The effects of intravenous and oral nifedipine on ex vivo platelet function

Summary We have studied the possible anti-platelet effects of an intravenous formulation of nifedipine (0.75 mg as a bolus and an infusion of 1.2 mg · h^–1 for 2 h), or equivalent volumes of the vehicle alone, or normal saline, in a double-blind crossover fashion in six healthy subjects. The effects of a standard oral formulation (20 mg sustained-release) compared to identical placebo were also studied in twelve other subjects. Platelet function was assessed by the addition of collagen, adenosine diphosphate, or adrenaline to whole blood followed by single platelet counting.Intravenous nifedipine had no effect on aggregation in response to any of the agonists, but oral nifedipine reduced aggregation caused by collagen by approximately 15%, despite similar plasma nifedipine concentrations after both formulations (18.5 ng · ml^–1 after intravenous and 21.5 ng · ml^–1 after oral administration). The lack of effect of intravenous nifedipine may be due to endothelial irritation caused by the vehicle.Intravenous nifedipine is unlikely to have a useful anti-platelet effect in patients who have acute coronary insufficiency.     

Clinical effects of intravenous diltiazem hydrochloride on renal hemodynamics

We administered diltiazem HCl i.v. (0.05 mg/kg in bolus followed by 0.01 mg/kg/min for 45 min), and determined the changes in blood pressure (BP), glomerular filtration rate (GFR), renal blood flow (RBF), total renal resistance, urinary volume (UV), urinary sodium (UNa) and potassium excretion, urea and osmolar clearance, and tubular reabsorption ratio of sodium (TRNa%). The serum concentration of diltiazem achieved was similar to the maximum level after a single oral dose of 120 mg. GFR and RBF were measured by i.v. infusion of sodium thiosulfate and sodium rho-amino-hippurate, respectively, as indicators. The subjects included 12 cases of essential hypertension (EH), 10 of chronic glomerular nephritis (CGN) with hypertension, 12 of CGN without hypertension, 12 of ischemic heart disease (IHD), and 10 of normotensive controls. BP decreased in hypertensives but not in normotensives. In patients with EH, GFR and RBF increased markedly (by 25.3 +/- 33.8% and 30.7 +/- 39.5%, respectively). In patients with IHD, GFR increased slightly by 9.8 +/- 17.6%, whereas in patients with CGN with hypertension, GFR decreased by -4.3 +/- 14.3%. No significant change of these indices was observed in normal subjects and in patients with CGN without hypertension. UV and UNa increased and TRNa% decreased in all groups. Urea and osmolar clearance increased in almost every group.     

The effect of nifedipine GITS on renal function in hypertensive patients with renal insufficiency

Twelve hypertensive patients with moderately severe renal dysfunction were entered into a protocol to assess the blood pressure and renal effects of the sustained release calcium antagonist, nifedipine GITS (30-180 mg/d given once a day) administered for 5 weeks. Nifedipine GITS monotherapy effectively lowered blood pressure in 50% of the patients. Glomerular filtration rate and effective renal plasma flow were increased 18% and 20%, respectively. The filtration fraction and urinary protein excretion remained unchanged. Changes that were observed in renal function were independent of the blood pressure responses of the patients; there was no correlation between the systemic and renal effect of nifedipine GITS monotherapy. Patients who had a poor systemic blood pressure response exhibited an increase in glomerular filtration rate (+11%) but had a decrease in effective renal plasma flow (-6%); patients who achieved a goal blood pressure response showed increases in both glomerular filtration rate (+35%) and effective renal plasma flow (+40%). These results show that nifedipine GITS monotherapy has the potential to improve renal function abnormalities that are encountered in hypertensive patients with renal disease; the improvement in renal function may be independent of their effect on systemic blood pressure.     

Effects of nifedipine, verapamil and diltiazem on renal function.

