Local NSAID gel (eltenac) in the treatment of osteoarthritis of the knee. A double blind study comparing eltenac with oral diclofenac and placebo gel

Several new, non-benzodiazepine hypnotic drugs have recently been marketed (zopiclone, zolpidem) or are in development (zaleplon, SX 3228). These compounds act at benzodiazepine (BZ) (omega) receptors but have mechanisms of action which are not identical to those of benzodiazepines; in particular, zolpidem, zaleplon and SX 3228 have been reported to have selectivity for the BZ1 (omega 1) receptor subtype. In the present study the effects of the four hypnotic drugs were investigated in rats trained to discriminate ethanol (1 g/kg). Comparisons were made with pentobarbital and the benzodiazepines, lorazepam and midazolam. The two benzodiazepines and the barbiturate produced dose-related substitution for ethanol. In contrast, zolpidem, zaleplon, SX 3228 and zopiclone gave rise to only partial (maximum effect 50-67%) substitution, even at doses which greatly reduced rates of lever pressing. The limited ethanol-like effects of zolpidem, zaleplon and SX 3228 may be related to the more selective mechanism of action of these compounds. It is not clear why the effects of zopiclone differed from those of the benzodiazepines.     

Antibody capture haemadherence tests for parvovirus B19-specific IgM and IgG

Repeated administration of benzodiazepines has been reported to produce tolerance in animals and humans. Using an elevated plus-maze test and an autoradiographic technique, we investigated whether repeated administration of chlordiazepoxide produced tolerance to its anxiolytic effects, and whether such repeated administration altered benzodiazepine and GABAA receptors. Tolerance to the anxiolytic effect of chlordiazepoxide was produced when it was administered at a dose of 30 mg/kg (i.p.) once a day for 10 and 14 days. In the quantitative autoradiographical study, although repeated chlordiazepoxide treatment had no effect on [3H]flunitrazepam and [3H]Ro 15-4513 binding to benzodiazepine receptors, such treatment reduced [3H]muscimol binding to GABAA receptors in the cortex, caudate putamen, and hippocampus. These results suggest firstly, the production of tolerance to the anxiolytic effects of chlordiazepoxide, and, secondly, that this tolerance may be due to the down-regulation of GABAA receptors, but not of benzodiazepine receptors.     

Comparative study on benzodiazepine use in Canada and Chile

Benzodiazepines are the most prescribed psychotropic drugs in the world. Comparative international data on benzodiazepine use, specifically among developed and developing countries, are unavailable. To determine the different patterns of benzodiazepine use in two representative countries, use of benzodiazepines in Chile (a developing country) and Canada (a developed country) was undertaken. Wholesale data as provided by the Intercontinental Medical statistics and drug import data were used as databases. Data on trends of benzodiazepine use was determined for 5 years using the methodology recommended by the WHO for drug use research, the defined daily dose/1000 inhabitants/day. Total benzodiazepine use was similar in both countries, but Canadian use had increased slowly. Patterns of use, however, differ widely among the two countries. A linear increase of rapidly eliminated benzodiazepines was observed in Canada, whereas the reverse occurs in Chile: the slowly eliminated benzodiazepines are the ones that have increased use. Hypnotic benzodiazepines are used twice as frequently in Canada than in Chile. Striking differences in the use of individual benzodiazepines are observed. Differences in healthcare systems determine wide differences in the way these drugs are prescribed. Demographic characteristics of the two countries also may account for the differences in benzodiazepine use. The authors conclude that, although total benzodiazepine consumption is similar in the two countries, patterns of benzodiazepine use vary widely. The different patterns of use may determine differences in the morbidity rates associated with the use of these drugs.     

Ventral tegmental area dopamine neurons mediate the shock sensitization of acoustic startle: A potential site of action for benzodiazepine anxiolytics.

