Combination Of Diazepam Research Articles

Additive Negative Inotropic Effect of a Combination of Diazepam and Fentanyl

Hearts were excised from 30 male Sprague-Dawley rats and perfused in a modified Langendorff system to examine the interactions of fentanyl and diazepam on myocardial contractility as measured by left ventricular dP/dtmax. Various concentrations of fentanyl and diazepam were added to the nonrecirculating 37 degrees C perfusate to determine ED25 and ED50 for depression of dP/dtmax. Combinations of fentanyl and diazepam at a fixed negative inotropic potency ratio of 1:1 were used to determine the ED25 and ED50 of this combination. Isobolographic analyses performed at ED25 and ED50 revealed that the negative inotropic interaction of fentanyl and diazepam is purely additive. It is unlikely that a supraadditive negative inotropic effect can explain the supraadditive hemodynamic depression reported in humans when diazepam and fentanyl are combined; perhaps systemic vascular effects of this drug combination account for the clinical drug interactions.

Evaluation by thoracic impedance cardiography of diazepam, placebo, and two drug combinations for intravenous sedation of dental outpatients

The cardiovascular and respiratory effects of three common intravenous premedicants were examined noninvasively in a population of 20 dental outpatients scheduled for surgical removal of third-molars. Two third molars from one side of the mouth were removed at each appointment. Group 1 received a diazepam titration (mean dose = 25.6 mgs) at one appointment and placebo at the other appointment. Group 2 received a combination of diazepam (12.5 mg), fentanyl (0.1 mg), and methohexital (mean dose = 18.0 mg) at one appointment and the combination of diazepam (15.0 mg) and methohexital (mean dose = 27.0 mg) at the other appointment. Noninvasive measurement of cardiac output revealed little change during intravenous drug administration, but a significant increase was seen in all groups following local anesthesia and during surgery. Heart rate was elevated and stroke volume decreased during administration of the two-drug combinations. Oxygen saturation was greatly decreased following the combination of diazepam, fentanyl, and methohexital. These findings indicate that the combination of diazepam, fentanyl, and methohexital results in decreased oxygen saturation, a transient decrease in stroke volume, and an elevated heart rate when used as an intravenous premedicant for dental outpatients.

RO 15–1788 ANTAGONIZES THE EFFECTS OF DIAZEPAM IN MAN WITHOUT AFFECTING ITS BIOAVAILABILITY

In a double-blind, placebo-controlled three-way cross over study, the efficacy of Ro 15-1788 200 mg, a new benzodiazepine antagonist, in blocking the amnesic, cognitive, psychomotor and subjective effects of diazepam 20 mg, was investigated in a group of six healthy male volunteers. The amnesic effects of diazepam were markedly attenuated by the combined administration of Ro 15-1788. The psychomotor and subjective effects of diazepam by mouth were most pronounced 2.5 h after administration. Concurrent oral administration of Ro 15-1788 completely prevented these effects at 2.5 h. Plasma diazepam concentrations observed after administration of the combination of diazepam and the antagonist did not differ from those observed following diazepam alone.

Interaction of the discriminative stimulus properties of diazepam and ethanol in pigeons

One group of pigeons (n=5) was trained to discriminate between the effects induced by 5.6 mg/kg of diazepam (DZP) and the vehicle whereas other pigeons (n=5) had to discriminate between 3.0 g/kg of ethanol (ETOH) and the vehicle, administered intragastrically (IG) 10 and 40 min prior to the training sessions respectively. Once trained, the pigeons were tested with either diazepam or ethanol alone and in combination. The birds trained to discriminate between DZP and the vehicle mostly performed non-drug associated responses when tested with ETOH (0.56 to 3.0 g/kg). Tests with other doses of DZP (0.3 to 3.0 mg/kg) in the diazepam-trained birds resulted in an ED 50 value of 1.4 mg/kg. The birds trained to discriminate between ETOH and the vehicle generalized DZP to ETOH, the ED 50 value for diazepam being 3.0 mg/kg. Tests with other doses of ETOH (0.56 to 2.0 g/kg) in this latter group resulted in an ED 50 value of 1.3 g/kg. Tests with combinations of DZP and ETOH produced a shift of the dose-response curves to the left indicating drug additivity. The discrimination of 5.6 mg/kg of IG administered DZP but not that of ETOH (3.0 g/kg) was attenuated by injections of the analeptic bemegride (ED 50=5.5mg/kg), thus suggesting a difference in the cueing processes of the two drugs. When tested singly, bemegride induced non-drug responding or complete suppression of responding in the birds at the doses of 3.0 and 10.0 mg/kg respectively. In conclusion, the discriminable effects of DZP and ETOH are additive or even supra-additive, but the stimulus properties of the two drugs are not identical.

