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PubMed1994

Evaluation of the discriminative stimulus effects of the novel sedative-hypnotic CL 284,846.

CL 284,846, N-[3-(3-cyanopyrazolo[1, 5-a]pyrimidin-7-yl)phenyl)]-N- ethylacetamide, is a novel non-benzodiazepine sedative-hypnotic with benzodiazepine-like sedative effects, but with less apparent liability for accompanying undesired side effects. In an effort to further characterize its pharmacological activity, CL 284,846 (3.0 mg/kg, IP, 30 min pretreatment) was established as a discriminative stimulus (DS) in rats (n = 7). CL 284,846 (0.3-10.0 mg/kg) showed a dose-related increase in drug-appropriate responding up to the training dose and a dose-related decrease in response rate. The benzodiazepine agonist triazolam (0.1-1.0 mg/kg), the benzodiazepine partial agonist Ro 17-1812 (0.3-3.0 mg/kg) and the triazolopyridazine CL 218,872 (1.0-3.0 mg/kg) substituted for CL 284,846 in all rats, whereas the imidazopyridines zolpidem (3.0-10.0 mg/kg) and alpidem (10.0-30.0 mg/kg), the benzodiazepine partial agonist bretazenil (0.03-10.0 mg/kg) and the novel putative anxiolytic CL 273,547 (10.0-56.0 mg/kg) substituted in most, but not all, rats. Ro 17-1812, bretazenil, and CL 218,872 had no effect on response rate while the other drugs showed a concomitant decrease in rate. The 5-HT1A agonist buspirone (1.0-10.0 mg/kg) and the barbiturate pentobarbital (3.0-17.0 mg/kg) failed to substitute for CL 284,846 up to rate-decreasing doses. The benzodiazepine antagonist flumazenil (3.0-10.0 mg/kg) blocked the DS effects of CL 284,846 in most rats with no effect on response rate. Taken together, these results suggest that the DS effects of CL 284,846 are mediated via benzodiazepine receptors; however, the DS profile of CL 284,846 remains distinct from both benzodiazepine and non-benzodiazepine sedative-hypnotic drugs.

Acetamides↗
PubMed1985

Drug level monitoring: sedative hypnotics.

Barbiturates and other traditional non-barbiturate sedative hypnotics are still extensively prescribed for the treatment of insomnia. There are a number of situations where identification or quantitative determination of these agents in biological fluids is required. Gas-chromatography offers highly sensitive and specific procedures for the determination of these compounds. The use of a nitrogen-specific detector allows a relatively simple sample preparation for sensitive detection and the use of capillary columns with bonded liquid phase allows separation of barbiturates without derivatization. In recent years liquid chromatography has also been extensively applied to the determination of these compounds. Sensitivity and selectivity of detection of barbiturates have been improved with the use of an alkaline mobile phase. Immunoassays for the determination of therapeutic concentrations of phenobarbital are very popular as the assays can be rapidly performed automatically. Use of these techniques has been extended for emergency detection of barbiturate overdose and for monitoring high-dose pentobarbital therapy.

Barbiturates↗
PubMed2001

Behavioral characterization of Co 134444 (3alpha-hydroxy-21-(1'-imidazolyl)-3beta-methoxymethyl-5alpha- pregnan-20-one), a novel sedative-hypnotic neuroactive steroid.

RATIONALE: Neuroactive steroids have been shown to exhibit a wide range of behavioral activities that are similar but not identical to those of benzodiazepines. These activities include anticonvulsant, anxiolytic and sedative-hypnotic effects. OBJECTIVE: The purpose of the present study was to characterize Co 134444 (3alpha-hydroxy-21-(1'-imidazolyl)-3 -methoxymethyl-5alpha-pregnan-20-one), a novel sedative-hypnotic neuroactive steroid, in a variety of behavioral procedures. METHODS: Anticonvulsant effects were determined by the ability to protect against pentylenetetrazol- and maximal electroshock-induced seizures in mice and rats. Anxiolytic-like effects were determined using a punished drinking procedure in rats. Ataxic effects were determined using a horizontal wire procedure in mice and a rotorod procedure in mice and rats. The discriminative stimulus effects were evaluated in rats trained to discriminate pregnanolone from vehicle. RESULTS: Co 134444 exhibited oral anticonvulsant activity against pentylenetetrazol and maximal electroshock with ED50s of 9.8 and 20.6 mg/kg, respectively, in mice and 23.6 and 25.3 mg/kg, respectively, in rats. Anxiolytic-like efficacy was observed at a dose as low as 3.0 mg/kg, PO, in rats. Ataxic effects were observed with rapid onset and short duration. TD50s were 17.4 and 21.2 mg/kg orally in mice in the horizontal wire and rotorod procedures, respectively, and 39.0 mg/kg in rats using the rotorod. Co 134444 completely substituted for pregnanolone as a discriminative stimulus with little effect on response rate. CONCLUSIONS: Co 134444 exhibits a wide variety of behavioral effects; however, its rapid onset and short duration are consistent with its potential use as a sedative-hypnotic drug.

