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PubMed1978

Plasma concentrations of diazepam, noradiazepam and amylobarbitone after short-term treatment of anxious patients.

Twenty-four anxious inpatients were treated with diazepam, amylobarbitone and placebo, each given in flexible dosage for one week, according to a fully-balanced design. Plasma concentrations of diazepam and of its metabolite nordiazepam and of amylobarbitone were determined after two, four and seven days of treatment. Clinical and psychological assessments were made after seven days of each treatment by means of psychiatrist rating scales, patient's self-rating and a comprehensive battery of performance measures. Diazepam and nordiazepam but not amylobarbitone were accumulating over the seven days of treatment. In patients on diazepam without previous amylobarbitone, nordiazepam accumulated more rapidly than diazepam over the week so that the ratio of diazepam to nordiazepam was 2.21 after two days but only 1.14 after seven days; those with previous amylobarbitone on the other hand always had nordiazepam concentrations higher than those of the administered drug and both were accumulating equally. Diazepam and nordiazepam were still detectable in most patients two weeks after the interruption of treatment. No correlations were found between drug concentrations and clinical and psychological effects.

Adult↗
PubMed1989

Double-blind study of metaclazepam versus diazepam treatment of outpatients with anxiety syndrome.

The therapeutic efficacy and tolerance of metaclazepam and diazepam were compared in a double-blind study of outpatients suffering from a generalized anxiety syndrome. The investigators were general practitioners. A total of 168 male and female patients aged between 18 and 60 years were included in the study and received either 15 mg metaclazepam or 15 mg diazepam per day. The analysis of tolerance was made for all 168 included patients, the evaluation of efficacy is based on the results of 131 patients (42 males and 89 females) with valid data over four weeks. During the four-week therapy period four examinations were made on days 0, 7, 14, and 28. A significant improvement of the severity of illness after administering the drugs was found for both drugs in the Clinical Global Impressions (CGI), in the Hamilton Anxiety Scale (HAMA), in the List of Complaints (B-L), and in the Adjective Checklist (EWL-K). Metaclazepam showed a statistically significant superiority over diazepam as far as the CGI items "severity of illness" and "global improvement" were concerned. Metaclazepam was slightly superior to diazepam in the two HAMA subscales "psychic anxiety" and "somatic anxiety". In the items of the selfrating scales (B-L and EWL-K) the therapeutic results of the metaclazepam group were, almost without exception, better than those of the diazepam group. A comparison of tolerance showed that metaclazepam was better tolerated. This can be seen in the greater frequency of side effects like tiredness and drowsiness under diazepam. Especially at the beginning of treatment, tiredness and drowsiness were recorded 2 1/2 times more frequently for the patients on diazepam than for those on metaclazepam.

Adolescent↗
PubMed1984

Clinical importance of the interaction of diazepam and cimetidine.

Cimetidine is known to impair the hepatic microsomal oxidation of diazepam, reducing its clearance and prolonging its half-life. We studied the clinical importance of this effect in 10 patients, who were receiving long-term treatment with diazepam for anxiety, tension, or difficulty in sleeping, in an eight-week double-blind controlled study during which the diazepam dosage remained constant. The study was in four two-week phases: base-line or adaptation, coadministration of cimetidine (300 mg) or matching placebo four times daily, crossover to the opposite treatment (placebo or cimetidine), and recovery treatment with diazepam alone. During the cimetidine phase, plasma concentrations of diazepam plus desmethyldiazepam rose an average of 57 per cent (P less than 0.005), then fell when cimetidine was withdrawn. However, there were no significant changes in scores on the digit-symbol-substitution test, a tracking task, or a reaction-time test. Clinical self-ratings indicated no increases in sedation, fatigue, or drowsiness. Patients experienced shortening of sleep latency (P less than 0.05) and an increase in self-rated depth or soundness of sleep (P less than 0.001) during the cimetidine period, but there were no changes in sleep duration or in the number of nocturnal awakenings. Although coadministration of cimetidine to diazepam-treated patients causes a large increase in plasma diazepam and desmethyldiazepam concentrations, the increase is of minimal clinical importance.

Adult↗
PubMed1998

A comparison of rectal diazepam gel and placebo for acute repetitive seizures.

