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PubMedDate not supplied

Interactive effects of diazepam and ethanol on baboon match-to-sample performance.

Four juvenile male baboons were trained to perform a match-to-sample (MTS) discrimination task. Diazepam (DZ) at doses of 0.5, 1.0, 2.0, 4.0, or 6.0 mg/kg resulted in a significant (p less than 0.05) increase in the mean response times (MRT) during the 2 hr test session in terms of percent change from baseline performance under nondrug conditions measured the day prior to drug treatment. Effects were maximal at 2.0 mg/kg diazepam and no further effects were observed at 4.0 or 6.0 mg/kg. Administration of 0.25 mg/kg of diazepam had no effect on MTS performance. Exposure to 0.5 g/kg of ethanol (EtOH) had no effect on response time, while 1.0 g/kg EtOH significantly (p less than 0.05) increased response time. Baboons receiving combined treatment with 0.5 or 1.0 g/kg EtOH plus 1.0 mg/kg diazepam displayed a significant (p less than 0.05) percent increase in mean response time compared to that observed under baseline conditions on the day prior to drug treatment. The 0.5 g/kg EtOH and 1.0 mg/kg diazepam combination increased MRT to an extent comparable to the effect observed at the same dose of diazepam alone. Effects observed with 1.0 mg/kg diazepam and 1.0 g/kg EtOH were similar to those produced by the DZ alone. Combinations of 0.5 g/kg EtOH and 0.5 mg/kg diazepam, 1.0 g/kg EtOH and 0.25 mg/kg diazepam, and 1.0 g/kg EtOH and 0.5 mg/kg diazepam had no significant effect on response times.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Perinatal diazepam exposure: behavioral and neurochemical consequences.

In the present study the effects of perinatal diazepam (DZP) exposure on behavior and benzodiazepine binding site characteristics in offspring were investigated. Pregnant F344 rats were treated during the last trimester of gestation with vehicle or diazepam (3 mg/kg, 5 mg/kg, or 10 mg/kg). Lactating dams were similarly treated on postnatal days 1-7. Both prenatal and postnatal exposure to diazepam resulted in significant effects on the acquisition and extinction of active avoidance behavior measured postweaning. The number of trials to extinction of one-way active avoidance behavior was significantly greater in offspring exposed gestationally to 3 mg/kg and 10 mg/kg diazepam and postnatally to 10 mg/kg diazepam. The mean response latencies for all diazepam treated groups were significantly shorter than those of the vehicle treated rats during the first 15 trials under extinction conditions. In contrast, neither gestational nor postnatal diazepam exposure significantly affected either acquisition or retention of a passive avoidance task. In addition, the binding affinity between the benzodiazepine type I selective ligand, CL218,872, and cortical membranes, as well as the degree to which GABA potentiated 3H-flunitrazepam were significantly altered by perinatal diazepam exposure. No treatment altered the approximate number of benzodiazepine binding sites in either the cortex, hippocampus, or cerebellum. The results of this study further support diazepam as a behavioral teratogen and give new evidence for neurochemical effects following gestational as well as postnatal diazepam exposure.

Animals↗
PubMedDate not supplied

Long-term effects of diazepam treatment of epileptic GABAA receptor beta3 subunit knockout mouse in early life.

The knockout mouse for the beta3 subunit of the GABAA receptor exhibits spontaneous epilepsy and hyperactivity, and has been proposed as a model for the severe developmental disorder, Angelman's syndrome, which is known to be of genetic origin. We have used this mutant to test an approach of therapeutic intervention prior to seizure onset by daily injection with diazepam during either the first or second postnatal week. Results showed differences between postnatal week 1 and week 2 injections both acutely, with respect to sedative effects, and in long-term outcome, with respect to EEG and behavioral tests measured at 12-14 weeks of age. The EEG of control mice remained unaffected under all conditions, but the EEG of beta3 (-/-) injected with diazepam in week 1 was worsened, showing increased oscillatory activity at 5-6Hz, and more myoclonic jerks, particularly among males. For beta3 (-/-) injected with diazepam in week 2, the EEG was normalized in half the mice but worsened similarly to week 1 in the other half. Neonatal diazepam injection had a long-term normalizing effect on behavior of beta3 (-/-) mice injected in week 1, but diazepam treatment in week 2 did not affect the hyperactive and circling behavior characteristic of the beta3 knockout mouse. Diazepam treatment in postnatal week 2 significantly decreased anxiety in the adult beta3 group. Diazepam treatment in both postnatal weeks 1 and 2 improved the motor coordination of beta3 (-/-) on the rotarod, although performance of control mice injected with diazepam in postnatal week 2 was significantly impaired. The observed long-term outcome of neonatal diazepam injections may result from interference with developmental processes, and shows that enhancing GABAergic activity with diazepam during the period where GABA can be excitatory can produce narrow stage-related effects on brain development.

