Contribution of GABAA receptor subtypes to the anxiolytic-like, motor, and discriminative stimulus effects of benzodiazepines: studies with the functionally selective ligand SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one].
Licata SC, Platt DM, Cook JM, Sarma PV, Griebel G, Rowlett JK.
Harvard Medical School, New England Primate Research Center, Southborough, MA 01772, USA. stephanie_licata@hms.harvard.edu
Benzodiazepines (BZs) are prescribed for a variety of disorders, including those involving anxiety and sleep, but have unwanted side effects that limit their use. Elucidating the GABA(A) receptor mechanisms underlying the behavioral effects of BZs will help develop new drugs having both maximum clinical benefit and minimum adverse side effects. A recently developed compound is SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one], which is a full agonist at GABA(A) receptors containing alpha(2)and alpha(3) subunits and a partial agonist at GABA(A) receptors containing alpha(1) and alpha(5) subunits. We assessed the ability of SL651498 to engender anxiolytic-like, motor, and subjective effects characteristic of BZ-type drugs in nonhuman primates. Anxiolytic-like activity was assessed with a conflict procedure in rhesus monkeys. Motor effects were evaluated in squirrel monkeys using observational techniques, and the subjective effects of SL651498 were assessed in squirrel monkeys trained to discriminate the nonselective BZ triazolam from saline. SL651498 engendered anxiolytic-like effects similar to conventional BZs. In addition, SL651498 fully induced muscle relaxation, but unlike conventional BZs, engendered minimal ataxia. In drug discrimination studies, SL651498 partially substituted for triazolam. This effect was blocked with the alpha(1) GABA(A) subtype-preferring antagonist beta-CCT (beta-carboline-3-carboxylate-t-butyl ester), implicating alpha(1) GABA(A) effects receptors in the subjective of SL651498. Together, these studies suggest that compounds such as SL651498 that have high intrinsic efficacy at alpha(2)GABA(A) and/or alpha(3)GABA(A) receptors may have clinical potential as anxiolytics and muscle relaxants. Moreover, a compound with reduced efficacy at alpha(1) GABA(A) and/or alpha(5) GABA(A) receptors may lack some of the motor and subjective effects associated with conventional BZs.
PMID: 15687371 [PubMed - in process]


Myofascial pain disorders: theory to therapy.

Voluntary muscle is the largest human organ system. The musculotendinous contractual unit sustains posture against gravity and actuates movement against inertia. Muscular injury can occur when soft tissues are exposed to single or recurrent episodes of biomechanical overloading. Muscular pain is often attributed to a myofascial pain disorder, a condition originally described by Drs Janet Travell and David Simons. Among patients seeking treatment from a variety of medical specialists, myofascial pain has been reported to vary from 30% to 93% depending on the subspecialty practice and setting. Forty-four million Americans are estimated to have myofascial pain; however, controversy exists between medical specialists regarding the diagnostic criteria for myofascial pain disorders and their existence as a pathological entity. Muscles with activity or injury-related pain are usually abnormally shortened with increased tone and tension. In addition, myofascial pain disorders are characterised by the presence of tender, firm nodules called trigger points. Within each trigger point is a hyperirritable spot, the 'taut-band', which is composed of hypercontracted extrafusal muscle fibres. Palpation of this spot within the trigger point provokes radiating, aching-type pain into localised reference zones. Research suggests that myofascial pain and dysfunction with characteristic trigger points and taut-bands are a spinal reflex disorder caused by a reverberating circuit of sustained neural activity in a specific spinal cord segment. The treatment of myofascial pain disorders requires that symptomatic trigger points and muscles are identified as primary or ancillary pain generators. Mechanical, thermal and chemical treatments, which neurophysiologically or physically denervate the neural loop of the trigger point, can result in reduced pain and temporary resolution of muscular overcontraction. Most experts believe that appropriate treatment should be directed at the trigger point to restore normal muscle length and proper biomechanical orientation of myofascial elements, followed by treatment that includes strengthening and stretching of the affected muscle. Chronic myofascial pain is usually a product of both physical and psychosocial influences that complicate convalescence.

The effect of use of pyridostigmine and requirement of vecuronium in patients with myasthenia gravis.