Animals↗
PubMed1996

Quantitative trait locus analyses of sleep-times induced by sedative-hypnotics in LSXSS recombinant inbred strains of mice.

The long-sleep (LS) and short-sleep (SS) selected lines of mice show highly significant differences in sleep-time for many sedative-hypnotic drugs, and the quantitative genetic nature of these differences has been well-established. Using an interval-mapping approach, quantitative trait locus (QTL) analyses of LSXSS recombinant inbred (RI) strains have been applied to sleep-time responses for various classes of sedative-hypnotic drugs: alcohols (ethanol, n-propanol, and n-butanol), the atypical anesthetic chloral hydrate, barbiturates (pentobarbital and secobarbital), and benzodiazepines (chlordiazepoxide and flurazepam). Several provisional QTLs were mapped to similar locations within and between drug classes, suggesting that some common loci are involved in sleep-times elicited by these drugs. Consistent with correlations of strain mean sleep-times between drugs tested in the LSXSS recombinant inbred strains, the number of provisional QTLs mapping to the locations of highest significance for ethanol decreases when the lipid solubility of a particular drug becomes less similar to that of ethanol. Provisional QTLs mapped for the benzodiazepines, however, revealed considerable overlap with those mapped for ethanol, although these drugs represented the most lipid-soluble category of sedative-hypnotics tested. Provisional QTLs for pentobarbital and secobarbital differed from most of those mapped for the alcohols, which supports the hypothesis that alcohols and barbiturates exert their effects mainly through different biological mechanisms in the LS and SS lines. Blood ethanol concentrations at regaining the righting reflex also mapped to several provisional QTLs corresponding to ethanol-induced sleep-times that support the contention that sleep-time is a reasonable index of the observed differences in central nervous system sensitivities to ethanol between LS and SS mice.

1-Butanol↗
PubMed1982

Alkylation of the prosthetic heme in cytochrome P-450 during oxidative metabolism of the sedative-hypnotic ethchlorvynol.

The clinically used sedative-hypnotic ethchlorvynol destroys hepatic microsomal cytochrome P-450 enzymes in a process catalyzed by the same hemoproteins. Abnormal porphyrins accumulate in the livers of phenobarbital-pretreated rats after administration of ethchlorvynol. The abnormal porphyrin fraction has been isolated and shown to consist of the four possible regioisomers of N-(5-chloro-3-ethyl-3-hydroxy-2-oxo-4-pentenyl)protoporphyrin IX. Cytochrome P-450 inactivation thus appears to result from alkylation of the prosthetic heme by the oxidatively activated acetylenic function in ethchlorvynol. The autocatalytic destruction of the hemoprotein is likely to alter the metabolism and elimination of ethchlorvynol and coadministered drugs and may be the cause of the porphyrinogenic properties of ethchlorvynol.

Alkylation↗
PubMed2006

Sedative hypnotic use in Alberta.

OBJECTIVE: Benzodiazepines and similar sedative-hypnotics (BDZ-SSHs) are associated with both beneficial and adverse effects. Pharmacoepidemiologic data describing the use of these medications in contemporary Canadian populations has not been readily available. Our objective was to examine the hypothesis that increasing use of antidepressant medications for anxiety and mood disorders during the past decade led to less frequent use of BDZ-SSH medications. METHOD: We used data from an Alberta Mental Health Survey to describe the pattern of BDZ-SSH use and to estimate provincial and health region frequencies of use. We supplemented the data with pharmacy dispensing data from IMS Health. RESULTS: The frequency of use was comparable to that reported in previous studies. Unexpectedly, in the survey data, we observed trends suggesting regional variation both in the frequency and pattern of use. Examination of prescription dispensing data confirmed this pattern. Clinical factors, including the use of other psychotropic medications and psychiatric diagnoses, were strongly associated with BDZ-SSH use. Among the drugs examined, zopiclone had the highest frequency of use. Prescription dispensing data confirmed that the frequency of zopiclone use in Alberta is higher than that in most other provinces. CONCLUSIONS: This descriptive study generates several new research questions and provides benchmarks for future pharmacoepidemiologic monitoring.

