[Delirium induced by drug treatment]. / Verwirrtheitszustände als wichtige Arzneimittelwirkung.

Delirium may be induced by a variety of reasons, among them drugs and in particular the combination of drugs. In elderly people a delirium is often misinterpreted as dementia. Anticholinergic activity is the mode of action by which drugs cause delirium. Antipsychotic drugs, antidepressants, antihistamines, and of course anticholinergic drugs themselves are the major anticholinergic classes of drugs. In addition some opioids have anticholinergic effects. Other drugs may induce delirium by dehydration (loop diuretics like furosemide) or sedation (benzodiazapines like lorazepam). Elderly people are at especially high risk to develop delirium, because of the multitude of drugs often prescribed to them, because they tend to drink to little, and because their brain is more sensitive to psychoactive drugs.

Fatal intoxication with a selective serotonin reuptake inhibitor, lorazepam, and codeine.

Selective serotonin reuptake inhibitors were introduced in 1987 as an alternative treatment option for patients with depression or certain anxiety disorders. Unfortunately, this greater use has prompted a corresponding increase in reports of more severe side effects and fatalities, with a majority of fatalities occurring due to coingestion of selective serotonin reuptake inhibitors with other substances or serotonergic drugs. We report a case which exemplifies one such fatality related to sertraline, lorazepam, and codeine coingestion. A brief discussion of the presumed mechanism by which death occurred will be offered.

The effect of chronic lorazepam administration in aging mice.

To assess benzodiazepine tolerance in aged animals, lorazepam or vehicle was administered chronically to male Crl: CD-1(ICR)BR mice. Pharmacodynamic and neurochemical endpoints were examined on days 1 and 14 of drug administration. There was no age-related significant difference in plasma lorazepam levels. Young and middle-aged animals demonstrated behavioral tolerance to lorazepam, while the aged animals showed a similar trend which failed to reach significance. In addition, aged animals also showed a trend toward tolerance to the anticonvulsant effects of lorazepam. There were no changes in alpha1 mRNA levels in cortex or hippocampus following administration of lorazepam when compared to vehicle-treated animals in any age group. Aged animals, however, had an initial increase in alpha1 mRNA expression in cortex and hippocampus on day 1 of vehicle treatment followed by decreased expression on day 14. These age-related changes were abolished by lorazepam administration. In summary, age-related sensitivity to the effects of lorazepam was not demonstrated in the present study. However, comparison of these data to other studies indicates that the effect of chronic benzodiazepine treatment may be specific to the benzodiazepine administered, the technique used to quantify mRNA expression changes, the subunits of the GABA(A) receptor investigated and the brain region analyzed. The phenomenon of benzodiazepine sensitivity in the elderly is an area of research which remains controversial and may well be compound specific. Determining benzodiazepines that do not produce pharmacodynamic sensitivity, such as lorazepam, may allow more careful prescribing and dosing of these drugs, and perhaps even the development of specific agents which could avoid this sensitivity.

Differential amnestic properties of short- and long-acting benzodiazepines.

It has been demonstrated previously that orally administered lorazepam can cause anterograde amnesia in young adults. In this study, the effects of 7.5 and 15 mg clorazepate and 1 and 2 mg lorazepam on recall were compared in 74 healthy adults. Word list presentation tests were administered to subjects at selected intervals to measure immediate and delayed recall. Statistically significant memory impairment was found with 2 mg lorazepam during both immediate and delayed recall testing. Clorazepate produced no statistically significant amnestic effects. The data suggest that benzodiazepines differ in their potential for causing memory impairment.

Effects of repeated dose nitrazepam and lormetazepam on psychomotor performance in the elderly.

The daytime psychomotor performance of 12 healthy subjects of mean age 81.4 years was examined in a double-blind crossover study following single and repeated nightly doses of nitrazepam 5 mg, lormetazepam 1 mg, and placebo. Accuracy of performance on the Gibson spiral maze was unaffected by both drugs. On a reciprocal tapping task, speed was similarly unaffected. However, while neither drug significantly impaired accuracy on reciprocal tapping after the first dose, nitrazepam, but not lormetazepam, significantly reduced overall accuracy after seven consecutive doses, an effect consistent with drug accumulation.

Intoxicating effects of lorazepam and barbital in rat lines selected for differential sensitivity to ethanol.