Eight healthy female volunteers were given single doses of nifedipine 10 mg, verapamil 80 mg, diltiazem 120 mg or placebo on 4 different study days. Urine and sodium output increased after all four drugs, but the increase after nifedipine was significantly greater than after verapamil or placebo. Nifedipine caused a significant increase in heart rate; none of the drugs caused any change in blood pressure. Potassium excretion, creatinine clearance, free water clearance and plasma renin activity did not change with any drug. The mechanism of the natriuresis and diuresis has still to be elucidated.     

Clinical pharmacokinetics of the nifedipine/co-dergocrine combination in impaired liver and renal function.

Following a single oral dose of 20 mg nifedipine combined with 2 mg co-dergocrine to 24 subjects, the pharmacokinetics of this drug were studied. 8 normotensive subjects had normal renal and hepatic function, 8 patients had chronic renal insufficiency (creatinine clearance less than 30 ml.min-1) and 8 patients had liver cirrhosis which was confirmed by liver biopsy. The area under the plasma level time curve (AUC infinity) of co-dergocrine increased from 0.59 +/- 0.41 ng.ml-1. (mean +/- SD) in the normals to 1.24 +/- 0.95 ng.ml-1.h in liver cirrhosis (P less than 0.05) and to 1.81 +/- 0.9 ng.ml-1.h in renal failure (P less than 0.05 compared with the control group). Corresponding values for the nifedipine AUC infinity were 564.5 +/- 268 ng.ml-1.h, 1547.5 +/- 1134 (P less than 0.05) and 929 +/- 533 ng.ml-1.h (P less than 0.05; gas chromatographic method). The incidence of adverse effects was lower in patients with renal failure than in subjects with normal renal and liver function as well as in those with liver cirrhosis.     

Effect of nifedipine and mefruside on renal function and platelet function in hypertensive patients

A study was carried out in 16 patients with moderately severe hypertension to investigate the effects of nifedipine, given alone or combined with a diuretic, on blood pressure and on renal and platelet function. After 4 weeks on placebo, patients were randomized to receive treatment for 6 weeks with either 20 mg, nifedipine twice daily or 25 mg mefruside once daily on a double-blind, double-dummy basis. All patients then received treatment for a further 6 weeks with a combination of the two drugs in the same dosage as before. The results of blood pressure measurements and laboratory investigations during the three phases of the study showed that significantly better blood pressure control was achieved with nifedipine alone than with mefruside alone. Mefruside had an additional hypotensive effect when added to nifedipine. There was no significant change in the renal blood flow or glomerular filtration rate, with a satisfactory control of blood pressure. There was also no detectable change in platelet aggregation with increasing concentrations of ADP and ristocetin. An adaptive mechanism could be responsible for the apparent lack of change compared with single dose studies.     

Effect of nifedipine and mefruside on renal function and platelet function in hypertensive patients

Summary

A study was carried out in 16 patients with moderately severe hypertension to investigate the effects of nifedipine, given alone or combined with a diuretic, on blood pressure and on renal and platelet function. After 4 weeks on placebo, patients were randomized to receive treatment for 6 weeks with either 20?mg nifedipine twice daily or 25?mg mefruside once daily on a double-blind, double-dummy basis. All patients then received treatment for a further 6 weeks with a combination of the two drugs in the same dosage as before. The results of blood pressure measurements and laboratory investigations during the three phases of the study showed that significantly better blood pressure control was achieved with nifedipine alone than with mefruside alone. Mefruside had an additional hypotensive effect when added to nifedipine. There was no significant change in the renal blood flow or glomerular filtration rate, with a satisfactory control of blood pressure. There was also no detectable change in platelet aggregation with increasing concentrations of ADP and ristocetin. An adaptive mechanism could be responsible for the apparent lack of change compared with single dose studies.     

