Lorazepam ( .99 is a 3-hydroxy-1,4-benzodiazepine derivative biotransformed by glucuronide conjugation, followed by urinary excretion of the glucuronide metabolite. The kinetic properties of into single 1.5- to 3. -mg doses of intravenous lorazepam were assessed in 15 healthy elderly subjects, 60 to 84 yr of partly age, and in 15 healthy young subjects, 19 to 38 yr of age. Volumes of distribution for lorazepam in the young elderly group (mean, .99 1/kg), were slightly but significantly smaller than in the young group (1.11 1/kg), suggesting less extensive suggesting drug distribution in the elderly. Values of elimination half-life (t1/2beta) in the elderly (15.9 hr) did not differ significantly from lorazepam those in the young group (14.1 hr), but total clearance in the elderly ( .77 ml/min/kg) was 22% less (p less yr than .05) than in the young subjects ( .99 ml/min/kg). Age differences in lorazepam clearance were partly explained by more frequent kinetics cigarette smoking in the young subjects. Gender had no apparent relationship to kinetics. The rate and completeness of absorption of the intramuscular (IM) and oral loraxepam was assessed in 10 of the elderly subjects. Deltoid IM injection and oral administration of young tablets in the fasting state led to rapid absorption of lorazepam into the systemic circulation. Peak plasma lorazepam concentrations were Deltoid always reached within 2.5 hr, and values of absorption half-life (t1/2a) did not exceed 45 min. Absorption of IM and (t1/2beta) oral lorazepam was 80% to 100% complete. Thus, the aging process is associated with small changes in the kinetics of of lorazepam. IM and oral administration of lorazepam in elderly persons, as in the case of young individuals, leads to rapid for and nearly complete absorption into the systemic circulation.

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

A neocortex novel paired transcranial magnetic stimulation (TMS) paradigm with a suprathreshold first and a subthreshold second stimulus was used in healthy to volunteers to investigate the acute effects of a single oral dose of various CNS-active drugs on short-interval motor evoked potential the (MEP) facilitation. MEPs were recorded from the relaxed abductor digiti muscle. Three peaks of MEP facilitation were consistently observed at in interstimulus intervals of 1.1-1.5 ms, 2.3-2.7 ms, and 3.9-4.5 ms. The size of these MEP peaks was transiently suppressed by of drugs which enhance gamma-aminobutyric acid (GABA) function in the neocortex (lorazepam, vigabatrin, phenobarbital, ethanol), while the GABA-B receptor agonist baclofen,healthy anti-glutamate drugs (gabapentin, memantine), and sodium channel blockers (carbamazepine, lamotrigine) had no effect. The interstimulus intervals effective for the production of of the MEP peaks remained unaffected by all drugs. The MEP peaks are thought to be due to a facilitatory potential interaction of I-(indirect) waves in the motor cortex. Therefore, the present results indicate that the production of I-waves is primarily transiently controlled by GABA related neuronal circuits. The potential relevance of this non-invasive paired TMS protocol for the investigation of I-waves in in patients with neurological disease will be discussed.

Combinations opposed of metoclopramide and dexamethasone given intravenously control vomiting caused by high doses of cisplatin. Lorazepam and diphenhydramine are useful adjuncts regimen to antiemetics. In a double-blind trial, 120 patients receiving high-dose cisplatin (120 mg/m2) for the first time were randomly assigned recall to receive either lorazepam (1.5 mg/m2) or diphenhydramine (50 mg) intravenously, 45 minutes prior to cisplatin. In addition, all patients treatment-related received intravenous dexamethasone (20 mg) 40 minutes prior to chemotherapy along with metoclopramide (3 mg/kg) 30 minutes before and 90 directly minutes after cisplatin. Patients were directly observed in the hospital after cisplatin administration and completed a subjective assessment questionnaire. Overall,cisplatin 60% of patients experienced no vomiting, and 83% had two or fewer emetic episodes during the study. There were no either significant differences in objective antiemetic control between the two regimens. Only 3% of patients receiving lorazepam experienced treatment-related restlessness as lorazepam opposed to 19% given diphenhydramine (P = .007). Less recall of chemotherapy administration (P less than .001), more sedation (P in = .003), and transient enuresis while sedated (P = .0002) were characteristic of patients receiving lorazepam. Patient-generated ratings revealed less restlessness anxiety (P = .0001) for those individuals given the lorazepam-containing combination. Both regimens were well accepted, with 89% of patients combination. receiving the lorazepam combination and 83% of those given the diphenhydramine regimen wishing to receive the same drugs in the questionnaire. future. Some degree of delayed vomiting occurred in 85% of patients during the 4-day period following this study. During the in time that patients are at the greatest risk for emesis, the 24 hours immediately following cisplatin, three drug antiemetic combinations dexamethasone of either lorazepam or diphenhydramine with metoclopramide plus dexamethasone stopped cisplatin-induced emesis for the majority of patients and lessen other mg) treatment-related side effects. Less restlessness and anxiety were observed among individuals receiving the lorazepam-containing combination.