The motor impairing effects and plasma concentrations of barbital and lorazepam were studied in the alcohol tolerant (AT) and alcohol non-tolerant (ANT) rat lines developed for low and high sensitivity to motor impairment from ethanol. The mixed (M) line, from which the AT and ANT rats were derived, was also included in the study. Like ethanol, barbital and lorazepam impaired the performance of the ANT rats more than that of the AT rats. The motor performance of the M rats was relatively more impaired after barbital than after lorazepam administration at the same dose used in the AT and ANT rats. At the two latter time points (2.5 and 3.5 h) the sensitive ANT rats had significantly higher serum barbital concentrations than the AT rats. The serum barbital concentrations of the AT and ANT rats did not differ, however, at the two first time points (0.5 and 1.5 h) of the tilting plane tests, although the ANT rats were significantly more intoxicated. The concentrations of lorazepam in plasma do not explain the differential motor impairment either, since the sensitive ANT rats had lower plasma concentrations than the insensitive AT rats. The results, thus, suggest that the selection involved in the development of the AT and ANT lines has not been specific for ethanol. The results also support the idea that ethanol, barbiturates and benzodiazepines have some modes of action in common.

A double-blind comparison of the efficacy and safety of lorazepam and diazepam in the treatment of the acute alcohol withdrawal syndrome.

The safety and efficacy of lorazepam and diazepam were compared in the treatment of the acute alcohol withdrawal syndrome during a five-day double-blind trial in alcoholic patients. The daily doses of lorazepam and diazepam were tapered from 6 or 8 mg to 2 mg and from 30 or 40 mg to 10 mg, respectively, during the first four days; no medication was given on day 5. Drug efficacy was measured by Total Severity Assessment Scores (TSAS), the three TSAS factor scores, and by the physician's global evaluation. Of the 55 inpatients enrolled, 47 completed the study. There were no statistically significant differences between the treatment groups in any of the efficacy assessment measures. The physical conditions of the majority of the patients treated with lorazepam (57%) and diazepam (59%) improved during therapy. There were no clinically significant differences between the treatment groups in vital signs or laboratory values. The results of this study indicate that lorazepam is as effective as diazepam in reducing the symptoms of acute alcohol withdrawal. When lorazepam and diazepam are compared in terms of their pharmacokinetics, lorazepam may have therapeutic advantages for the management of the acute alcohol withdrawal syndrome.

Cyclopyrrolones, unlike some benzodiazepines, do not induce physical dependence in mice.

In a model of physical dependence in mice, treatment with cyclopyrrolones such as zopiclone and suriclone (from 4 to 400 mg/kg/day), did not modify the sensitivity of the gamma-aminobutyric acid (GABA) receptor complex to the partial inverse agonist FG 7142 following their withdrawal, whereas sensitivity changes were observed after treatment and withdrawal from some benzodiazepines (e.g. lorazepam, diazepam, flunitrazepam and triazolam). These data suggest that, in contrast to some benzodiazepines, zopiclone and suriclone may not produce physical dependence.

Circadian variations of lorazepam-induced neurologic deficits.

Circadian variations of lorazepam-induced neurologic deficits were tested in mice. The duration of the impairment after administration of 3 mg/kg lorazepam was considerably shorter at 2100 h compared to other times of the day. No significant variations could be found for brain concentrations of drug at recovery and 15 or 30 min after drug administration. Food intake did not seem to account for the circadian pattern observed. It was therefore concluded that chronergy of lorazepam is a result of altered sensitivity of the animal over time rather than to altered pharmacokinetics.

Induction of cognitive impairment by scopolamine and noncholinergic agents in rhesus monkeys.

In primates, treatment with scopolamine impairs performance of a spatial delayed response task in a way which mimics deficits seen spontaneously in aged primates and demented patients. Despite their efficacy in reversing scopolamine induced disruption, the effects of cholinergic agonists on cognition in aged primates and dements are unimpressive, suggesting that other neurotransmitter systems are also involved in this type of deficit. We have induced a scopolamine-like impairment of spatial delayed response performance in rhesus monkeys using phencyclidine (0.1-0.2 mg/kg i.m.), lorazepam (0.4-0.6 mg/kg s.c.) or tetrahydrocannabinol (1-4 mg/kg p.o.), but not amphetamine (0.1-0.4 mg/kg i.m.), yohimbine (0.1-1.0 mg/kg i.m.) or morphine (2-4 mg/kg i.m.). Our findings suggest that disruption of specific neurotransmitter systems other than acetylcholine may contribute importantly to cognitive decline in aging and dementia.