INFLUENCE OF PREMEDICATION ON PLASMA ACTH AND CORTISOL CONCENTRATIONS IN CHILDREN DURING ADENOIDECTOMY

The endocrine response to stress, as reflected by the plasma concentrations of ACTH and cortisol, was investigated in 14 children receiving two different premedications during halothane anaesthesia for adenoidectomy. Seven children (group A) were premedicated with diazepam 5 mg rectally and atropine 0.3-0.4 mg sublingually and seven (group B) received a rectal combination of diazepam 0.5 mg kg-1, morphine 0.15 mg kg-1 and hyoscine 0.01 mg kg-1. Before and after surgery plasma concentrations of ACTH and cortisol were lower in group B than in group A. In group A mean values for ACTH increased from 40.7 ng line-1 before adenoidectomy to 352.9 ng litre-1 (P less than 0.001) after adenoidectomy. The corresponding increase in group B was from 12.1 ng litre-1 to 82.1 ng litre-1 (P less than 0.01). In group A mean cortisol concentrations increased from 235.7 nmol litre-1 to 655.7 nmol litre-1 after adenoidectomy (P less than 0.01) and in group B from 121.4 nmol litre-1 to 427.9 nmol litre-1 (P less than 0.01). End-tidal carbon dioxide tension was approximately the same in both groups. It was concluded that the combination of diazepam, morphine and hyoscine decreased the endocrine response to stress.

Diazepam-cimetidine drug interaction: a clinically significant effect.

Cimetidine has been shown to inhibit the liver microsomal metabolism of the benzodiazepines diazepam and chlordiazepoxide, resulting in an increase in half-life and decrease in the clearance of these two drugs. Patients receiving the combination of diazepam and cimetidine have been noted to be more sedated than when given an equal dose of diazepam alone. Many benzodiazepines undergo N-dealkylation and hydroxylation via the cytochrome P450 oxidase system. Cimetidine is thought to bind to cytochrome P450 oxidase and to interfere with many drugs using this path way. Oxazepam and lorazepam are two benzodiazepines not oxidatively metabolized by cytochrome P450, but are glucuronidated by glucuronyl transferase and are, therefore, not subject to metabolic inhibition by cimetidine. Thus, when clinically indicated, oxazepam and lorazepam may be the benzodiazepines of choice to use in combination with cimetidine to eliminate the clinically significant drug interaction seen with diazepam and chlordiazepoxide.

Comparison of Anesthesia with Diazepam and Ketamine Vs. Morphine in Patients undergoing Heart-Valve Replacement

Because of its analgesic and amnesic effects, ketamine has potential advantages as a primary agent for patients undergoing open-heart surgery. However, the undesirable positive inotropic and chronotropic effects associated with ketamine have deterred its use. Diazepam pretreatment appears to block these unwanted effects. Sixteen randomly selected patients were given a combination of diazepam, 0.4 mg/kg, followed by ketamine, 2 mg/kg, and nitrous oxide, 50 per cent. The authors compared the circulatory responses to induction, intubation, and operation with those obtained in a matched group of patients who received morphine, 3 mg/kg, and nitrous oxide, 50 per cent. All patients underwent mitral- or aortic-valve replacement. Circulatory responses were not significantly different between the two groups. In both groups, heart rate, mean arterial blood pressure, and rate-pressure product increased significantly with intubation of the trachea, incision of the skin, and sternotomy. The incidences of hypertension, hypotension, and arrhythmias, and the need for inotropic drugs were not significantly different between the two groups. No intraoperative awareness occurred in either group. It is concluded that diazepam-ketamine anesthesia is a satisfactory alternative to morphine anesthesia for patients undergoing heartvalve replacement.

Intravenous diazepam and pentazocine for peroral endoscopies

The combination of diazepam and pentazocine given intravenously was used in 60 patients for laryngoscopy and bronchoscopy. Xylocaine 4% was sprayed over the vocal cords for local anaesthesia. There was cardiovascular stability and initial depression of respiration. Undesirable side-effects were negligible. The advantages of the technique are discussed.

Acute and Subacute Effects of Diazepam on Psychomotor Skills: Interaction with Alcohol

Effects of diazepam and alcohol on psychomotor skills were measured in two trials. In the first one, 200 healthy students volunteered for a double-blind single-dose study. Three doses of diazepam (5, 10 and 20 mg) and alcohol (0.5, 0.8 and 1.2 g/kg) were used alone and combined to construct dose-response graphs. All doses of alcohol impaired divided attention while co-ordinative skills were impaired by the 1.2 g/kg dose. Diazepam alone did not impair reactive or co-ordinative skills whereas the combinations of diazepam and alcohol did so. To further elucidate the subactue effects, a double-blind randomized study was conducted administering 2 and 10 mg of diazepam t.i.d. for two weeks to 18 healthy volunteers. The psychomotor tests were performed on the 7th and 14th days of drug administration, and 0.5 g/kg of alcohol was given on either day. Diazepam 2 mg, alone or with alcohol, did not differ from placebo. 10 mg of diazepam slightly increased reaction times but not reaction mistakes, and impaired both co-ordination and attention. Alcohol did not enhance diazepam effects. We suggest that a development of tolerance to diazepam may compensate the deleterious interaction of the agents found in acute studies.

