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PubMed1986

Serum protein binding of diazepam and propranolol in the feto-maternal unit from early to late pregnancy.

Paired samples of maternal and fetal serum were obtained in 65 pregnancies between 13 and 41 weeks gestation. Concentrations of albumin, alpha 1-acid glycoprotein (alpha 1-AGP) and free fatty acids (FFA) were estimated in all samples and the in-vitro binding of diazepam and propranolol was estimated. The free fraction of diazepam in fetal serum was very high in early gestation and decreased with advancing gestation to reach maternal values around the 30th week. After 35 weeks gestation, values were generally lower in fetal than in maternal serum. Fetal serum binding of diazepam correlated with fetal albumin levels and gestational age. The ratio of the fetal/maternal free diazepam fraction correlated negatively with the fetal/maternal serum albumin concentration ratio. The maternal/fetal free diazepam fraction ratio correlated positively with gestational age. The free fraction of propranolol in fetal serum was higher than in maternal serum in early pregnancy and decreased with advancing gestation but always remained higher than the maternal values. The fetal/maternal free propranolol fraction ratio was negatively correlated with the fetal/maternal alpha 1-AGP serum concentration ratio. The maternal/fetal free propranolol fraction ratio was positively correlated with gestational age. Serum protein binding of propranolol was correlated with serum albumin concentrations in fetal samples but not in maternal samples. Serum FFA concentrations were not correlated with serum protein binding except for maternal serum binding of diazepam. For toxicological reasons it is advisable to monitor maternal blood for free concentrations of drugs that exhibit concentration-dependent protein binding or which can be displaced from binding sites by other drugs or endogenous compounds such as FFA.

Adolescent↗
PubMed1979

Negative dromotropic effect of diazepam on the AV node of dog heart in situ.

Effect of diazepam on the AV nodal conductivity was studied using a direct perfusion technique of the canine AV node artery in situ. As compared to acetylcholine which induced a rapid onset of third degree AV block with prompt recovery, diazepam injected into the AV node artery in doses from 300 micrograms to 3 mg elicited first to third degree AV blocks of longer duration following gradual prolongation of PR interval. The response was not affected by bilateral vagotomy and sympathectomy. Pretreatment of the AV node with hexamethonium or atropine also failed to modify the diazepam-induced AV blocks. Thus, diazepam seemed to suppress conductivity of the AV node by a direct action. The AV nodal tachycardia induced by infusion of norepinephrine was readily antagonized by a single injection of diazepam, but norepinephrine failed to reverse the AV block induced by diazepam infusion.

Acetylcholine↗
PubMed1979

[Effects of diazepam and baclofen on the anemic decerebrate rigidity in rats (author's transl)].

Effects of diazepam and baclofen on the anemic decerebrate rigidity in rats were studied by using the drugs that modify GABAergic mechanisms of deplete catecholamine. Rigid forelimb tension in anemic decerebrate rats took the form of tonically sustained tension (tonic component), while the phasic tension (phasic component) was induced by mechanical stimulation of hindlimbs. Diazepam exerted a marked dose-dependent inhibition of the phasic component, whereas baclofen produced a similar effect on both tonic and phasic components. In rats pretreated with semicarbazide, the inhibitory effect of diazepam on phasic component was reduced, and the effect of semicarbazide was antagonized by pyridoxine. The effect of diazepam was slightly enhanced by pretreatment with aminooxyacetic acid, and antagonized by picrotoxin. In contrast to diazepam, the depressant actions of baclofen on both components were not affected by semicarbazide, aminooxyacetic acid or picrotoxin. Catecholamine depletion produced by alpha-methyltyrosine or disulfiram significantly reduced the effect of baclofen on the phasic component. It thus appears that GABA is involved in the effect of diazepam on the phasic component, and noradrenaline is involved in the same effect of baclofen in anemic decerebrate rats.