Effects of nifedipine on renin release and renal function in anesthetized dogs

The effects of nifedipine, classed as a calcium entry blocker, on urinary excretion and renin release were investigated in anesthetized dogs. Nifedipine was infused into one renal artery for three consecutive 10-min periods, at incremental rates of 0.3, 1, and 3 micrograms/min. Intrarenal infusion of nifedipine (3 micrograms/min) produced marked increases in urine flow rate (by 200%) and in urinary sodium (by 210%) and potassium (by 40%) excretion rates of the infused kidney without changes in mean systemic blood pressure, heart rate, glomerular filtration rate, and filtration fraction. Urinary osmolarity was slightly decreased by the drug, but this change was not statistically significant. There were no consistent changes in these parameters for the contralateral noninfused kidney. Renin secretion rate was increased to three times the preinfusion level during infusion of the highest nifedipine dose. The blood flow to the infused kidney was increased, and ipsilateral renal vascular resistance was simultaneously decreased upon nifedipine infusion. These results suggest that a nonhypotensive dose of nifedipine causes an increase in renin secretion and that this drug has a striking effect on the reabsorption of sodium and water by the renal tubules.     

The influence of diltiazem and nifedipine on renal function in the rat.

The effect of intravenous administration of the calcium-entry blocking drugs, diltiazem and nifedipine, on renal haemodynamic and tubular function was examined in denervated kidneys of pentobarbitone-anaesthetized rats. Infusion of vehicle for the compounds had no effect on renal function which was stable for the duration of the experiments. Diltiazem was infused at 5, 10 and 20 micrograms kg-1 min-1. Blood pressure did not change following 5 micrograms kg-1 min-1 diltiazem but was significantly reduced, by 12 mmHg, after 10 micrograms kg-1 min-1 and by 17 mmHg after 20 micrograms kg-1 min-1. Renal blood flow was not affected by any dose of diltiazem while at the lowest dose of drug, glomerular filtration rate (g.f.r.) was significantly increased, by 24%. Absolute and fractional sodium excretion were increased significantly, 154% and 77% respectively, by 5 micrograms kg-1 min-1 diltiazem, 20% and 24% respectively, by 10 micrograms kg-1 min-1 diltiazem, but were unchanged by 20 micrograms kg-1 min-1. Infusion of nifedipine at 0.5, 1.0 and 2.0 micrograms kg-1 min-1 decreased systemic blood pressure by 9, 9 and 20 mmHg, respectively. Renal blood flow was increased (7%) by 1.0 microgram kg-1 min-1 only, while g.f.r. did not change at any dose. Urine flow, absolute and fractional sodium excretions were increased, 127%, 96% and 90% respectively, by 0.5 microgram kg-1 min-1 nifedipine, 127%, 197% and 194% respectively, by 1.0 microgram kg-1 min-1, while these variables remained unchanged by a dose of 2.0 micrograms kg-1 min-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

静脉滴注右旋糖酐铁注射液治疗慢性肾功能不全伴肾性贫血的临床疗效

目的观察静脉滴注(静滴)右旋糖酐铁注射液治疗慢性肾功能不全伴缺铁性贫血的疗效及安全性。方法103例慢性肾功能不全伴贫血患者,随机分为静滴组和肌注组。静滴组用进口右旋糖酐铁注射液100mg溶于100mLNS,ivgtt,每周2次;肌注组用国产右旋糖酐铁注射液100mg,im,每周2次,疗程均10wk。观察治疗前后红细胞计数(RBC)、血红蛋白(Hb)、血细胞比容(Hct)、血清铁蛋白(SF)、转铁蛋白饱和度(TSAT)、肝肾功能及药物不良反应。结果65例患者完成本研究,其中静滴组30例,肌注组35例。静滴组不良反应发生率为6.0%,低于肌注组(18.9%),P<0.01。治疗10wk后,2组贫血症状均有明显改善。静滴组SF、TSAT、Hb、Hct分别为(516.8±68.8)μg·L-1、(34.5±7.2)%、(88.8±14.4)g·L-1、(27.2±3.2)%;肌注组分别为(426±88.7)μg·L-1、(30.2±5.8)%、(79.0±11.4)g·L-1、(24.9±3.1)%,2组相比差异有统计学意义(P<0.05或P<0.01)。结论静滴右旋糖酐铁注射液治疗慢性肾功能不全伴缺铁性贫血是有效、安全的。     

