Antispasticity medications: uses and limitations of enteral therapy.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, and the UPMC Health System, Pittsburgh, Pennsylvania, USA.

Ryanodine receptors in peritoneal mast cells: possible role in the modulation of exocytotic activity.

Previous studies have shown that ryanodine in low concentrations and caffeine increase intracellular [Ca(2+)] in the absence of external Ca(2+), suggesting Ca(2+) release from intracellular stores through ryanodine receptors (RyR). In the present study we employed amperometry to examine the effect of RyR agonists and antagonists on serotonin release elicited with compound 48/80 (10 micro g/ml). Ryanodine (1 micro M) or, similarly, 20 mM caffeine, in the absence of external Ca(2+), enhanced the amperometric response to compound 48/80 and all the individual amperometric spike parameters. Ryanodine (50 micro M), dantrolene (20 micro M) and tetracaine (50 micro M), putative antagonists of the RyR, attenuated the amperometric response significantly, decreasing the number and frequency of events as well as their amplitude. This is the first demonstration that Ca(2+) availability from RyR-operated Ca(2+) sources may contribute to the modulation of secretory activity in mast cells, affecting not only the cellular exocytotic response, but also the characteristics of single amperometric events. Immunocytochemical labelling, using a monoclonal RyR antibody, confirmed the presence of RyR in this preparation.

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.

Electroconvulsive therapy in myasthenia gravis.
Calarge CA, Crowe RR.
The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Department of Psychiatry, Iowa city, Iowa 52242-1057, USA. chadi-calarge@uiowa.edu
BACKGROUND: Myasthenia gravis (MG) is a neuromuscular disease sometimes associated with severe psychiatric complications. The use of electroconvulsive therapy (ECT) in MG raises certain challenges. METHODS: We describe a patient with MG and a steroid-induced major depressive episode with psychotic features treated with ECT. We also review the literature on similar cases and on the safety of ECT with muscle relaxation in this condition. RESULTS: The use of ECT in patients with MG is a viable therapeutic option when psychiatric complications secondary to MG or its treatment do not respond to psychotropic medications. CONCLUSION: ECT with muscle relaxants / relaxant could be administered safely, with appropriate precautions kept in mind.


Can first responders achieve and maintain normocapnia when sequentially ventilating with a bag-valve device and two oxygen-driven resuscitators? A controlled clinical trial in 104 patients.

BACKGROUND AND OBJECTIVE: To evaluate the capability of first responders to achieve and maintain normal ventilation of the lungs of victims employing a bag-valve device and two oxygen-driven resuscitators. METHODS: Prospective, controlled, blinded, single-centre clinical trial using a bag-valve device and one of two FR-300 devices, with 20 cmH2O working pressure, and flows of either 24 or 30 L min(-1). One hundred and four patients were analysed. Induction of anaesthesia followed by ventilation of the lungs with a bag-valve device and an Oxylator in manual and automatic modes performed by a fireman first responder. Each series was repeated for three conditions (anaesthesia; anaesthesia plus muscle relaxation, both with facemask; anaesthesia plus relaxation using an endotracheal tube). RESULTS: Patients age 49 +/- 17 yr; 47% males, 48-132 kg. Normocapnia was achieved and maintained in 66% (bag-valve device), 82% (Oxylator). CONCLUSIONS: The use of an oxygen-driven device improves the ability of first responders to achieve and maintain normocapnia even when distracted. Use of the Oxylators improves performance (P < 0.001) vs. the bag-valve device significantly.