Age Factors↗
PubMed1993

The action of diazepam in the isolated rat detrusor muscle.

Diazepam is one of the benzodiazepines, a group of drugs that depresses the central nervous system. It also inhibits the contractility of smooth muscles in the periphery, but the mechanism of this inhibitory action has not been clarified. Our study was undertaken to investigate the effect of diazepam on the contractility of the detrusor muscle. Detrusor muscle strips isolated from rat urinary bladder were examined by isometric myography. Diazepam, as well as baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, reduced the electric field stimulation-induced contractions; delta-aminovaleric acid, a GABAB receptor antagonist, completely antagonized the inhibitory effect of baclofen, but not the inhibitory action of diazepam. Diazepam reduced the basal tone of detrusor muscle concentration dependently, and this inhibitory action was not affected by tetrodotoxin. Diazepam suppressed the contractile responses to bethanechol, adenosine triphosphate and potassium chloride. Diazepam diminished the calcium-induced recovery of tension in calcium-free PSS. A23187, a calcium ionophore, partially recovered the basal tone which had been reduced by diazepam in normal physiologic salt solution (PSS). The loss of tension in calcium free PSS containing diazepam could not be recovered by addition of A23187. On the other hand, the loss of tension in calcium-free PSS containing 3,4,5-trimethoxybenzoic acid 8(diethylamino)octyl ester (TMB-8), an inhibitor of intracellular calcium release, was considerably recovered by addition of A23187. Based on these results, it is suggested that diazepam inhibits the contractility of detrusor muscle acting directly on the smooth muscle cell, which is unrelated to the activation of GABA receptors. Its inhibitory action appears to be mediated through interference with the influx of extracellular calcium.

Adenosine Triphosphate↗
PubMed1997

Diazepam alters caffeine-induced effects on beta-endorphin levels in specific rat brain regions.

The present study was conducted to evaluate the effects of caffeine and the benzodiazepine agonist diazepam, and a combination of both on beta-endorphin (beta-EN) levels in specific rat brain regions. Male Sprague-Dawley rats (150-200 g) adapted to a 12-hour light: 12-hour dark illumination cycle were used in this study. Caffeine (10 mg/kg), diazepam (2 mg/kg) or a combination of caffeine (10 mg/kg) and diazepam (2 mg/kg) were administered intraperitoneally to rats at 11:00 hr. Control animals were injected with saline. Animals were sacrificed by decapitation 1 h after injection, the brains were immediately removed; the cortex, hippocampus, hypothalamus and midbrain were dissected and their B-EN levels measured by radioimmunoassay. Caffeine administration significantly increased B-EN levels in the cortex. Similarly, administration of diazepam alone resulted in a significant increase of B-EN levels in cortex. However, concurrent administration of diazepam and caffeine resulted in higher increase of B-EN levels in cortex. No significant changes in B-EN levels were detected in hippocampus and midbrain after administration of either caffeine or diazepam alone. On the other hand, when diazepam and caffeine were concurrently administered a significant increase of B-EN levels were observed in the midbrain. Moreover, administration of diazepam alone resulted in a significant increase of B-EN levels in hypothalamus. This increase was still observed following concurrent administration of diazepam and caffeine. These results clearly indicate that diazepam alters caffeine-induced effects on B-EN in specific rat brain regions.

Animals↗
PubMed1997

Tolerance develops to the spatial learning deficit produced by diazepam in rats.