Acetamides↗
PubMed1990

[Sedative-hypnotic effect of caulis Polygoni multiflori decoction].

The sedative-hypnotic effect of Caulis Polygoni multiflori decoction (CPMD) was studied by the rolling cylinder method in mice and by the somnopolygraphic recording method in rats. The result from the rolling method in mice showed that CPMD (9g/kg) did have synergic action with the subthreshold hypnotic dose of sodium pentobarbital (20mg/kg). The result from the somnopolygraphic recording experiment showed that the immediate hypnotic effect of an effective dose of CPMD (20g/kg) was basically similar to that of diazepam (5mg/kg) used under the same experimental condition, chiefly an increase in the duration of slow wave sleep phase (SWS) and a decrease in the duration of paradoxical sleep phase (PS). By the end of a three-day session in dose of twice a day the hypnotic effect appeared more prominent and the reduction of SWS latency became significant.

Animals↗
PubMed2006

Alpha5GABAA receptors mediate the amnestic but not sedative-hypnotic effects of the general anesthetic etomidate.

A fundamental objective of anesthesia research is to identify the receptors and brain regions that mediate the various behavioral components of the anesthetic state, including amnesia, immobility, and unconsciousness. Using complementary in vivo and in vitro approaches, we found that GABAA receptors that contain the alpha5 subunit (alpha5GABAARs) play a critical role in amnesia caused by the prototypic intravenous anesthetic etomidate. Whole-cell recordings from hippocampal pyramidal neurons showed that etomidate markedly increased a tonic inhibitory conductance generated by alpha5GABAARs, whereas synaptic transmission was only slightly enhanced. Long-term potentiation (LTP) of field EPSPs recorded in CA1 stratum radiatum was reduced by etomidate in wild-type (WT) but not alpha5 null mutant (alpha5-/-) mice. In addition, etomidate impaired memory performance of WT but not alpha5-/- mice for spatial and nonspatial hippocampal-dependent learning tasks. The brain concentration of etomidate associated with memory impairment in vivo was comparable with that which increased the tonic inhibitory conductance and blocked LTP in vitro. The alpha5-/- mice did not exhibit a generalized resistance to etomidate, in that the sedative-hypnotic effects measured with the rotarod, loss of righting reflex, and spontaneous motor activity were similar in WT and alpha5-/- mice. Deletion of the alpha5 subunit of the GABAARs reduced the amnestic but not the sedative-hypnotic properties of etomidate. Thus, the amnestic and sedative-hypnotic properties of etomidate can be dissociated on the basis of GABAAR subtype pharmacology.

Action Potentials↗
PubMed1982

Alteration of convulsive threshold and sensitivity to CNS acting drugs in sedative-hypnotics-experienced rat offspring.

The present study was made to investigate the developmental toxicity of ethanol and several sedative-hypnotics (barbital, diazepam, phenobarbital) administered to rat pups via dams for 18 days (day 3-21 after parturition) from the relatively early postnatal stage in terms of changes in the threshold for pentetrazol (PTZ)-induced convulsion, tolerance to, and physical dependence on barbital (B). In the pups of all dosed groups, the convulsive threshold for PTZ is reduced significantly compared with that in the naive group. The sleeping time with B in phenobarbital-exposed offspring was also reduced significantly compared with that in the naive pups. No difference was however, noted in the B concentration of the brain or plasma upon awaking between these groups of pups, which proved that the phenobarbital-exposed pups had obviously acquired a functional tolerance to B. B-dependence formation and the ensuring weight loss and appearance of withdrawal signs, especially clonic-tonic convulsion, were made intense in the phenobarbital-experienced pups. From these results, it may be concluded that exposure to sedative-hypnotics from the early CNS developing stage makes a lowered state of convulsive threshold for PTZ, and therefore, tends to enhance B-withdrawal convulsion. These phenomena were discussed from the viewpoint of monoamine metabolism in the brain.