Aminooxyacetic Acid↗
PubMed1980

Anxiolytic efficacy and safety of ketazolam compared with diazepam and placebo.

A 28-day, double-blind study involving 56 outpatients ws initiated to compare the anxiolytic efficacy and safety of ketazolam once a day at bedtime (HS) with diazepam given three times a day (TID) and placebo HS or TID. Ketazolam HS was at least equivalent, and in some respects superior, to diazepam TID with fewer, less severe side effects. The superiority of ketazolam over placebo was demonstrated on all five instruments used to evaluate efficacy, three rated by the physician and two by the patient. The efficacy of ketazolam was significant at all three follow-up evaluations, whereas significant results for diazepam were achieved mainly at weeks 1 and 2, with little seen at week f. Fewer side effects were reported with ketazolam than with diazepam and were mild in 84% of cases. One-third of the side effects reportd in the diazepam group were moderate or severe. The optimum daily dose was 54.5 mg ketazolam or 24.7 mg diazepam.

Adolescent↗
PubMed1983

Psychomotor effects of diazepam in anxious patients and healthy volunteers.

Psychomotor effects of diazepam, 5 and 10 mg, were compared to placebo in 30 highly anxious, nonpsychotic outpatients and age and sex-matched healthy volunteers. Diazepam did not reduce anxiety according to psychiatrists' ratings, but 10 mg of diazepam three times a day reduced the scores of the self-rated visual analogue scale for anxiety compared to placebo. Diazepam, 5 mg, was devoid of adverse psychomotor effects, but diazepam, 10 mg, impaired tracking and divided attention task performance in patients and volunteers alike. Plasma, erythrocyte, and saliva diazepam and N-desmethyldiazepam concentrations did not correlate with the impairment of psychomotor skills over time.

Adult↗
PubMed1981

Long-term use of diazepam.

Plasma concentrations of diazepam and its major active metabolite nordiazepam were measured in 108 neurosurgical patients taking diazepam in doses of 5 to 40 mg/day for periods from one month to 16 years. Diazepam was used for relief of pain or muscle spasm, or anxiety and sleeplessness associated with these two symptoms, and was considered to be beneficial by 83% of the patients, although use of other drugs confounded this evaluation. Concentrations of total diazepam-nordiazepam ranged from 0 to 2,584 ng/mL, with nordiazepam being the predominant metabolite. "Low" concentrations (less than 250 ng/mL) were found in 35 of the 108 patients, with 19 having concentrations lower than 100 ng/mL. "High" concentrations (greater than 900 ng/mL) were found in 20 patients and did not occur more frequently than in other studies of long-term diazepam ingestion. Even with long-term use, diazepam seemed to retain its efficacy and did not lead to any clear-cut abuse.

Adult↗
PubMed1982

Effects of chemicals on delayed matching behavior in pigeons. II: tolerance to the effects of diazepam and cross tolerance to phencyclidine.

Pigeons were trained under a 2-sec matching to sample schedule. Diazepam, phencyclidine and pentobarbital all decreased matching accuracy. Chronic administration of diazepam after the session produced no effect on matching accuracy on the next day; however, two weeks of postsession diazepam administration produced tolerance to the effects of presession diazepam administration and cross tolerance to phencyclidine, but not to pentobarbital. After 6 weeks without chronic diazepam administration, both the tolerance to the effects of diazepam on matching accuracy and the cross tolerance to phencyclidine had disappeared.

Animals↗
PubMed1981

Withdrawal and pseudowithdrawal from diazepam therapy.

