The effect of oral flunitrazepam on the secretion of human growth hormone.
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Adult↗
Biomedical subjects
J Kanto
Publications and source records attributed to J Kanto.
Effect of age and cardiopulmonary bypass on the pharmacokinetics of lorazepam.
The pharmacokinetics of lorazepam after 0.03 mg/kg intravenous administration was investigated in 14 surgical patients (nasal surgery under local anaesthesia) ranging in age from 25 to 86 years (8 males and 6 females). No statistically significant changes in the kinetics of lorazepam associated with the aging process were found. In these premedicated patients a slow onset of the drug action of lorazepam was assessed both subjectively and objectively with no apparent relationship to the age. These findings are of potential clinical importance, because it is highly desirable to use drugs for which age-related alterations are of minimum degree. In 5 male patients undergoing surgery with cardiopulmonary bypass, lorazepam disappeared from the plasma after a single 4 mg intravenous injection with an apparent comparable half-life (10.0 +/- 3.2 min.) to that of the above mentioned surgical patients. The concentrations of both unconjugated and conjugated lorazepam dropped abruptly at the start of extracorporeal circulation followed by an increase in the postperfusion period. After this peak effect the mean apparent half-life of lorazepam was 15.5 +/- 5.8 hours of indicating no great change in its elimination in comparison with patients operated under local anaesthesia (half-life 12.1 +/- 3.7 hours). Pharmacokinetically, lorazepam appears to be a useful agent in connection with cardiopulmonary bypass operation.
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Comparison of old and new types of premedications.
By random allocation 41 patients received 1 mg flunitrazepam orally the night before operation and 1 mg on the morning of operation (group 1), and another 41 received 100 mg pentobarbital orally the night before operation, followed by intramuscular scopolamine (0.006 mg/kg) + morphine (0.02 mg/kg) on the morning of operation (group 2). All patients received 0.5 mg atropine intravenously just before the induction of anesthesia. The patients in group 2 were better sedated and had less salivary secretion than those in group 1, but otherwise both were comparable. In group 2 the induction requirements of thiopentone were significantly decreased in comparison with group 1, again indicating a more potent sedative effect. Because even in the total scoring of the results there was no significant difference between the two groups, the easy oral route of administration of flunitrazepam offers a clinically relevant alternative to the conventional premedication. In some of these E.N.T. patients who received flunitrazepam, intravenous atropine given just before the induction of anesthesia was unable to prevent salivary secretion. Oral benzodiazepine derivatives (flunitrazepam) appear to be useful before surgery as the old type of premedication (oral pentobarbital + i.m. scopolamine and morphine).
Administration, Oral↗
Tofizopam: a benzodiazepine derivative without sedative effect.
In a single-blind randomized study 47 patients received 100 mg tofizopam orally as a premedication before minor surgery, 50 patients received placebo, an 50 patients no premedication. Both tofizopam and placebo significantly increased the subjective sedative effect of the patients, but there was no significant difference in any of the measured parameters between tofizopam and placebo. In another double-blind randomized study, 49 patients received 100 mg tofizopam three times orally before gynecologic operations and 49 patients received placebo. Compared with placebo, tofizopam had a stimulant action and decreased the excitement of the patients. The effect of tofizopam on apprehension + excitement was significantly better than that of placebo. According to these results, the active component seems to be an unknown metabolite of tofizopam causing a clear drug effect only after repeated oral doses of the parent drug. A slow accumulation in the central nervous system is also possible. In the drug response a wide interindividual variation was found.
Adult↗
A comparative study of the clinical effects of oral flunitrazepam, medazepam, and placebo.
In a double-blind randomized study 40 patients received 1 mg flunitrazepam, 40 patients received 10 mg medazepam, and 40 patients received placebo p.o. the night before surgery. On the morning of surgery each patient received another identical oral dose of the product or placebo taken the previous night. On the average, the flunitrazepam group slept better, was better sedated, and was less anxious than the medazepam or placebo groups. Similarly, as a reflection of diminished autonomic reactions, the patients receiving flunitrazepam had fewer cardiovascular changes. Flunitrazepam significantly decreased the amounts of thiopentone needed for induction of anesthesia. Medazepam did not. The pronounced sedative, sleep-inducing, and anxiolytic effects of flunitrazepam appear to be of great clinical importance for its use in anesthesiology. Repeated administrations of medazepam seem to be required to produce an evident clinical effect of the drug, possibly via the slow accumulation of metabolites. The main difference between these two benzodiazepine derivatives as regards clinical response therefore seems to be pharmacokinetic in origin.
Adult↗
A pharmacokinetic and pharmacodynamic study of flunitrazepam.
