Dantrolene use in 3,4-methylenedioxymethamphetamine (ecstasy)-mediated hyperthermia.

Sprague JE.

Clinical pharmacology of GW280430A in humans.

BACKGROUND: An ultrashort-acting nondepolarizing neuromuscular blocking agent that could be an alternative to succinylcholine has been the focus of a concerted effort in the field of muscle relaxants. GW280430A showed a promising pharmacodynamic profile in preclinical work and a wide margin of safety and so was selected for study in humans. METHODS: Thirty-one volunteers participated in this study, which determined the dose producing 95% block (ED95) and the safety and pharmacodynamics of increasing ED95 multiples. Anesthesia was induced and maintained with propofol, midazolam, and fentanyl. Neuromuscular transmission was measured at the adductor pollicis using ulnar nerve stimulation, and responses were recorded continuously by standard mechanomyographic monitoring. RESULTS: The ED95 for GW280430A is 0.19 mg/kg. The time to onset of 90% block ranged from 1.3 to 2.1 min, depending on the dose. Clinical durations ranged from 4.7 to 10.1 min and increased with increasing dose. Five to 95% and 25-75% recovery rates were approximately 7 and 3 min, respectively, and were independent of the dose administered. Transient cardiovascular side effects were observed at doses beginning at 3 x ED95 and above and were suggestive of histamine release. Most volunteers receiving 4 x ED95 exhibited plasma histamine concentrations indicative of significant histamine release. CONCLUSIONS: GW280430A has a rapid onset and ultrashort duration of action. The recovery rate is rapid, predictable, and independent of dose. Doses at least up to 2.5 x ED95 seem to be free of side effects and seem to be able to provide relaxation within 60-90 s.

Diazepam augments gender differences in cutaneous LD flux response to local cooling.
Melik Z, Cankar K.
Institute of Physiology, School of Medicine, Zaloska 4, 1000 Ljubljana, Slovenia. ziva.melik@mf.uni-lj.si
Cutaneous vasoconstriction in response to local cooling is normally greater in females than in males. Cold induces amplification of alpha2-adrenoceptor affinity for norepinephrine and increases reflex sympathetic thermoregulatory output. Benzodiazepines are drugs with very well-known binding to the central and peripheral benzodiazepine receptors. Besides these effects they decrease sympathetic output and as it was shown in the last decade they act synergistically with alpha-adrenoceptors. In the present study we tested the hypothesis that the benzodiazepine diazepam interacts with an alpha-adrenoceptor mechanism at the level of microcirculation. We measured laser-Doppler blood flux changes provoked by local cooling before and after oral application of a low dose of diazepam (5 mg) in 9 healthy males and in 11 healthy females with regular menstrual cycles. The results of our experiments show that in females there is a significant reduction (ANOVA, p < 0.05) in laser-Doppler flux during the first four minutes of cooling after taking of diazepam. In males, there is no significant difference in the responses to cold before and after an application of diazepam. Our results suggest that diazepam, in addition to its well-known effect on BZ receptors may also interact with alpha2C-adrenoceptors in the vessel wall during local cooling.

Genetic testing for enzymes of drug metabolism

STUDY DESIGN: This is a structured review of genomic (genetic) testing for enzymes of drug metabolism. OBJECTIVES: Recently, industry began offering genomic testing for enzymes of drug metabolism. As such, the objective of this review was to determine if genomic testing for enzymes of drug metabolism has any imminent clinical relevance for the practice of pain medicine. METHODS: Relevant references relating to pharmacogenetics, pharmacogenomics, and the metabolizing of drugs used in pain medicine by cytochrome P-450 enzymes were located and reviewed in detail. The P-450 enzymes that metabolize each drug and whether that drug had been identified as being subject to a clinical consequence of a genetic polymorphism of the P-450 enzyme involved in its metabolism were placed into tabular form. RESULTS OF DATA SYNTHESIS: 1) For a large number of drugs, we do not yet know which cytochrome P-450 enzymes are involved in their metabolism; 2) For a large number of drugs, the consequences of a P-450 genetic polymorphism have yet to be determined; 3) Genetic polymorphism can lead to important potential clinical consequences for some opioids, anticonvulsants (phenytoin), benzodiazepines (diazepam), muscle relaxants / relaxant (succinylcholine), antidepressants (imipramine, nortriptyline, venlafaxine), typical neuroleptics, alcohol, antihypertensives (propranolol, timolol), local anesthetics (procainamide), L-dopa, nicotine, and warfarin. Based on these results, factors for and against using genomic testing were reviewed. CONCLUSIONS/RECOMMENDATIONS: It was concluded that genomic testing for enzymes of drug metabolism has significant potential for improving the efficacy of drug treatment and reducing adverse drug reactions. Recommendations for when such testing would be useful are outlined. Copyright American Academy of Pain Medicine

Complications of anaesthesia in neuromuscular disorders.
Klingler W, Lehmann-Horn F, Jurkat-Rott K.
Department of Anaesthesiology, Ulm University, Albert-Einstein-Allee 11, 89069 Ulm, Germany.
The purpose of this review is to alert non-anaesthesiologists to the various complications from which patients with neuromuscular disorders and those susceptible to malignant hyperthermia can suffer during anaesthesia. The patient's outcome correlates with the quality of consultation between anaesthesiologists, surgeons, neurologists and cardiologists. Special precautions must be taken, since many anaesthetics and muscle relaxants / relaxant can aggravate the clinical features or trigger life-threatening reactions. Complications frequently occur in these patients, although anaesthetic procedures have become safer by the reduced administration of suxamethonium and the use of total intravenous anaesthesia, new volatile anaesthetics and non-depolarising relaxants. This review provides a synopsis of pre-operative anaesthetic considerations and adverse drug effects on skeletal, cardiac and smooth muscle tissue. It describes the pathogenetic aspects of typical complications and introduces anaesthetic procedures for the various neuromuscular disorders, including regional anaesthesia for patients in whom a restriction of respiratory and/or cardiac function is predicted.


