Pharmacokinetic-pharmacodynamic analysis of mnesic effects of lorazepam in healthy volunteers.
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AIMS: To describe the pharmacokinetic-pharmacodynamic modelling of the psychomotor and mnesic effects of a single 2 mg oral dose of lorazepam in healthy volunteers. METHODS: This was a randomized double-blind, placebo-controlled two-way cross-over study. The effect of lorazepam was examined with the following tasks: choice reaction time, immediate and delayed cued recall of paired words and immediate and delayed free recall and recognition of pictures. RESULTS: The mean calculated EC50 values derived from the PK/PD modelling of the different tests ranged from 12.2 to 15.3 ng ml-1. On the basis of the statistical comparison of the EC50 values, the delayed recall trials seemed to be more impaired than the immediate recall trials; similar observations were made concerning the recognition vs recall tasks. CONCLUSIONS: The parameter values derived from PK/PD modelling, and especially the EC50 values, may provide sensitive indices that can be used, rather than the raw data derived from pharmacodynamic measurements, to compare CNS effects of benzodiazepines. (+info)
Mechanisms of use-dependent plasticity in the human motor cortex.
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Practicing movements results in improvement in performance and in plasticity of the motor cortex. To identify the underlying mechanisms, we studied use-dependent plasticity in human subjects premedicated with drugs that influence synaptic plasticity. Use-dependent plasticity was reduced substantially by dextromethorphan (an N-methyl-d-aspartate receptor blocker) and by lorazepam [a gamma-aminobutyric acid (GABA) type A receptor-positive allosteric modulator]. These results identify N-methyl-d-aspartate receptor activation and GABAergic inhibition as mechanisms operating in use-dependent plasticity in intact human motor cortex and point to similarities in the mechanisms underlying this form of plasticity and long-term potentiation. (+info)
Can we use anxiolytics during pregnancy without anxiety?
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QUESTIONOne of my patients suffers from anxiety and was using lorazepam to treat it. When she became pregnant, she stopped the medication immediately, but now she is worried about the potential effect on the baby because she was using the drug just after conception. Is this class of drugs safe during pregnancy? What should she do if she needs antianxiety treatment during the rest of her pregnancy?ANSWEREvidence to date from cohort studies did not identify a notable association between use of benzodiazepines and increased risk of major malformations, including oral cleft. In contrast, data from case-control studies show a slightly increased risk of oral cleft. Hence, level 2 ultrasonography is recommended to rule out visible forms of cleft lip. Using benzodiazepines late in pregnancy could cause withdrawal syndrome in newborns. (+info)
Benzodiazepine toxicity with profound suppression of the electroencephalogram.
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The authors report the case of a 60-year-old man with respiratory distress secondary to exacerbation of chronic obstructive pulmonary disease, right lower lobe pneumonia, and severe bronchospasm. High doses of lorazepam were given intravenously after failure to control bronchospasm and agitation with bronchodilators and mucolytic agents; the patient was unresponsive to all stimuli while receiving lorazepam. Electroencephalography revealed a profoundly suppressed pattern without accompanying low-voltage fast activity--this was reversible following withdrawal of the lorazepam. (+info)
Autonomic reactivity to mental stressors after single administration of lorazepam in male alcoholics and healthy controls.
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Clinically unaffected sons of male alcoholics differ from controls without a family history of alcoholism in two respects: increased autonomic reactivity to aversive as well as non-aversive stimuli and increased attenuation of these responses by alcohol. This pattern of autonomic hyper-reactivity and alcohol-induced stress response dampening (SRD) might be a trait marker of genetic vulnerability and is often interpreted in terms of a diathesis stress model of alcohol dependence. Forty-five alcohol-dependent men (mean age: 39.20 years) and 37 healthy controls (mean age: 35.03 years) participated in a double-blind cross-over study in two experimental sessions each. The benzodiazepine lorazepam was selected as an alcohol substitute. Autonomic reactivity and lorazepam-induced SRD were assessed during incentive and non-incentive reaction time tasks as well as mental arithmetics. Alcohol-dependent men showed elevated resting heart rate levels and increased number of non-specific electrodermal responses. Evidence for autonomic hyper-reactivity was found for a subgroup of alcoholics with a family history of alcoholism. (+info)
Drug discrimination: stimulus control during repeated testing in extinction.
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Rats were trained, under a two-lever drug-discrimination procedure, to respond differentially depending upon whether lorazepam (1.0 mg/kg) or no injection had been administered before the session. Responses on the appropriate lever produced a food pellet under a modified fixed-ratio (FR) 10 schedule, in which the 10 responses had to be emitted consecutively. In reinforcement tests, completing an FR 10 on either lever produced a pellet. In extinction tests, stimulus changes paired with reinforcement occurred but no pellet was delivered. Training sessions were conducted between test sessions. Each of four extinction phases consisted of six tests preceded by one stimulus (e.g., lorazepam). Repeated exposures to extinction reduced response rates for all rats, but stimulus control, as inferred from either percentage of total responses or percentage of total FR 10s on the drug-appropriate lever, remained high. The percentage of total FR 10s measure was less subject to skewing under low-rate conditions than was the percentage of total responses measure and provided an evaluation of stimulus control in terms of meeting the consecutive response contingency. These results demonstrate a level of independence between response rate and stimulus control in drug discrimination, which has positive implications for the validity of interpreting discriminative effects of novel test conditions in well-trained animals, even when overall response rates are low. (+info)
Benzodiazepines and hip fractures in elderly people: case-control study.
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OBJECTIVE: To determine whether benzodiazepines are associated with an increased risk of hip fracture. DESIGN: Case-control study. PARTICIPANTS: All incident cases of hip fracture not related to traffic accidents or cancer in patients over 65 years of age. 245 cases were matched to 817 controls. SETTING: Emergency department of a university hospital. MAIN OUTCOME MEASURES: Exposure to benzodiazepines and other potential risk or protective factors or lifestyle items. RESULTS: The use of benzodiazepines as determined from questionnaires, medical records, or plasma samples at admission to hospital was not associated with an increased risk of hip fracture (odds ratio 0.9, 95% confidence interval 0.5 to 1.5). Hip fracture was, however, associated with the use of two or more benzodiazepines, as determined from questionnaires or medical records but not from plasma samples. Of the individual drugs, only lorazepam was significantly associated with an increased risk of hip fracture (1.8, 1.1 to 3.1). CONCLUSION: Except for lorazepam, the presence of benzodiazepines in plasma was not associated with an increased risk of hip fracture. The method used to ascertain exposure could influence the results of case-control studies. (+info)
Discontinuing antidepressants and benzodiazepines upon becoming pregnant. Beware of the risks of abrupt discontinuation.
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QUESTION: Two of my patients are planning to become pregnant. One is taking paroxetine and the other lorazepam. We have discussed what to do when they become pregnant and have decided they should stop taking these drugs as soon as pregnancy is confirmed. Is this the right decision? ANSWER: The decision to discontinue these drugs during pregnancy should be based on scientific evidence rather than "hearsay" that women should not take psychotropic medications during pregnancy. Recent epidemiologic studies have documented the relative safety of these drugs, so women should not feel compelled to stop taking them when they become pregnant. If, after receiving appropriate evidence-based information, a woman decides to stop taking the drugs, they should be gradually tapered off to avoid abrupt discontinuation syndrome. (+info)