Prenatal benzodiazepine administration. II. Lorazepam exposure is associated with decreases in [35S]TBPS binding but not benzodiazepine binding.

Prenatal benzodiazepine exposure has been associated with neurobehavioral alterations in humans and animals. To determine effects of prenatal benzodiazepine exposure on binding at the benzodiazepine and t-butylbicyclophosphorothionate (TBPS) sites on the GABAA receptor in mature offspring, we treated mice with lorazepam, 2 mg/kg/day, during days 13-20 of gestation. Binding was assessed at 6 weeks of age. There were no differences among controls, vehicle- or lorazepam-exposed mice in benzodiazepine receptor binding determined in vivo or in vitro. However, receptor density for [35S]TBPS binding sites was decreased in lorazepam-exposed offspring compared to the other groups. These data are consistent with prior neurochemical results indicating decreased TBPS binding and GABAA receptor function in several systems.

Physical dependence after benzodiazepine treatments in rats: Comparison of short and long treatments with diazepam and lorazepam.

OBJECTIVE: This study examined the development of physical dependence after different durations of treatments with two benzodiazepines (diazepam and lorazepam). METHOD: Increased excitation in the central nervous system during a 2-week withdrawal period after 4-day and 4-week treatments with diazepam and lorazepam was examined with an EEG threshold method in male rats. Increased excitation was measured as a decreased sensitivity to hexobarbital (i.e., increased threshold doses). The concentrations of hexobarbital in two different brain regions, serum, fat and muscle tissue after 4-week treatment with diazepam were determined with a high-pressure liquid chromatography method. RESULTS: The duration of withdrawal was influenced by the duration of treatment but the maximum level of withdrawal excitation was similar for both drugs. Equieffective doses of diazepam (20 mg/kg) and lorazepam (2 mg/kg) induced similar patterns of withdrawal excitability after both treatments. The brain concentrations of hexobarbital were significantly higher on Days 1 and 3 of withdrawal after diazepam treatment. Significant correlations between the threshold doses and brain concentrations were found on Day 1, but these correlations disappeared on day 3. At the same time, a difference between the concentrations of hexobarbital in different brain areas emerged. CONCLUSIONS: The duration of treatment had a minor influence on the pattern of withdrawal excitation. Equieffective doses of diazepam and lorazepam induced comparable withdrawal excitability indicating no significant difference in their potential to induce physical dependence. The time-dependent change in the hexobarbital concentrations in the brain suggests that withdrawal excitation after diazepam treatment is a complex phenomenon probably involving several different systems at different times.

Thermo-sensitive gels containing lorazepam microspheres for intranasal brain targeting.

Thermo-sensitive gels containing lorazepam microspheres were developed and characterized for intranasal brain targeting. Pluronics (PF-127 and PF-68) have been selected since they are thermo-reversible polymers with the property of forming a solution at low temperatures (4-5 °C), and a gel at body temperature (37 °C). This property makes them an interesting material to work with, especially in case of controlled release formulations. The present study focuses on the development of an intranasal formulation for lorazepam, as an alternative route of drug delivery to the brain. Direct transport of drugs to the brain circumventing the brain barrier, following intranasal administration, provides a unique feature and better option to target brain. The presence of mucoadhesive microspheres in the gel vehicle via nasal route can achieve a dual purpose of prolonged drug release and enhanced bioavailability. To optimise the microsphere formulation, Box Behnken design was employed by investigating the effect of three factors, polymer concentration (chitosan), emulsifier concentration (Span 80) and cross-linking agent (glutaraldehyde) on the response variable which is the mean particle size. The concentration of 21% PF-127 and 1% PF-68 were found to be promising gel vehicles. The results showed that the release rate followed a prolonged profile dispersion of the microspheres in the viscous media, in comparison to the microspheres alone. Histopathological studies proved that the optimised formulation does not produce any toxic effect on the microscopic structure of nasal mucosa.

A comparative study on the cytogenetic activity of three benzodiazepines in vitro.