BACKGROUND: Acute repetitive seizures are readily recognizable episodes involving increased seizure frequency. Urgent treatment is often required. Rectal diazepam gel is a promising therapy. METHODS: We conducted a randomized, double-blind, parallel-group, placebo-controlled study of home-based treatment for acute repetitive seizures. Patients were randomly assigned to receive either rectal diazepam gel, at a dosage varying from 0.2 to 0.5 mg per kilogram of body weight on the basis of age, or placebo. Children received one dose at the onset of acute repetitive seizures and a second dose four hours later. Adults received three doses -- one dose at onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a care giver, such as a parent, who had received special training. The number of seizures after the first dose was counted for 12 hours in children and for 24 hours in adults. RESULTS: Of 125 study patients (64 assigned to diazepam and 61 to placebo) with a history of acute repetitive seizures, 91 (47 children and 44 adults) were treated for an exacerbation of seizures during the study period. Diazepam treatment was superior to placebo with regard to the outcome variables related to efficacy: reduced seizure frequency (P<0.001) and improved global assessment of treatment outcome by the care giver (frequency and severity of seizures and drug toxicity) (P<0.001). Post hoc analysis showed diazepam to be superior to placebo in reducing seizure frequency in both children (P<0.001) and adults (P=0.02), but only in children was it superior with regard to improvement in global outcome (P<0.001). The time to the first recurrence of seizures after initial treatment was longer for the patients receiving diazepam (P<0.001). Thirty-five patients reported at least one adverse effect of treatment; somnolence was the most frequent. Respiratory depression was not reported. CONCLUSIONS: Rectal diazepam gel, administered at home by trained care givers, is an effective and well-tolerated treatment for acute repetitive seizures.

Acute Disease↗
PubMed2001

A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.

BACKGROUND: It is uncertain whether the administration of benzodiazepines by paramedics is an effective and safe treatment for out-of-hospital status epilepticus. METHODS: We conducted a randomized, double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus. Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg), lorazepam (2 mg), or placebo. An identical second injection was given if needed. RESULTS: Of the 205 patients enrolled, 66 received lorazepam, 68 received diazepam, and 71 received placebo. Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (59.1 percent) or diazepam (42.6 percent) than patients given placebo (21.1 percent) (P=0.001). After adjustment for covariates, the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 4.8 (95 percent confidence interval, 1.9 to 13.0). The odds ratio was 1.9 (95 percent confidence interval, 0.8 to 4.4) in the lorazepam group as compared with the diazepam group and 2.3 (95 percent confidence interval, 1.0 to 5.9) in the diazepam group as compared with the placebo group. The rates of respiratory or circulatory complications (indicated by bag valve-mask ventilation or an attempt at intubation, hypotension, or cardiac dysrhythmia) after the study treatment was administered were 10.6 percent for the lorazepam group, 10.3 percent for the diazepam group, and 22.5 percent for the placebo group (P=0.08). CONCLUSIONS: Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults. Lorazepam is likely to be a better therapy than diazepam.

Adult↗
PubMed1996

Diazepam binding inhibitor is a potent cholecystokinin-releasing peptide in the intestine.

Pancreatic proteases in the duodenum inhibit the release of cholecystokinin (CCK) and thus exert feedback control of pancreatic exocrine secretion. Exclusion of proteases from the duodenum either by the diversion of bile-pancreatic juice or by the addition of protease inhibitors stimulates exocrine pancreatic secretion. The mechanism by which pancreatic proteases in the duodenum regulate CCK secretion is unknown. In this study, we isolated a trypsin-sensitive peptide that is secreted intraduodenally, releases CCK, and stimulates pancreatic enzyme secretion in rats. This peptide was found to be identical to the porcine diazepam binding inhibitor by peptide sequencing and mass spectrometry analysis. Intraduodenal infusion of 200 ng of synthetic porcine diazepam binding inhibitor1-86 in rats significantly stimulated pancreatic amylase output. Infusion of the CCK antagonist MK-329 completely blocked the diazepam binding inhibitor-stimulated amylase secretion. Similarly, diazepam binding inhibitor33-52 [corrected] also stimulated CCK release and pancreatic secretion in a dose-dependent manner although it was 100 times less potent than the whole peptide. Using a perfusion system containing isolated mucosal cells from the proximal intestine of rats, porcine diazepam binding inhibitor 10(-12) M) dose dependently stimulated CCK secretion. In separate studies, it was demonstrated that luminal secretion of the diazepam binding inhibitor immunoreactivity (7.5 X 10(11) M) could be detected in rat's intestinal washing following the diversion of bile-pancreatic juice. The secretion of this peptide was inhibited by atropine. In conclusion, we have isolated and characterized a CCK-releasing peptide that has a sequence identical to the porcine diazepam binding inhibitor from pig intestinal mucosa and that stimulates CCK release when administered intraduodenally in rat. This peptide may mediate feedback regulation of pancreatic enzyme secretion.