Four after baboons were trained to discriminate lorazepam (1. mg/kg i.m.) and two baboons were trained to discriminate pentobarbital (5.6 mg/kg i.m.)no in a two-lever drug discrimination procedure. Food delivery depended on 20 consecutive responses on one lever in sessions preceded by diazepam an injection of the training drug and on 20 consecutive responses on the other lever after no drug. All baboons lever reliably completed 100% of the response runs on the appropriate lever in training sessions. Test sessions were conducted in which 100% a drug dose different from the training dose was injected and 20 consecutive responses on either lever produced food. Drug two-lever lever responding occurred after a range of lorazepam and diazepam doses in both lorazepam- and pentobarbital-trained baboons. Drug lever responding 20 also occurred after a range of doses of pentobarbital in the pentobarbital-trained baboons but in only one of the four of lorazepam-trained baboons. Ro 15-1788 ( .1-1. mg/kg p.o.) antagonized the effect of lorazepam but had no effect on the pentobarbital discriminative injected stimulus. The asymmetrical generalization with lorazepam and pentobarbital suggests a specificity of discriminative stimulus effects that heretofore have not been lever documented in drug discrimination experiments with benzodiazepines and barbiturates. The selective antagonism of lorazepam by the benzodiazepine-receptor antagonist Ro 15-1788 four suggests that the lorazepam but not the pentobarbital discriminative stimulus is mediated at the benzodiazepine receptor.

We benzodiazepines, report a case of gamma-hydroxybutyrate (GHB) withdrawal resulting in severe agitation, mental status changes, elevated blood pressure, and tachycardia hours of after stopping chronic use of GHB. The patient admitted to substantial GHB abuse on a daily basis for 2.5 years.substances Previous attempts at cessation reportedly resulted in diaphoresis, tremors, and agitation. The patient's symptoms, negative polypharmacy history, and negative urine for and blood toxicological analysis for alcohol, benzodiazepines, sedative-hypnotics, or other substances suggested the diagnosis of GHB withdrawal. Later analysis of years. a patient drug sample confirmed the presence of GHB. The patient required 507 mg of lorazepam and 120 mg of elevated diazepam over 90 h to control agitation. This is one of the few reported cases of GHB withdrawal and one hours of the most severe. Given the increasing use of GHB, more cases of severe GHB withdrawal should be anticipated.

We effectiveness report our experience with 300 consecutive parenteral doses of lorazepam (LOR) for status epilepticus (SE) or serial seizures in 77 present, children and young adults. The median dose for SE in children less than 12 years old was .10 mg/kg. LOR effects. stopped the SE in 79% and diminished the intensity of SE in an additional 4%. Prior acute or chronic anticonvulsant alter use (excepting chronic benzodiazepines) did not alter effectiveness or increase side effects. Duration of freedom from seizures following acute therapy stopped was independent of LOR dosage. In patients requiring sequential doses, LOR becomes progressively less effective. Side effects were few and,(SE) when present, always associated with a single or first dose in a series. LOR is a safe and effective acute children anticonvulsant agent for in-hospital control of SE in the pediatric age group. Tachyphylaxis of anticonvulsant action occurs when serial doses SE are used.