Dopamine (DA)-containing neurons in the ventral tegmental area (VTA) are thought to play an important role in fear motivation. The primary objective of the present study was to determine the connection between DA D?, gamma aminobutyric acid (GABA)A, and benzodiazepine receptors in the VTA and footshock-associated emotionality. Microinfusion of the DA D? receptor agonist quinpirole, the GABAA receptor agonist muscimol, and the benzodiazepine receptor agonist flurazepam into the VTA was observed to suppress the shock enhancement of acoustic startle amplitudes. None of the drugs depressed baseline startle responding or footshock reactivity. The results indicate the involvement of VTA DA neurons in the fear-arousing properties of footshock and implicate the VTA as a possible neural site for the anxiolytic actions of benzodiazepines. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluation of the prevalence of drug and alcohol abuse in motor vehicle trauma in south western Sydney

This study estimated prospectively the prevalence of high drug and alcohol levels in road trauma cases who met the criteria for activation of the Liverpool Hospital's trauma team. Urine analysis of road trauma victims between October 1992 and October 1993 was undertaken for drug and alcohol estimation. A total of 164 drivers were studied. A urine alcohol concentration (UAC) exceeding 0.08 g/dL was detected in 27 drivers (16.5%). Cannabinoids were detected in the urine of 25 drivers (15.2%), in 17 the concentrations exceeded 400 ng/mL. In one instance amphetamine, cocaine and heroin were detected in the same injured driver. Combined use of alcohol with some other drugs was detected in only four drivers. Alcohol and cannabinoid levels were prevalent in the urine of injured drivers in this study, particularly in young males who remain over-represented in the group of injured drivers. In the population surveyed other drugs were rarely detected. The role of cannabinoids in road trauma and the use of cannabinoids in young male drivers will however need to be monitored more extensively.     

Drug use among adolescents and their parents: Closing the generation gap in mood modification.

Assessed the relationship between adolescent and parental drug use among 8,865 Grade 6-13 students. A positive association was found between parental use of psychoactive drugs, alcohol, and tobacco, as reported by Ss, and S psychoactive and hallucinogenic drug use. The relationship was strongest when both used psychoactive drugs. A family pattern, characterized by only mothers' use then use by both parents was found but was common to S drug users and nonusers. There was no sex relationship in S-parent drug use. Data suggest that adolescents model their drug use after parental use and that in order to reduce adolescent use parental use would have to be reduced. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cannabis versus other illicit drug use among methadone maintenance patients.

Few data exist on the prevalence and consequences of cannabis use among methadone maintenance patients. Weekly urine toxicology data from 70 patients in a methadone program were analyzed for evidence of cannabis as well as cocaine and benzodiazepines, and the relationship between use of these drugs and opiate use was examined. Patients who were positive for both cocaine and benzodiazepine, but not those positive for cannabis, were more likely also to test positive for opiates. Related literature is reviewed, and the issue of illicit drug use among such patients is discussed in the context of harm reduction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-term treatment with abecarnil does not induce diazepam-like dependence in mice

Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a metabolically stable anxiolytic and anticonvulsant beta-carboline derivative with few sedative and muscle relaxant effects in rodents. Abecamil binds with high affinity to benzodiazepine receptors. Because long-term treatment with benzodiazepines leads to development of dependence, we evaluated in mice whether abecarnil also possesses a potential for producing dependence, using electroencephalographic and electromyographic monitoring, and behavioral assessment of anxiety to detect withdrawal responses after chronic treatment. Diazepam was used as a reference. Mice withdrawn from chronic treatment with diazepam (15 mg/kg/day for 12 days) showed a time-related evolution of anxiety, muscle rigidity and seizures between days 4 and 21 after discontinuation of the treatment. A period between withdrawal days 1 and 3 was symptom free. Mice withdrawn from chronic administration of abecarnil (6 mg/kg/day for 12 days) showed no anxiety and no changes in seizure susceptibility and muscle tone. The doses of diazepam and abecarnil used for chronic treatment were equivalent in terms of kinetics and binding to benzodiazepine receptors. These data indicate that long-term treatment with abecarnil does not induce benzodiazepine-like dependence in mice. Thus, it may be predicted that chronic treatment with abecarnil in humans may offer an important alternative to benzodiazepines in the treatment of anxiety.     

