Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026837 (muscle rigidity)
 1,077 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. In genetically susceptible pigs, MH can be induced by volatile, halogenated anaesthetics such as halothane. Within a series of pharmacological investigations, a fulminant MH could be induced in 59 of 66 homozygous halothane-susceptible pigs by a challenge with 3% halothane for 15 minutes. The typical MH was characterized by sudden appearance of tachycardia, muscle rigidity with typical extension of the hindlimbs, increase of body temperature, acidosis-caused by rapid increase of CO2 and lactate production-, hyperkalaemia and increased activity of creatine kinase (CK) and aspartate transaminase (AST). In seven homozygous MH-susceptible pigs, this typical MH could not be induced by halothane. These animals responded with sudden appearance of bradyarrhythmia and decrease of arterial pressure. In these MH-atypical pigs (MHA) neither the typical extension of hindlimbs nor a hyperthermia occurred. Compared to a group of 6 MH-susceptible pigs with typical reactions to halothane (MHS), the biochemical alterations were significantly retarded in MHA-pigs. These atypical reactions to halothane could be the effect of decreased cardiac output. Concerning the atypical reactions, we observed a familiar predisposition in MH-susceptible pigs. Although atypical reactions were not found in a group of homozygous halothane-nonsusceptible pigs (MHN), a possible explanation for atypical reactions could be a MH-independent halothane-susceptibility of the myocardium+ in MHA-pigs. On the other side the data may indicate that a primary defect in both the skeletal muscle and also the myocardium is involved in MH. The different reactions to halothane in MH-susceptible pigs could point to a genetic heterogeneity.
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PMID:Atypical reactions to halothane in a subgroup of homozygous malignant hyperthermia(MH)-susceptible pigs: indication of a heterogenous genetic basis for the porcine syndrome. 142 16

In pigs, the serotonin-2 (5-HT2) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 0.8 mg/kg, induced "psychotic" behaviour (e.g., grimacing, backward locomotion, blank stare) and a muscular syndrome, which is known as malignant hyperthermia (MH) in pigs and humans. This syndrome is characterized by generalized skeletal muscle rigidity, leading to an increase in body temperature, marked acidosis, hyperkaliaemia, cyanosis and elevation of lactate, carbon dioxide and the muscle enzyme creatine kinase (CK) in plasma. In pigs which were selectively bred for susceptibility to MH induction by known triggering agents, such as halothane, the administration of DOI was fatal in 3 out of 5 animals. In genetically susceptible pigs, MH was also induced by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 0.5-1.8 mg/kg, and D-lysergic acid diethylamide (LSD), 60-110 micrograms/kg. Furthermore, 5-MeO-DMT and LSD induced head shakes in the animals, which had not been observed after DOI and could not be blocked by 5-HT2-antagonists, ketanserin (0.5-5 mg/kg) and ritanserin (1-2.5 mg/kg). The psychotomimetic effects of 5-MeO-DMT could be blocked by ketanserin or ritanserin, which, depending on the dose, also reduced or totally prevented the hyperthermia and metabolic changes induced by 5-MeO-DMT in pigs. Administration of 5-MeO-DMT, 1.8 mg/kg, was fatal in 4 of 5 MH-susceptible pigs, whereas pigs injected with this dosage after pretreatment with ketanserin (0.5-5 mg/kg) or ritanserin (1-2.5 mg/kg) did not die. In pigs from MH-resistant littermates, administration of 5-MeO-DMT was not fatal. Comparison of metabolic changes in susceptible and non-susceptible pigs suggested that the marked increase in plasma potassium, which arises principally from damaged muscle cells, is primarily responsible for the fatal effect of DOI and 5-MeO-DMT in genetically susceptible individuals. In MH-susceptible pigs, which were anesthetized, relaxed and artificially ventilated, 5-MeO-DMT did not induce hyperthermia, thus substantiating that the marked hyperthermia observed in conscious pigs was a result of muscle activation and not due to effects on thermoregulation or blood pressure. The results indicate that hallucinogenic drugs with 5-HT2 agonistic effects trigger a life-threatening syndrome, MH, in genetically susceptible pigs. 5-HT2 antagonists, such as ketanserin or ritanserin, are capable of counteracting the fatality of this syndrome.
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PMID:Pharmacodynamic effects of serotonin (5-HT) receptor ligands in pigs: stimulation of 5-HT2 receptors induces malignant hyperthermia. 211 35