Cardiomyopathy developed in the postoperative period in a patient with amyotrophic lateral sclerosis

Department of Intensive and Critical Care Medicine, Dokkyo University School of Medicine, Tochigi 321-0207. A 75-year-old woman with amyotrophic lateral sclerosis (ALS) underwent surgical gastrostomy and repair of incisional hernia. Anesthesia was induced with propofol and high concentrations of sevoflurane. Tracheal intubation was performed without muscle relaxants. Anesthesia was maintained with sevoflurane and thoracic epidural anesthesia (bupivacaine and fentanyl). Surgery, emergence and extubation were completed uneventfully. She was transferred to ICU for postoperative observation. On the 2 nd POD, however, she was re-intubated due to sudden dyspnea and desaturation caused by failed sputum exhaustion. Simultaneously, her ECG showed ischemic change in leads I, III, aVF, and V3-6. Left ventriculogram showed an "Ampulla" or so called "Takotsubo" shape with intact coronary angiogram. After medication with nitroglycerin and diltiazem, her ECG returned to normal. She showed no deterioration of neurological symptoms. No respiratory and cardiac events were reported until her discharge from hospital. We conclude that an extreme care is required in patient with ALS to avoid perioperative complications.

Dantrolene stabilizes domain interactions within the ryanodine receptor.
Kobayashi S, Bannister ML, Gangopadhyay JP, Hamada T, Parness J, Ikemoto N.
Boston Biomedical Research Institute, Watertown, Massachusetts 02472, USA.
Interdomain interactions between N-terminal and central domains serving as a "domain switch" are believed to be essential to the functional regulation of the skeletal muscle ryanodine receptor-1 Ca(2+) channel. Mutational destabilization of the domain switch in malignant hyperthermia (MH), a genetic sensitivity to volatile anesthetics, causes functional instability of the channel. Dantrolene, a drug used to treat MH, binds to a region within this proposed domain switch. To explore its mechanism of action, the effect of dantrolene on MH-like channel activation by the synthetic domain peptide DP4 or anti-DP4 antibody was examined. A fluorescence probe, methylcoumarin acetate, was covalently attached to the domain switch using DP4 as a delivery vehicle. The magnitude of domain unzipping was determined from the accessibility of methylcoumarin acetate to a macromolecular fluorescence quencher. The Stern-Volmer quenching constant (K(Q)) increased with the addition of DP4 or anti-DP4 antibody. This increase was reversed by dantrolene at both 37 and 22 degrees C and was unaffected by calmodulin. [(3)H]Ryanodine binding to the sarcoplasmic reticulum and activation of sarcoplasmic reticulum Ca(2+) release, both measures of channel activation, were enhanced by DP4. These activities were inhibited by dantrolene at 37 degrees C, yet required the presence of calmodulin at 22 degrees C. These results suggest that the mechanism of action of dantrolene involves stabilization of domain-domain interactions within the domain switch, preventing domain unzipping-induced channel dysfunction. We suggest that temperature and calmodulin primarily affect the coupling between the domain switch and the downstream mechanism of regulation of Ca(2+) channel opening rather than the domain switch itself.

Carisoprodol ( Soma ) intoxications and serotonergic features.
Bramness JG, Morland J, Sorlid HK, Rudberg N, Jacobsen D.
Division of Forensic Toxicology and Drug Abuse, Norwegian Institute of Public Health, Oslo, Norway. jorgen.bramness@labmed.uio.no
The symptoms and signs of Carisoprodol ( Soma ) intoxications do not resemble those caused by its metabolite meprobamate. Meprobamate most probably produces its effects through the GABAergic neurotransmitter system. The signs and symptoms of Carisoprodol ( Soma ) intoxications, however, are not easily explained by interaction with this neurotransmitter system. In the present study, four cases of Carisoprodol ( Soma ) intoxications are presented with emphasis on the presence of serotonergic signs and symptoms. All four cases fulfilled three different sets of criteria for the diagnosis of serotonin syndrome. These findings could indicate that an increased serotonin level in the central nervous system could explain some of the symptoms and signs of Carisoprodol ( Soma ) intoxications. This may have implications for the clinical evaluation and treatment of such intoxications. Since few laboratories routinely screen for Carisoprodol ( Soma ) it is important to keep this drug in mind when encountering intoxications displaying serotonergic symptoms.


Acute intoxication with baclofenWisniewski M.

