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At least 19 recordsLinked to original sources
PubMed1976

Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam.

Eight healthy male subjects received single 2-mg oral doses of lorazepam containing 24 muCi/mg of 2-14C-lorazepam. Multiple venous blood samples were drawn during the first 96 hr after the dose, and all urine and stool were collected for 120 hr after dosing. Concentrations of lorazepam and its metabolites in body fluids were determined by appropriate analytic techniques. Following a lag time, lorazepam was absorbed with an apparent first-order half-life of 15 min. The peak plasma concentration was 16.9 ng/ml, measured in the pooled sample drawn 2 hr after the dose, This corresponded to the time at which clinical effects appeared to be maximal. The apparent elimination half-life of lorazepam was about 12 hr. Biotransformation to a pharmacologically inactive glucuronide metabolite appeared to be the major mechanism of lorazepam clearance. A mean of 88% of administered radioactivity was recovered in urine, and 7% was recovered in stool. Lorazepam glucuronide comprised 86% of urinary reactivity; its renal clearance was 37 ml/min. Other identified metabolites included hydroxylorazepam, a quinazolinone derivative, and a quinazoline carboxylic acid; all of these were quantitatively minor.

Administration, Oral↗
PubMed1978

Analysis of lorazepam and its glucuronide metabolite by electron-capture gas--liquid chromatography. Use in pharmacokinetic studies of lorazepam.

This paper describes a rapid and sensitive method for analysis of lorazepam and its glucuronide metabolite in plasma and urine following therapeutic doses of lorazepam in humans. After addition of the structurally related benzodiazepine derivative, oxazepam, as the internal standard, 1-ml samples of plasma or urine are extracted twice at neutral pH with benzene (containing 1.5% isoamyl alcohol). The combined extracts are evaporated to dryness, reconstituted, and subjected to gas chromatographic analysis using a 3% OV-17 column and an electron-capture detector. Lorazepam glucuronide in urine is similarly analyzed following enzymatic cleavage with Glusulase. The sensitivity limits are 1--3 ng of analyzed following enzymatic cleavage with Glusulase. The sensitivity limits are 1--3 ng of lorazepam per ml of original sample, and the variability of identical samples is 5% or less. The applicability of the method to pharmacokinetic studies of lorazepam is demonstrated.

Administration, Oral↗
PubMed1976

Lorazepam as a premedication.

A double-blind random study compared the effects of lorazepam and pantopon an intra-muscular premedication in healthy women for uterine curettage (D & C). Anxiety, as assessed by a self-rating test by the patient and by a trained observer, showed a significant reduction at one and one-half hours after lorazepam and a smaller reduction after pantopon, which was not significant. Sedation was satisfactory with no significant difference between the two drugs in the change before and after the premedication. Lorazepam showed much more amnesia than pantopon (p less than 0.001). The patients who had lorazepam required higher doses of thiopentone for the operation, and this, in part, led to longer intervals in recovery times after lorazepam. However, it is suggested that lorazepam itself was partly responsible for the longer recovery. Pantopon was followed by more nausea, vomiting and headaches, than lorazepam. The intra-muscular injection of lorazepam hurt more patients than did pantopon, but other local complications were negligible and comparable in both groups. The results of this study show that lorazepam produces better reduction of anxiety and much more amnesia than pantopon, with comparable sedation and much less nausea and vomiting. The only disadvantage of lorazepam is the lack of analgesia and, therefore, the need for more anaesthesia during the operation. The conclusion is that lorazepam is a very satisfactory premedication and warrants more use as such.

Adult↗
PubMed1979

Lorazepam kinetics in the elderly.

Lorazepam is a 3-hydroxy-1,4-benzodiazepine derivative biotransformed by glucuronide conjugation, followed by urinary excretion of the glucuronide metabolite. The kinetic properties of single 1.5- to 3.0-mg doses of intravenous lorazepam were assessed in 15 healthy elderly subjects, 60 to 84 yr of age, and in 15 healthy young subjects, 19 to 38 yr of age. Volumes of distribution for lorazepam in the elderly group (mean, 0.99 1/kg), were slightly but significantly smaller than in the young group (1.11 1/kg), suggesting less extensive drug distribution in the elderly. Values of elimination half-life (t1/2beta) in the elderly (15.9 hr) did not differ significantly from those in the young group (14.1 hr), but total clearance in the elderly (0.77 ml/min/kg) was 22% less (p less than 0.05) than in the young subjects (0.99 ml/min/kg). Age differences in lorazepam clearance were partly explained by more frequent cigarette smoking in the young subjects. Gender had no apparent relationship to kinetics. The rate and completeness of absorption of intramuscular (IM) and oral loraxepam was assessed in 10 of the elderly subjects. Deltoid IM injection and oral administration of tablets in the fasting state led to rapid absorption of lorazepam into the systemic circulation. Peak plasma lorazepam concentrations were always reached within 2.5 hr, and values of absorption half-life (t1/2a) did not exceed 45 min. Absorption of IM and oral lorazepam was 80% to 100% complete. Thus, the aging process is associated with small changes in the kinetics of lorazepam. IM and oral administration of lorazepam in elderly persons, as in the case of young individuals, leads to rapid and nearly complete absorption into the systemic circulation.