Even though benzodiazepines (BDZs) possess a leading place among drugs used as anxiolytics, sedatives, muscle relaxants, and anticonvulsants, their cytogenetic effects have not been widely studied in humans. Alprazolam (AZ), bromazepam (BZ), diazepam, and lorazepam (LZ) are some of the most commonly prescribed BDZs. Previous positive findings on diazepam's cytogenetic effects in human lymphocytes suggested additional investigation. In the present research, we explored the cytogenetic potential of AZ, BZ, and LZ in human lymphocyte cultures, using an expanded sample set, administering the under-investigation medications at final concentrations equivalent to oral dosage. As a biomarker of genotoxicity we used sister chromatid exchanges, one of the most sensitive methods reflecting DNA damage and/or subsequent DNA repair, and as a marker of cytostaticity we estimated the proliferation rate index. After 72 h of incubation in the cultures, all three BDZs caused a concentration-dependent, statistically significant increase of sister chromatid exchange frequency (p < 0.001) followed by a statistically significant decrease of proliferation rate index (p < 0.001) of lymphocytes. Our conclusive results suggest that AZ, BZ, and LZ, at concentrations equivalent to oral doses, exhibit statistically significant genotoxicity in human lymphocyte cultures.

Metabolites of lorazepam: Relevance of past findings to present day use of LC-MS/MS in analytical toxicology.

The advent of liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the sensitivity it confers, permits the analysis of both phase I and II drug metabolites that in the past would have been difficult to target using other techniques. These metabolites may have relevance to current analytical toxicology employing LC-MS/MS, and lorazepam was chosen as a model drug for investigation, as only the parent compound has been targeted for screening purposes. Following lorazepam administration (2 mg, p.o.) to 6 volunteers, metabolites were identified in urine by electrospray ionization LC-MS/MS, aided by the use of deuterated analogues generated by microsomal incubation for use as internal chromatographic and mass spectrometric markers. Metabolites present were lorazepam glucuronide, a quinazolinone, a quinazoline carboxylic acid, and two hydroxylorazepam isomers, one of which is novel, having the hydroxyl group located on the fused chlorobenzene ring. The quinazolinone, and particularly the quinazoline carboxylic acid metabolite, provided longer detection windows than lorazepam in urine extracts not subjected to enzymatic hydrolysis, a finding that is highly relevant to toxicology laboratories that omit hydrolysis in order to rapidly reduce the time spent on gas chromatography-mass spectrometry (GC-MS) analysis. With hydrolysis, the longest windows of detection were achieved by monitoring lorazepam, supporting the targeting of the aglycone with free drug for those incorporating hydrolysis in their analytical toxicology procedures.

Association of anxiolytic drugs diazepam and lorazepam, and the antiepileptic valproate, with heart defects--effects on cardiomyocytes in micromass (MM) and embryonic stem cell culture.

Maternal exposure to antidepressant and antiepileptic drugs has been controversially associated with embryological malformations. The underlying mechanisms are unclear. Embryonic chick heart micromass (MM) and D3 mouse embryonic stem cell (ESC) derived cardiomyocyte cultures were treated with a series of concentrations of diazepam (DZ), lorazepam (LZ) and valproic acid (VPA). It was found that DZ and LZ significantly reduced cell beating at concentrations above and including 8 µM (P<0.05), whilst not affecting cell viability and total protein up to 50 µM in both systems, indicating teratogenic rather than cytotoxic effects. At high concentrations (>50 µM), LZ also proves to be cytotoxic in MM. Exposure of the embryonic chick heart MM cultures to 100-2000 µM VPA also showed no cytotoxic effects but the contractile activity of the cultures was significantly inhibited at those concentrations (P<0.05). These experiments provide evidence that antidepressant drugs and valproate may perturb heart development.

Acute and rebound effects of lorazepam on orolingual motor function in young versus aged Fischer 344/Brown Norway rats.