The safety of etomidate for induction of anesthesia in malignant hyperthermia-susceptible (MHS) pigs was evaluated in a two-phase experiment. Two litters of Purebred Poland China pigs, one MHS (n = 4) and the other malignant hyperthermia-resistant (MHR) (n = 4) were used. Phase I compared MHS vs MHR animals in terms of cardiovascular, metabolic, and skeletal muscle rigidity responses to etomidate and fentanyl anesthesia and to a subsequent malignant hyperthermia (MH) challenge with halothane-succinylcholine. When three of the four criteria for the diagnosis of MH occurred (rigidity, tachycardia, or increases in temperature or end-tidal CO2) in an animal, phase I was terminated. In phase II, only the MHS animals were used and experimental procedures were as in phase I except thiopental replaced etomidate. In phase I, evidence was inadequate to support the diagnosis of MH based upon responses of MHS pigs to the infusion of etomidate even though the infusion of etomidate in MHS pigs was associated with statistically significant increases in body temperature and plasma lactate levels above those observed in MHR pigs. Heart rate and bicarbonate levels were lower in MHS than in MHR pigs during etomidate infusion. With discontinuation of etomidate and a subsequent challenge with halothane-succinylcholine, all four pigs developed the MH syndrome within 15-30 min. Thiopental replacement of etomidate in the phase II experiment resulted in a twofold greater time (45-75 min) for halothane-succinylcholine to trigger MH in the susceptible pigs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Malignant hyperthermia: is etomidate safe? 398 91

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. In humans, MH is inherited in an autosomal dominant fashion; in swine, the principal model for MH, it is in a recessive fashion. Those with MH susceptibility usually are asymptomatic except in the presence of certain "triggering" anaesthetic agents such as isoflurane, enflurane and the muscle relaxant succinylcholine. Upon such exposure hypermetabolism, increased CO2 production, acidosis, muscle rigidity, rhabdomyolysis and hyperthermia occur. Untreated, death may result in 70% of patients. With prompt diagnosis and treatment with dantrolene sodium, the mortality is less than 10%. The overall incidence of MH is low (perhaps 1:50,000 anaesthetics), but it is more common in children. Children also display a paradoxical increase in jaw muscle tone to succinylcholine which often presages MH, but confusing clinically, may also be a normal response to succinylcholine. The pathophysiology of MH centres around a defect in calcium flux in skeletal muscle. A specific base pair change in the gene that codes for the ryanodine receptor calcium channel in muscle has been demonstrated in susceptible swine, but occurs rarely in humans. It is hoped that the understanding of the molecular genetics of MH will lead to a simpler diagnostic test than is currently available, and enhance our understanding of MH and its relation to other myopathies.
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PMID:An update on the malignant hyperthermia syndrome. 771 Feb 42

A 6-year old female child received succinylcholine (1 mg.kg-1) and isoflurane (concentrations of 1.5-2 percent) and developed at the end of surgery a hypermetabolic syndrome suggestive of malignant hyperthermia (MH) with masseter muscle spasm, muscle rigidity, tachypnea, systolic hypertension (140 mm Hg), tachycardia (205 beats.min-1), hypercarbia (end expiratory CO2 71 mmHg), and an increase in body temperature (39.2 degrees C). The child responded well to therapy which included cooling, hyperventilation with pure oxygen and dantrolene administration. However, blood creatine kinase and myoglobin elevations were moderate (respectively 375 IU.L-1 and 114 micrograms.L-1) and an in vitro halothane and caffeine contracture test was negative. Differential diagnostic proposals are discussed and compared to the clinical incident.
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PMID:Malignant hyperthermia suggestive hypermetabolic syndrome at emergence from anesthesia. 871 51

Malignant hyperthermia is an autosomal-dominant inherited disorder of the skeletal muscle cell characterized by a hypermetabolic response to all commonly used inhalational anaesthetics and depolarizing muscle relaxants. The clinical syndrome includes muscle rigidity, hypercapnia, tachycardia and myoglobinuria as result of increased carbon dioxide production, oxygen consumption and muscle membrane breakdown. In human beings and animals susceptible to malignant hyperthermia, it is generally accepted that an increase in the level of myoplasmic free calcium is the cause of the syndrome. Various hypotheses have been proposed to account for the increase of intracellular calcium levels, e.g. a defect in the calcium release channel of the sarcoplasmic reticulum (ryanodine receptor), an abnormality of the excitation-contraction coupling mechanisms, or alterations in second messenger systems of skeletal muscles. This review gives an overview of the main features of this disease and recent advances in research including pathophysiology, treatment, diagnosis and genetics as well as association with other disorders.
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PMID:Malignant hyperthermia. 1155 40

