Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Dantrolene”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1991

Is dantrolene safe to administer in sepsis? The effect of dantrolene after endotoxin administration in dogs and rats.

Hyperthermia from septic shock may be indistinguishable from malignant hyperthermia. Dantrolene may be given in septicemia if the diagnosis is unclear. To determine if dantrolene is safe to use in sepsis, two studies were performed. In study 1, 18 anesthetized dogs in which profound septic shock was induced with 5 mg/kg of intravenous Escherichia coli endotoxin were randomized to receive (30 min later) intravenous injections of 10 mg/kg of dantrolene solution, the diluent of dantrolene, or maintenance intravenous fluids alone. The use of dantrolene solution and the diluent of dantrolene resulted in similar but transient statistically significant increases in the cardiac filling pressures and cardiac outputs and decreases in the vascular resistances compared with the control dogs. In a second study, 185 rats were randomized into five equal groups. Groups 1, 2, and 3 received 15 mg/kg of intraperitoneal Escherichia coli endotoxin followed 30 min later by 10 mg/kg of dantrolene solution, the diluent of dantrolene, or normal saline. Groups 4 and 5 received normal saline followed by dantrolene or normal saline. The survival of groups 1, 2, and 3 was less at 24 h (P less than 0.0001) than that of either control group, but was not significantly different from one another. The results suggest dantrolene can be administered safely under clinical conditions where the cause of hyperthermia and shock cannot clearly be ascribed to malignant hyperthermia or septicemia.

Analysis of Variance↗
PubMed1988

Hyperkalemia after dantrolene and verapamil-dantrolene administration in dogs.

The concurrent administration of dantrolene and verapamil has the theoretical advantage of being more efficacious than dantrolene alone in the treatment of malignant hyperthermia. However, the combination has been reported to cause fatal hyperkalemia in pigs. The present study evaluated the serum concentrations of cations, serum osmolarity, and cardiovascular responses in 20 mongrel dogs after dantrolene with and without the concurrent administration of verapamil. The dogs were randomly classified into four groups of five dogs each: group 1 received neither dantrolene nor verapamil; group 2 received three successive intravenous doses of dantrolene (1, 3, and 6 mg/kg) at 30-minute intervals; group 3 received verapamil 0.1 mg/kg IV bolus, followed by a continuous infusion of 5 micrograms.kg-1.hr-1; and group 4 received verapamil as in group 3, followed by dantrolene as in group 2. Measurements were made at 15-minute intervals for 2 1/2 hours. Progressive and similar statistically significant increases in mean serum potassium occurred after 105 minutes in dogs given dantrolene (group 2, mean peak serum potassium levels 5.4 +/- 0.5 mmol/L) and after 90 minutes in dogs given verapamil-dantrolene (group 4, 5.2 +/- 1.6 mmol/L). A statistically significant decrease in serum sodium levels was also found in groups 2 and 4. One dog in group 4 developed intermittent second-degree heart block after the final dose of dantrolene. Serum calcium levels (ionized and total) tended to decrease in groups 2 and 4. There were no statistically significant differences in osmolarities, cardiac outputs, or mean arterial blood pressures among groups. In summary, significant elevations of serum potassium were observed in this dog model given dantrolene with and without verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Simultaneous determination of dantrolene and its metabolites, 5-hydroxydantrolene and nitro-reduced acetylated dantrolene (F 490), in plasma and urine of man and dog by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic method is described for the simultaneous determination of the skeletal muscle relaxant dantrolene and its metabolites, 5-hydroxydantrolene and nitro-reduced acetylated dantrolene (F-490), in plasma and urine of man and dog. The substances are detected spectrophotometrically at 375 nm. The detection limits are 0.02 mg/l. A preliminary extraction step into a choloroform-butanol mixture is required for the plasma samples. The method is suitable for pharmacokinetic studies of dantrolene.

Animals↗
PubMed1979

Dantrolene and suxamethonium. The effect of pre-operative dantrolene on the action of suxamethonium.