Many authors have noticed an increase in suicidal intoxication with baclofen, a lipophilic analog of gamma-aminobutyric acid (GABA). Although morbidity and mortality is low in baclofen overdosage however may cause serious respiratory failure as also cardiac and neurological system disturbances. The aim of the study was to evaluate some clinical aspects of acute intoxication with baclofen. We analyzed 18 patients (8 females and 10 males) aged from 15 to 58 (mean 33+/-15.4) years. Patients were admitted to the Department of Toxicology in the years 1996-2003 because of suicidal intoxication with baclofen. Number of patients intoxicated with baclofen during the last four years of analysis was two times more than in the first four years. The doses of baclofen were from 150 to 1500 (mean 388) mg. There were twelve patients (66%) admitted to the Clinic in deep coma (III and IV grade of Matthew scale) with the hyporeflexia and low muscle tone. Acute respiratory failure which required mechanical ventilation (6 to 96--mean 53.2 hours) was observed in 10 cases (55.5%). Cardiac abnormalities included bradycardia (44.4%), hypertension (33.0%) and hypotension (5.5%). Toxic psychoses were observed in 6 cases (33.3%). Flumazenil administration had no impact on clinical advancement of coma. An increase in creatine kinase activity was observed in 12 patients (66.6%). Conclusions: There was no correlation between the dosage of baclofen and the clinical outcome. Baclofen poisoned patients should be admitted to hospitals with adequate medical equipment, especially respirators.

Increased cAMP as a positive inotropic factor for mammalian skeletal muscle in vitro.

To test the hypothesis that an increased cAMP concentration improves skeletal muscle force development, we stimulated mouse soleus and extensor digitorum longus (EDL) in the presence of isoproterenol (1 x 10(-5) mol.L-1), a beta-adrenergic agonist, or N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dcAMP) (1 x 10(-3) mol.L-1), a membrane-permeable cAMP analogue. Drugs used in the challenges were dissolved in Krebs-Henseleit bicarbonate buffer (Krebs) at 27 degrees C and gassed with 95% O2 - 5% CO2. Stimulation at 50 impulses.s-1 for 0.5 s produced an isometric tetanic contraction. Over 25 min of contractions at 0.6 contractions.min-1, developed force increased significantly with the addition of isoproterenol (soleus, 2.5% +/- 1.1%; EDL, 13.8% +/- 2.0%) or dcAMP (soleus, 2.3% +/- 0.5%; EDL, 10.9% +/- 1.9%) as compared with vehicle controls (cont) with Krebs added (soleus, 0.0% +/- 0.2%; EDL, -2.5% +/- 0.7%). To investigate the role of Ca2+ availability, we amplified or attenuated sarcolemmal L-type Ca2+ channels with Bay K 8644 (Bay K) (5.6 x 10(-6) mol.L-1) or diltiazem hydrochloride (dilt) (10(-4) mol.L-1), respectively. Ca2+ release from the sarcoplasmic reticulum was increased with caffeine (2 x 10(-3) mol.L-1) or decreased with dantrolene sodium (dant) (4.2 x 10(-7) mol.L-1). With Ca2+availability modified, dcAMP addition in soleus significantly increased force development above control (cont, 2.3% +/- 0.4%; Bay K, 4.0% +/- 1.0%; dilt, 52.3% +/- 3.6%; caffeine, 2.3% +/- 0.7%; dant, 6.0% +/- 2.0%; dilt + dant, 55.0% +/- 23.0%). In EDL, the addition of dcAMP also increased force development above control (cont, 13.7% +/- 1.9%; Bay K, 17.0% +/- 4.0%; dilt, 170.0% +/- 40.0%; caffeine, 23.0% +/- 4.0%; dant, 72.0% +/- 10.0%; dilt + dant, 54.0% +/- 14.0%). Thus, a positive inotropic effect of cAMP existed in both fast- and slow-twitch mammalian skeletal muscle with both normal and altered Ca2+ flux into the sarcoplasm.