Malignant hyperthermia (MH) is an uncommon, life-threatening, acute pharmacogenetic disorder of the skeletal muscle cell. It manifests in susceptible individuals as a hypermetabolic response on exposure to halogenated volatile anaesthetics and depolarizing muscle relaxants. There may also be a relationship between susceptibility to MH, heat stroke and exercise-induced rhabdomyolysis. The pathophysiology of the crisis involves an uncontrolled release of cytoplasmic free calcium from the sarcoplasmic reticulum leading to activation of energy-producing biochemical pathways. Organ system failure and rhabdomyolysis may occur as a result of high fever, hyperkalaemia and acidosis. The ryanodine receptor, the calcium-release channel of the sarcoplasmic reticulum, is the primary locus for malignant hypothermia susceptibility. Multiple mutations in the gene for the ryanodine receptor protein are causative. Other genes may also be involved. A classical fulminant crisis presents with a rising end-tidal carbon dioxide, skeletal muscle rigidity, tachycardia, hyperthermia and acidosis. Mortality may be as high as 70% if the syndrome is not recognized and treated. Immediate discontinuation of triggering agents, oxygenation, and correction of acidosis and electrolyte abnormalities, cooling and dantrolene are essential for treatment of the syndrome. Thanks to clinical and research investigations, widespread education and the introduction of dantrolene sodium, the mortality from MH is less than 5%. This chapter provides an overview and an update of MH.
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PMID:Malignant hyperthermia. 1466 55

Malignant hyperthermia (MH) is a pharmacogenetic clinical syndrome that manifests as a hypermetabolic crisis when a susceptible individual is exposed to an anesthetic triggering agent. Clinical signs include unexplained elevation of end-tidal carbon dioxide, muscle rigidity, acidosis, tachycardia, tachypnea, hyperthermia, and evidence of rhabdomyolysis. This process is a result of an abnormally increased release of calcium from the sarcoplasmic reticulum, which is often caused by an inherited mutation in the gene for the ryanodine receptor (RYR1) that resides in the membrane of the sarcoplasmic reticulum. The gold standard for determination of MH susceptibility is the caffeine-halothane contracture test. However, it is invasive, requiring skeletal muscle biopsy and is not widely available. Researchers have begun to map mutations within the ryanodine receptor gene (chromosome 19q13.1) responsible for conferring MH susceptibility. Ryanodine receptor mutations are found in at least 25% of known MH susceptible individuals in North America. Mutation analysis has recently become available in the United States and is expected to play an integral role in the diagnosis of MH susceptibility in the future.
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PMID:Malignant hyperthermia: update on susceptibility testing. 1595 37

A 69-year-old woman was admitted to our hospital due to an interval form of carbon monoxide (CO) poisoning one month after acute CO poisoning. On admission, she had disorientation, memory disturbance, apathy, masked face, muscle rigidity, bradykinesia and parkisonian gait. An MRI (FLAIR image) revealed high signal intensity lesions in the bilateral globus pallidus and the white matter of the frontal lobe. Hyperbaric oxygen (HBO) therapy at 2 atmospheres for 60 min was given every day, in addition to citicoline, levodopa/DCI and selegiline hydrochloride. Cognitive disturbance and parkinsonism gradually decreased, and abnormal signals in the bilateral globus pallidus and the cerebral white matter were attenuated after the treatment. Neuropsychiatric abnormalities except for a slight gait disturbance disappeared one and a half month after starting the treatment. In addition to HBO therapy, administration of citicoline, lovodopa and selegiline may be useful in the case of the interval form of CO poisoning.
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PMID:[A case of interval form of carbon monoxide poisoning with a remarkable recovery]. 1598 66

We report on a patient who developed two episodes of severe muscle rigidity, increased endtidal CO2 and increased creatine phosphate kinase associated with sevoflurane anesthesia. Dysrhythmias and hyperthermia were not observed and dantrolene was not administered. Genetic testing for the 17 known mutations associated with malignant hyperthermia (MH) was negative. Although we cannot rule out MH or other neuromuscular diseases we suggest that this rare event may be a direct effect of sevoflurane.
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PMID:Repeat episodes of severe muscle rigidity in a child receiving sevoflurane. 1697 40


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