Amino Acid Sequence↗
PubMed1976

Diazepam: routes of administration and rate of absorption. A study of women with pre-eclampsia.

Plasma diazepam concentrations were determined following oral, i.m. and i.v. administration to a group of pregnant women with pre-eclampsia and a group of normal pregnant women. Diazepam concentrations were greater following oral as compared with i.m. administration in the control group, who received a single 5-mg dose, and this confirms previous similar reports. In the patients with pre-eclampsia, who were pre-loaded with diazepam, the i.m. route provided much higher plasma diazepam concentrations than did the oral route. This was probably a result of reduced gastric motility and gastric secretion caused by diazepam which affected the absorption of subsequent diazepam administered orally, and it is unlikely that pre-eclampsia contributed to these differences. Mist. magnesium trisilicate seemed to improve the rate of absorption of diazepam from the intestine in five patients studied, although this effect is unlikely to have much clinical importance.

Administration, Oral↗
PubMed2002

A comparison of metoclopramide and lidocaine for preventing pain on injection of diazepam.

UNLABELLED: We compared the ability of metoclopramide with IV lidocaine pretreatment to abolish pain from a diazepam injection. In a randomized, prospective, double-blinded, placebo-controlled clinical trial, 159 patients (ASA physical status I and II), aged 20-70 yr old, were allocated to one of three groups. Placebo and study drugs were injected IV immediately before 0.1 mg/kg of diazepam into a dorsal hand vein. Patients in Groups 1, 2, and 3 received 2 mL of placebo, 2 mL of lidocaine 1%, and 2 mL of metoclopramide (10 mg), respectively. The patient's response was graded using a 4-point scale. Any score other than 0 represented pain on injection. We observed that the incidence of pain on diazepam injection was 83% in the placebo group, which was decreased to 70% and 39% in patients pretreated with metoclopramide and lidocaine, respectively. Although there was no significant difference in the incidence of pain in Groups 1 and 3 (P > 0.05), Group 3 showed significantly less patients with severe pain scores than Group 1 as diazepam was injected (P < 0.000). Group 2 showed a significantly less frequent incidence of pain than the saline (P < 0.000) and the metoclopramide (P < 0.002) groups as diazepam was injected. The intensity of pain in Group 2 was significantly less than Group 3 (P = 0.012). The intensity of diazepam injection pain was intense with placebo as compared with other groups (P < 0.000). Metoclopramide, rather than lidocaine pretreatment, may be a reasonable analgesic alternative for painful injections. IMPLICATIONS: Metoclopramide, rather than lidocaine pretreatment, may be a reasonable analgesic alternative to decrease pain from a diazepam injection, especially when there is a medical condition in which lidocaine should be used very cautiously.

Adjuvants, Anesthesia↗
PubMed1989

Anxiety neurosis in general practice. A double-blind comparative study of diazepam and clovoxamine, a novel inhibitor of noradrenaline and serotonin reuptake.

This was a multicentre prospectively randomized double-blind parallel comparison of clovoxamine (n = 37) and diazepam (n = 35) in 72 patients suffering from anxiety neurosis, in general practice. Patients were seen weekly. Treatment was for 4 weeks (50 mg clovoxamine b.d. or 5 mg diazepam b.d.) rising according to response to a maximum of 300 mg clovoxamine or 30 mg diazepam daily. Drug was tapered off in week 5 and patients were seen again in week 6 after they had been off drug for at least a week. A treatment period of 4 weeks was selected in line with WHO guidelines for the testing of anxiolytic drugs. Although more patients dropped out due to intolerance on clovoxamine (24%) compared with diazepam (11%), analysis of completed patients showed that clovoxamine was equally effective with significant improvement in both groups at week 4 (p less than .001) compared with baseline Morbid Anxiety Inventory scores and Hamilton Anxiety Scale scores. Diazepam patients had a more rapid response which levelled off, whereas those on clovoxamine continued to improve after 2 weeks. At 6 weeks after taper off the improvement on clovoxamine was sustained whereas on diazepam there was evidence of deterioration after stopping the drug. Clovoxamine appears to have potential as an alternative treatment to diazepam for anxiety in general practice.