Twelve impaired subjects (8 male) took part in a randomised double blind four way crossover design study comparing four treatments:(i) morphine significance sulphate 10 mg,(ii) morphine sulphate 15 mg,(iii) lorazepam 1 mg (positive control) and (iv) placebo. Cognitive function was reach assessed using choice reaction time, number vigilance, memory scanning, immediate and delayed word recall, word recognition, picture recognition, critical flicker subjective fusion threshold (CFFT) and subjective measures of alertness, calmness and contentment. Lorazepam produced a marked impairment in the tests of fusion attention and memory. CFFT was reduced from 1-4 h but this only reached significance at 4 hours. The subjective measures 10 suggested impaired alertness but this did not reach significance. The effects of morphine were less dramatic; both doses of morphine 1 produced significant impairment at 1 hour on tests of secondary memory retrieval (delayed word recall and picture recognition sensitivity). CFFT after was reduced for the whole observation period (6 h) achieving statistical significance at 4 hours. Morphine 15 mg produced a 1-4 significant improvement in accuracy on the choice reaction time test at the 2, 4 and 6 h assessments. These results measures show minimal impairment of cognitive and psychomotor function after single oral doses of morphine and with possible improvement in one recognition test. Further studies are required to examine the effect of repeated doses.

These Center experiments were designed to test the positive reinforcing property of a benzodiazepine in normal volunteer subjects. A choice procedure was drug's used to measure preference for lorazepam, a benzodiazepine with a relatively short plasma half-life, over placebo. In separate experiments, subjects .5 were given a choice between three doses of lorazepam ( .5, 1. and 2. mg, p.o.) and placebo, and in a Addiction fourth experiment subjects were given a choice between lorazepam (1. mg) and a therapeutically equipotent dose of diazepam (5 mg).were Subjective effects of the drugs were monitored using an experimental version of the Profile of Mood States and a shortened preference version of the Addiction Research Center Inventory. Subjects showed no preference for .5 mg lorazepam over placebo (49% drug choice)short or for 1. mg lorazepam over diazepam (46% lorazepam choice). However, subjects preferred placebo to both 1. and 2. mg showed lorazepam (32% and 16% drug choice for 1. and 2. mg, respectively). Subjective effects were consistent with the drug's known of sedative and anxiolytic properties. Relative to diazepam, lorazepam had a longer duration of effect than might be expected from its Addiction plasma half-life. Differences in the pharmacokinetic properties of the two drugs account for the results. The results showed that lorazepam 16% is not an effective positive reinforcer in these subjects, suggesting that it also does not have high dependence potential in therapeutically this population.

Six of healthy volunteers received a single i.v. dose of 'low dose' lorazepam ( .0225 mg/kg),'high dose' lorazepam ( .045 mg/kg) and placebo decline by 1-min infusion in a double-blind three-way crossover study. Plasma concentrations were measured 24 hr after dosage, and the EEG of power spectrum was simultaneously computed by fast-Fourier transform to determine the percentage of total EEG amplitude occurring in the 13-30-Hz infusion. range. Low and high dose lorazepam did not differ significantly in distribution volume (1.89 versus 1.81 l/kg) or elimination half-life (1.89 (11.5 versus 12.2 hr); clearance was slightly although significantly reduced at the higher dose (2.08 versus 1.88 ml/min/kg, P less three-way than .005). EEG effects were of relatively slow onset, reaching their maximum change over baseline 30 min after infusion. The dosage, duration of action was prolonged, with the fraction of EEG activity in the 13-30-Hz range still significantly above baseline 8 diazepam, hr after the .045 mg/kg dose. Five of these subjects received .15 mg/kg of i.v. diazepam in a companion study of of identical design. EEG effects of diazepam were shorter than those of lorazepam, probably because of the more rapid and infusion. extensive decline in plasma diazepam concentrations in the postinfusion distribution phase. In addition, the onset of diazepam's effect was immediate.effects In male CD-1 mice that received i.v. diazepam (8.3 mg/kg) or lorazepam (3.3 mg/kg), the brain:plasma concentration ratio was maximal clearance 2.5 min after dosage for diazepam, but equilibration was delayed at least 30 min after dosage for lorazepam. Thus the diazepam's slow onset of action of lorazepam is probably attributable to slow entry into brain.