The present experiment sought to determine in rats if 1) tolerance develops to the amnesic effect of diazepam after chronic treatment, 2) the sedative and amnesic effects of diazepam can be dissociated via differential rates of tolerance development, and 3) withdrawal from long-term diazepam treatment affects mnemonic processes. Rats were given diazepam (3 mg/kg) acutely or chronically for 5, 15, or 30 d prior to behavioral testing. Sedation was assessed as exploratory activity in an open field and amnesia was assessed as spatial learning in the Morris water maze. Tolerance to the sedative effect of diazepam was exhibited after 5 d pretreatment whereas tolerance to the amnesic effect of diazepam was exhibited only after 30 d pretreatment. Withdrawal from diazepam produced a transitory and mild disruption of spatial learning. The data demonstrate 1) tolerance can develop to the amnesic effect of diazepam with extended treatment, 2) the sedative and amnesic effects of diazepam are largely independent, and 3) withdrawal from chronic diazepam treatment can retard optimal learning.

Amnesia↗
PubMed1999

Effects of SR141716A on diazepam substitution for delta9-tetrahydrocannabinol in rat drug discrimination.

Interaction of cannabinoids with GABAergic systems has been noted in a number of previous studies. In the present study, this interaction was examined in a drug-discrimination paradigm. Rats were trained to discriminate either delta9-tetrahydrocannabinol (delta9-THC; 3 mg/kg) or diazepam (2.5 mg/kg) from vehicle in two-lever drug discrimination procedures for food reinforcement. As in previous studies, diazepam partially substituted for delta9-THC, but only at high doses that also decreased response rates. In contrast, delta9-THC did not substitute for diazepam in any of the rats. Hence, cross-generalization of these two drugs was asymmetrical. When tested in combination with diazepam, the brain cannabinoid (CB1) receptor antagonist SR141716A did not block the partial substitution of diazepam for delta9-THC, nor did it antagonize the discriminative stimulus effects of diazepam in diazepam-trained rats. These results suggest that the partial overlap in the discriminative stimulus effects of delta9-THC and diazepam is not mediated by diazepam action at CB1 receptors. However, the fact that diazepam produced partial substitution for delta9-THC is consistent with a GABAergic component to cannabinoid drug discrimination.

Animals↗
PubMed1994

Flumazenil induces seizures and death in mixed cocaine-diazepam intoxications.

STUDY HYPOTHESIS: Administration of the benzodiazepine antagonist flumazenil may unmask seizures in mixed cocaine-benzodiazepine intoxication. DESIGN: Male Sprague-Dawley rats received 100 mg/kg cocaine IP alone, 5 mg/kg diazepam alone, or a combination of diazepam and cocaine. Three minutes later, groups were challenged with vehicle or flumazenil 5 or 10 mg/kg IP. Animal behavior, seizures (time to and incidence), death (time to and incidence), and cortical EEG tracings were recorded. INTERVENTIONS: Administration of flumazenil to animals after they had received a combination dose of cocaine and diazepam. RESULTS: In group 1, animals received cocaine followed by vehicle. This resulted in 100% developing seizures and death. Group 2 received diazepam alone followed by vehicle. Animals became somnolent and none died. Group 3 received diazepam followed by 5 mg/kg flumazenil. Animals became somnolent after diazepam and then active after flumazenil administration. In group 4, a combination of cocaine and diazepam was administered simultaneously. This resulted in no overt or EEG-detectable seizures and a 50% incidence of death. Group 5 received a similar combination of cocaine and diazepam, followed later by 5 mg/kg flumazenil. This resulted in an increased incidence of seizures, 90% (P < .01), and death, 100% (P < or = .01), compared with group 4. Group 6 received cocaine and diazepam followed by 10 mg/kg flumazenil. This also resulted in an increased incidence of seizures, 90% (P < or = .01), and death, 90% (P < or = .05), compared with group 4. CONCLUSION: Flumazenil can unmask seizures and increase the incidence of death in a model of combined cocaine-diazepam intoxications.

Animals↗
PubMed2000

The influence of diazepam on the electroencephalogram-evoked potential interrelation in rats.

Though being a sedative, diazepam increases beta-activity in the electroencephalogram (EEG). Diazepam also affects auditory evoked potentials (AEPs). We investigated if the effect of diazepam on AEPs could be ascribed to its beta-increasing effect. Eight rats received vehicle and diazepam counterbalanced. AEPs were ranked in ten categories according to the percentages of beta-activity in the pre-stimulus electroencephalogram (EEG). With vehicle, the P(29), N(51) and P(67) AEP components increased and cross-correlation coefficients (CCCs) declined with increasing beta-activity. With diazepam AEP components and CCCs remained unchanged. All AEPs with diazepam closely resembled the AEP of the lowest beta-category obtained with vehicle. We conclude that the effect of diazepam on AEPs can not be ascribed to its beta-enhancing effect. Diazepam disrupts the normal AEP-EEG relation such that diazepam-effects on AEPs seem to reflect the sedative effects of diazepam and not its beta-increasing effects.