CONTEXT: Patients with myasthenia gravis receive pyridostigmine, an anticholinesterase agent, as a part of therapy. These patients demonstrate a heightened sensitivity towards non-depolarising muscle relaxants. Continuing pyridostigmine till the day of the surgery or omitting it on the night before surgery could provide variable results with regards to the effect of vecuronium. AIMS: Myographic evaluation of a dose of vecuronium in patients with myasthenia gravis on pyridostigmine therapy. SETTING AND DESIGN: A randomised, double-blind, clinical study conducted in a teaching hospital. SUBJECTS AND METHODS: Medically (oral pyridostigmine) well-controlled adult patients with myasthenia gravis who were posted for thymectomy, were randomly divided into two groups. Patients in Group 1 received their last dose of pyridostigmine on the night before surgery while those in Group 2 received even the morning dose of the drug on the day of surgery. Neostigmine (1-2 mg) intravenously was used as rescue medication. Vecuronium (0.01 mg/kg) was used for intubation and muscle relaxation during trans-sternal thymectomy and its effect was reversed using neostigmine and atropine. RESULTS: Fourteen patients (7 in each group) belonging to both sexes were enrolled in the study. The intubating dose of vecuronium showed quicker onset time (155 sec or 2.7 min approx.) and peak effect (99% T1 suppression) in patients belonging to Group 1, and 3/7 (43%) complained of respiratory discomfort while waiting for surgery. By giving the morning dose of pyridostigmine (Group 2), an identical intubating dose of vecuronium showed relative resistance (peak effect-97% T1 suppression) and delayed onset time (198 sec approx.). However, the reversal was complete at the end of surgery in both the regimens. CONCLUSIONS: Omission of the pyridostigmine dose on the day of surgery predisposed patients with myasthenia gravis to the possibility of respiratory discomfort and sensitivity to vecuronium. Continued administration significantly prolonged the onset time of vecuronium and the patients required a higher dose of vecuronium.

Bedtime diazepam enhances well-being in children with spastic cerebral palsy.
Mathew A, Mathew MC.
Continuing Medical Education Department, Christian Medical College, Vellore, T.Nadu, India. ashirvad@cmcvellore.ac.in
In work with children with cerebral palsy at Ashirvad, Child Development and Research Centre, Chennai, India, the authors were confronted with fretful children who resisted any attempt to mobilize their limbs due to hypertonia and muscle spasm. It was found that administering a bedtime dose of diazepam to reduce hypertonia and muscle spasm alongside passive stretching exercises significantly improved the behaviour of the child. There was significant improvement in the well-being of the child during the activities of daily living and this reduced the family's burden of caring for the child. In this double blind, placebo-controlled, randomized clinical trial, each child received a bedtime dose of diazepam or placebo. The bedtime diazepam relaxed the muscles and this made the passive stretching easy and the movements sustained the muscle relaxation during the day. There were fewer unwarranted crying spells during the day and less wakefulness during the night. The adverse effect of day time sedation was not observed with the use of a single dose of diazepam at bedtime.


Synthesis and bladder smooth muscle relaxing properties of substituted 3-amino-4-aryl-(and aralkyl-)cyclobut-3-ene-1,2-diones.
Butera JA, Jenkins DJ, Lennox JR, Sheldon JH, Norton NW, Warga D, Argentieri TM.
Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. buteraj@wyeth.com
We have reported on the design, synthesis, and biological characterization of (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile (1), a novel, potent, and selective adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel opener with potential utility for the treatment of urge urinary incontinence (UUI). Excising the aniline-derived nitrogen atom of 1 or replacing it with an aralkyl group, led to bladder smooth muscle relaxant / relaxants chemotypes 3 and 4, respectively. Prototype compounds in these series were found to produce significant increases in an iberiotoxin (IbTx)-sensitive hyperpolarizing current, thus suggesting that these relatively modest structural modifications resulted in a switch in the mechanism of action of these smooth muscle relaxants / relaxant from K(ATP) channel openers to activators of the large-conductance Ca2+-activated potassium channel (BK(Ca)). We report herein the syntheses and biological evaluation of a series of substituted 3-amino-4-aryl-(and aralkyl-)cyclobut-3-ene-1,2-diones.


Operating conditions for ocular surgery under general anaesthesia: an eccentric problem.
Rossiter JD, Wood M, Lockwood A, Lewis K.
1Moorfields Eye Hospital, London, UK.
CONCLUSIONS: Eccentric ocular positions are likely to occur in light planes of general anaesthesia. In the case of ocular surgery, this phenomenon may create surgical difficulty and increase the risk of complication and patient morbidity. Arguments for the planned use of balanced general anaesthesia with non-depolarizing muscle relaxants / relaxant are presented.Eye advance online publication, 14 January 2005; doi:10.1038/sj.eye.6701789.

Use of antivenin to treat priapism after a black widow spider bite.

Black widow spider envenomation (BWSE) is commonly associated with severe abdominal pain, muscle cramping, and hypertension. Treatment is primarily symptomatic with the use of opiates and benzodiazepines. Priapism is a complication of BWSE that has only rarely been reported. We describe a 17-month-old male who developed priapism after known BWSE. His priapism did not respond to opiates or benzodiazepines, and he was treated with black widow spider antivenin. Complete detumescence followed within several hours. The patient required no additional opiates for pain and was discharged from the hospital the following day. The patient's rapid improvement after antivenin suggests its efficacy in treating BWSE-associated priapism.

