Safety and tolerance of intravenous nimodipine.
OBJECTIVE
To evaluate the safety and tolerance of intravenous nimodipine administered via a peripheral vein in healthy male volunteers.


METHODS
Double-blind, placebo- and vehicle-controlled trial with three fixed-dose panels.


METHODS
Inpatient infusion and observation periods.


METHODS
61 healthy male volunteers, aged 18-40 years.


METHODS
Subjects in panel 1 received nimodipine 0.4 mg/h, vehicle 2 mL/h, or placebo 2 mL/h; subjects in panel 2 received nimodipine 1 mg/h, vehicle 5 mL/h, or placebo 5 mL/h; subjects in panel 3 received nimodipine 2 mg/h, vehicle 10 mL/h, or placebo 10 mL/h. All infusions were administered intravenously for 48 hours and volunteers were observed for 48 hours after cessation of the infusion. In addition to standard safety assessments (physical examination, electrocardiogram, laboratory studies, and adverse event reporting), supine and standing blood pressures and pulse rates were measured frequently. Plasma samples were also analyzed for nimodipine and its two demethylated metabolites.


RESULTS
Of 61 subjects, 55 completed the 48-hour infusion and 6 discontinued the study because of adverse events. Intravenous nimodipine was well tolerated at 0.4 and 1 mg/h. However, all six subjects who received nimodipine 2 mg/h experienced moderate-to-severe adverse events, and one subject was discontinued because of dizziness, diaphoresis, and postural hypotension. The matched vehicle (10 mL/h) also was not well tolerated, with three subjects who discontinued because of phlebitis. Two subjects who received placebo were also discontinued during the study. Small (2 mm Hg) decreases in mean supine diastolic blood pressure were observed in the 0.4- and 1-mg/h nimodipine groups, but the 2-mg/h group showed a slight (5 mm Hg) increase in blood pressure. These changes were not clinically significant. Clearance and half-life of nimodipine and its metabolites were similar at all three dosages.


CONCLUSIONS
Using peripheral vein administration, nimodipine 2 mg/h and matched vehicle at 10 mL/h were not well tolerated in this healthy normal population. The maximum tolerated dose of nimodipine was found to be 1 mg/h.
California Clinical Trials, Beverly Hills 90211.
J J
JJ
Sramek
A H
AH
Heller
P R
PR
Sundaresan
J
J
Lettieri
S
S
Sawin
N R
NR
Cutler
D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D004361:Drug Tolerance; D004562:Electrocardiography; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009553:Nimodipine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D010808:Physical Examination; D011187:Posture
D009553:Nimodipine