Animals↗
PubMed1997

Localization and pharmacological characterization of pigeon diazepam-insensitive GABAA receptors.

Transduction mechanisms associated with ligand binding at diazepam-insensitive subtypes of GABAA receptors remain largely unknown, but unique behavioral effects of ligands binding at these sites have been reported in pigeons. The present study further evaluated the pharmacological characteristics of diazepam-insensitive GABAA receptors in pigeon brain, using [3H]Ro 15-4513. Autoradiography detected diazepam-insensitive benzodiazepine sites on GABAA receptors in a number of brain regions, with the highest densities present in the olfactory bulb, hippocampus, thalamic nuclei and cerebellar granule cell layers, with densities of approximately 10-20% of total benzodiazepine receptor binding. Saturation analysis revealed significant densities (approximately 10% of total benzodiazepine receptor binding) of extracerebellar diazepam-insensitive benzodiazepine receptors in optic lobe, hippocampus, and brainstem compared to 27% in cerebellum. As reported for mammalian diazepam-sensitive benzodiazepine receptors, GABA (50 microM) generally increased the affinities of agonists and partial agonists, had little effect on the affinities of antagonists, and decreased the affinity of an inverse agonist for pigeon cerebellar diazepam-sensitive benzodiazepine receptors. GABA modulation of ligand binding to diazepam-insensitive benzodiazepine receptors was less than that observed for diazepam-sensitive sites, and no positive modulation was observed. These results demonstrate the presence of cerebellar and extracerebellar diazepam-insensitive benzodiazepine receptors in pigeon brain, with distribution patterns and pharmacology similar to those reported in mammals. The comparable central localization and pharmacological properties of drugs at diazepam-sensitive and -insensitive benzodiazepine receptors in pigeons and rats attests to the evolutionary conservation of GABAA systems.

Affinity Labels↗
PubMed1981

Diazepam interaction with antituberculosis drugs.

The influence of antituberculosis drugs on diazepam disposition was assessed in a series of volunteers and patients who received single intravenous doses of diazepam. In study 1, nine healthy subjects received diazepam in the drug-free control state and again during treatment with isoniazid (INH), 180 mg/day. INH did not alter diazepam volume of distribution (Vd) or protein binding, but prolonged mean elimination half-life (t1/2) from 34 to 45 hr (p less than 0.02), and reduced total clearance from 0.54 to 0.40 ml/min/kg (p less than 0.02). In study 2, diazepam disposition in a group of seven tuberculous patients on triple therapy with INH, ethambutol (EMB), and rifampin (RIF) was compared with that in healty drug-free controls matched for age and sex. Diazepam Vd and protein binding were nearly identical between groups, but mean t1/2 among patients (14 hr) was significantly shorter than in controls (58 hr, p less than 0.01) and total clearance correspondingly increased (to 1.50 from 0.37 ml/min/kg, p less than 0.01). Study 3 compared six newly diagnoses tuberculous patients receiving initial therapy with EMB alone with age- and sex-matched controls. Diazepam unbound fraction in patients tended to be higher than in controls, and diazepam Vd and clearance tended to be lower but the differences were not statistically significant. Thus, diazepam clearance is impaired and t1/2 prolonged by administration of INH alone. Markedly increased clearance and shortened t1/2 in triple-therapy patients is probably due to enzyme-inducing effects of RIF. Dosage of diazepam may require adjustment in patients with tuberculosis on chemotherapy.

Adult↗
PubMed1984

Circadian stage-dependent changes in diazepam kinetics.

The effect of dosing time on diazepam kinetics was investigated in 28 healthy men. A 5-mg dose of diazepam was given orally or intravenously on two occasions, in the morning (9:30 A.M.) or in the evening (9:30 P.M.) under the postprandial condition or after a 9-hr fast. After oral doses under postprandial conditions, the mean peak total diazepam concentration in plasma was higher and the time to peak concentration was faster after morning dosing than after evening dosing, but neither mean elimination t1/2 nor AUC between morning and evening dosings differ. Intravenous diazepam did not eliminate the time-dependent changes in diazepam kinetics occurring soon after injection under postprandial conditions, although it diminished the difference. During the 9-hr fast, time-dependent changes in diazepam kinetics were marked, especially after intravenous injection. Diazepam free fraction was lower 0.5 hr after intravenous dosing in the morning, and there was a negative correlation (r = -0.678) between the diazepam free fraction and total diazepam plasma concentration. These results suggest that diurnal variations in rate of drug distribution because of alterations in protein binding as well as in absorption from the gastrointestinal tract contribute to time-dependent changes in diazepam kinetics.