A single oral dose of dantrolene (100--150 mg) given at least 2 hr pre-operatively has been found to reduce significantly the strength of muscular fasciculations, the hyperkalaemia and the incidence of muscle pains following suxamethonium (from 56 to 4%) in a series of forty-eight patients compared with controls. The biceps EMG of the fasciculations was unchanged by dantrolene; the incidence of troublesome side effects was low (9%) and there did not appear to be any alteration in the duration of action of suxamethonium.

Adult↗
PubMed1989

Pharmacokinetics of intravenous dantrolene in children.

To determine the pharmacokinetics of iv dantrolene and its metabolites in children, ten children 2-7 yr of age scheduled for minor elective surgery, were studied. After induction of anesthesia and tracheal intubation, dantrolene (2.4 mg/kg) was administered iv over 10.2 +/- 0.83 min. Venous blood samples (3 ml) were obtained 1, 5, 10, 20, and 30 min and 1, 2, 4, 8, 12, and 20 h after the dantrolene infusion. Whole blood concentrations of dantrolene, 5-hydroxydantrolene, and nitroreduced acetylated dantrolene were measured by high-performance liquid chromatography. The whole blood concentration of dantrolene decreased rapidly from a mean (+/- SD) of 6.03 +/- 0.93 microgram/ml 1 min after the end of the dantrolene infusion to 3.56 +/- 0.49 microgram/ml at 1 h. Between 1 and 4 h, the concentration of dantrolene either remained constant or increased slightly. Thereafter, the concentration of dantrolene decreased slowly with an elimination half-life (mean +/- SD) of 10.0 +/- 2.6 h. The mean (+/- SD) time for the concentration of dantrolene to decrease to 3.0 micrograms/ml was 6.55 +/- 2.88 h. The whole blood concentration of 5-hydroxydantrolene reached a maximum of 0.60 +/- 0.18 microgram/ml approximately 7 h after the dantrolene and decreased thereafter with an elimination half-life of 9.0 +/- 2.5 h. The concentration of nitroreduced acetylated dantrolene was below the limit for detection at all times. All children recovered without complications. Intravenous dantrolene, 2.4 mg/kg, produces safe and predictable blood concentrations in children similar to those reported in adults.

Child↗
PubMed1980

Porcine malignant hyperthermia--failure of dantrolene dose response to diagnose susceptibility (halothane effect).

Dantrolene, a skeletal muscle relaxant, has been proven prophylactic and therapeutic for malignant hyperthermia (MH) in swine. This study examined the feasibility of using a dantrolene dose response as measured by indirectly evoked foretoe twitch depression as a means to safely discriminate MH susceptibility in swine. The effect of halothane on the dantrolene response was quantified. Subjects were five Poland China malignant hyperthermia susceptible (MHS) and five Hampshire malignant hyperthermia resistant (MHR) swine. Dantrolene dose response was determined twice in each anaesthetized subject, once with thiopentone and subsequently with thiopentone and halothane. Dantrolene in incremental doses, 0.15 mg.kg-1, was given to a cumulative dose of 2--3 mg.kg-1. Under thiopentone anaesthesia, the dantrolene dose responses were similar in MHS and MHR animals. The presence of halothane augmented dantrolene twitch depression in MHS but not MHR animals when compared to their response under thiopentone. Under halothane, the MHS animals had significantly augmented dantrolene response compared to MHR pigs, but three MHS animals had developed the MH syndrome prior to receiving dantrolene. We conclude that dantrolene muscle relaxant dose response cannot be used as a diagnostic test for MHS in swine. Halothane augments dantrolene twitch depression in MHS swine.

Animals↗
PubMed1987

Comparison of the skeletal muscle relaxant properties of Portulaca oleracea extracts with dantrolene sodium and methoxyverapamil.