Adolescent↗
PubMed1990

Efficacy and safety of a diazepam and meperidine combination for pediatric gastrointestinal procedures.

Little has been published about outpatient sedation for pediatric patients. We designed a study to evaluate the efficacy and adverse effects of diazepam and meperidine in combination for sedation in ambulatory pediatric patients undergoing endoscopy, colonoscopy, or liver biopsy. Thirty patients (7 months-20 years) were observed. Each patient received a single combined dose of intravenous diazepam and meperidine. The standard dose was 0.1 mg/kg for diazepam and 2.0 mg/kg for meperidine. In patients weighing greater than 100 lb, set doses of meperidine (100 mg) and diazepam (5 mg) were used. The time to achieve sedation and the vital signs were measured; cooperation, emotional state, and drowsiness were rated before, during, and after procedures. The amnesic effect was noted, as were any adverse effects. Diazepam and meperidine were effective in 26 of 30 patients, with sedation generally produced within 2-3 min. Cooperation and emotional state improved significantly following drug administration (p less than 0.05). When a prospective 24-h telephone follow-up study was instituted in 40 consecutive patients receiving diazepam and meperidine no significant adverse effects were noted. Only 20% of patients old enough to be questioned remembered the procedure. Diazepam and meperidine in combination appear to be effective and safe in pediatric patients undergoing gastrointestinal procedures. Prolonged monitoring of patients does not appear necessary in this patient population.

Adolescent↗
PubMed1987

Diffusion of [2-14C]diazepam across hairless mouse skin and human skin.

The objectives of this study were to investigate the absorption of diazepam applied topically to the hairless mouse in vivo and to determine the diffusion of diazepam across isolated hairless mouse skin and human skin. [14C]Diazepam was readily absorbed after topical administration to the intact hairless mouse, a total of 75.8% of the 14C-label applied being recovered in urine and feces. Diazepam was found to diffuse across human and hairless mouse skin unchanged in experiments with twin-chambered diffusion cells. The variation in diffusion rate or the flux for both human and mouse tissues was greater among specimens than between duplicate or triplicate trials for a single specimen. Fluxes for mouse skin (stratum corneum, epidermis, and dermis) were greater than for human skin (stratum corneum and epidermis): 0.35-0.61 microgram/cm2/h for mouse skin vs 0.24-0.42 microgram/cm2/h for human skin. The permeability coefficients for mouse skin ranged from 1.4-2.4 X 10(-2)cm/h compared with 0.8-1.4 X 10(-2)cm/h for human skin. Although human stratum corneum is almost twice the thickness of that of the hairless mouse, the diffusion coefficients for human skin were 3-12 times greater (0.76-3.31 X 10(-6) cm2/h for human skin vs 0.12-0.27 X 10(-6) cm2/h for hairless mouse) because of a shorter lag time for diffusion across human skin. These differences between the diffusion coefficients and diffusion rates (or permeability coefficients) suggest that the presence of the dermis may present some barrier properties. In vitro the dermis may require complete saturation before the diazepam can be detected in the receiving chamber. [14C]Diazepam was not detected in the receiving chamber of the Franz cell apparatus in experiments with human skin. This indicated that the rate of diffusion was less than 0.09 microgram/cm2/h. Since this diffusion technique more closely resembles topical administration to humans, these results appear to indicate that achieving therapeutic concentrations in humans may be difficult. In addition, the hairless mouse may not be a suitable model for predicting percutaneous absorption of diazepam in humans.

Absorption↗
PubMed1984

The psychopharmacological effects of premazepam, diazepam and placebo in healthy human subjects.

Pharmacological studies of premazepam in animals predicted antianxiety activity without sedation and, in combination with diazepam, a reduction in the sedative effects of the latter. The effects of single doses of premazepam (25 and 50 mg), diazepam (10 mg), premazepam (25 mg) plus diazepam (10 mg), and a placebo on subjective feelings, psychological tests and the EEG were studied in a double-blind cross-over study in 10 healthy subjects. In a repeated dose study in eight subjects, the effects on subjective feelings, psychological tests and the EEG of premazepam (5 and 10 mg twice-daily), diazepam (5mg twice-daily) and a placebo were compared. Premazepam had a different EEG profile from diazepam, producing more slow and less fast wave activity. In the single dose study its effects were similar to diazepam for sedative action and most of the psychological tests, with a tendency towards greater psychomotor impairment. In the repeated dose study, however, premazepam caused less sedation and also tended to produce less psychomotor impairment. The combination dose of premazepam (25 mg) plus diazepam (10 mg) in the single dose study indicated an additive effect rather than an antagonistic one.

