Experiences with GCP in the pharmaceutical industry [corrected].

The Declaration of Helsinki and the "new" Germany Drug Law of 1976 may be regarded as the first and all important step in the evolution of Good Clinical Practices (GCP) in Germany. "Regulations on the orderly conduct of clinical studies" (published in 1987), reflecting most elements of the GCPs, caused the German industry to make provisions for more successful drug approvals in the future. Pharmaceutical companies have improved their documentation systems with regard to study protocols and reports, increased their monitoring capacity, and began setting up SOPs. In preparation for the issuing of the E.C. GCP guidelines companies established Clinical Quality Assurance (CQA) units responsible for various CQA tasks such as training of monitors and investigators, auditing of protocols, reports, systems, and data. Typical problems connected with the implementation of GCP in Germany appear to be contradictory opinions of the various ethics committees, reluctancy on the part of investigators to assume additional bureaucratic workload, difficulties on the part of the sponsor resulting from the high financial and manpower requirements, as well as the relatively unfavorable political and public opinion of clinical research. The benefits achieved by the introduction of GCP are already visible, i.e., increased quality of study protocol, conduct and report of studies, reduced number of studies, transparency at all stages of clinical research and increased ethical awareness.

Pharmacodynamics and pharmacokinetics of oral nitrendipine solution in hypertensive patients with advanced renal failure.

Nitrendipine solution 5 mg.ml-1 in the dose of 5 mg was given orally to 20 patients with chronic renal failure and elevated diastolic blood pressure (> or = 110 mmHg), of whom 10 were on maintenance haemodialysis (endogenous creatinine clearance < 5 ml.min-1) and 10 were at the predialysis stage (endogenous creatinine clearance 5-20 ml.min-1). The aim of the study was to investigate the influence of kidney function and/or dialysis treatment on the pharmacokinetic and pharmacodynamic profile of a solution of nitrendipine and to assess its antihypertensive efficacy. After 10 min there was a significant reduction in blood pressure from 188/113 to 173/100 (patients not dependent on dialysis) and from 197/112 to 161/94 mmHg (patients dependent on dialysis). The maximum fall in blood pressure (approximately 30%) was attained after 90 min in the dialysis patients and after 120 min in the non-dialysis group. Blood pressure increased again about 3 h after the administration of nitrendipine but it was still below baseline after 12 h. The terminal elimination half-life (4.1 h in the dialysis patients and 3.6 h in non-dialysis patients) was similar to that observed in patients with normal renal function. The pharmacokinetics of nitrendipine did not differ between the dialysis and non-dialysis groups. There was a correlation between plasma concentration and the blood pressure reduction. The maximum plasma concentration of nitrendipine was reached after 0.5 h (median) and did not differ between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of the H2-receptor antagonists cimetidine and ranitidine on the pharmacokinetics of nimodipine in healthy volunteers.

A possible interaction between the calcium antagonist nimodipine and the H2-receptor antagonists cimetidine and ranitidine has been investigated in two separate studies in healthy subjects. In eight young volunteers the concomitant administration of nimodipine 30 mg t.i.d. and cimetidine 1000 mg/d for 7 days led to a significant increase of the relative bioavailability of nimodipine. The changes in the pharmacokinetic parameters were not accompanied by discernible haemodynamic effects or any change in the tolerability of nimodipine. There was no evidence of any significant change in the steady-state pharmacokinetics of nimodipine during five days of combined treatment with 30 mg t.i.d. nimodipine and ranitidine 300 mg/d given as single morning dose to twelve healthy, elderly subjects. Analysis of haemodynamics, clinical chemistry and tolerance also did not reveal any difference between the two treatment periods.

Effect of the calcium antagonists nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal motility in man.

Nifedipine has been proven to be effective and safe in the treatment of primary oesophageal motility disorders which can cause angina-like chest pain and/or dysphagia. The effects of the calcium channel blockers nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal smooth muscle function in healthy male volunteers were studied by oesophageal manometry using the rapid pull-through-technique, in two randomized, double-blind crossover studies. Lower oesophageal sphincter pressure, oesophageal contraction amplitude and duration after a wet swallow (measured 5 cm and 10 cm above the lower oesophageal sphincter) were determined 30 min before and at 10 minute intervals up to 90 min after the administration of nimodipine and up to 120 min after nifedipine, nitrendipine and nisoldipine. The plasma drug concentration was measured at baseline (-15 min) and in parallel with the manometric measurements. Compared to placebo, lower oesophageal sphincter pressure was significantly decreased by 24% by nifedipine and 17% by nimodipine, whereas the effects of nitrendipine (decrease of 15%) and nisoldipine (9%) were not significant. Nifedipine significantly decreased by 17% the oral contraction amplitude compared to placebo and nimodipine by 11%. The duration of the contraction amplitudes was not altered. The decrease in sphincter pressure was correlated with the corresponding plasma drug levels of nifedipine r = 0.92, nitrendipine r = 0.80 and nisoldipine r = 0.79. Nimodipine showed no such correlation.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of nitrendipine in patients with chronic liver diseases.