Animals↗
PubMed1976

Is the use of hypnotics, sedatives and minor tranquilizers really a major health problem?

An analysis has been made of individual purchases of hypnotics, sedatives and minor tranquilizers made during 1973 by patients who had bought such drugs either only once (group S, n= 417) or regularly (group R, n=76) during a 16-month period five years earlier from pharmacies in the town of Ostersund, county of Jmtland, Sweden. By 1973, 17% of the patients in each group had either died or moved out of the country and were therefore excluded from the comparison. In group S, 81 patients (23%) bought the above drugs once or more in 1973, while the corresponding figure for group R was 55 (87%). Compared with 1968-69, there was a decrease in the number of prescriptions and also in the number of tablets obtained per individual. Furthermore, the number of tablets per prescription was lower in 1973. Among the drugs prescribed, benzodiazepines dominated during both periods, followed by barbiturates. In 1973 there was a substantial increase in the use of nitrazepam, mostly at the expense of diazepam and combined products. One patient in group S and one in group R showed a tendency to decrease the interval between purchases. The latter was already known to be a drug abuser five years earlier. Without knowing the reason why the drugs were prescribed and to what extent they were actually taken, it is impossible to say whether the other patient should be classified as drug abuser or not. Although the number of patients in this study is limited, it might be concluded that the risk of an occasional user of hypnotics, sedatives and minor tranquilizers living in this area becoming an abuser of such drugs within a five-year period is less than 1/345.

Adolescent↗
PubMed2001

Sensitivity to the effects of sedative-hypnotics on motor performance: influence of task difficulty and chronic phenobarbital administration.

The present investigation examined sensitivity to the effects of various sedative-hypnotics on motor performance in rats treated chronically with phenobarbital. Eight rats were trained to walk on a rotorod treadmill at low (8 r.p.m.) and high (24 r.p.m.) rotational speeds. Prior to the chronic regimen, phenobarbital, pentobarbital, amobarbital, diazepam and clonazepam produced dose-dependent impairments in motor performance at both speeds. During chronic treatment with phenobarbital (100 mg/kg/day), tolerance was conferred to the effects of all the drugs examined, as evidenced by rightward shifts in their dose-effect curves. For all drugs, the magnitude of this tolerance was generally consistent across the two speeds. Following a 6-week washout period, during which no drugs were administered, dose-effect curves for each drug shifted back toward their original (i.e. pre-chronic) positions. Under all conditions, the doses required for each drug to impair motor performance at the low speed were higher than those required to impair motor performance at the high speed. These data suggest that sensitivity to the motor-impairing effects of sedative-hypnotics is influenced by the difficulty of the behavioral task, but that task difficulty does not modulate the maximal extent to which tolerance and cross-tolerance are expressed.

Amobarbital↗
PubMed2000

The treatment of sedative-hypnotic dependence: evaluating clinical predictors of outcome.

BACKGROUND: The objectives of this 6-month prospective study were to evaluate the efficacy of detoxification treatment for sedative-hypnotic dependence, examine the demographic and clinical predictors of outcome, and determine whether anxiety or other psychiatric comorbidity has a negative impact on outcome. METHOD: Eighty-two patients with alcohol or benzodiazepine dependence (DSM-IV diagnostic criteria) were consecutively recruited upon entering treatment and were assessed by clinical and semistructured interviews, the Global Assessment Scale, the Hamilton Rating Scale for Depression, the Beck Depression Inventory, the revised 90-item Symptom Checklist, and urine drug screening. RESULTS: Both alcohol- and benzodiazepine-dependent patients succeeded in reducing their reported use of sedative-hypnotic substances during the follow-up period. However, at 3 months, benzodiazepine-dependent patients fared less well than alcohol-dependent patients in terms of several outcome measures: they reported a lower rate of achieving abstinence, shorter periods of continuous abstinence, and more frequent drug use. At 6 months, the differences in outcome among the drug groups were not maintained. Variables such as sex, drug group, and indicators of psychiatric status had little impact on outcome measures. Benzodiazepine-dependent patients reported significant decreases in their level of anxiety over the follow-up period despite substantial reductions in benzodiazepine use. CONCLUSION: Clinicians may be encouraged regarding the detoxification of patients who have used benzodiazepines at high doses or for long periods of time, or who have comorbid anxiety or other psychiatric disorders.