Absorption↗
PubMed1977

Clinical pharmacokinetics of lorazepam. II. Intramuscular injection.

A single dose of 4 mg of lorazepam was injected into the deltoid muscles of six healthy male volunteers. Multiple venous blood samples were drawn during 48 hr after the dose and all urine was collected for 24 hr after the dose. Concentrations of lorazepam and its major metabolite, lorazepam glucuronide, were determined by electron-capture gas-liquid chromatography. Lorazepam was rapidly absorbed from the injection site, reaching peak concentrations within 3 hr. Mean pharmacokinetic pamrameters for unchanged lorazepam were: apparent absorption half-life: 21.2 min; elimination half-life: 13.6 hr; volume of distribution: 0.9 L/kg; total clearance: 58.2 ml/min. Lorazepam glucuronide rapidly appeared in plasma, reached peak concentrations within 12 hr of the dose, then was eliminated approximately in parallel with the parent drug. Within 24 hr a mean of 47.6% of the dose was recovered in the urine as lorazepam glucuronide and less than 0.5% was recovered as unchanged lorazepam.

Adult↗
PubMed1976

Metabolism of lorazepam.

The metabolism of lorazepam by man and four other species is reviewed. Lorazepam and its metabolites in blood, urine and faeces were identified by thin-layer and gas chromatography and by mass spectrometry. The principal metabolite in man, dog, pig and cat is the glucuronide, but the rat produces other metabolites after small doses of lorazepam, and significant amounts of the glucuronide only after high doses. Since all metabolites, except the glucuronide, occur in small quantities only in man, most studies in man have been confined to an estimation of gree and conjugated lorazepam. Blood concentrations of unconjugated lorazepam peak at 1-4 h, significant concentrations persisting for 24 h and decreasing slowly over the next 24 h. About 95% of a dose of lorazepam was accounted for in urine and faeces over a period of 5 days; 74.5% was excreted in the urine as lorazepam glucuronide and 13.5% as minor metabolites. The excretory half-life was 12 h. The blood concentrations and excretion rates are compatible with the clinical effects of lorazepam.

Animals↗
PubMed1977

Respiratory effects and amnesia after premedication with morphine or lorazepam.

Lorazepam, a new benzodiazepine, was compared with morphine for premedication. Ten patients received morphine 10 mg/70 kg i.m. and 10 received lorazepam 4 mg/70 kg i.m. Respiratory effects were assessed from the change in slope (S) and intercept (B) of the carbon dioxide response line, using a development of Read's rebreathing method. Morphine depressed S by 47% (P less than 0.01), but after lorazepam S increased by 27% (P less than 0.05), neither drug altering B significantly. In two volunteers lorazepam was assessed by both the rebreathing and the steady-state methods; after lorazepam S was smaller by the steady-state than by the rebreathing technique. The findings for lorazepam are consistent with the known effects of sleep on carbon dioxide sensitivity. Amnesia lasting 4-8 h occurred in all patients who received lorazepam so that pain and nausea during this period were not recalled, but no patient who received morphine experienced amnesia. We conclude that lorazepam merits further study, particularly where sedation without respiratory depression is needed, as in obstetrics, and where amnesia for uncomfortable procedures is required.

Adolescent↗
PubMedDate not supplied

Clinical pharmacokinetics of lorazepam. IV. Long-term oral administration.

Fifteen healthy male volunteers received long-term daily treatment with oral lorazepam at doses as high as 10 mg per day for a period of 26 weeks. Steady-state plasma concentrations of lorazepam and its glucuronide metabolite were measured in all subjects at least every two weeks. At daily doses of 6 mg per day, the mean steady-state lorazepam level was 88 ng/ml and that of lorazepam glucuronide was 170 ng/ml. Mean levels among seven subjects who received 10 mg per day were 164 and 266 ng/ml, respectively. Lorazepam concentrations fluctuated from week to week despite constant dosage, but there was no evidence of systematic variation. Mean steady-state lorazepam levels were highly correlated with daily dose in mg/kg, but were not related to age. Lorazepam was not detected in any plasma samples drawn one week after discontinuation of treatment.

Administration, Oral↗
PubMed1976

Lorazepam and diazepam in the treatment of neurotic anxiety: a double-blind trial.