Acid-catalyzed ethanolysis of temazepam in anhydrous and aqueous ethanol solutions

The benzodiazepines are a family of anxiolytic and hypnotic drugs. When taken concurrently with ethanol, a pharmacological interaction may occur, potentiating the central nervous system depression produced by either drug. In addition to this pharmacological interaction, this report describes a novel chemical reaction between temazepam (a 3-hydroxy-1,4-benzodiazepine) and ethanol under acidic conditions similar to those found in vivo, resulting in a 3-ethoxylated product. Optimal conditions, kinetics, equilibrium, and the mechanism of this acid-catalyzed ethanolysis are reported. The results raise the possibility that the ethanolysis reaction may occur in the stomach of people who consume alcohol and 3-hydroxy-1,4-benzodiazepine on a regular basis. The acid-catalyzed ethanol-drug reaction is a relatively unexplored area and may alter the pharmacological action of some drugs.     

Serotonin syndrome resulting from drug interactions

We describe six patients diagnosed with serotonin syndrome after exposure to drugs with serotonergic activity. Drug interactions occurred as a result of a combination of tricyclic antidepressants, selective serotonin reuptake inhibitors, selective noradrenaline reuptake inhibitors or monoamine oxidase inhibitors. Management included supportive care and the use of non-specific serotonin antagonists (cyproheptadine, benzodiazepines and chlorpromazine). All patients made uneventful recoveries.     

Dihydroergosine: anticonflict effect in rats and enhancing effects on [3H]muscimol binding in the human brain post mortem

The anticonflict activity of the ergot alkaloid, dihydroergosine, a drug which binds to 5-hydroxytryptamine1 (5-HT1) receptors and to gamma-aminobutyric acidA (GABAA) receptor-associated Cl- ionophore, was studied in water-deprived rats. In vitro effects of this drug on [3H]muscimol and [3H]flunitrazepam binding to the crude synaptosomal pellet of the human frontal cortex post-mortem were also investigated. Dihydroergosine, given 2 h prior to testing, enhanced drinking under punished (0.8 mA) conditions, and diminished it under unpunished conditions. The mechanism of this effect was (-)-propranolol- and pindolol-insensitive and picrotoxin-sensitive. Flumazenil either failed to affect, or at a higher dose (10 mg/kg), counteracted the dihydroergosine-induced enhancement of punished drinking. This dose of flumazenil was itself anxiogenic. Dihydroergosine had mild sedative and analgesic properties. Low concentrations of dihydroergosine (10 nM to 100 microM) enhanced the binding of [3H]muscimol but not of [3H]flunitrazepam. The results suggest that dihydroergosine may possess anxiolytic properties presumably mediated by its specific action at the GABA/benzodiazepine/chloride channel complex.     

The effects of theophylline on serum alprazolam levels

Theophylline and benzodiazepines are frequently combined in clinical practice. Because of a number of case reports about antagonism of benzodiazepine-induced sedation by theophylline, we investigated serum alprazolam levels in a convenient sample of pulmonary medicine inpatients receiving theophylline and no theophylline. One mg of alprazolam was given daily for seven days to 6 patients receiving theophylline and 7 patients not receiving theophylline treatment. On days 2 through 7, trough serum alprazolam levels were measured. On day 7, blood samples were collected before (0 hour), and at 3, 6, 9 and 12 hours after alprazolam administration. In patients receiving theophylline, serum trough alprazolam levels were significantly lower during each day of the study. In patients receiving no theophylline, serum alprazolam levels were in the therapeutic range, except for two patients who had high alprazolam levels. In this small study, serum alprazolam levels were found to be consistently below the therapeutic range in patients receiving chronic theophylline treatment. Previously reported antagonism of anxiolytic effects of benzodiazepines by theophylline is probably due to the lower serum benzodiazepine levels in these patients.