The effects of aqueous (AEE), dialysable (DIF) and methanol (MEE) extracts of Portulaca oleracea stems and leaves were compared with those of dantrolene sodium and methoxyverapamil (D-600) with respect to inhibition of twitch tension on the rat phrenic nerve-hemidiaphragm and with respect to contracture induced by nicotinic agonists on the frog rectus abdominis preparations. The extracts, dantrolene and D-600 inhibited twitch tension due to indirect electrical stimulation via the phrenic nerve (NS) on hemidiaphragm muscle, whereas the extracts and dantrolene inhibited, in addition, twitch amplitude due to direct muscle stimulation (MS). The extracts, dantrolene and D-600 also attenuated K+- and caffeine-induced contractures with the extracts and D-600 also reducing the time taken for the K+-induced contracture to fall to basal tension. In addition, the tetanic tension due to NS and MS was attenuated with only the extracts and dantrolene reducing the twitch/tetanus ratio (MS). There was a non-significant but consistent tendency for mutual potentiation between the extracts and dantrolene with respect to their inhibitory effect on twitch amplitude (MS) resulting in a shift to the left of the concentration-response curves to the extracts or dantrolene. This was not evident with the extracts and D-600 or dantrolene and D-600. Simultaneous addition of the extracts and dantrolene resulted in an increase in the rate of twitch tension inhibition and a decrease in the time to maximum relaxation of twitch amplitude (MS). The extracts and D-600 proved more effective in attenuating nicotinic agonist (acetylcholine, carbachol and nicotine)-induced contractures on the rectus abdominis muscle than dantrolene. From these observations, it appears that the Portulaca oleracea extracts mimic, in part, the effect of D-600 and dantrolene on the rat hemidiaphragm and frog rectus abdominis muscles; therefore, the muscle relaxant properties of the extracts may be due, in part, to inhibition of trans-membrane Ca influx, interference with the Ca-induced Ca release process and/or inhibition of the release of intracellular Ca from stores in the sarcoplasmic reticulum.

Animals↗
PubMed1982

In vitro binding of dantrolene to bovine serum albumin and rabbit red blood cell ghosts.

The binding of dantrolene to rabbit red blood cell (RBC) ghosts and bovine serum albumin as models of receptor sites was studied using fluorescence techniques. Dantrolene upon binding to rabbit RBC ghosts and bovine serum albumin showed fluorescence with emission maxima at 495 and 500 nm, respectively. Dantrolene bound to rabbit RBC ghosts with an association constant of 6.06 X 10(4) M-1 and there were 2.4 X 10(6) dantrolene binding sites per ghost. The binding of dantrolene to bovine serum albumin showed an anomaly with respect to dantrolene concentration. Dantrolene at concentrations of 1.25-3.75 microM bound to bovine serum albumin with an association constant of 1.72 X 10(4) M-1 and there were 1.078 binding sites/mol bovine serum albumin. The higher affinity of dantrolene toward blood cells was confirmed by studying the distribution of dantrolene between blood cells and plasma after a single i.p. injection of dantrolene sodium (3 mg/kg) to albino rabbits. It was found that the concentration of dantrolene in rabbit blood cells was 2.76 times that of plasma.

Animals↗
PubMed1986

Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity.

Dantrolene sodium acts primarily by affecting calcium flux across the sarcoplasmic reticulum of skeletal muscle. Recently, dantrolene has been used very successfully in the treatment of several rare hypercatabolic syndromes which have previously been associated with high mortality rates. In malignant hyperthermia, where early diagnosis and treatment usually with intravenous dantrolene in association with other supportive measures (and often subsequent dantrolene therapy) is performed, recovery is seen in virtually 100% of patients. There is a rapid resolution of hyperthermia, dysrhythmias, muscle rigidity, tachycardia, hypercapnia, mottled or cyanotic skin, and metabolic acidosis, and a slower normalisation of myoglobinuria and elevated serum creatine phosphokinase levels. In patients with family history or previous episodes of malignant hyperthermia, prophylactic treatment with dantrolene prior to anaesthesia prevents the syndrome occurring in most cases. Where malignant hyperthermia has developed patients have been successfully treated with further dantrolene therapy. Dantrolene has also been used successfully in the treatment of a few cases of heat stroke and the neuroleptic malignant syndrome--both of which have many similarities to malignant hyperthermia. Dantrolene is well established in the treatment of patients with muscle spasticity where it generally improves at least some of the components of spasticity (i.e. hyper/hypotonia, clonus, muscle cramps and spasms, resistance to stretch and flexor reflexes, articular movement, neurological and motor functions and urinary control). However, in some patients, particularly those with multiple sclerosis, dantrolene may not be effective, and in many cases muscular strength may diminish. Long term dantrolene therapy has been associated with hepatic toxicity and may cause problems in patients treated for disorders of muscle spasticity. Thus, dantrolene offers a unique advance in the therapy available for the treatment of hypercatabolic disorders and is also useful in the treatment of muscle spasticity of various aetiology.

