (area under the concentration-time curve [AUC] values > 70 and < 120 mg x h/L per 24 hours) than postdialysis dosing.     

重组人脑钠肽对急性心衰患者心肾功能及脑利钠肽的影响

目的 探讨重组人脑钠肽对急性心衰患者心肾功能及脑利钠肽（BNP）的影响。方法 选取2011年1月-2016年12月郑州市第七人民医院收治的急性心力衰竭患者120例。随机分为两组，对照组在常规治疗的基础上给予硝普钠，观察组在常规治疗的基础上给予重组人脑钠肽。用药48 h后，观察两组患者的心功能改善情况、左心室射血分数、血浆BNP水平、排尿量、血肌酐、血钾浓度变化情况。结果 用药后48 h，观察组心功能改善的总有效率为83.34%，显著优于对照组的56.67%，差异有统计学意义（P<0.05）。与用药前相比，两组患者用药后LVEF均明显的升高，组内差异有统计学意义（P<0.05）；且观察组明显高于对照组，差异有统计学意义（P<0.05）；用药后两组的血浆BNP水平均明显降低，组内差异有统计学意义（P<0.05），且观察组明显低于对照组，差异有统计学意义（P<0.05）；用药后两组的尿量均明显增加，组内差异有统计学意义（P<0.05）；且观察组的多于对照组，差异有统计学意义（P<0.05）。与用药前相比，两组患者的血肌酐浓度均轻度升高，观察组血钾浓度轻微升高，对照组血钾浓度轻微下降，差异均无统计学意义；停药后，未见进一步加剧。结论 应用重组人脑钠肽治疗急性心力衰竭患者，可以改善患者的心功能情况，降低血浆BNP水平，利尿，对肾功能未见不良影响。     

移植肾输尿管狭窄的临床诊治及预防措施分析

目的 探讨肾移植术后移植肾输尿管狭窄的临床诊治及预防措施。方法 回顾性分析2013年1月至2015年4月安徽医科大学第一附属医院移植中心收治的肾移植术后移植肾输尿管狭窄5例患者的临床资料,并结合文献进行分析。结果 经B超及移植肾输尿管造影等检查,5例患者均存在不同程度的移植肾输尿管狭窄,其中4例行移植肾输尿管膀胱再植术,1例行移植肾输尿管双J管置入术,术后移植肾功能均恢复。结论 对于肾移植术后出现少尿、肌酐进行性升高的患者,应及早行移植肾B超、移植肾输尿管造影及CT尿路造影等检查,明确有无狭窄及狭窄位置,移植肾输尿管膀胱再植术及输尿管双J管置入术是有效的治疗方法,若在手术过程中注意某些环节,则可减少部分移植肾输尿管狭窄的发生。     

Influence of spironolactone treatment on gentamicin-induced nephrotoxicity in rats

The effect of treatment of rats with gentamicin (80 mg/kg/day for 6 days), oral doses of spironolacatone (20 mg/kg/day for 6 days), and the combined treatment (spironolactone + gentamicin) on renal histology and reduced glutathione (GSH) concentration, and some serum constituents indicative of kidney function were studied. The serum concentrations of creatinine and urea were not significantly affected by spironolactone treatment, but were significantly elevated (P<0.05) by gentamicin administration. The antibiotic treatment also reduced GSH concentration and caused a moderate renal cortical necrosis. However, rats exposed to spironolactone + gentamicin revealed drastic increases in the serum urea and creatinine concentrations amounting to about 1.8 and 2.1 times those of rats treated with gentamicin alone, respectively. The histological examination of slides of the renal cortex of rats exposed to the combined drugs exhibited more extensive necrosis in the tubules when compared to those treated with gentamicin alone. The reduction in GSH induced by gentamicin was unaffected by the concomitant treatment of gentamicin and spironolactone. The concentration of gentamicin accumulated in the renal cortex was significantly larger (twofold) in rats treated concomitantly with spironolactone + gentamicin than in rats treated with gentamicin alone. The present results indicate that spironolactone aggravates gentamicin-induced nephrotoxicity in the rat.     

Enhancement by potent diuretics of renal tubular necrosis induced by cephaloridine

1. Administration of frusemide or ethacrynic acid to cephaloridine-treated mice increased both the incidence and extent of proximal renal tubular necrosis compared with that obtained in cephaloridine-treated control mice.2. Administration of frusemide to cephaloridine-treated rats produced significant changes in urine output, electrolyte excretion and proteinuria, and plasma urea nitrogen and creatinine values were significantly increased compared with controls or rats that received frusemide or cephaloridine alone.3. Histological examination of the kidneys showed a higher incidence and greater extent of tubular necrosis in rats that received both frusemide and cephaloridine.4. It is suggested that this adverse drug interaction may have contributed to the deterioration in renal function observed in some patients treated with diuretics and cephaloridine concurrently.     

Enhancement of high dose cyclosporin A toxicity by frusemide

Adult Sprague-Dawley rats were given cyclosporin A (CyA), frusemide (Fr) or both drugs daily for 14 days. The doses of CyA (50 mg/kg) and Fr (5 mg/kg) were approximately 3-6 times and twice respectively those used in man. Fr on its own produced a diuresis lasting approximately 3 hr. This was characterized by a 10-fold increase in urine flow rate, a 40-fold increase in the rate of sodium excretion, and by 2- and 4-fold increases in urea and creatinine clearance rates, respectively. In addition, there was a doubling in urinary N-acetyl-beta-D-glucosaminidase (NAG) activity. After 4 days of combination treatment with CyA and Fr, the diuretic-induced increases in urine flow rate, sodium excretion and urinary NAG activity were similar to those following frusemide alone. However, urea and creatinine clearances did not increase during the diuresis. Fr itself did not impair renal function, but rats receiving only CyA did show elevations in serum urea and creatinine, with reductions in clearance rates, which progressed with time. There was also an increase in NAG enzymuria. When the two drugs were exhibited together, renal function was more severely impaired. All animals given CyA showed proximal renal tubular cell vacuolation: in half the damage was confined to the straight segment, while the rest showed additional severe convoluted segment change. Renal function was most abnormal in those rats in which both segments were affected. All animals given both drugs showed both straight and convoluted tubular abnormalities and a 2-fold increase in serum CyA levels. CyA-induced disturbances in hepatic function and lymphoid tissue atrophy were unaffected by the addition of Fr, nor did Fr affect the immunosuppressive action of CyA.     

Effects of Long-Term Oral Carvedilol on the Steady-State Pharmacokinetics of Oral Digoxin in Patients With Mild to Moderate Hypertension

The effect of multiple oral doses of carvedilol on steady-state plasma digoxin pharmacokinetics was evaluated in 12 patients with mild to moderate hypertension. Area under the curve (AUC), mean maximum plasma concentration (C_max), mean time to maximum concentration (T_max), concentration at 24 hours after the dose (C₂₄), creatinine clearance, renal digoxin clearance, and urinary digoxin excretion were determined after patients took oral digoxin 0.25 mg once/day for 2 weeks. Carvedilol was added to the regimen, and digoxin pharmacokinetics were assessed after 2 weeks of concurrent treatment. The AUC and C_max for digoxin increased by 14% and 32%, respectively (p<0.05), with no change in T_max. The 24-hour urinary digoxin excretion and 24-hour renal digoxin clearance increased by 45% and 26%, respectively (p<0.05), with no change in creatinine clearance. Carvedilol appears to increase digoxin's oral bioavailability as well as renal elimination. The absolute change in digoxin pharmacokinetics was small and not clinically significant. The significance of the interaction in other patient populations remains to be studied.