Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity. 31 89

After a clarifying outline on the most recent anatomo-physiopathologic acquisitions about muscular tone and spasticity, the Author presents the results of a prolonged administration (three months) which was daily controlled, in an Institute for dyskinetic subjects. At the dose of 1 mg/kg/die during the first week, 2 mg/kg/die during the second week and 3 mg/kg/die during the third and the following ones (total posology pro die divided into 3 post-prandium administrations), Dantrolene was administered to 16 subjects of both sexes, whose average age was 13, who presented marked spasticity sometimes accompanied by dystonia. An evaluation was given on these parameters: 1) spasticity estimated in three degrees according to Morosini, 2) passive articular movement (wideness and easiness of maximum excursion), 3) capability of voluntary decontraction, 4) motoricity of relation (motorial difficulty) and 5) dystonic component if present. As a global results, out of 16 cases, nine improved (56%) and seven (44%) remained unaltered. Since the drug resulted to be inefficacious in all cases with dystonia, the global improvement recorded among "pure spastics" rised to 66% of cases. Neither intolerances nor negative secundary effects were noticed.
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PMID:[Dantrolene in juvenile spasticity: 3 months of daily observation]. 45 97

Spasticity is a hyper-excitable state of the reflex arcs in the spinal cord below the level of injury. Not only is the skeletal motor system affected, but bladder, bowel, blood pressure, and erection reflex mechanisms are also involved. Spasticity gradually emerges from the initial phase of spinal shock one to two months after the injury, and usually reaches a plateau of a mild to moderate degree in 3 to 4 months. Neurophysiological mechanisms indicate an increase in the alpha and gamma reflex systems and that central excitability through the interneurons is also involved in these systems. Excessive spasticity should be recognized as a substitute for pain in the spinal cord injured patient, as infections, calculi, pressure ulcers, and other normally painful conditions set off the hyper-sensitive reflexes causing more spasticity. Education and health maintenance is the best prevention of severe spasticity. Definitive treatment of incapacitating spasticity is to find and treat the underlying disease condition, as well as to introduce medication which will also suppress the spasm (Valium and/or Dantrolene). Muscle motor points and/or nerve blocks with neurolytic agents is perhaps the best technique for quietening excessive spasticity. Intrathecal neurolytic agents, anterior or posterior rhizotomies and cordectomies are not advocated even in severe incapacitating spasticity as they are too destructive. Selective longitudinal myelotomy is by far the best surgical technique for disrupting excessive spasticity, if any such procedure is to be done. Tendonotomies may be necessary in chronic contractures of joints after the muscle spasticity has been reduced. Excessive spasticity is not regarded as a normal state in the spinal cord injured patient. The cause should be sought and treated. Nerve destruction techniques should not be used unless medical and nursing techniques have failed. Prevention is so important and can be achieved by education, health maintenance, and especially motivation.
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PMID:Spasticity following spinal cord injury. 119 52

The author gives a literature review of the management of spasticity carried out. Physical agents used such as ice, heat and vibration are described. Methods used by physical therapists are discussed. Drugs most commonly used in the treatment of spasticity are Diazepam, Baclofen and Dantrolene. Phenol has been used by injection into motor points, peripheral nerves and intrathecally. Other drugs that have been used are also discussed. Neurosurgical procedures include neurectomies, neurotomies, rhizotomies and more radical procedures such as myelotomies and cordectomies. Orthopaedic procedures involve muscle and tendon lengthening, release of contractures and tendon transfers. Surgery is discussed in terms of function. In considering the options, available care must be taken to achieve and maintain optimal functional level.
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PMID:The management of spasticity--a review of options available in rehabilitation. 129 22

Dantrolene, a direct acting muscle relaxant used orally for spasticity, has appeared to be effective in the prevention and treatment of malignant hyperthermia in man and animals when administered intravenously. Its pharmacokinetics following intravenous administration have been studied in dogs. Concentrations of dantrolene and its metabolites in plasma, urine, and bile were determined by high-performance liquid chromatography. Recovery of unchanged drug and reduced metabolites was negligible; of the hydroxy metabolite 2% was found in the urine and about 25% in the bile. The half-life of 5-hydroxydantrolene was shorter than that of the parent drug as demonstrated by administration of the metabolite. The apparent renal clearance of 5-hydroxydantrolene was independent of creatinine clearance, urine flow and pH, and appeared to be reduced in the presence of probenecid. Bile to plasma ratios of the hydroxy metabolite were high with biliary concentrations far exceeding the maximum solubility in water. The results of this pilot study indicate that hydroxylation is primarily responsible for the excretion of the dantrolene molecule from the body.
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PMID:Pharmacokinetics of intravenously administered dantrolene and its 5-hydroxy metabolite in dogs. 207 79