Influence of haemodialysis on the pharmacokinetics and haemodynamic effects of nifedipine during continuous intravenous infusion

The pharmacokinetics and haemodynamic effects of nifedipine were studied in 5 patients on long term haemodialysis. In addition, clearance of the drug on 2 different types of artificial kidneys were measured in vitro. Nifedipine was administered intravenously (1.3 mg/h) from 6 hours before starting haemodialysis to the end of haemodialysis, performed according to the standard protocol of each patient. Before and during haemodialysis, blood samples were taken for determination of free and total plasma nifedipine concentrations. Recovery was determined by measuring nifedipine concentrations in the dialysate. Heart rate and systolic and diastolic blood pressures were determined serially. The haemodynamic changes during nifedipine were compared with those of 3 previous dialysis sessions. Haemodialysis was accompanied by a slight decrease in steady-state nifedipine concentrations. The recovery in dialysate varied between 0.6 and 0.9% of the amount infused during the period of dialysis. Artificial kidney clearance of nifedipine varied between 2.8 and 8.3 ml/min, which was in agreement with in vitro data. Changes in steady-state nifedipine concentrations were most likely due to changes in systemic clearance caused by haemodialysis itself. Systolic and diastolic blood pressure dropped by approximately 15% and 25%, respectively, in comparison with dialysis without nifedipine, but changes in heart rate were not different. It is concluded that nifedipine is poorly dialysable. During haemodialysis, blood pressure is markedly reduced but dose schedules need not to be changed.     

阿奇霉素对肾功能的影响

支原体肺炎是儿童下呼吸道感染的常见病。阿奇霉素已成为治疗该病的常用药。本文对阿奇霉素治疗前后支原体肺炎患儿晨尿进行尿微蛋白的放射免疫测定（RIA）．以了解该药对肾功能的影响。     

The effects of intravenous L-dopa on plasma renin activity, renal function, and blood pressure in man

Summary L-dopa 7 µg·kg^–1·min^–1 was given intravenously over 2 h to six healthy subjects, controlled by an infusion of saline on a separate occasion, with measurement of plasma renin activity (PRA), urinary sodium and potassium excretion, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), blood pressure, and pulse rate.Mean PRA fell by 50% following L-dopa, which was significantly different from the slight rise which occurred after saline infusion. There was a significant increase in urinary sodium excretion and effective renal plasma flow on infusion of L-dopa. Mean diastolic blood pressure fell during L-dopa infusion, in contrast to the slight increase which occurred during the control study.These observations confirm the anticipated renal dopaminergic effects of L-dopa and also suggest a dopaminergic influence on renin release in man.     

Clinical and rheological effects of nifedipine in Raynaud's phenomenon.

Thirty-four patients with Raynaud's phenomenon, 28 primary and six secondary, were entered into a double-blind placebo controlled, randomized cross-over trial of nifedipine treatment. Nifedipine was given as a 20 mg biphasic release formulation twice daily. Twenty-nine patients completed the study, during which the mean number of attacks was reduced by 25% during nifedipine treatment (P less than 0.001). Twenty patients scored nifedipine higher than placebo on a five point rating scale (P less than 0.001). Unwanted effects were experienced by 26 patients during active treatment, resulting in withdrawal from the study in five. Red cell deformability and fibrinogen concentrations were not altered by nifedipine.     