Fifty-eight neurotic patients with intense anxiety were treated with either lorazepam or diazepam in a double blind between-patients trial. Statistical analysis indicated that the two groups were homogeneous before treatment and that the results of treatment were similar for both drugs. According to the global rating of illness week after week, after four weeks of treatment more patients on lorazepam than on diazepam were normal or had mild illness (82.1% vs. 70.8%). In the investigators' judgment, 71.9% of the patients treated with lorazepam had an excellent or good response compared with 56.7+ of those treated with diazepam. The mean reduction in score on the Hamilton Anxiety Scale was 17.7 for lorazepam and 16.5 for diazepam. However, none of the above differences in results were statistically significant. The largest dose of lorazepam required in treatment was 6 mg, compared with 30 mg of diazepam. Two patients treated with lorazepam had side effects, against six with diazepam. Six patients in the diazepam group did not complete the trial, including three who discontinued because of side effects (rash, tremors, agitation); no patients in the lorazepam group dropped out.

Adult↗
PubMedDate not supplied

Lorazepam: glucuronide formation in the cat.

The excretion and metabolism of lorazepam was studied in domestic cats. After oral administration of 14-C-lorazepam (1 mg/kg), the mean percent of the dose excreted in urine was 47.3 plus or minus 6.7% (SD) and in feces 54.0 plus or minus 6.1% (SD). The main urinary metabolite was lorazepam glucuronide; its mean excretion over the first 3 days amounted to 29% of the dose (66% of urinary radioactivity). When 20 mg of unlabeled drug per kg was given, about 40% of the dose was excreted into urine as lorazepam glucuronide within 6 days. Conculsive evidence for the glucuronide structure was obtained by chemical analysis and mass spectrometry of the lorazepam conjugate isolated from cat urine. The radioactivity in urine which was not attributable to several minor metabolites. In plasma, both lorazepam and lorazepam glucuronide were present. These findings indicate that the cat is capable of using glucuronidation as a major route of conjugation, contrary to the many reports that cats conjugate exogenous materials poorly with glucuronic acid.

Administration, Oral↗
PubMedDate not supplied

Clinical pharmacokinetics of lorazepam. III. Intravenous injection. Preliminary results.

Four healthy male volunteers received 5 mg lorazepam as a single intravenous injection. Concentrations of lorazepam and its glucuronide metabolite were determined in multiple venous blood samples drawn during the 48 hours after dosing and in all urine collected during 96 hours after the dose. Mean pharmacokinetic parameters for lorazepam were: apparent elimination half-life, 13.2 hours; volume of distribution, 0.84 liter/kg; total clearance, 55.3 ml/min. Lorazepam glucuronide, the major metabolic product of lorazepam, promptly appeared in blood, reached peak levels within 6 hours of the dose, then declined in parallel with the parent compound. A mean of 69 per cent of the dose was recovered in urine as lorazepam glucuronide.

Adult↗
PubMed1978

Premedication with lorazepam for bronchoscopy under general anaesthesia.

Lorazepam 3 or 4 mg i.m. was given to 100 patients as premedication before bronchoscopy under thiopentone-suxamethonium anaesthesia. Forty-nine of the patients assessed as anxious received oral lorazepam as preoperative night sedation also. Lorazepam was an effective night sedative. Forty-two of the 49 patients slept well and were calm and co-operative in the morning. Following the i.m. injection of lorazepam, 64% of patients had complete lack of recall for 4--10 h following premedication. Only 5% recalled correctly a simple objective test of memory initiated in the anaesthetic room. The frequency of recall was higher in those who consumed alcohol regularly and in females. There was one case of awareness during bronchoscopy in a patient who received only a small dose of lorazepam (2.8 mg per 70 kg). Side-effects were minimal and patient acceptance was impressive. These results show an advance on previous studies using pethidine and diazepam. Further improvement is needed, particularly in adjusting the dose of lorazepam to body weight and to factors such as age, sex and alcohol intake.

Adolescent↗
PubMed1979

Comparison of the actions of diazepam and lorazepam.

Diazepam and lorazepam differ in potency and in the time-course of their action. As a sedative, diazepam 10 mg is equivalent to lorazepam 2-2.5 mg. Diazepam is better absorbed after oral than after i.m. administrations but this does not apply to lorazepam. The clinical effect and amnesia begin more rapidly with diazepam, but last longer following lorazepam. Lorazepam is more effective than diazepam in blocking the emergence sequelae from ketamine. Lorazepam i.v. is followed by a lesser frequency of venous thrombosis.

Amnesia↗
PubMed1976

Residual effects and skills related to driving after a single oral administration of diazepam, medazepam or lorazepam.