Flunitrazepam was given as an induction agent i.v. to 12 patients undergoing otologic operations. Pharmacokinetics were evaluated from serum samples at 5 min-72 h by 63Ni-EC-GLC. Pharmacodynamic characteristics were estimated subjectively by simple questionnaire and objectively by the anesthetist during and after anesthesia. The dose of flunitrazepam required for anesthesia varied from 14 to 33 (mean 21) micrograms/kg and was not related to age. The mean distribution volumes of flunitrazepam, calculated by the three-compartment open model, were Vd1 0.61 (SD = 0.36) l/kg, Vd2 1.4 (SD = 0.70) l/kg, and Vd3 3.6 (SD = 1.39) l/kg. The mean elimination half-life was 25 h and serum clearance was 94 ml/min. The maximum decreases in blood pressure during anesthesia correlated with the age of the patients. The general assessment of the anesthetist about this form of anesthesia was positive in 75% of the 12 cases. A clear anterograde amnesia was found.
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The effect of intravenously administered sincalide on the human gallbladder during oral cholecystography.
Sincalide, the C-terminal octapeptide fragment of the cholecystokinin, was used to contract the gallbladder during routine oral cholecystography in 18 patients. In 14 patients clinically important contraction occurred. The average reduction in gallbladder size for these patients was 32.7% of the preinjection size (range 15.1%-67.9%). Within 8-12 minutes cystic duct visualisation occurred in 8 and common bile duct visualisation in 3 patients. Spasm of the gallbladder neck was found in 2 cases. The blood pressure and heart rate did not change significantly during the study. Six patients felt slight nausea for 1-4 minutes and two vomited. We conclude that sincalide may be useful in biliary tract function studies in special clinical conditions (i.e. upper abdominal pain with unknown aetiology).
Adult↗
Changes in hormonal excretion and urinary flow rate during CPPV and CPAP in healthy volunteers.
In healthy volunteers plasma antidiuretic hormone level, renin activity, and human growth hormone level remained unchanged during successive CPPV, CPAP, and control periods. The plasma level of insulin C-peptide was higher during CPPV than during the control period. Urine flow, glomerular filtration rate, free water clearance, and sodium excretion rate were lower during CPPV than during the successive CPAP and control periods. The renal function changes during CPPV may be a consequence of diminished cardiac output.
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Bioavailability and clinical effects of three brands of clonidine: the relationship between plasma level and effect.
The bioavailability and effect on the systolic and diastolic blood pressure, heart rate, salivary flow, skin temperature, and subjective sedation of three brands of clonidine were studied in nine healthy volunteers after a single 300-micrograms oral dose. In the gas chromatographically determined plasma concentrations there was no significant difference, nor was there any difference in the clinical effects studied. Highly significant correlations between the plasma concentrations and drug effects were found.
Adult↗
The pharmacokinetics of disopyramide and mono-N-dealkyl-disopyramide in humans.
The pharmacokinetics of disopyramide and its metabolite mono-N-dealkyl-disopyramide (MND) were studied after a single oral and intramuscular dose and at steady state in healthy volunteers, after an intravenous dose in post-surgery patients, and after a single oral dose in two patients with renal insufficiency. After an oral dose in healthy volunteers the plasma elimination half-life of total disopyramide was 8.65 +/- 1.37 h, and that of the non protein-bound disopyramide, 4.74 +/- 1.20 h. The protein binding of disopyramide varied from 0.58 to nearly 1.0, and was concentration dependent. All subjects had detectable amounts of MND in plasma. Its elimination half-life was 12.9 +/- 6.43 h. The ratio of MND to disopyramide was 0.23 +/- 0.09 in plasma and 0.46 +/- 0.11 in urine. There was a close correlation (r = 0.868) between the renal clearances of free disopyramide and creatinine. The renal clearances of disopyramide (both free and total), MND, and creatinine varied with time; this resembled variation in the urine flow. The kinetics of one dose at steady state did not differ markedly from that of a single dose. The elimination half-lives of total disopyramide varied from 4.4 to 17.1 in post-surgery patients, and those of the renal patients were 10.6 and 8.7 h.
Administration, Oral↗
Hemodynamic effects of labetalol in healthy volunteers.
The hemodynamic effects of intravenous injection of 1 mg/kg of labetalol were measured in eight healthy volunteers, using impedance cardiography and systolic time intervals. The mean systolic blood pressure was reduced by 10% (p less than 0.01) and diastolic by 6% (p less than 0.05) 30 min after the injection, and they had returned to pre-drug level 2 h after administration. Heart rate declined consistently throughout the observation period. Cardiac index was reduced by 16% (p less than 0.05), but the changes in stroke volume (- 6%) and peripheral resistance (+ 23%) were not statistically significant. Left ventricular ejection time index increased by 2% (p less than 0.05), and nonsignificant changes were found for pre-ejection period index (- 3%), total electromechanical time index (+ 1%), and PEP/LVET ratio (+ 5%). In healthy subjects resting supine the intravenous dose of 1 mg/kg of labetalol had predominantly beta-blocking effects.