Comparison of Anesthesia with Diazepam and Ketamine vs. Morphine in Patients Undergoing Heart-valve Replacement

Because of its analgesic and amnesic effects, ketamine has potential advantages as a primary agent for patients undergoing open-heart surgery. However, the undesirable positive inotropic and chronotropic effects associated with ketamine have deterred its use. Diazepam pretreatment appears to block these unwanted effects. Sixteen randomly selected patients were given a combination of diazepam, 0.4 mg/kg, followed by ketamine, 2 mg/kg, and nitrous oxide, 50%. The authors compared the circulatory responses to induction, intubation, and operation with those obtained in a matched group of patients who received morphine, 3 mg/kg, and nitrous oxide, 50%. All patients underwent mitral- or aortic-valve replacement. Circulatory responses were not significantly different between the two groups. In both groups, heart rate, mean arterial blood pressure, and rate-pressure product increased significantly with intubation of the trachea, incision of the skin, and sternotomy. The incidences of hypertension, hypotension, and arrhythmias, and the need for inotropic drugs were not significantly different between the two groups. No intraoperative awareness occurred in either group. It is concluded that diazepam-ketamine anesthesia is a satisfactory alternative to morphine anesthesia for patient undergoing heart-valve replacement.

Ketamine-Diazepam Anaesthesia for Abdominal Surgery

During a twenty-one month period, over 1000 patients who underwent various types of intra-abdominal operations were anaesthetized with a combination of diazepam and ketamine using a continuous Micro-Mini drip administration technique. The results obtained from 1000 cases were eminently satisfactory. This paper also reviews all the previous literature on ketamine anaesthesia related to abdominal surgery. All the undesirable adverse side effects associated with ketamine anaesthesia in adult patients have been almost completely eliminated using this technique. Overall, the excellent results clearly indicate that ketamine has a definite place in anaesthesia for intra-abdominal operations.

KETAMINE AND DIAZEPAM AS ANAESTHESIA FOR FORCEPS DELIVERY A COMPARATIVE STUDY

In a clinically controlled trial in forceps delivery, a comparison was made between the general anaesthesia induced by ketamine and that by a combination of diazepam and N2O. Local anaesthesia was added in the diazepam group for episiotomy and suturation. The indication for operative delivery was in all cases a prolonged second stage of labour. In the katamine group, awareness was noted in four cases out of 13, even if the analgesic effect was found to be good. Four patients showed marked, short-lasting elevation of blood pressure and seven had unpleasant dreams. All thirteen mothers in the diazepam group found the anesthesia effective and the recovery pleasant. The blood pressure was stable. One mother in each group required ventilation with oxygen due to respiratory depression of short duration. Three of the children in the ketamine group and two in the diazepam group had subnormal Apgar score with slight acidosis. This was probably not attributable to the anaesthesia.

Ketamine and Diazepam as Anaesthesia for Forceps Delivery. A Comparative Study

In a clinically controlled trial in forceps delivery, a comparison was made between the general anaesthesia induced by ketamine and that by a combination of diazepam and N2O. Local anaesthesia was added in the diazepam group for episiotomy and suturation. The indication for operative delivery was in all cases a prolonged second stage of labour. In the katamine group, awareness was noted in four cases out of 13, even if the analgesic effect was found to be good. Four patients showed marked, short-lasting elevation of blood pressure and seven had unpleasant dreams. All thirteen mothers in the diazepam group found the anesthesia effective and the recovery pleasant. The blood pressure was stable. One mother in each group required ventilation with oxygen due to respiratory depression of short duration. Three of the children in the ketamine group and two in the diazepam group had subnormal Apgar score with slight acidosis. This was probably not attributable to the anaesthesia.

Ethanol and oral diazepam absorption.

Despite widespread use and abuse of ethanol and diazepam in combination, little is known about the effects of ethanol on diazepam absorption. We administered diazepam (0.07 mg per kilogram of body weight) with water and with 30 ml of 50 per cent ethanol to seven normal volunteers. Plasma diazepam levels were significantly higher at 60 minutes (P less than 0.05), 90 minutes (P less than 0.01), 120 minutes (P less than 0.01), and 240 minutes (P less than 0.01) when diazepam was administered with ethanol than with water alone. Since maximum mean plasma diazepam levels after combined ingestion with ethanol were nearly twice as high than after diazepam and water (373 ng per milliliter versus 197 ng per mililiter at 60 minutes) we conclude that ethanol enhanced diazepam absorption.