We present two cases from a double-blind placebo-controlled study of diazepam in treatment of anxiety that illustrate the importance of attitudes of patients and physicians towards use of diazepam. Patient 1 exhibited symptoms of nausea, depression and increased anxiety, which both he and the research psychiatrist interpreted as a withdrawal reaction. Examination of the treatment code, however, revealed that the patient had been kept on the same dose of diazepam throughout this period and that he had maintained therapeutic plasma diazepam levels. This case illustrated a "pseudowithdrawal reaction" in a patient being maintained on active drug treatment. Patient 2 benefited remarkably from maintenance diazepam therapy and had manifested considerable anxiety during double-blind placebo substitution but his private physician expressed great reluctance to continue this treatment regimen because he had been influenced by unfavorable publicity. Further information on maintenance diazepam therapy and problems with withdrawal must be obtained under carefully controlled conditions.

Adult↗
PubMed1981

Diazepam dosage and timing in ketamine combination anaesthesia. A double-blind study.

A form of combination anaesthesia using ketamine, diazepam, alcuronium and nitrous oxide was used in 41 patients over 65 years requiring abdominal surgery. The patients were premedicated with droperidol 2.5-7.5 mg im. At induction the patients received diazepam 5 mg. ketamine 2 mg/kg and alcuronium 0.2 mg/kg. Anaesthesia was maintained with a continuous, steady injection of ketamine 2.5 mg/kg/h and nitrous oxide-oxygen with controlled ventilation. Four minutes before incision the patients received 1 ml of coded solution and at the end of anaesthesia the same solution, which contained either 5 mg/ml diazepam or its solvent only. There were no statistically significant differences between the two groups, i.e. patients receiving either 15 or 5 mg of diazepam. The incidence of bad dreams was 5 per cent, i.e. one patient in each group. Only one patient vomited and one had pronounced nausea in group D5. According to the anaesthesiologist's, the anaesthesia nurse's and the patient's subjective evaluations this type of combination anaesthesia was found to be highly acceptable. Despite there being no statistically significant differences between the patients who received 5 + 5 + 5 mg of diazepam compared to those receiving 5 + 0 + 0 mg, the figures in results per se incline in favour of the use of 5 + 5 + 5 of diazepam.

Aged↗
PubMed1981

[Effect of diazepam on cardio-vascular and psychotomimetic action of ketamine administered as continuous intravenous drip. Double-blind study (author's transl)].

Sixty-four women undergoing non-abdominal operations were anaesthetized with ketamine administered as a continuous intravenous drip combined or not with diazepam. This double-blind, randomised study assessed the effects of diazepam on the dosage, the cardio-vascular stimulation, and the psychotomimetic side-effects of ketamine. At the induction, ketamine was given in a dose of 2 mg/kg in combination with diazepam 10 mg or placebo i.v. followed by a continuous infusion of ketamine at variable rate. The amounts of ketamine necessary for anaesthesia was significantly reduced by diazepam, from 4.51 mg/kg to 3.55 mg/kg (p less than 0.001). The sympathomimetic effect of ketamine was significantly decreased by diazepam, as the increase in pulse rate as well as in blood pressure was less important (p less than 0.05). The frequency of hallucinations dropped from 30.0 p. cent to 2.9 p. cent with diazepam, while the total frequency of psychotomimetic side-effects fell from 36.6 p. cent to 11.8 p. cent (p less than 0.05). Although the frequency of psychotomimetic side-effects is still high with this method, it may be recommended to use a continuous drip of ketamine administration for anaesthesia of hypovolaemic and other poor risk patients.

Adult↗
PubMedDate not supplied

[Etiologic study of the GABAergic mechanisms of diazepam tolerance].

Etiologic analysis used in experiments on isolated mice has shown that each biologically important category of intraspecies behavior (aggression, communicability, etc) is characterized by its own time course of diazepam tolerance. Participation of the GABAergic mechanisms in acute and chronic effects of diazepam was demonstrated to vary. Acute effect of diazepam was dominated by the sedative component whose action was reversed by picrotoxin and bicuculline that activated motor rather than zoosocial activities. In the course of diazepam tolerance induction, picrotoxin and bicuculline counteracted antiaggressive action of diazepam and diazepam-induced activation of intraspecies communicability. However, they did not fully inhibit the communicability.