Adult↗
PubMed1994

Lack of interaction between diazepam and nimodipine during chronic oral administration to healthy elderly subjects.

1. Nimodipine (30 mg three times daily) and diazepam (10 mg once daily), were given orally to 24 elderly healthy subjects in a randomized, non-blinded, threefold-crossover study. Each of the three treatment periods lasted 5 days separated by 2 week washout phases. 2. Plasma concentrations of nimodipine and diazepam were not affected by the combined treatment. 3. No clinically relevant changes in haemodynamics, ECG recordings, clinical chemistry or haematology were observed after all of the three treatments. The overall frequency of side effects was lowest during monotherapy with nimodipine and highest during diazepam monotherapy. 4. In the test of subjective rating of tiredness (VAS) and the Pauli calculation test, diazepam, alone and with nimodipine co-medication, produced an increase in tiredness and a clear reduction in performance and endurance. After nimodipine monotherapy an improvement was observed only in the Pauli test. Using the critical flicker fusion frequency test (CFF) significant decrements in performance were found after diazepam monotherapy only. 5. In summary, there was no evidence that either nimodipine or diazepam affected the pharmacokinetics, safety and tolerance of each other. However, the CNS-effects of diazepam were compensated partially by nimodipine.

Administration, Oral↗
PubMed1996

A study of the sedative effect of home-administered oral diazepam for the dental treatment of children.

This study investigated the effects of oral diazepam administered at home to fearful child patients prior to dental treatment. Twenty-five healthy, uncooperative children, mean age 3 years 8 months (+/- 1 year 3 months), requiring at least three visits for the treatment of dental caries, were studied. Each child's behaviour was assessed during three treatment sessions: (i) control, with no diazepam or placebo; (ii) with diazepam; and (iii) with a placebo. Each child acted as his/her own control, being initially assigned to the control session. Subsequently each was randomly assigned to receive either diazepam or placebo for the second session and the other for the third session. The diazepam and placebo were administered by the parents at home approximately 60 minutes before treatment. Each patient's behaviour was assessed on a scale of 1 (definitely positive) to 4 (definitely negative) by two calibrated examiners who were blind to the medications given and independent of the treatment. Vital signs were monitored at 5-minute intervals. Behaviour was significantly better with diazepam than with the placebo or with neither. No significant differences were observed between the placebo and control sessions. At no time were any adverse effects noted, such as vomiting or respiratory depression. It was concluded that oral administration of 0.3 mg/kg diazepam at home by the parent is an effective and safe technique for preoperative sedation of fearful child patients.

Administration, Oral↗
PubMed1985

Myorelaxant effect of diazepam. Interactions with neuromuscular blocking agents and cholinergic drugs.

Experiments were performed, using electrophysiological techniques, to investigate the effects and interactions of diazepam with commonly-used neuromuscular blocking agents and cholinergic agonists in chick and rat isolated nerve-muscle preparations. The results showed that in low concentrations (3.4-340 mumol/l, i.e. 1-100 micrograms ml-1) diazepam increased, in a dose-dependent manner, the twitch contractions in response to motor nerve stimulation of the chick and rat. High concentrations of diazepam (greater than 340 mumol/l) decreased the twitch tension and greatly reduced the contractures produced by acetylcholine (ACh) and tetraethylammonium (TEA) in the chick skeletal muscle. However, in the concentration range studied (close to a therapeutic dose of 0.15 mg kg-1), diazepam had no significant effect on the neuromuscular blockade produced either by tubocurarine or by succinylcholine. It was concluded that diazepam may either increase or decrease the twitch tension, in rat and chick skeletal muscle, the effect being dependent on the concentrations used. The mechanism of action of diazepam may depend on an increasing intracellular calcium concentration, which is directly involved in the increase of the twitch tension by low concentrations of diazepam.

Acetylcholine↗
PubMed1970

Corory vasodilatation following diazepam (Valium).