Animals↗
PubMed1988

Dantrolene in pregnancy: lack of adverse effects on the fetus and newborn infant.

Twenty malignant hyperthermia-susceptible pregnant patients were given dantrolene sodium orally for 5 days before delivery and 3 days after delivery. When cesarean section was necessary, triggering agents were avoided. No patient had a malignant hyperthermia reaction. No adverse effect of dantrolene sodium was detected by extensive testing of the fetus and neonate. The maternal predelivery dantrolene level was correlated with the noenatal cord blood dantrolene level (r = 0.837). The mean maternal predelivery dantrolene level was 0.99 +/- 0.5 microgram/ml, and the mean neonatal cord blood dantrolene level 0.68 +/- 0.3 microgram/ml. The time from the last dose of dantrolene to delivery was correlated with both the maternal dantrolene level and the neonatal cord blood level (r = 0.65). The half-life of dantrolene in the neonatal circulation was 20 hours. The controversy of oral dantrolene prophylaxis and the implications of this study with regard to further investigation are discussed.

Administration, Oral↗
PubMed1988

Plasma levels of dantrolene following oral administration in malignant hyperthermia-susceptible patients.

Reports of the lack of protection following oral dantrolene prophylaxis have led some authors to recommend only intravenous administration of dantrolene for prophylaxis against malignant hyperthermia at induction of anesthesia. The authors determined whether a specific regimen of preoperative oral dantrolene would result in protective blood levels at induction of anesthesia, and in the postoperative period. Ten malignant hyperthermia-susceptible (MHS) patients were given a total dose of 5 mg.kg-1 of oral dantrolene in three or four divided doses, every 6 h, with the last dose 4 h preoperatively. Plasma dantrolene levels were determined by reverse phase high pressure liquid chromatography at induction of anesthesia and every 6 h thereafter for 48 h. All ten patients had plasma dantrolene levels over 2.8 micrograms.ml-1 at induction of anesthesia, for at least 6 h and, in three patients, up to 18 h after induction. Every patient had an uneventful perioperative course. Side effects (drowsiness, weakness) occurred in seven patients. An elimination half-life of 15.8 +/- 6.0 h was determined. In contrast to intravenous dantrolene, this specific oral dantrolene regimen resulted in protective plasma levels for 6-18 h after induction of anesthesia. These results were likely due to the relatively high bioavailability of oral dantrolene and, possibly, to continued absorption of dantrolene in the postoperative period.

Administration, Oral↗
PubMed1979

The effect of dantrolene sodium on rat skeletal muscle in relation to the plasma concentration.

Dantrolene sodium is a muscle relaxant used in the treatment of spasticity. It has been shown to interfere with calcium release from the sarcoplasmic reticulum and thus to inhibit excitation--contraction coupling. The effect of dantrolene sodium on the twitch tension of the tibialis anterior muscle of the rat was measured after 2 mg/kg i.v. or 25 mg/kg orally. Plasma concentrations were estimated at maximum twitch depression and during recovery from the block. In a separate series of experiments the half-life of labelled dantrolene sodium was measured in blood plasma, skeletal muscle and heart muscle of rats. Dantrolene sodium 2 mg/kg i.v. gave a maximal block of approximately 47%, the mean dantrolene sodium concentration was then 5.8 microgram/ml. A half-life for distribution of 1.1 min and an elimination half-life of 31 min after intravenous administration were observed, elimination rate constants in skeletal and heart muscle were comparable. Recovery from the block went much slower, the half-time of the process being approximately 80 min. Dantrolene sodium 25 mg/kg orally gave a maximal block of approximately 38% at a mean plasma concentration of 3.6 microgram/ml after 14 min. The recovery was again very slow. These experiments demonstrated that dantrolene sodium acts according to a two-compartment pharmacokinetic model. There was a discrepancy between duration of effect and plasma concentration of dantrolene sodium in the rat. This suggests that the receptor for dantrolene sodium is not located in the central compartment.