Adult↗
PubMed1984

Diazepam and methadone interactions in methadone maintenance.

Survey study data and high rates of diazepam use/abuse in methadone maintenance suggest that acute administration of diazepam with daily methadone doses may enhance methadone effects. Acute subjective and physiologic effects of single oral doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150%, and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose) were assessed under double-blind conditions. The subjects were five adult male patients on methadone maintenance with histories of diazepam abuse who were receiving 50 to 60 mg methadone a day. Physiologic measures were continuously monitored for 30 min before and for 2 hr after dosing. Pupil diameter and subjective responses were measured 15 min before dosing and 15, 30, 45, 60, 90, and 120 min after dosing. Methadone induced dose-dependent increases in pupil constriction and scores on a subjective opioid effects rating scale, but diazepam had no significant effect on either. The combination of methadone at 150% of the maintenance dose with 40 mg diazepam induced increases in these measures greater than those induced by either drug dose alone. Drug combinations, however, were more frequently identified as being benzodiazepine/barbiturate-like than as methadone-like. Thus although the subjective effects of the drug combination are distinguishable from those of methadone alone, diazepam with methadone in methadone maintenance appears to increase some physiologic and subjective opioid effects that may be related to the relatively great use/abuse of diazepam in this population.

Administration, Oral↗
PubMed1988

The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam.

To determine the effect of fluoxetine on diazepam's pharmacokinetic and psychomotor responses, single oral doses of 10 mg diazepam were administered to six normal subjects on three occasions, either alone or in combination with 60 mg fluoxetine. Diazepam was given alone, after a single dose of fluoxetine, and after eight daily doses of fluoxetine. Psychometric data showed that fluoxetine had no significant effect on the psychomotor responses to diazepam. However, the pharmacokinetic data indicated a change in diazepam disposition after fluoxetine administration. Diazepam AUC was larger, the half-life was longer, and the plasma clearance was lower after fluoxetine administration, suggesting that fluoxetine inhibited the metabolism of diazepam. The reduced formation of an active metabolite, N-desmethyldiazepam, also suggested that fluoxetine inhibited diazepam's metabolism. The clinical implications of this pharmacokinetic drug-drug interaction are minor because psychomotor responses were unaffected and offsetting changes in the kinetics of diazepam and its metabolite occurred. Dosage modification of either fluoxetine or diazepam is unlikely to be necessary.

Adult↗
PubMed1996

Disposition of diazepam in young and elderly subjects after acute and chronic dosing.

1. The pharmacokinetics of diazepam were examined in seven young (20-30 years) and six elderly (60-75 years) males prior to and also after chronic oral dosing of diazepam. 2. Following intravenous administration, the half-life and volume of distribution of 14C-labelled diazepam in the elderly were approximately twofold greater than corresponding estimates in younger subjects (mean +/- s.d., 71.5 +/- 27.6 vs 44.5 +/- 16.5 h and 1.39 +/- 0.32 vs 0.88 +/- 0.30 1 kg-1, respectively). Clearance did not differ between the two groups (0.26 +/- 0.09 vs 0.29 +/- 0.09 ml min-1 kg-1). 3. The accumulation of diazepam and its major metabolite, desmethyldiazepam, were extensive during chronic administration. A radioreceptor assay that measured total benzodiazepine activity, including diazepam and its active metabolites, indicated that the accumulation of 'benzodiazepine equivalents' was similar to the sum of the accumulated diazepam and desmethyldiazepam concentration levels. However, the level of 'benzodiazepine equivalents' on multiple-dosing was about double that of the predicted steady-state 'equivalent' concentration from single-dose studies. This was due to the insensitivity of the radioreceptor assay for desmethyldiazepam following single-dose diazepam administration. 4. There were no age- or dosing-related differences in diazepam clearance (0.37 +/- 0.22 vs 0.32 +/- 0.18 ml min-1 kg-1, young vs elderly, single-dose; 0.37 +/- 0.11 vs 0.27 +/- 0.12 ml min-1 kg-1, young vs elderly, multiple-dose) and no age-related differences in the levels of accumulated 'benzodiazepine equivalents' (243.7 +/- 60.1 vs 288.0 +/- 125.8 ng ml-1, young vs elderly). 5. Thus, changes that occur in diazepam disposition with ageing after acute administration do not appear to be important during chronic dosing. On the other hand, accumulation of diazepam and desmethyldiazepam are considerable and would be expected to be clinically relevant.