Quinine intoxications reported to the Scottish Poisons Information Bureau 1997-2002: a continuing problem.

Quinine is widely prescribed in the UK for night cramps. Its potential toxicity in overdose is well known. We have reviewed the Scottish experience of enquiries regarding quinine overdose to the poisons information service responsible for Scotland over a 6-year period. Between 1997 and 2002 there were 96 reports of suspected quinine toxicity from Scotland (population 5.2 million), 19 of which were in children. The largest quantities of drug ingested were in patients between the ages of 11 and 30. In comparison with older studies the pattern of quinine poisoning does not appear to have changed in the UK over 20 years, despite recognition that it is a toxic agent in overdose, and particularly in children.

Calcium release from sarcoplasmic reticulum is facilitated in human myotubes

Malignant hyperthermia (MH) is caused by increased calcium release from sarcoplasmic reticulum, triggered by volatile anesthetics or depolarizing muscle relaxants. Numerous mutations associated with MH have been detected in the skeletal muscle type ryanodine receptor gene (RyR1), but so far facilitated calcium release has only been demonstrated for a few of them. This is a prerequisite for confirming the causative role of an RyR1 mutation for MH. Calcium release from sarcoplasmic reticulum induced by 4-chloro-m-cresol (4CmC), caffeine, and halothane was determined in human myotubes by calcium imaging. The RyR1 Ile2182Phe mutation and the RyR1 Gly2375Ala mutation have been identified in individuals susceptible to MH. In myotubes of individuals carrying the RyR1 Ile2182Phe or the RyR1 Gly2375Ala mutation, the EC(50) for caffeine and halothane was reduced; in the Ile2182Phe myotubes, the EC(50) for 4CmC was also reduced, all consistent with facilitated calcium release from the sarcoplasmic reticulum. From these data we conclude that both mutations are pathogenic for MH.

Heat stroke : a review of cooling methods.

The prognosis of heat stroke in patients is directly related to the degree of hyperthermia and its duration. Therefore, the most important feature in the treatment of heat stroke is rapid cooling. Several cooling methods have been presented in the literature including immersion in water at different temperatures, evaporative cooling, ice pack application, pharmacological treatment and invasive techniques. This article describes the various cooling techniques in terms of efficacy, availability, adverse effects and mortality rate. Data suggest that cooling should be initiated immediately at time of collapse and should be based on feasible field measures including ice or tepid water (1-16 degrees C), which are readily available. In the emergency department, management should be matched to the patient's age and medical background and include immersion in ice water (1-5 degrees C) or evaporative cooling.

Electrophysiological assessment of the effect of intrathecal baclofen in dystonic children.

OBJECTIVE: To evaluate the effect of intrathecal baclofen in a group of dystonic children using electrophysiological procedures previously validated in spastic children. METHODS: Seven children (aged 2-16 years) with dystonia of various aetiologies (dyskinetic cerebral palsy, pantothenate kinase-associated neurodegeneration and Aicardi-Goutieres syndrome) underwent transcranial magnetic stimulation, H-reflex and flexor reflex studies before and after intrathecal injection of baclofen. The Barry-Albright Dystonia Scale (BADS) was used for clinical evaluation of dystonia. RESULTS: Motor-evoked potentials, present in 2 of 5 patients before baclofen, were preserved after injection. Before baclofen, H reflex was present in 6 of 7 patients (mean H(max)/M(max:) 0.45+/-0.21). It was markedly reduced after the injection (mean H(max)/M(max:) 0.09+/-0.11) (P<0.001). Area of flexor reflex significantly decreased after baclofen (P=0.047), while threshold significantly increased (P=0.01). No significant clinical improvement of the BADS scores was observed (P=0.058). CONCLUSIONS: These electrophysiological procedures, previously demonstrated to quantify the action of intrathecal baclofen in spastic adults and children, also appear sensitive in dystonic children. The electrophysiological changes are consistent with primarily spinal sites of action of baclofen. They appear more sensitive than clinical evaluation.

The use of muscle relaxant / relaxants medications in acute low back pain.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: To determine the characteristics of patients who take muscle relaxants / relaxant for back pain after seeking care and to determine the relationship of muscle relaxant / relaxants use with recovery from the episode of low back pain. SUMMARY OF BACKGROUND DATA: Low back pain is a common condition with a generally favorable short-term prognosis. Physicians in the acute setting commonly prescribe muscle relaxants. The indications for use and outcomes are not clear. METHODS: We performed a secondary data analysis of a cohort of 1633 patients who sought care from a variety of practitioners (primary care, physician of chiropractic, orthopedic surgeon, Health Maintenance Organization) for low back pain. Patients were enrolled in the physician's office and interviewed at baseline, 2, 4, 8, 12, and 24 weeks. Pain, functional status, medication use, health care utilization, and satisfaction with care were assessed. RESULTS: muscle relaxants / relaxant were used by 49% of patients; among those who sought care from doctors, 64% used muscle relaxants. muscle relaxant / relaxants users were more impaired at baseline. Over time, among patients with greater functional status impairment (Roland disability score > 12) at baseline, muscle relaxant / relaxants users had somewhat slower recovery from the episode of back pain. This finding persisted after controlling for baseline functional status, age, worker's compensation status, and use of nonsteroidal inflammatory agents. CONCLUSIONS: Use of muscle relaxants / relaxant was very common among patients with acute low back pain. muscle relaxant / relaxants use was not associated with more rapid functional recovery.