Animals↗
PubMed1977

Inhibition of the intracellular release of calcium by Dantrolene in barnacle giant muscle fibres.

1. Ca movements in resting and in activated single giant muscle fibres of the barnacle were analysed before and after exposure to Dantrolene Na, a synthetic hydantoin derivative. 2. In fibres micro-injected with the photoprotein aequorin, the resting rate of light emission (resting glow) reversibly decreased upon exposure to Dantrolene. Similar results were obtained if the fibre had first been equilibrated in a O Ca-1 mM-EGTA medium. 3. The influx of 45Ca into resting muscle fibres was not modified by 35 micronM Dantrolene which also failed to significantly reduce the influx of 45Ca into muscle fibres which had been depolarized by exposure to external solutions in which K+ had been increased to 60 or 200 mM. 4. In fibres micro-injected with 45Ca, the calcium efflux was reversibly decreased by Dantrolene. This effect was still observed in O Ca medium and in O Ca-ONa medium. A possible effect of Dantrolene on the Na-Ca exchange process at the outer membrane was excluded by showing that when the direction of the Ca2+ movement was inverted in aequorin-loaded fibres by the sudden removal of Na+ from the external medium, a marked increase in the resting glow was recorded which was not affected by exposure to Dantrolene. 5. It is argued that the reduction of Ca2+ efflux by Dantrolene does not result from any direct inhibitory effect on the metabolically driven Ca pump at the outer membrane, but that it is rather related to the reduction of the concentration of myoplasmic Ca2+ which is indeed demonstrated by the reduced resting glow. This in turn is thought to result from a shift in the balance between Ca2+ movements into and out of the intracellular storage sites, and namely the sarcoplasmic reticulum (SR). 6. The Ca2+ transient in aequorin-loaded fibres and the force of the isometric contraction elicited by imposed membrane depolarizations were markedly reduced by Dantrolene. The electrochemical threshold for eliciting intracellular Ca2+ release was not significantly modified. The linear relation between membrane depolarization and Ca2+ transient became less steep. The process of sequestration of myoplasmic Ca2+ back into SR was not significantly affected by Dantrolene which appeared to inhibit rather selectively the Ca2+ release from SR into the cytosol.

Animals↗
PubMed1981

The effect of dantrolene on the enhancement and diminution of tension evoked by staircase and by tetanus in rat muscle.

1. The effect of Dantrolene on the potentiation of isometric twitch tension was examined during and after the staircase (5/sec, 250 stimuli) and after the tetanus (167/sec, 250 stimuli) in the extensor digitorum longus muscle of adult Lewis rats at 37-38 degrees C.2. The study confirmed that Dantrolene decreased the twitch tension much more than the tetanic tension. The drug shortened the contraction time of the twitch. The rate of force development of the twitch was diminished by only half that of the twitch tension. The findings may suggest that the drug both shortened and diminished the activation of the muscle during the twitch.3. Dantrolene decreased the potentiation produced by a given number of stimuli early in the staircase. At the 250th stimulus the staircase was about 25% larger after than before application of the drug. Dantrolene increased the potentiation 2 sec after the tetanus by about 60%.4. After application of Dantrolene, the decay of potentiation after the staircase indicated that the process that diminished the twitch during the staircase, present before application of the drug, was absent. The size of the process causing potentiation was the same with and without the drug. Both events of potentiation after the tetanus were increased by Dantrolene. Both after the staircase and after the tetanus, Dantrolene increased the slow phase of decay by 60-70%. The fast rate of decay after the tetanus was unchanged by the drug.5. The contraction time was prolonged less in the potentiated twitch after than before application of Dantrolene. This was presumably due to a greater relative increase in activation rather than to a prolongation of the time during which the muscle was activated.6. A model is proposed where the delay in potentiation during the staircase and the increase in potentiation after the tetanus are due to the proportion of sites in the excitation-contraction coupling occupied by Dantrolene being reduced by repetitive depolarizations of the transverse tubules during trains of repetitive stimuli.

Action Potentials↗
PubMed1977

Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity.