Dantrolene sodium is a drug used in the treatment of spasticity and malignant hyperthermia. It is known to have a myorelaxant effect related to inhibition of the "release" of calcium by the sarcoplasmic reticulum of striated skeletal muscle. A direct cardiac effect which has only recently been suspected was demonstrated in vitro on isolated preparations of sheep Purkinje fibres and ventricular myocardium. Dantrolene caused a spectacular lengthening of the duration of the action potential of Purkinje fibres. This could be due either to an action on the slow calcium current or to stimulation of an ingoing sodium current sensitive to tetrodotoxin (TTX). This effect on the cardiac action potentials could explain the antiarrhythmic properties of dantrolene sodium during attacks of malignant hyperthermia.
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PMID:[In vitro electrophysiological effects of sodium dantrolene on isolated preparations of Purkinje fibers and ventricular myocardium of sheep]. 242 77

Several different drugs are now used, or are potentially useful, to treat patients with spasticity. Although these compounds vary in their actions on spinal neurons and reflex arcs, it is possible to formulate reasonable hypotheses regarding their modes of action. The benzodiazepines bind to specific benzodiazepine receptors linked to classic gamma-aminobutyric acid (GABA) receptors located on the terminals of primary afferent fibers. This binding results in an increased affinity of the GABA receptor for the amino acid, an augmented flux of chloride ions across the terminal membrane, and an increase in the amount of presynaptic inhibition. Baclofen activates GABAB receptors putatively located on the same terminals. Activation of these receptors retards the influx of calcium ions into the terminals, thereby reducing the evoked release of excitatory amino acids and possibly other transmitters. Progabide and its metabolites act on both classic and GABAB receptors. Glycine works on specific inhibitory receptors located on spinal interneurons and motoneurons. The phenothiazines act on the brainstem to alter the function of fusimotor fibers. Phenytoin and carbamazepine reduce the afferent output of muscle spindles. Dantrolene diminishes the activation of the contractile process in muscle fibers by reducing the release of calcium ions from the sarcoplasmic reticulum. This review summarizes the data supporting these concepts.
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PMID:Antispasticity drugs: mechanisms of action. 285 76

An overview is presented of pathophysiology, classification and measurement of spasticity and of its treatment, especially with dantrolene and baclofen. In spasticity, the balance between excitatory and inhibitory neurotransmitters in the central nervous system is impaired by mechanisms that are for the greater part unknown. Spasticity includes various disorders of motor control, and classification is needed for a meaningful evaluation of antispastic therapy. Cerebral palsy is a specific disorder, sometimes also called spasticity. Measurement of spasticity is complicated and should include signs characteristic of spasticity and parameters for clinical improvement. Dantrolene and baclofen have established their place in the treatment of spastic disorders, but a preference for either drug is hard to give. For tizanidine it is still too early to determine its place in therapy. Dantrolene is a direct acting muscle relaxant which should be avoided in patients with pre-existing liver damage. Its mechanism of metabolism and excretion is for the greater part unknown. The GABAB agonist baclofen is a centrally acting muscle relaxant. In patients with impaired renal function the dose should be reduced. Abrupt withdrawal carries the risk of unwanted reactions. The R(-)-enantiomer has proved to be the active isomer. This means that human trials need reappraisal, especially those relating to the pharmacokinetics of the racemate.
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PMID:Spasticity and drug therapy. 332 51

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.
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PMID: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. 352 59

Spasticity has been defined as velocity-dependent hyperactivity of stretch reflexes; it is therefore only one aspect of the complex syndrome produced by a lesion of the upper motoneuron. Although spasticity may be partially responsible for joint contractures, it does not produce most of the functional disability experienced by patients with upper motoneuron lesions. Paresis, fatigability, lack of dexterity, etc., account for most of these patients' complaints. The pathophysiology of spasticity is poorly understood but appears to be related to an increased excitatory state at the segmental spinal level; there is no evidence for increased sensitivity of muscle spindles in spastic patients. Several mechanisms for this increased excitability within the spinal cord have been proposed. There are different types as well as degrees of spasticity. Clinical neurophysiologic recordings of reflex activity in patients with spasticity provide the means to differentiate among the various types of spasticity, to select the therapy most likely to be effective in a particular patient, and to see the results of its employment objectively. The latter will prove whether a specific therapy is useful or not. Ablative treatment at the level of the peripheral nerve or dorsal root may be useful, particularly when spasticity is severe. Drugs such as baclofen or diazepam relieve flexor spasms but are not particularly effective against spasticity itself. Dantrolene acts to weaken muscles, but that is not often helpful. Rarely do any of these therapies increase function; there are no effective cures for paresis or related negative manifestations of chronic spasticity.
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PMID:Spasticity. 358 84


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