Adult↗
PubMed1981

Use of gastric fistula rats for the study of sedative, hypnotic and antianxiety drugs.

A rat gastric fistula preparation has been developed for the ready and safe administration of water-insoluble drugs. Graded doses of five sedative hypnotics - pentobarbital, secobarbital, methaqualone, diazepam and chloral hydrate - were studied using this preparation and a behavioral scale. The effect of these drugs on respiratory rate was also studied. The rat gastric fistula preparation is a stable one which allows the execution of crossover studies lasting for several months. Valid assays were obtained in comparisons of pentobarbital, secobarbital and methaqualone using both total behavior scale scores (BSS) and depression of respiratory rate. Secobarbital was equipotent to and methaqualone one-fourth as potent as pentobarbital. The slope of the chloral hydrate BSS dose-response line was statistically significantly steeper than that of pentobarbital. The diazepam BSS dose-response line was not only significantly less steep than that of pentobarbital but a plateau was seen. Neither chloral hydrate nor diazepam produced a dose-related depression of respiratory rate. The rat gastric fistula preparation has thus proved useful in characterizing the pharmacologic profiles, dose-response relationship and relative potencies of sedative hypnotics.

Animals↗
PubMed2005

Claims data studies of sedative-hypnotics and hip fractures in older people: exploring residual confounding using survey information.

OBJECTIVES: To identify the magnitude of confounding bias caused by factors not measured in claims data studies of sedative-hypnotic use and fractures. DESIGN: Cross-sectional survey data. SETTING: Medicare Current Beneficiary Survey (MCBS). PARTICIPANTS: Eight thousand seven hundred eighty-five survey participants aged 65 and older. MEASUREMENTS: To determine the association between sedative-hypnotic use and potential confounding factors, five factors not measured in Medicare claims data but measured in the MCBS were assessed: body-mass index, smoking, activity of daily living (ADL) score, cognitive impairment, and Rosow-Breslau physical impairment scale. The association between benzodiazepine or zolpidem use and these five factors was estimated. Combined with literature estimates of the associations between confounders and fractures, it was possible to compute the extent of residual confounding bias caused by a failure to adjust for them. RESULTS: Comparing zolpidem users with nonusers, there was considerable overestimation of an association with hip fractures if ADL scores (21.5% bias) or Rosow-Breslau impairment scales (10.6%) were unobserved in claims data. All five unmeasured confounders together resulted in net confounding of 9.8% (range 0-39%). Comparing benzodiazepine users with nonusers, effect estimates were moderately biased (6.1%). After correction for this bias, the association observed in claims data (relative risk (RR)=1.38; 95% confidence interval (CI)=1.14-1.66) was comparable with that found in a recent study using clinical data (RR=1.20, 95% CI=0.72-2.00). In contrast to the clinical study, the claims data study achieved formal statistical significance because of its much larger size (288 vs 1,222 hip fractures). CONCLUSION: Claims data studies tend to overestimate the relationship between benzodiazepine use and hip fractures. After correcting for such bias, a statistically significant association persists. Concluding that there is no relationship at all based on small clinical studies that did not reach statistical significance may be misleading.

Activities of Daily Living↗
PubMed1981

Sedative-hypnotic tolerance testing and withdrawal comparing diazepam to barbiturates.

A study was conducted to assess the feasibility of substituting diazepam for pentobarbital and phenobarbital in sedative-hypnotic tolerance testing and withdrawal of tolerant patients. Nineteen patients potentially dependent on sedative-hypnotics were tolerance tested with either diazepam or pentobarbital and, if tolerant, were withdrawn with diazepam or phenobarbital, respectively. Seventy-eight subjects previously described in the literature with drug dependencies similar to the diazepam and barbiturate groups provided a basis for comparing the diazepam group to untreated patients to determine whether diazepam was able to prevent abstinence symptoms. Withdrawal was successfully completed in all patients. The expected and observed incidence of seizures, delirium, and minor withdrawal for the barbiturate group and seizures and delirium for the diazepam group did not differ significantly, although a large type II error compromised these conclusions. A significant difference was seen between the observed and expected incidence of minor withdrawal symptoms in the diazepam-withdrawn patients.

Adult↗