Dantrolene sodium or dantrolene1 is 1([5-(nitrophenyl)furfurylidend] amino) hydantoin sodium hydrate. It is indicated for use in chronic disorders characterised by skeletal muscle spasticity, such as spinal cord injury, stroke, cerebral palsy and multiple sclerosis. Dantrolene is believed to act directly on the contractile mechanism of skeletal muscle to decrease the force of contraction in the absence of any demonstrated effects on neural pathways, on the neuromuscular junction, or on the excitable properties of the muscle fibre membranes. Controlled trials have demonstrated that dantrolene is superior to placebo in adults or children with spasticity from various causes, as evidenced by clinical assessments of disability and daily activities, and by muscle and reflex responses to mechanical and electrical stimulation. It is somewhat less effective in patients with multiple sclerosis than in those with spasticity from other causes. There has been a general clinical impression in controlled trials that dantrolene caused less sedation than would have been expected from therapeutically comparable doses of diazepam. In 2 controlled trials, there was no significant difference between dantrolene and diazepam in terms of reductions in spasticity, clonus, and hyperreflexia, but side-effects such as drowsiness and inco-ordination occurred significantly more frequently on diazepam. Long-term studies have indicated continuing benefit for patients taking dantrolene, though the incidence of side-effects has often been high and there has been a suggestion of exacerbation of seizures in children with cerebral palsy. Dantrolene may be of value in the medical treatment of spasm of the external urethral sphincter due to neurological and non-neurological disease, and animal studies suggest a potential use in the management of malignant hyperpyrexia. Chemical evidence of liver dysfunction may occur in 0.7 to 1% of patients on long-term treatment with dantrolene, with symptomatic hepatitis in 0.35 to 0.5% and fatal hepatitis in 0.1 to 0.2%. The drug commonly causes transient drowsiness, dizziness, weakness, general malaise, fatigue and diarrhoea at the start of therapy. Muscle weakness may be the principal limiting side-effect in ambulant patients, particularly in those with multiple sclerosis, and therapy could be hazardous in patients with pre-existing bulbar or respiratory weakness. The dosage of dantrolene has been fixed in most controlled trials, though long-term studies have indicated the need for individualisation of dosage. The initial dose is usually 25mg once daily, increasing to 25mg two, three or four times daily, and then by increments of 25mg up to as high as 100mg two, three or four times daily. The lowest dose compatible with optimal response is recommended.

Adult↗
PubMed1986

Effects of dantrolene and verapamil on atrioventricular conduction and cardiovascular performance in dogs.

The effects of intravenous dantrolene sodium, alone and in combination with verapamil, upon atrioventricular conduction, cardiovascular function, and neuromuscular function were studied in chloralose-urethane anesthetized dogs. Hemodynamic variables (systemic arterial, central venous, and pulmonary arterial pressures and cardiac output) and His-bundle electrograms were monitored, and measurements were made during atrial pacing at 175 beats/min, as well as at the spontaneous heart rate. In one part of the study animals received dantrolene sodium incrementally at 30-min intervals to cumulative doses of 1, 2.5, 5, and 10 mg/kg. Subsequently, verapamil was administered incrementally at 30-min intervals to cumulative doses of 0.1, 0.2, 0.4, and 0.6 mg/kg. In the second part of the study, dogs received identical dosage sequences, but verapamil preceded dantrolene administration. Dantrolene caused no significant depression of atrioventricular conduction or cardiac performance but did increase systemic vascular resistance at doses above 2.5 mg/kg. Verapamil alone (greater than or equal to 0.2 mg/kg) or with dantrolene (greater than or equal to 0.1 mg/kg) increased the atrial-His-bundle conduction interval. In the presence of verapamil, dantrolene (greater than or equal to 2.5 mg/kg) decreased cardiac index and increased pulmonary artery occlusion pressure. Although 0.6 mg/kg verapamil depressed cardiac index and increased pulmonary artery occlusion pressure, this effect was observed at 0.4 mg/kg after prior treatment with dantrolene. Verapamil did not augment the dose-dependent twitch depression observed with dantrolene. Dantrolene alone had no apparent effect on atrioventricular conduction and caused little enhancement of the effects of verapamil. However, each drug appeared to enhance the myocardial depressant effects of the other.

Animals↗