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.

GW280430A: pharmacodynamics and potential adverse effects.
Lien CA, Belmont MR, Heerdt PM.


Orally delivered baclofen to control spastic hypertonia in acquired brain injury.

To determine if oral/systemic delivery of baclofen can effectively decrease spastic hypertonia due to acquired brain injury (traumatic brain injury, stroke, anoxia, or encephalopathy). Tertiary care outpatient rehabilitation center directly attached to a university hospital. Patients were a convenience sample recruited consecutively who had been referred for treatment of their spastic hypertonia to our spasticity clinic over a 5-year period. The spastic hypertonia was due to an acquired brain injury by either traumatic brain injury (TBI), stroke, or anoxic brain injury. All patients were more than 6 months postinjury or illness. Retrospective review of patients before and after initiation of treatment with oral baclofen, per standardized clinical data sheets. Thirty-five patients (22 TBI patients) were started on oral baclofen and were reevaluated between 1 to 3 months after initiation of treatment. Data for motor tone (Ashworth scores), spasm scores (Penn spasm frequency score), and deep tendon reflex scores were collected on the affected upper extremity (UE) and lower extremity (LE) side(s). Normal extremities were not assessed. Differences over time were assessed via descriptive statistics and Wilcoxon signed-rank. After 1 to 3 months of treatment when subjects had reached their maximal tolerated dosage, the average LE Ashworth score in the affected lower extremities (LEs) decreased from 3.5 to 3.2 (P =.0003), the reflex score decreased from 2.5 to 2.2 (P =.0274), and there was no statistical difference in the spasm score (P >.05). When the 22 TBI patients are analyzed separately, the average LE Ashworth score decreased from 3.5 to 3.2 (P =.0044) and the reflex score decreased from 2.7 to 2.0 (P =.0003). There was no statistically significant change in UE tone, spasm frequency, or reflexes after 1 to 3 months of treatment (P >.05). The average dosage at follow-up was 57 mg/day of baclofen (range 15-120 mg/day). There was a 17% incidence of somnolence that limited the maximum daily dosage of the medication. The oral delivery of baclofen is capable of reducing LE spastic hypertonia resulting from acquired brain injury. The lack of effect upon the upper extremities may be due to receptor specificity issues. GABA-B receptors may be less involved in the modulation of UE spastic hypertonia.

Benzodiazepines affect channel opening of GABA A receptors induced by either agonist binding site.
Baur R, Sigel E.
Department of Pharmacology, Friedbuehlstrasse 49, CH-3010 Bern, Switzerland.
Benzodiazepines are widely used as anxiolytics, sedatives, muscle relaxants, and anticonvulsants. They allosterically modulate GABA type A (GABA(A)) receptors by increasing the apparent affinity of the agonist GABA to elicit chloride currents. Such an increase in apparent affinity of channel gating could either be caused by an increase in affinity for GABA or by a facilitation of channel opening. In the first case, conformation of the affected sites would have to be altered. In the second case, the affected sites are not necessarily altered, because diazepam could facilitate conformational changes leading to the open channel. It is controversial as to whether benzodiazepines affect only channel opening induced by the occupation of one of the two agonist binding sites or by both. We used receptors formed by concatenated subunits to selectively destroy one of the two agonist sites by point mutation. Both of the receptors harboring only one active agonist site could be stimulated by diazepam. We therefore present evidence that binding of diazepam can affect channel opening induced by either agonist binding site.

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.

A fatality involving Metaxalone ( Skelaxin ).
Moore KA, Levine B, Fowler D.
Office of the Chief Medical Examiner, State of Maryland, 111 Penn St., Baltimore, MD 21201, USA. kamoore2@juno.com
A case is presented of a 54-year-old white female found dead in a secured apartment. Postmortem toxicologic analysis of the heart blood identified acetaminophen (97 mg/L), citalopram (0.4 mg/L), gabapentin (24 mg/L) and Metaxalone ( Skelaxin ) (21 mg/L). The Metaxalone ( Skelaxin ) concentration is within the range of previously reported fatalities involving Metaxalone ( Skelaxin ). The medical examiner ruled that the cause of death was Metaxalone ( Skelaxin ) and gabapentin intoxication and the manner of death was suicide.


Drug therapy of back pain

The importance of analgesic drugs in the treatment of low back pain is a matter of intense debate. Based on the current literature, a multidisciplinary approach combining drug treatment with physical and psychotherapy has proven to be the most successful treatment of back pain. This perspective is challenged by various anesthesiologists who claim that early use of opioids in back pain therapy is the concept of choice. The results of recent studies regarding this matter are controversial. This chapter reviews the historical background of analgetic drugs and provides an overview of the current diagnostic and therapeutic options in the treatment of back pain. Recommendations are given based on the results of current randomized controlled studies.

Total intravenous anesthesia for repair of congenitral diaphragmatic hernia: a case report.

Congenital diaphragmatic hernia is a cardiopulmonary anomaly that causes severe respiratory disorder. Traditionally, inhalational anesthetics with mechanical hyperventilation, opioids, and muscle relaxants / relaxant are used in anesthesia for repair surgery. In this case, we used total intravenous anesthesia combined with high-frequency oscillatory ventilation and inhaled nitric oxide for surgical repair of the diaphragm. After surgery, the patient recovered well and was discharged from hospital 1 month later.

Intrathecal baclofen for the treatment of tetanus.

Tetanus remains a serious problem in public health, particularly in developing countries, despite efficient prevention programs. A retrospective study was conducted at an infectious diseases intensive care unit during 1998-2003 involving patients admitted with grade III tetanus. The aim of the study was to evaluate the efficacy and safety of intrathecal baclofen for the treatment of tetanus. Lumbar puncture was performed, and a subarachnoid catheter was inserted for drug administration. An intrathecal bolus of baclofen was followed by a continuous infusion of 20 microg/h, until a maximum daily dose of 2 mg was provided. Twenty-two patients were treated overall. Control of the symptoms was achieved in all patients but one. Seven patients had colonization of the catheter, and 1 patient developed meningitis. All patients except one recovered. In our study, this means of treatment was efficacious and well tolerated.

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.