Adult↗
PubMed1994

Effects of repeated intravenous administration of diazepam on food intake in rats.

Effects of repeated intravenous (i.v.) administration of diazepam on food intake were investigated in freely moving rats implanted with a chronic i.v. cannula. Diazepam (0.2 and 2 mg/kg) was automatically injected i.v. at 3-h intervals for 3 consecutive days. Food intake was measured twice daily, ie for the light phase (7 00-19 00) and dark phase (19 00-7 00). Food intake during the light phase was increased in a dose-dependent manner following diazepam. Each injection of diazepam provoked hyperphagia, followed by a compensatory hypophagia until the next diazepam injection. Body weight, however, was increased significantly in rats treated with diazepam. When diazepam (2 mg/kg) was automatically injected at 3-h intervals for 10 consecutive days, tolerance did not develop to the hyperphagia and body weight was increased significantly following diazepam injection. After cessation of diazepam injection, both food intake and body weight decreased. These findings suggest that such excessive i.v. treatment with diazepam induces hyperphagia showing no tolerance accompanied by an increase in body weight, thus resulting in a trend toward obesity in rats.

Animals↗
PubMedDate not supplied

The effect of intravenous diazepam on solid phase gastric emptying in normal cats.

Intravenous diazepam has been advocated as an appetite stimulant in anorexic cats. Diazepam has also been used to stimulate the intake of radiographic contrast medium-food mixture to determine the gastric emptying time of a solid meal. Diazepam has been suspected to delay gastric emptying in cats. One study found diazepam combined with valium to have little effect on gastric transit times in cats while diazepam alone accelerates gastric emptying in humans. The purpose of this study was to determine if diazepam influences gastric emptying times in normal cats. The gastric emptying half-time of solid food in normal, non-diazepam treated cats has been previously determined using a scintigraphic technique using 99mTc-sulfur colloid to radiolabel solid dry food. The median gastric emptying half-time was 2.3 hours and the mean meal size was 16.1 grams. Gastric emptying half-times were determined in this study using diazepam as an appetite stimulant. The median gastric emptying half-times of diazepam treatment groups given both a 16.1 gram meal and a large meal were both significantly longer than the normal non-treated group (P < 0.05). Solid phase gastric emptying is therefore significantly delayed when diazepam is used as an appetite stimulant, irrespective of the volume of the meal.

Animals↗
PubMedDate not supplied

Diazepam as a treatment for metronidazole toxicosis in dogs: a retrospective study of 21 cases.

The currently recommended treatment for metronidazole toxicosis is drug discontinuation and supportive therapy. Reported recovery times are 1-2 weeks. The records of 21 dogs with metronidazole toxicosis were retrospectively analyzed to determine whether diazepam improved recovery. The dosage and duration of metronidazole therapy and the response and recovery times of 13 dogs treated with diazepam were compared to those of 8 dogs receiving only supportive care. Response time was defined as the time to resolution of the debilitating clinical signs. Recovery time was the time to resolution of all residual clinical signs. The average dosage and duration of metronidazole administration for the diazepam-treated and untreated groups were 60.3 mg/kg/d for 44.9 days and 65.1 mg/kg/d for 37.25 days. The protocol for diazepam administration consisted of an initial i.v. bolus and then diazepam PO q8h for 3 days. The average dosage of both the i.v. and PO diazepam was 0.43 mg/kg. The average response time for the diazepam-treated dogs was 13.4 hours compared to 4.25 days for the untreated group. Recovery time also was markedly shorter for the diazepam-treated dogs (38.8 hours) compared to the untreated group (11 days). Results of this study showed that dogs with metronidazole toxicosis recover faster when treated with diazepam. Although the mechanism of metronidazole toxicosis or how diazepam exerts its favorable effect is not known, it is likely related to modulation of the gamma-aminobutyric acid (GABA) receptor within the cerebellar and vestibular systems.

Aging↗