The purpose of this study was to measure the acute effects of lorazepam [a short-acting benzodiazepine (BZ) with no active metabolites] on orolingual motor function in young (6 months) versus aged (24 months) Fischer 344/Brown Norway hybrid (F344/BN) rats. Rats licked water from an isometric force-sensing operandum so that the number of licks per session, licking rhythm (licks/second), and lick force could be measured during daily sessions. Acute doses (1.0 and 2.0 mg/kg) of lorazepam were administered 30 min before the testing sessions, 4 days apart. Whereas aged rats produced more licks per session, lorazepam increased this measure primarily in the young group. On the days after each lorazepam dose, rats licked less than they did before receiving the drug. This effect was shown by both groups. Aged rats showed significantly slower licking rhythm than young rats. Lorazepam slowed this measure in both groups. Peak tongue forces were significantly increased by lorazepam. These findings suggest that BZs such as lorazepam can affect tongue force output and exacerbate age-related tongue motility deficits. They also suggest that although BZs can directly influence motivation to engage in water-reinforced tasks, opposite 'rebound' effects may occur, even after acute dosing.

Limited in vivo bioassays on some benzodiazepines: lack of experimental initiating or promoting effect of the benzodiazepine tranquillizers diazepam, clorazepate, oxazepam and lorazepam.

Four benzodiazepine tranquillizers were tested for their ability to initiate or promote the development of preneoplastic and neoplastic rat liver lesions. In comparison with the liver carcinogen, N-2-fluorenylacetamide, the benzodiazepines exhibited no initiating activity during a 14-week period of daily administration by gavage. To study the promoting activity, N-2-fluorenylacetamide was used to initiate altered foci and neoplastic nodules in rat liver during 8 weeks and then the benzodiazepines were administered by daily gavage for a period of 12 weeks. The liver tumor promoter phenobarbital had a substantial enhancing effect upon the persistence of nodules but none of the benzodiazepines showed a similar effect. Thus, in the process model systems used, to detect initiating or promoting potential effect, the benzodiazepine tranquillizers failed to exhibit either an initiating or a promoting action.

Behavioral changes persisting into adulthood after neonatal benzodiazepine administration in the rat.

The day after birth male pups of hooded Lister rats were randomly fostered to form experimental litters of eight. Within each litter pups were randomly assigned among the following groups: vehicle control; diazepam (1, 5 or 10 mg/kg); lorazepam (0.25, 0.5, 1 or 2.5 mg/kg). Injections were given daily from day 1 until weaning at day 21. The pups were then tested as adults, from day 65. There were no effects of neonatal treatment when the pups were tested undrugged in 3 animal tests of anxiety, but in the social interaction test the neonatal diazepam treatment significantly reduced the anxiogenic effects of yohimbine. The neonatal diazepam treatment significantly enhanced the sedative effects of a challenge dose of chlordiazepoxide in the holeboard. Passive avoidance acquisition and retention were unaffected by the early treatment. Neonatal treatment with both benzodiazepines reduced the incidence of myoclonic jerks when the pups were challenged with pentylenetetrazole. Both neonatal treatments enhanced aggressive acts displayed when the residents were confronted with an intruder in their home-cages. However, when the rats that had been treated neonatally with lorazepam were themselves intruding into another's territory, they were significantly more submissive.

Cleft palate and open eyelids inducing activity of lorazepam and the effect of flumazenil, the benzodiazepine antagonist.

Lorazepam (Ativan, Wyeth) at dosages of 20-36 mg/kg was used to test for developmental toxicity in the mouse embryo/foetus model. Two separate regions were considered: (1) the central nervous system and (2) the roof of the mouth and the eyelids. In the first case a single administration of lorazepam was applied at the very beginning of the 9th gestation day. In the second, it was administered in preliminary tests on two consecutive gestation days between the 11th and 14th days and in later experiments once only on the 13th or 14th gestation day. In the first part of investigations regarding the development of the central nervous system, lorazepam unlike many other neurotropic drugs, was found not to induce any aberrations in the process of the neural tube closure. In the second part, in which palate closure and the temporary closure of eyelids were monitored, it was found that lorazepam does interfere with these processes. In order to test whether lorazepam's neurocristopathic activity can be prevented, suggesting the presence of benzodiazepine receptors in the neural crest cells, we used the benzodiazepine antagonist, flumazenil (Anexate, Roche). The results of these experiments indicated the flumazenil was able to prevent cleft palate and open eyelids cases almost completely if it was administered 3 hr after administration of lorazepam. If the treatments were administered in the reverse order, the frequency of neurocristopathy cases was unaffected, i.e. flumazenil did not influence the teratogenic activity of lorazepam.