Metabolism of nitrendipine occurs principally in the liver. Therefore, an alteration of pharmacokinetics has to be discussed in patients with hepatic impairment. To evaluate steady-state plasma concentrations and pharmacokinetics, a low dose of nitrendipine (5 mg/day for 3 weeks) was administered orally to patients with different chronic liver diseases (fatty liver, n = 3; chronic hepatitis, n = 2; and cirrhosis of the liver, n = 5). Nitrendipine plasma concentrations were analyzed by using a gas-liquid chromatography procedure. Twenty-two days after beginning the study, steady-state plasma concentrations were lower than 1.0 microgram/L in one patient without liver disease and in seven patients with chronic liver diseases, in contrast to three patients with alcoholic cirrhosis (5.5, 1.3, and 2.9 micrograms/L). The maximum concentration (Cmax) was 2.3 micrograms/L in the patient without liver disease and 8.3 +/- 3.9 micrograms/L in the hepatic patients. The elimination half-life was prolonged in three of five patients with cirrhosis of the liver (35, 67, and 43 h), whereas in the other patients the half-life was in a normal range (4.2-21.3 h). The area under the concentration-time curve (AUC) was enhanced in three patients with liver cirrhosis (387, 69, and 126 h/micrograms/L); in the other seven hepatic patients, results were normal (35-49 h/micrograms/L). There were no alterations observed in any patient in blood pressure and laboratory data. Oral administration of a low dose of nitrendipine resulted in slightly enhanced steady state plasma concentrations only in patients with advanced cirrhosis of the liver. The half-life, AUC, and bioavailability also seem to be altered only in a more severe state of liver disease.

Plasma concentration-response relationships for some cardiovascular effects of dihydropyridines in healthy subjects.

The pharmacokinetics and some hemodynamic effects of three dihydropyridine (DHP) calcium channel blockers were studied in healthy subjects. In a randomized order, each subject was given 24 micrograms/kg nifedipine, 40 micrograms/kg nitrendipine, or 10 micrograms/kg nisoldipine intravenously. The three DHPs differed as to their total clearance and volume of distribution (nifedipine less than nisoldipine less than nitrendipine) but showed similar values for elimination half-lives. All three drugs evoked increases in heart rate and forearm blood flow (FBF) and small decreases in blood pressure. Whereas the observed peak changes in heart rate were virtually identical for the three drugs (about 45% above baseline), the peak changes in FBF were more pronounced in response to nitrendipine and nisoldipine (greater than 200% above baseline) than in response to nifedipine (79% above baseline). The heart rate and FBF responses to the DHPs were related directly to the drug concentrations in plasma. The plasma level-response curves obeyed Hill's equation. They showed that the DHPs differ mainly in their potencies at dilating the forearm resistance vessels (nifedipine less than nitrendipine less than nisoldipine).

Overview on pharmacokinetics of nimodipine in healthy volunteers and in patients with subarachnoid hemorrhage.

The pharmacokinetics of Nimodipine were studied in healthy volunteers and in patients with subarachnoid hemorrhage (SAH) following cerebral aneurysm rupture. Nimodipine was absorbed rapidly. After an oral dose of 120 mg an average maximal plasma concentration 106 micrograms/l was recorded 45 to 60 minutes later. During a 7-day oral therapy with 40 mg t.i.d. no accumulation or change in the absorption or elimination kinetics occurred. After i.v. administration a biphasic elimination with half lives of 7 min and 1 hour was observed. In patients with subarachnoid hemorrhage receiving a continuous infusion of 2 mg/hour the mean nimodipine plasma concentrations ranged between 36 and 72 micrograms/l. Subsequent oral dose of 60 mg q.i.d. to the same patients resulted in concentrations ranging between 17 to 42 micrograms/l on the average one hour after the dosage. Mean cerebrospinal fluid (CSF) levels amounted to 0.3 +/- 0.2 microgram/l in patients whose mean plasma concentrations were 76.9 +/- 34.0 micrograms/l.

Nifedipine: kinetics and dynamics after single oral doses.

Serum nifedipine concentrations and hemodynamic changes were evaluated in ten healthy volunteers after a single 40-mg oral dose of nifedipine. Peak serum concentrations averaged 45 micrograms/l, attained 2.7 h after dosage. The mean elimination half-life was 5.9 h (range: 3-12 h). Blood pressure, ventricular rate, and echocardiographically-determined rate of circumferential fiber shortening did not differ between placebo and nifedipine trials. Five additional subjects ingested nifedipine once in the control state and on a second occasion with a standard breakfast. Coingestion of food delayed the peak serum nifedipine concentration but did not alter the area under the serum concentration curve. Thus the pharmacokinetic profile of nifedipine indicates that a three- or four-times-daily dose is, in general, appropriate in clinical practice. Completeness of absorption is not altered by coadministration with food. Adverse hemodynamic effects of single oral doses in healthy persons are not evident.

Clinical pharmacokinetics of nimodipine in normal and impaired renal function.

Twelve patients with different degrees of renal function were investigated. Six of them had moderately impaired renal function (glomerular filtration rate-GFR 20-60 ml/min) and six were preuraemic (GFR less than 20 ml/min). Patients received a single oral dose of 30 mg nimodipine on the first and eighth day, from the second to the seventh day they received 30 mg thrice daily. The results of this study were compared with the data of a similar study with six healthy volunteers (GFR greater than 90 ml/min) who also received for one week nimodipine 40 mg three times daily. In these subjects peak plasma levels of nimodipine ranged between 15.5 and 106.7 micrograms/1 on first treatment day and did not differ significantly from those on the 7th day of therapy ranging between 17.0 and 80 micrograms/1. Mean terminal elimination half-life of nimodipine was 2.77 +/- 0.46 h in normal renal function, but was 22.23 +/- 6.94 h in patients with impaired renal function (12 patients with GFR less than 60 ml/min). The mean area under the plasma level time curve (AUC) with 541.5 +/- 16.93 ng ml-1 h increased in patients with renal insufficiency compared to those with normal renal function (74.65 +/- 9.44 ng ml-1 h). Dosage adjustment of nimodipine appears to be necessary in renal failure.