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Benzodiazepines as oral premedicants.
The advantages of the benzodiazpines as oral premedicants are: clear anxiolytic and sedative effect; less clear amnesic action which may prevent the recall of the time spent lying on an uncomfortable theatre trolley, but not necessarily recall of the journey to the operating theatre, or induction of anaesthesia; convenient route of administration; long duration of action of 5-8 h which simplifies timing of drug administration; adverse autonomic, hormonal and circulatory system reactions seem to be prevented, thus preventing the stress reaction even before induction of anaesthesia; anticonvulsant and muscle-relaxing actions may be of value in patients receiving local anaesthesia, or in preventing the side-effects of depolarizing muscle relaxants; nausea before and after operation may be decreased; reduced frequency of side-effects before and after operation.
Administration, Oral↗
ADH concentrations and premedication.
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Female↗
The effect of metoclopramide and propantheline on the gastrointestinal absorption of cimetidine.
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Adult↗
Bioavailability of rectal aspirin in neurosurgical patients.
Serum salicylate levels were determined fluorimetrically in 12 neurosurgical patients after rectal and oral administration of 1.0 g aspirin. There was no significant difference in the AUC-value between the two routes of administration, but a slower rate of absorption with no clear peak effect was found after rectal administration. Rectal aspirin is useful in clinical situations in which mediation is difficult by the oral route, e.g. after neurosurgical and open-heart surgical interventions.
Administration, Oral↗
Placental transfer and pharmacokinetics of atropine after a single maternal intravenous and intramuscular administration.
The placental transfer and pharmacokinetics of atropine were studied in 44 healthy parturients undergoing caesarean section. The concentrations in the plasma were determined by a new radioimmunoassay after intravenous (n=32) or after intramuscular (n=12) administration of 0.01 mg/kg of atropine. A fast placental transfer with apparent foetal uptake of the drug was found after intravenous injection. There was also a difference in the umbilical vein and artery concentrations after intramuscular administration. The maternal pharmacokinetics of i.v. atropine obeyed and two-compartment open model with a fast distribution phase (mean ta1/2=1.02 min) and quite fast elimination (t1/2=2.56h). The total apparent volume of distribution was 1.01/kg and the total plasma clearance 6.36 ml/min/kg. The mean peak maternal plasma levels after i.m. atropine administration were found at 1.59 h and the mean calculated half-life of elimination was then 2.1 h. No atropine was found in the amniotic fluid.
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Blood glucose, insulin, antidiuretic hormone and renin activity response during caesarean section performed under general anaesthesia or epidural analgesia.
Glucose loading caused a significant increase in insulin response (IRI) in patients undergoing caesarean section both under general anaesthesia and under epidural analgesia. After a fast intravenous glucose loading given just before the administration of epidural bupivacaine, similar but more variable serum immunoreactive insulin levels were found as compared with those determined after a slower intravenous glucose infusion in patients under general anaesthesia. Plasma renin activity values did not change significantly in either group, but, differing from general anaesthesia, antidiuretic hormone levels (ADH) increased significantly in patients under epidural analgesia. The changes in IRI and ADH response may be caused by a higher psychic stress reaction of the conscious patients during caesarean section under epidural analgesia.
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The passage of flunitrazepam into cerebrospinal fluid in man.
The passage of flunitrazepam into cerebrospinal fluid (CSF) was studied in 23 surgical patients (group 1), after a single 0.02 mg/kg intravenous injection, in 9 otherwise healthy patients undergoing neurological examination (group 2), after a single 2 mg oral dose, and in 9 chronically-ill neurological patients (group 3), after 2 to 4 successive 2 mg oral doses. Flunitrazepam in plasma and the CSF was determined by gas chromatography and its plasma protein binding by equilibrium dialysis. Uptake of flunitrazepam into human CSF was found to very fast: even 5 min. after intravenous injection the drug level in the CSF was 2.8% of the corresponding plasma concentration. CSF levels increased up to 77 min. after intravenous injection. In group 2 the mean percentage level in the CSF was 23.5 +/- 13.0 (S.D.) and in group 3 it was 16.7 +/- 3.1. In group 1, 22.9+/- 8.0% of flunitrazepam was not bound to plasma protein, in group 2, 12.1 +/- 8.3% and, in group 3, 30.3 +/- 14.1%. Groups 1 and 2 (P less than 0.01) and 2 and 3 (P less than 0.01) differ significantly from each other. In groups 2 and 3 there was no significant correlation between the percentage not bound to protein and CSF levels of flunitrazepam. The uptake of flunitrazepam by CSF provides an explanation for its rapid drug effects. Its binding to plasma protein is affected by disease and, possible, by other drugs.
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