Recent advances in neuromuscular blocking agents.
Zlotos DP.
Pharmaceutical Institute, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany. zlotos@pzlc.uni-wuerzburg.de
Since the introduction of (+)-tubocurarine into anaesthetic and surgical practice (1942), a number of non-depolarizing neuromuscular blocking agents (NMBs) with improved pharmacological properties have been developed during the last sixty years. However, after withdrawal of rapacuronium from clinical use, there is still a need for an ultra-short acting non-depolarizing muscle relaxant / relaxants with rapid onset as substitution for the polarizing suxamethonium, which has several undesirable side-effects. In this paper, structure-activity relationships within four different series of NMBs (tetrahydroisoquinolinium, bistropinyl diester, aminosteroid, and amino peptide analogues) published in this millennium have been reviewed. The NMB properties of the most promising drug candidates from each series were discussed and compared to those of the already existing muscle relaxants.


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.

Simple and sensitive liquid chromatography-tandem mass spectrometry method for determination of the S(+)- and R(-)-enantiomers of baclofen in human plasma and cerebrospinal fluid.

A simple and sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method to determine the enantiomers of the muscle relaxant / relaxants baclofen in human plasma and cerebrospinal fluid (CSF) has been developed. A commercially available ultrafiltration membrane is used to prepare the sample. A chiral CROWNPAK CR(+) stationary phase column is then used to perform complete resolution of the S(+)- and R(-)-enantiomers of baclofen. This method was used to analyze human plasma and CSF spiked with baclofen, and the calibration curves for both biologic samples were linear over a concentration range of 0.15-150 ng enantiomer/ml. The lower limit of quantification was 0.15 ng enantiomer/ml in both fluids. Finally, the method was tested with an artificial CSF as an alternative to authentic human CSF. The results showed that no matrix effects and no interfering peaks were observed using this artificial CSF.

Prescription of nonsteroidal anti-inflammatory drugs and muscle relaxants / relaxant for back pain in the United States.
Luo X, Pietrobon R, Curtis LH, Hey LA.
Center for Clinical Effectiveness, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27710, USA. luo00003@mc.duke.edu
STUDY DESIGN: Secondary analysis of the 2000 Medical Expenditure Panel Survey (MEPS). OBJECTIVE.: To examine national prescription patterns of nonsteroidal anti-inflammatory drugs (NSAIDs) and muscle relaxants / relaxant among individuals with back pain in the United States. SUMMARY OF BACKGROUND DATA: There is a lack of information on national prescription patterns of NSAIDs and muscle relaxants / relaxant among individuals with back pain in the United States. METHODS: Traditional NSAIDs, cyclooxygenase-2-specific (COX-2) inhibitors, and muscle relaxants / relaxant were investigated. Individuals with back pain were stratified by socio-demographic characteristics and geographic regions. For each medication category, overall prescribing frequency was compared across different strata and individual drug prescription was analyzed. RESULTS: Traditional NSAIDs, COX-2 inhibitors, and muscle relaxants, respectively, accounted for 16.3%, 10%, and 18.5% of total prescriptions for back pain in 2000. Among individual drugs, ibuprofen and naproxen accounted for most of the prescriptions for traditional NSAIDs (60%), whereas two thirds of the prescriptions for muscle relaxants / relaxant were attributable to Cyclobenzaprine, Flexeril, Carisoprodol ( Soma ), and methocarbamol. Prescription of COX-2 inhibitors or muscle relaxants / relaxant demonstrated wide variations across different regions. Several individual characteristics including age, race, and educational level were associated with the prescription of some of the medications. CONCLUSIONS: Neither traditional NSAIDs, nor COX-2 inhibitors, nor muscle relaxants / relaxant dominated prescriptions for back pain. However, a small number of individual drugs were attributable to most of the prescriptions for traditional NSAIDs or muscle relaxants. The prescription of some of the medications demonstrated wide variations across different regions or different racial and educational groups. More studies are needed to understand the source of the variations and what constitutes optimal prescribing.