Electrophysiological studies on the "stiff-man" syndrome.

In addition to anamnestic and clinical data electrophysiological and pharmacokinetic investigations may be necessary for the diagnosis of stiff man syndrome. Continuous activity of motor units with superimposed bursts during muscular spasms was found by electromyography in the two patients reported. Rigidity and continuous activity disappears during sleep, after i.v. application of Tubocurarine and Diazepam, during Thiopenal anesthesia and after neural block with Procaine. Dipropylacetate and Baclofen improved the condition but did not lead to complete relaxation. Biperidenlactat and Magnesiumlaevulinat have only a temporary effect on rigidity. Neostigmine, Phenytoine, Glycine, Dopa and 5-Hydroxy-Tryptophan had no effect. Passive shortening or stretching of the m. biceps brachii as well as touching the skin increased motor activity which spread to other segments and to the contralateral side. The H/M ratio was increased but the silent period was normal. A combination of Diazepam and Dipropylacetate or Clonazepam was therapeutically effective in the cases reported. A central genesis, of the pathogenetic mechanisms discussed, is the most probable in our cases.

Cerebral blood flow and metabolism under "diazanalgesia" (author's transl)

"Diazanalgesia" employs the combination diazepam + fentanyl. Its effects were studied on regional cerebral blood flow and oxygen metabolism in 8 normal subjects, who were examined angiographically. During diazanalgesia, cortical blood flow falls by 56 p. 100. The mean hemispheric flow calculated over 10 min falls by 34 p. 100. Cerebral O2 consumption (VcO2) falls by 34 p. 100. However, large individual variations are found which suggests that the fall in blood flow is not due solely to the decrease in O2 metabolism. The decreases in flow are not proportional to the amount fentanyl, and there is no direct relation between falls in VcO2 and amount of fentanyl. Cerebral vaso-reactivity to CO2 persists but is reduced under diazanalgesia compared with the waking state.

A COMPARISON OF MEMORY UNDER THREE METHODS OF ANAESTHESIA WITH NITROUS OXIDE AND CURARE

Sixty-three volunteer patients participated in an investigation designed to evaluate memory of the surgical experience with three different methods of balanced nitrous oxide-curare anaesthesia. Two of the methods (Liverpool and Roosevelt protocols) used thiopentone for induction but did not utilize any neuroleptic drug, while the third (Diazepam protocol) used the tranquilizer diazepam in combination with morphine for both premedication and induction. In general, the results suggest that all three variations are successful in producing anaesthesia and that patients have no recall of the major portion of the surgical procedure. The major differences among the groups were exhibited in the post-operative periods. These findings suggest that diazepam affects the emotional quality associated with memory and thus aids the patients by reducing both the incidence of noxious psychological reactions and the possibility of severe emotional trauma. Finally, the findings also suggest the importance of using a narcotic analgesic as part of nitrous oxidecurare anaesthesia.

Treatment of acute isoniazid toxicity

The clinical symptoms and treatment of acute isoniazid toxicity are presented. The use of supportive measures and chemotherapy are discussed in detail. The pharmacology and biochemistry underlying the symptons of isoniazid poisoning are aslo presented. It is concluded that diazepam in combination with pyridoxine is the treatment of choice for the management of convulsions associated with isoniazid toxicity. Pyridoxine should be administered intravenously in amounts equal to the estimated quantity of isoniazid ingested, even if seizures have not occurred.

Reduction by diazepam of repetitive electrical activity and toxicity resulting from soman

The organophosphate cholinesterase inhibitor soman (methyl pinacolylphosphufluoridate) produces potentiation of twitch tension in rat anterior tibial and phrenic nerve-diaphragm preparations by initiating repetitive electrical activity in the vicinity of the motor nerve terminals. Diazepam abolished this repetitive electrical activity and hence the associated potentiation of muscle twitch tension. These effects are produced by concentrations of iazepam that are without other apparent effects on neuromuscular transmission, as indicated by the absence of effect on normal twitch responses. The combination of diazepam with atropine provides additional protection against soman toxicity in rabbits.

Drug interaction on psychomotor skills related to driving: Diazepam and alcohol

The effects of combinations of diazepam (5 and 10 mg) and alcohol (0.5 and 0.8 g/kg) on skills related to driving were studied in 200 volunteer students. A choice reaction test and two co-ordination tests were employed, one of which was carried out at a fixed speed, and in the other the speed was chosen by the subject himself. — On their own these drugs either did not affect or even slightly improved the skills measured, but their various combinations definitely impaired the subjects' performances. This effect was greatest before the peak levels of blood alcohol were reached. — The combination of these drugs is considered dangerous for driving. The practical effect of taking one of these drugs on its own is more difficult to assess.