Animals↗
PubMed1981

Long-term treatment with diazepam. Investigation of consumption habits and the interaction between psychotherapy and psychopharmacotherapy: a prospective study.

In a prospective study over 6 months involving 54 psychiatric outpatients with neurotic disorders, the habits of diazepam or placebo intake and the attitudes towards psychotherapy and the medication were studied. The patients, divided into two groups, received in a double-blind setting either diazepam or placebo. They were also seen for psychotherapy every 14 days. The patients were advised to use the medication according to their personal needs but not to take more than 6 tablets of 6 mg diazepam (or placebo) daily. All patients showed controlled use of the drug. No dependency was observed. The patients stopped taking the medication gradually in each group, but faster in the placebo group. 18% of the placebo group and 52% of the diazepam group were 'high' consumers (more than 200 tablets within a period of at least 20 weeks). The intake of the drug was mainly dictated by the symptoms. A second important factor modifying the intake habits was the fear of possible adverse effects of the medication. At the end of the treatment period the attitude towards psychotherapy was more favorable than that towards psychopharmacotherapy irrespective of the drug taken. Long-term intake of diazepam did not lead to a decrease in the motivation of working through the existing problems. In contrast, the diazepam group felt less than the placebo group that medication could be a long-term solution for personal or social problems.

Adult↗
PubMed1994

The interaction of diazepam with vecuronium: a clinical study.

BACKGROUND: Diazepam, known to possess myorelaxation property, has been widely used clinically to control muscular rigidity and spasticity. The interactions of diazepam with neuromuscular blocking agents have been extensively studied, yet the results reported are somewhat controversial and inconclusive. METHODS: The interaction of diazepam with one of the neuromuscular blocking agents, vecuronium, was studied in 20 ASA I-II patients undergoing elective surgery. They were randomly assigned to two groups with ten in each group. Anesthesia was induced with fentanyl, thiopental and vecuronium and maintained with 1% halothane and 70% N2O in O2. The experimental group received diazepam (0.2 mg/kg) 3 minutes prior to vecuronium (0.1 mg/kg) during induction while the control group received vecuronium (0.1 mg/kg) straight without diazepam. Control records of the integrated electromyography showed the response to train-of-four supramaximal stimulation by a Datex Relaxograph during induction. In no time when the first twitch (T1) recovered to 25% of the control, it was topped up again with another intraoperative dose of vecuronium (0.025 mg/kg). From the derived data, the following parameters were calculated and analysed: (1) onset time T10 (the time from the end of injection of vecuronium during induction to depression of T1 to 10% of control twitch height); (2) duration time T25 (the time from administering vecuronium during induction to the time when T1 recovered to 25% of the original twitch height); (3) topup time T25-25 (the time from administering the top dose of vecuronium to the time when T1 returned to 25% of control twitch height again) and (4) recovery time T25-50 (the time of recovery of T1 from 25% to 50% of the control twitch height at the end of the operation). RESULTS: Significant differences between both groups were found in T10 (221.8 +/- 62.2 vs 135.4 +/- 23.3 sec, p < 0.01) and T25 (41.9 +/- 10.2 vs 50.6 +/- 9.4 min, p < 0.05). The results of T25-25 and T25-50 did not differ much (26.6 +/- 6.9 vs 29.3 +/- 4.4 min, p > 0.05 and 15.0 +/- 8.9 vs 16.9 +/- 8.7 min, p > 0.05 respectively). CONCLUSIONS: The administration of diazepam (0.2 mg/kg) three minutes prior to vecuronium (0.1 mg/kg) during induction may hasten the onset of vecuronium and prolong its duration of action.

Aged↗
PubMed1993

[Propofol versus diazepam. Sedation in ophthalmologic surgery under local anesthesia].