1. The effects of diazepam (Valium) on coronary and systemic vascular resistance were studied in anaesthetized dogs on cardiopulmonary bypass under conditions of constant heart rate and aortic pressure.2. Pharmacological doses of diazepam uniformly produced coronary vasodilation lasting 30 min; systemic vascular resistance also decreased, but to lesser degree.3. When coronary blood flow was maintained constant at physiological levels, diazepam produced no changes in left ventricular contractility, as assessed by peak LV isovolumetric pressure, dp/dt max, force-velocity, and length-tension relations, whereas previous experiments had demonstrated a positive inotropic effect in a similar preparation in which coronary blood flow was responsive to alterations in coronary vascular resistance.4. In five dogs, complete separation of the coronary and systemic circulations was accomplished by a double pump-oxygenator system; direct intracoronary administration of diazepam produced coronary vasodilatation, but coronary pressure and flow were not altered by administration of diazepam to the systemic circulation.5. It is concluded that diazepam augments myocardial contractility by increasing coronary blood flow. This relationship is independent of extracardiac humoral mechanisms, and appears to require the delivery of diazepam to the coronary circulation.

Anesthesia, Intravenous↗
PubMed1983

Studies on the interaction between cerebral 5-hydroxytryptamine and gamma-aminobutyric acid in the mode of action of diazepam in the rat.

The effect of the benzodiazepine, diazepam, administered for 7 days in doses between 1.25 and 5 mg kg-1 was studied on the turnover of 5-hydroxytryptamine (5-HT) in rat cerebral cortex. 5-HT turnover was assessed by calculating the ratio of the concentration of the major metabolite 5-hydroxyindoleacetic acid (5-HIAA) to that of 5-HT (i.e., 5-HIAA:5-HT). Diazepam (2.5 and 5 mg kg-1 i.p. daily for 7 days) significantly reduced cerebral cortical 5-HT turnover. The effect of manipulating cerebral gamma-aminobutyric acid (GABA) mechanisms on this action of diazepam was studied. Treatment of animals with a subconvulsive dose of picrotoxin (3 mg kg-1 i.p.) reversed the fall in cortical 5-HT turnover seen following diazepam. In contrast, however, treatment with the GABA transaminase inhibitors, amino-oxyacetic acid (25 mg kg-1) or ethanolamine-O-sulphate (250 mg kg-1, 7 days) which elevated cerebral GABA concentrations, enhanced the reduction in cortical 5-HT turnover following diazepam. Focal injection of picrotoxin (0.1 micrograms) into the region of the dorsal raphé nucleus reversed the decrease in cortical 5-HT turnover caused by diazepam. The hypothesis that doses of diazepam which result in total plasma concentrations comparable to those observed in man produce a reduction in 5-HT turnover mediated via GABA neurones is discussed.

Aminobutyrates↗
PubMed1989

Physical dependence on diazepam in the dog: precipitation of different abstinence syndromes by the benzodiazepine receptor antagonists Ro 15-1788 and ZK 93426.

1. The effects of the benzodiazepine receptor antagonists Ro 15-1788 (flumazenil) and the beta-carboline ZK 93426 were compared in dogs before and after chronic treatment with diazepam. 2. In diazepam-naive dogs, the most prominent behavioural alterations occurring during or after i.v. infusion of Ro 15-1788 up to a dose of 20 mg kg-1 were transient sedation, ataxia, and 'hot foot' behaviour, whereas behavioural alterations observed after ZK 93426 were not different from those observed after i.v. infusion of vehicle alone. This indicates that, in contrast to Ro 15-1788, ZK 93426 did not exert partial agonistic activity at benzodiazepine receptors. 3. In dogs treated 3 times daily with diazepam, 1 mg kg -1 orally, for 1 week, both benzodiazepine antagonists precipitated abstinence symptoms but the number and severity of withdrawal signs induced by Ro 15-1788 were greater than with ZK 93426. 4. In dogs treated 3 times daily with diazepam, 2 mg kg-1 orally, for 2 weeks, severe abstinence symptoms were precipitated in all animals by infusion of either antagonist but differences were found in the type of the symptoms: Ro 15-1788 induced rigid postures or rigid walking with increased muscle tone, tremor, twitches and jerks, whereas ZK 93426 did not alter motility but induced generalized myoclonic jerks and tonic-clonic seizures. A generalized tonic-clonic seizure was also observed in one dog of the trial with infusion of Ro 15-1788. 5. Plasma level determinations during chronic treatment diazepam showed marked accumulation of the major active metabolite desmethyldiazepam, whereas diazepam levels were at least 15 times lower, which might suggest that desmethyldiazepam was responsible for the development of physical dependence on diazepam.

Animals↗