Pleiotropic effects of nifedipine on atherosclerosis

Impaired endothelial cell (EC) growth and function have been proposed to be an initial event that leads to the development of atherosclerosis. There is a growing body of evidence that atherosclerosis is an inflammatory-fibroproliferative disease, and ECs are target for cytokines and growth factors released during inflammation. Recently, nifedipine, one of the most widely used dihydropyridine-based calcium antagonists (DHPs) for treatments of patients with hypertension, was shown to inhibit vascular inflammation and subsequently improve endothelial function in many cardiovascular diseases, thus slowing the development and progression of atherosclerosis. However, the molecular mechanisms underlying this are not fully understood, because ECs do not possess voltage-operated L-type calcium channels. In this review, we discuss the pleiotropic effects of nifedipine on atherosclerosis, especially focusing on its anti-oxidative properties.     

Acute renal effects of intravenous bisphosphonates in the rat

Bisphosphonates are potent osteoclast inhibitors that have been associated with renal toxicity following rapid intravenous administration of high doses, which was hypothesised to be due to precipitation of bisphosphonate aggregates or complexes in the kidney. Five studies were conducted in rats investigating the characteristics of bisphosphonate-related acute renal effects. These studies included single intravenous injections of the nitrogen-containing bisphosphonates (1) ibandronate (1-20 mg/kg), or (2) zoledronate (1-10 mg/kg); (3) a single nephrotoxic dose of the non-nitrogen-containing bisphosphonate, clodronate (2 x 200 mg/kg intraperitoneal injection); (4) a single low dose of ibandronate (1 mg/kg); (5) a single high dose of zoledronate (10 mg/kg). Clinical biochemistry and kidney histopathology were performed 1 and/or 4 days after bisphosphonate dosing. The proximal convoluted tubules were the primary target for renal injury. Tubular degeneration and single cell necrosis of the these tubules were observed with all three bisphosphonates on the fourth, but not the first day after dosing. Differences between the bisphosphonates in the type and/or localisation of the lesions were apparent. Granular deposits in the lumen of distal tubules were apparent with the highest dose of zoledronate (10 mg/kg). However, intraluminal debris was proteinaceous with no evidence of any precipitation of bisphosphonate, or formation of aggregates or complexes in the kidney. Generally, biochemical parameters of renal safety and urinary enzymes did not differ significantly from controls. In summary, bisphosphonate-related renal changes did not appear to be due to the precipitation, aggregation or complexation of bisphosphonate, and biochemical parameters of renal safety did not reliably detect this renal injury.     

Dose-dependent effects of verapamil and nifedipine on in vivo platelet function in normal volunteers

The effects of 1 week of treatment with low and moderate doses of verapamil or nifedipine upon platelet function has been studied in 12 healthy volunteers. The ex vivo platelet aggregation threshold for ADP or adrenaline was not altered by verapamil or nifedipine. The plasma concentrations of beta-thromboglobulin and platelet factor 4 were significantly reduced by low but not by moderate doses of verapamil and nifedipine. Low doses of verapamil and nifedipine inhibit in vivo platelet activity in healthy volunteers.     

Specificity of acute effects of Cd on renal function

Renal reabsorption of a typical low-molecular weight protein (cytochrome c) by rats was compared in controls and in rats acutely poisoned with CdCl2 (20 mumol/kg i.p., together with 300 mumol mercaptoethanol), HgCl2 (3 mg/kg i.m.), or NiCl2 (10 mg/kg i.p.). The effects of these metals on reabsorption of filtered cytochrome c were expressed in terms of changes induced in total protein excretion and in urinary concentrating ability. On this basis, only Cd exerted an acute specific effect on transport of cytochrome c, similar to its production of low molecular weight proteinuria following chronic exposure. At the time of the experiments the animals contained only low Cd levels in the renal cortex (7 micrograms/g). We conclude that the acutely injected rat can serve at least to some extent as a valid model for the study of Cd nephrotoxicity and that cytochrome c is a useful probe for the study of Cd-induced low molecular weight proteinuria.