This prospective study was designed to evaluate the sedative effect of two different anaesthetic drugs in patients undergoing ophthalmic surgery. Propofol is an intravenous hypnotic agent with a short half-life of about 30 min. A constant high oxygen saturation in continuous pulse oximetry was achieved in previous studies using propofol for sedation. Furthermore, an IOP-lowering effect was proved. Propofol was compared to diazepam, a well-established sedative, which has been used for many years for sedation of patients in local anaesthesia. METHOD. One hundred patients of comparable anaesthesiologic risk (ASA classes 2-4) undergoing identical surgical procedures received either propofol (n = 50), or diazepam (n = 50). Propofol was infused at a rate of 0.8-3.0 mg/kg/h, while diazepam was given as a slow intravenous bolus of 5 mg before surgery. All patients were monitored by continuous pulse oximetry. RESULTS. Oxygen saturation of patients receiving propofol was never less than 96%. In contrast, oxygen saturation of patients sedated by diazepam dropped to 85%, especially for the first 5 min following administration, before improving to 95% during the next 10 min. None of the patients who received propofol showed signs of motor unrest, a great handicap in ophthalmic surgery, while four patients who received diazepam were restless enough to hamper the procedure. None of the patients who received propofol developed respiratory depression. In contrast, marked respiratory depression, motor agitation, and postoperative fatigue slowing mobilization were common in patients who received diazepam.

Aged↗
PubMed1995

Higher environmental temperature: effect of multiple exposures on long-term diazepam-induced changes in brain regional GABA.

The measurement of steady state level and accumulation rate of GABA and the activities of GAD and GABA-T in brain regions of adult male albino rats treated with diazepam (diazepam, 5 mg/kg/day, i.p.) and/or exposed (2 h/day) to higher environmental temperatures (higher environmental temperature, 40 degrees C) under long-term conditions (7-30 consecutive days) shows that long-term treatment with diazepam (5 mg/kg/day, i.p., for 15-30 consecutive days) reduced the GABAergic activity in the hypothalamus, corpus striatum (CS) and cerebellum (CM) without any alteration in the cerebrocortical region (CC). Multiple exposures to higher environmental temperatures for 7 consecutive days, on the other hand, enhanced GABAergic activity in hypothalamus, corpus striatum and cerebrocortical region of the rat. This higher environmental temperature-induced increase in GABAergic activity was further enhanced in the hypothalamus, but it was attenuated in the corpus striatum and became normalized in the cerebrocortical region upon the prolongation of exposure (15-30 consecutive days) to higher environmental temperature. The long-term diazepam-induced inhibition in GABAergic activity in hypothalamus and corpus striatum (but not in the cerebellum) disappeared and was finally activated following exposures (2 h/day) to higher environmental temperatures (40 degrees C) along with diazepam-treatment (5 mg/kg day, i.p.) for 7, 15 and 30 consecutive days. In the cerebellum, multiple exposures to higher environmental temperature did not significantly alter the long-term diazepam-induced inhibition of GABAergic activity or GABAergic activity in the normal rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

[Effect of diazepam on myocardial contraction and on the response to dopamine. Study in isolated rat hearts].

PURPOSE: The myocardial contractility variations and the cardiac rate were studied in isolated hearts of rats with injection of diazepam, dopamine and the association of both. METHODS: In all animals, after anesthesia, the hearts were removed and perfused with Krebs-Henseleit solution enriched by 95% O2 under a constant pressure of 90 cm H2O, until complete stabilization, for control value recordings. The following groups were studied: I) ten hearts: after stabilization the control values were recorded and dopamine (3 micrograms/ml) injected; IIA and IIB): also ten hearts were used and submitted to 50 micrograms and 100 micrograms of diazepam injections respectively. III) ten hearts studied with 50 micrograms of diazepam and 3 micrograms/ml of dopamine injection in a sequential form. RESULTS: Myocardial contractility arose in group I, from 37 g.seg-1 (control mean-value) to 70 and 53 g.seg-1 (1st and 3rd min); p < 0.001. In the groups IIA and IIB the dT/dt fell considerably in relation to the control: 35 g.seg-1 to 24 and 30 g.seg-1 (1st and 3rd min)--group IIA; p < 0.001 -32 g.seg-1 to 22 and 25 g.seg-1 (1st and 3rd min)--group IIB; p < 0.001. In the group III, a partial inhibition of the inotropic effects of dopamine by the injection of diazepam was observed. Heart rate follows fully the dT/dt variations in the groups IIA, IIB and III. CONCLUSION: Diazepam presents inotropic and chronotropic negative effects with the 50 micrograms as well as with 100 micrograms injection and the chronotropic and inotropic effect of dopamine (3 micrograms) injection was partially inhibited by the previous injection (50 micrograms) of diazepam.