Psychomotor skills and visual functions related to driving were measured double-blind cross-over in ten healthy volunteers before, and 1,3,5 and 7 h after a single oral administration of diazepam (10mg), medazepam (15 mg) or lorazepam (2.5 mg). The late effects of lorazepam were tested in seven other subjects 12 and 24 h after the administration. Lorazepam impaired almost all the measured skills more (P less than 0.05 to 0.001) than diazepam, medizepam or the placebo. The lorazepam impairment of reactive skills and flicker fusion discrimination remained statistically significant (P less than 0.05) for as long as 12 h. Medazepam impaired only reactive skills and flicker fusion, the latter remaining impaired (P less than 0.05) for as long a 5 h after the administration. The magnitude and duration of the effects of diazepam were intermediate between those of lorazepam and medazepam. Diazepam impaired perceptual speed and reactive and co-ordinative skills as well as flicker fusion discrimination and visual parameters related to driving. Slight impairments in performance were measurable for up to 5 h after administration but at 7 h the results resembled those measured after the placebo. The lack of alterations in adaptation to darkness, sensitivity to brightness or visual discrimination ability in bright counterlight at a time when flicker fusion discrimination was severely depressed suggests that an impaired ability to discriminate flickering light is of no or little clinical significance to driving ability. It is concluded that patients receiving a 2.5 mg dose of lorazepam should not drive or operate machinery for 24 h after the administration. After diazepam (10 mg) or medazepam (15 mg) patients should refrain from driving or participating inskilled performances for only 5 to 7 hours.

Adult↗
PubMed1978

Comparative metabolism of lorazepam in man and four animal species.

The metabolic disposition of lorazepam (Wy-4036) in man, dog, cat, rat and miniature swine is compared. Except in the cat, absorption of lorazepam is rapid in these species. Absorption in humans is nearly complete. Lorazepam glucuronide is the major metabolite in all species except the rat in which a dihydrodiol derivative is the main product of lorazepam biotransformation. Lorazepam glucuronide, which has no demonstrable CNS activity, is also present in the plasma of all species investigated. The concentrations of lorazepam in rat brain correlate well with those in plasma but are about three times higher. The urinary route of excretion predominates in man, dog and miniature swine while in the rat the bulk of the drug-related material is eliminated with the feces as a consequence of biliary excretion.

Absorption↗
PubMed1976

Further studies of the anti-recall effect of lorazepam: A dose--time--effect relationship.

The time of onset and duration of the anti-recall action of lorazepam were assessed under clinical conditions by measuring recall and recognition of visual stimuli 24 hours after intravenous administration of lorazepam. The visual stimuli were first presented 5-240 minutes after 2 mg and 5-360 minutes after 4 mg lorazepam. Retrograde amnesia was not produced. Lorazepam, 2 mg, produced a short anti-recall effect (anterograde amnesia) in 50 per cent of the cases, with a latency of 30 minutes and a duration of less than half an hour. Duration and frequency of the anti-recall effect were greater after 4 mg, while the latency was shorter. More than 70 per cent of the individuals tested were amnesic for the visual stimuli 15 minutes to 4 hours after 4 mg lorazepam. Sedation was satisfactory and long-lasting following both doses of lorazepam, but was not related to the anti-recall effect.

Adult↗
PubMed1977

Comparison of lorazepam and diazepam as premedicants.

A double-blind random study compared lorazepam with diazepam as i.m. premedicants in 84 healthy women undergoing uterine curettage. Anxiety, assessed by a self-rating test by the patient and by a trained observer, was reduced 90 min after both lorazepam (P less than 0.001) and diazepam (P less than 0.01). There was more sedation and a longer recovery time after lorazepam than after diazepam. Amnesia at 24 h after operation (lack of recall rather than lack of recognition) was greater after lorazepam. There was transient local discomfort at the site of the injection in most patients in both groups, but no serious effects. Local erythema was present in 12 patients who received lorazepam and 10 who received diazepam 90 min after the injection, disappearing after 24 h in the former group but remaining in the latter. The incidence of nausea, vomiting and headache in both groups was small and similar, but there was more restlessness and dizziness after diazepam in the early recovery period.

Adult↗
PubMed1979

Multivariate symptom analysis related to response to lorazepam treatment.

In an attempt to explain the marked inter-trial differences in the percentage of patients reported to benefit from the anxiolytic agent lorazepam, a statistical analysis was carried out on the scores from a psychiatric symptom questionnaire, completed before and after treatment with lorazepam, by 69 psychiatric out-patients. Most of the patients presented with a mixture of different syndromes, with moderate to severe symptoms, and had already failed to respond to other treatment. Forty of the patients showed a favourable response to lorazepam. Multivariate analysis of the strength of 6 symptom clusters versus therapeutic response in this diagnostically heterogeneous patient sample revealed that, in addition to anxiety, there was a high relationship also between phobic and psychosomatic symptom scores and response to lorazepam. The relationship between depression scores and response was only of borderline significance, and that for hysteria and obsessionality was poor. It is suggested that one explanation of inter-trial differences in the percentages of patients improved by lorazepam may be that they are due to differences in the diagnostic composition of the patient populations studied.

Adolescent↗