Anesthesia in the obese patient: pharmacokinetic considerations.
Casati A, Putzu M.
Department of Anesthesiology and Pain Therapy, University of Parma, Parma, Italy. acasati@ac.pr.it
The prevalence of obesity has increased 15% up to 20% and represents an important challenge for the anesthesiologist in drug-dosing management. The aim of this work is to provide an overview on physiological changes and pharmacokinetic implications of obesity for the anesthesiologist. Obesity increases both fat and lean masses; however, the percentage of fat tissue increases more than does the lean mass, affecting the apparent volume of distribution of anesthetic drugs according to their lipid solubility. Benzodiazepine loading doses should be adjusted on actual weight, and maintenance doses should be adjusted on ideal body weight. Thiopental sodium and propofol dosages are calculated on total body weight (TBW). The loading dose of lipophilic opioids is based on TBW, whereas maintenance dosages should be cautiously reduced because of the higher sensitivity of the obese patient to their depressant effects. Pharmacokinetic parameters of muscle relaxants / relaxant are minimally affected by obesity, and their dosage is based on ideal rather than TBW. Inhalation anesthetics with very low lipid solubility, such as sevoflurane and desflurane, allow for quick modification of the anesthetic plan during surgery and rapid emergence at the end of surgery, hence representing very flexible anesthetic drugs for use in this patient population. Drug dosing is generally based on the volume of distribution for the loading dose and on the clearance for maintenance. In the obese patient, the volume of distribution is increased if the drug is distributed both in lean and fat tissues whereas the anesthetic drug clearance is usually normal or increased.


Intraoperative effects of combined versus general anesthesia during major liver surgery.

AIM: The study compares the intraoperative effects of combined versus general anesthesia during major liver surgery. METHODS: In this prospective randomized study, 70 patients were divided into 2 group of 35 subjects. Group A received general anesthesia (thiopentone, fentanyl, vecuronium, sevoflurane in a closed circuit) 15 minutes after placement of an epidural catheter (D9-D10) and induction of epidural anesthesia (6 ml 2% naropine). Continuous epidural infusion was initiated before surgical incision and continued with 0.2% naropine (7 ml/h) until the end of the operation. Group B received combined intraoperative anesthesia wit fentanyl doses according to hemodynamic parameters and 0.1 mg/kg morphine 30-4 minutes before cutaneous suture. Hemodynamic values were measured at base line (T0), and then at 15, 30, 60, 120 and 180 minutes after induction of general anesthesia (T1, T2, T3, T4 and T5, respectively). On recovery, patients were assessed for pain at rest and on movement reported on a visual analog scale; degree of motor blockade according to the Bromage scale; appearance of side effects; use af analgesic. RESULTS: A statistically significant decrease in the mean arterial blood pressure (ABP) and heart rate (HR) was noted within each group at 15 minutes after induction of general anesthesia. Significant differences in ABP were found between the 2 groups at T1 to T5, whereas HR values were substantially similar. The mean intraoperative use of fentanyl was significantly higher in Group B than in Group A, as was that of vecuronium. Pain intensity on recovery in patients who received epidural anesthesia was lower both at rest and on movement; only the patients in Group B required additional analgesics. No motor blockade was observed in either group. Nausea and vomiting were more frequent in Group B; hypotension was more frequent in Group A. CONCLUSION: The study confirms the safety of locoregional anesthesia in liver surgery, with good hemodynamic stability and absence of major side effects. The lower intraoperative use of opioids and muscle relaxants / relaxant in patients who received epidural anesthesia confirms the neurovegetative protection this method provides. The data support the hypothesis that greater intraoperative use of opioids may be responsible for the higher incidence of side effects. Therefore, the intraoperative use of combined low-concentration anesthetic agents alone appears to offer a reasonable treatment option that provides adequate pain control at recovery from general anesthesia, with only minor side effects typically associated with analgesic (motor blockade) and opioids (nausea and vomiting). Given the complications associated with the technique, it should be performed by an expert anesthetist.

Drug management of low back pain.
Matsudaira K, Kawaguchi H.
Department of Orthopedic Surgery, Faculty of Medicine, The University of Tokyo.
NSAIDs and muscle relaxants / relaxant effectively reduce acute nonspecific low back pain (LBP), different types of both drugs being equally effective. In general, there is no strong evidence for the effectiveness of medication for chronic nonspecific LBP. However, there is a possibility that administration of antidepressants is an intervention worthy of consideration in cases of LBP with no identifiable organic cause and resistant to other treatments.