Animals↗
PubMed1996

Effects of (-)-baclofen, clonazepam, and diazepam on tone exposure-induced hyperexcitability of the inferior colliculus in the rat: possible therapeutic implications for pharmacological management of tinnitus and hyperacusis.

Recent investigations in the authors' laboratory have shown that acute tone exposure (4 kHz continuous tone, 104 dB sound pressure level (SPL), 30-min duration) induces increases in the amplitude of click-evoked potentials in the inferior colliculus (IC). These increases have been attributed to a decrease in GABAA-mediated inhibition on IC neurons. In the present study, we examined the effects of three compounds (diazepam, clonazepam, and (-)-baclofen) that are known to enhance GABAergic inhibition on these tone exposure-induced increases and on changes in temporal integration in the IC. (-)-Baclofen was the only one of the three compounds tested that reversed in a dose-dependent manner the effects of tone exposure on both the amplitude of the click-evoked potentials recorded from the IC and on measures of the changes in temporal integration based on these potentials. Diazepam and clonazepam exhibited remarkably different effects on the click-evoked potentials recorded from the surface of the IC. Diazepam caused a dose-dependent decrease in one of the components of the IC potentials that reflects postsynaptic activity in the IC, whereas clonazepam caused a dose-dependent decrease in a peak that reflects input to the IC from the superior olivary complex (SOC). At dosages up to 40 mg/kg, neither diazepam nor clonazepam reversed the changes in temporal integration in the IC that were induced by the tone exposure; diazepam caused a small, but statistically significant, enhancement of the effects of tone exposure on this function. The results of this study show that (-)-baclofen is a potent modulator of both the excitability of neurons in the ascending auditory pathway and the processing of auditory information by IC neurons. The finding of the present study that two benzodiazepines (clonazepam and diazepam) have remarkably different effects on evoked potentials, which reflects both input to the IC and postsynaptic events in the IC neurons, suggests heterogenicity of the GABAA receptor from one structure to another in the ascending auditory pathway. We suggest that (-)-baclofen may be clinically useful in treating disorders of the auditory system that are caused by plasticity in the ascending auditory pathway.

Acoustic Stimulation↗
PubMedDate not supplied

Locomotor activity pattern induced by diazepam in control and caffeine-treated mice.

The effect of diazepam on locomotor activity was tested by measuring the number of crossings between two compartments of a toggle-floor box, in control mice (water drinking) and in mice receiving caffeine solution (0.5 g/I) instead of drinking water. In control mice, diazepam did not produce any significant change in total activity measured on the whole 60-min test, but animals showed phases of increased activity broken by periods of immobility. After chronic ingestion (18 days) of caffeine, doses of 0.5, 1 and 2 mg/kg ip diazepam significantly increased total locomotor activity. Caffeine slightly reduced diazepam-induced immobility and increased the frequency of crossings in active periods. Taken together, these two effects may explain the significant increase in total activity induced by diazepam in caffeine-treated mice. Mixed stimulatory-depressant action was also produced by 3 mg/kg diazepam, a dose that slightly decreased the total activity.

Animals↗