Chronic daily headache and medication-induced headache.
Takase Y.
Department of Neurology, Toyonaka Municipal Hospital.
Chronic daily headache (CDH) and medication-induced headache are refractory headaches to treatment. I evaluate the classification and pharmacological treatment of CDH and medication-induced headache. The subjects of this study are 508 patients with CDH (out of 2,241 patients with chronic headache who were examined and treated in Toyonaka Municipal Hospital for six years from November 1997 to October 2003). CDH was classified into three types of chronic migraine in 232 cases (45.7%), chronic tension-type headache in 223 cases (43.9%) and new daily-persistent headache in 53 cases (10.4%). 245 cases overused medication (analgesic in 230 cases, ergotamine in eight cases and triptan in seven cases). 108 cases abused medication (analgesic in 95 cases, ergotamine in seven cases and triptan in six cases). For treatment, muscle relaxants, calcium-channel blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, antiepleptic drugs and leukotriene receptor antagonists were administered to 231 patients for two months from September to October 2003. Awareness of CDH and medication-induced headache is important to physicians who treat patients with headache.


Acute akinesia or akinetic crisis in Parkinson's disease.

In 22 patients with idiopathic Parkinson's disease we observed a sudden worsening of motor symptoms and severe akinesia during hospitalization because of infectious diseases, bone fractures, surgery for gastrointestinal tract diseases, and iatrogenic causes. Of these patients, 12 recovered completely, 6 had a partial recovery, and 4 died. Treatments included subcutaneous apomorphine/lisuride infusion and dantreolene (with a creatine phosphokinase level higher than 200 IU). In all patients a definite refractoriness to therapy was shown with a transient lack of response to apomorphine.

Infected CNS infusion pumps. Is there a chance for treatment without removal?

Review of Reported Cases

Malignant hyperthermia.

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.

Postoperative hyperthermia of unknown origin treated with dantrolene sodium.
Inada H, Jinno S, Kohase H, Fukayama H, Umino M.
Section of Anesthesiology and Clinical Physiology, Department of Oral Restitution, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. inada.anph@tmd.ac.jp
An 11-year-old girl was scheduled for alveolar cleft bone grafting with an iliac bone under general anesthesia. Anesthesia was performed with 70% nitrous oxide, 30% oxygen, and propofol. On the first and second postoperative day, persistent hyperthermia was observed. Because the administration of diclofenac sodium had not been effective for the hyperthermia, dantrolene sodium was given. Her body temperature gradually dropped and returned to normal level on the fifth postoperative day. The hyperthermia in the present case might have been caused by a rapidly elevated muscle metabolism in response to pain and stress after the propofol anesthesia. The oral administration of dantrolene sodium successfully lowered the patient's high body temperature.


Onset and duration of rocuronium-induced neuromuscular blockade in patients with Duchenne muscular dystrophy.
Wick S, Muenster T, Schmidt J, Forst J, Schmitt HJ.
Department of Anesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
BACKGROUND: In patients with Duchenne muscular dystrophy (DMD) the response to nondepolarizing muscle relaxants / relaxant is scarcely documented and conflicting. The current study was conducted to determine the time to peak effect and the time for complete spontaneous recovery after a single dose of 0.6 mg/kg of rocuronium in patients with DMD. METHODS: Twenty-four patients (12 with DMD, 12 controls, aged 10-16 yr) were studied. All patients were anesthetized with propofol and fentanyl/remifentanil. Neuromuscular transmission was monitored by acceleromyography. After induction all patients received a single dose of 0.6 mg/kg of rocuronium. The complete time course of onset and spontaneous recovery were recorded RESULTS: Significant (P < 0.01) increase in the onset times to 95% neuromuscular block was observed in DMD patients (median, 203 s; range, 90-420 s) compared with controls (median, 90 s; range, 60-195 s). The time between rocuronium administration and recovery of first twitch of the train-of-four to 90% was significantly (P < 0.01) prolonged in DMD compared with controls (median, 132 min; range, 61-209 min versus 39 min; 22-55 min). The recovery index was also significantly prolonged in the DMD group compared with controls (median, 28 min, range, 15-70 min versus 8 min; 3-14 min). CONCLUSIONS: The most striking and surprising result of this study is the delayed onset of blockade in DMD after a standard dose of rocuronium. This effect should be kept in mind in situations when a rapid airway protection is necessary in DMD patients. The documented very long recovery from rocuronium-induced block emphasizes the need for careful assessment of neuromuscular function in DMD patients.