Survey of clinical experience with nimodipine in patients with subarachnoid hemorrhage.

The present studies show that nimodipine prevents and/or improves permanent ischemic neurological deficits in patients with subarachnoid hemorrhage. This was particularly marked in four double-blind, placebo-controlled studies in which statistically significant reductions in mortality and morbidity as consequence of cerebral vasospasm were found. The drug has been shown to increase cerebral blood flow, to reduce vasoconstriction, although not to fully prevent angiographic vasospasm, and to improve central conduction time. Nimodipine did not increase the rate of rebleeding. Its administration during anesthesia does not result in management problems. In general, nimodipine was well tolerated. Side effects were recorded mainly in open studies using the intravenous formulation and consisted mainly of decreases in blood pressure and headaches. Transient increases in liver enzymes may be due to the organic solvent. Hence, all results indicate that patients with subarachnoid hemorrhage will benefit from preventive or therapeutic nimodipine treatment.

Calcium agonists and antagonists of the dihydropyridine type: antinociceptive effects, interference with opiate-mu-receptor agonists and neuropharmacological actions in rodents.

The calcium antagonist dihydropyridine derivative nimodipine and its enantiomers BAY N 5247, BAY N 5248, as well as BAY R 4407 (calcium antagonist (+)-enantiomer of the calcium agonist dihydropyridine BAY K 8644) do not exert antinociceptive effects in the rat as measured by the vocalization test in doses up to 100 micrograms/kg IV, and in the mouse as measured by the hot plate test in oral doses up to 100 mg/kg. The calcium agonists BAY K 8644 and BAY R 5417 ((-)-enantiomer of BAY K 8644) are also ineffective in the rat vocalization test but BAY K 8644 increases reaction time in the hot plate test (mouse) dose-dependently (1-10 mg/kg PO). mu-receptor agonist (fentanyl) antinociceptive effects are potentiated by simultaneous IV administration of the calcium antagonists, the (-)-enantiomer of nimodipine BAY N 5248 being the most potent. This applies for the rat (vocalization test) and the mouse (hot plate test). The influence on fentanyl antinociception in the rat of the calcium agonist BAY K 8644 and its (-)-enantiomer BAY R 5417 is biphasic: low doses attenuate, high doses potentiate fentanyl antinociception. In the mouse (hot plate test) antinociceptive, effects of BAY K 8644 plus fentanyl are less than additive, indicating that the calcium agonist decreases fentanyl effects. The relative potency of calcium antagonists in potentiation of fentanyl antinociception correlates with their relative potency as calcium antagonists as measured by receptor binding studies, effects on vascular and cardiac muscle, and with their neuropharmacological actions (anticonvulsive effects, inhibition of balance and spontaneous motility as well as tranquilizing effects in the mouse).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Blood pressure and heart rate during treatment with nimodipine in patients with subarachnoid hemorrhage.

Careful observation of blood pressure and heart rate in patients with subarachnoid hemorrhage during therapy with nimodipine showed that blood pressure decreases mainly in hypertensive patients during the first hours of therapy or when treatment is started immediately with 2 mg per hour instead of the recommended initial dose of 1 mg per hour. Predominantly mild or moderate reversible falls in blood pressure were reported as side effects in 21/421 patients (5%). Electrocardiographic abnormalities such as tachycardia, bradycardia, arrhythmia or extrasystoles were reported as side effects during treatment with nimodipine in 18 patients (4,3%). Since the association of ECG abnormalities with subarachnoid hemorrhage has been known for many years it is likely that these abnormalities are not typical side effects of nimodipine but belong to the natural course of the disease.

International clinical experience with azlocillin.

Clinical studies with azlocillin were conducted in North America and Europe to assess its efficacy and to monitor its safety. The results of studies from these two areas are compared retrospectively. In North America 631 multiple-dose courses were monitored, while 887 were given in Europe. The most frequently administered daily dose was 18 g in North America and 15 g in Europe. In 71% of the courses a Pseudomonas species was the causative infecting organism in the former area and 51% in the latter. Over 60% of the patients were seriously ill, and about a third were over 60 years of age. A satisfactory bacteriological response, as defined by the eradication or a marked reduction of the organism causing infection was obtained in 74% of patients in North America and in 75% in Europe. 89% of the patients in America responded clinically compared to 92% in Europe. Ps. aeruginosa was eradicated in over 70% of instances. Azlocillin, like other penicillins, possesses a low potential for toxicity. Hypersensitivity reactions and gastrointestinal effects were the most common adverse experiences. No serious problems were encountered with impairment of renal or hepatic function, or blood coagulation. Azlocillin was effective for treating serious infections caused primarily by Ps. aeruginosa.

[The biliary excretion of azlocillin]. / Die biliäre Exkretion von Azlocillin.

The excretion of azlocillin into the human biliary tract was investigated in 8 patients with a T-tube in the common bile duct after intravenous injection of 2 g. Samples of serum and common duct bile were assayed from 15 min to 12 hours after injection. Biliary tract levels generally run parallel to serum levels but were about 15 times higher than those. Peak levels in T-tube bile averaged 1137 mg/l 60 to 90 min after administration. 12 hours after administration there were still mean concentrations of 13 mg/l to be found. It is concluded that azlocillin concentrations in bile exceed for a long time the minimum inhibitory concentrations for gram-negative and gram-positive causative organisms (above all E. coli, enterococci, Klebsiella spp., Proteus spp., staphylococci) of biliary tract-infections.

[Mezlocillin: tissue concentration and efficacy (author's transl)]. / Mezlocillin: Zur Gewebekonzentration und Wirksamkeit.

Studies on serum and tissue (cutis, muscle and liver) concentrations were carried out with mezlocillin (Baypen), a semi-synthetic new acyl ureidopenicillin, in 51 patients. Serum half life was 59 minutes. The highest concentrations were measured in the cutis, the lowest in the muscles. Concentrations in the liver were found to be relatively constant and persistent.--The efficacy and tolerance of mezlocillin were examined in 48 patients affected by 56 mostly severe infections, which were treated with a dose of 5 g twice or three times daily. The indications for antibiotic treatment were bronchopulmonary infections, peritonitis, soft tissue infections, biliary and urinary tract infections and postoperative febrile conditions of unknown origin. Clinical cure was achieved in 78.5% and an improvement of symptoms in 5.4% of infections. 76% of the causative microorganisms were eliminated. Mezlocillin was locally and systemically well tolerated.