Propofol decreases waste anesthetic gas exposure during pediatric bronchoscopy.

OBJECTIVE: This study compared the anesthetic gas exposure and operating conditions during insufflation anesthesia with halothane-alone versus halothane-propofol in children undergoing direct laryngobronchoscopy. STUDY DESIGN: Forty-six children were enrolled in this randomized prospective study, with institutional review board approval and informed consent. METHODS: All children were anesthetized by halothane mask induction and anesthesia was maintained using spontaneous ventilation with insufflation. No muscle relaxants / relaxant or opioids were used. In the halothane group, halothane was titrated as needed. In the propofol group, halothane was decreased to 1% inspired concentration and the propofol was titrated as needed to maintain spontaneous ventilation and a still patient. Trace anesthetic gases, hemodynamic stability, and operating conditions were measured. RESULTS: The groups were similar in age, weight, and bronchoscopy time. There was significantly less gas exposure in the propofol group (25 +/- 33 parts per million) versus the halothane group (66 +/- 97 ppm; P <.02). There was a trend toward earlier emergence in the halothane group (33 +/- 13 minutes) versus the propofol group (41 +/- 17 minutes). Postoperative stridor was common, occurring in 30% of children. CONCLUSIONS: Insufflation anesthesia with spontaneous respiration provides excellent surgical conditions for laryngobronchoscopy. The addition of propofol resulted in fewer airway complications (P =.047). Although the addition of propofol significantly decreased anesthetic gas exposure in the operating room, both techniques resulted in operating room pollution that exceeded the maximum levels of 2 ppm per hour recommended by the US National Institute for Occupational Safety and Health (NIOSH).

Intrathecal baclofen in severe spasticity due to multiple sclerosis

Intrathecal administration of baclofen via programmable pump is a highly effective treatment method in severe spasticity resistant to oral medications. The authors describe a case of severe spasticity with tetraplegia and painful (> 10 a day) muscle spasms in the upper and lower limbs and paraspinal muscles, in a patient with clinically definite diagnosis of multiple sclerosis (MS). The 34-year-old female patient with a 15-year history of MS, suffering from lower limb spasticity with pes equinovarus since 1995, was treated with very good results with botulinum toxin injections of calf muscles (14 sessions of Dysport 1500iu till 2002). In the early 2002 she developed tetraplegia with severe, generalized and intractable spasticity. After 4 months of ineffective polytherapy (with high doses of oral baclofen, Tizanidine ( Zanaflex ), gabapentine, clonidine, diazepam) and the patient's enormous sufferings (she could neither sit up nor voluntarily change her position in bed), a programmable baclofen pump (Medtronic) was implanted. As soon as a few days after the surgery she could stand, sit and move voluntarily, her painful spasms disappeared, and her bladder catheter was removed. At a 6-month follow-up the effect was stable--she was able to walk a long distance outdoors with the aid of a crutch. The daily dose of the drug is 500 micrograms. No side effects of complications were noted.

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.


muscle relaxants / relaxant for non-specific low back pain: a systematic review within the framework of the Cochrane collaboration. Spine 2003;28:1978-92.

Jordan A.

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.

Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: a comparison with nonalcoholics.
Liangpunsakul S, Kolwankar D, Pinto A, Gorski JC, Hall SD, Chalasani N.
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Alcohol consumption is known to induce hepatic CYP2E1 activity, but its effect on hepatic and intestinal CYP3A in humans is not known. We have conducted a study to compare the CYP2E1 and CYP3A activities in 20 individuals with moderate alcohol consumption and 20 gender-, race-. and body mass index (BMI)-matched nonalcoholics. Intravenous and oral midazolam (MDZ) clearances were used to measure the in vivo CYP3A activity, and chlorzoxazone (CHZ) oral clearance was used to assess in vivo CYP2E1 activity. Furthermore, we assessed the relationship between hepatic CYP2E1 and CYP3A activities and their messenger RNA (mRNA) expression in the peripheral lymphocytes. The systemic clearance (CL) of MDZ was not different between alcoholics (36.9 +/- 12 L/hr) and nonalcoholics (36.6 +/- 14.1; P = .9). The oral availability of MDZ was significantly lower in alcoholics than in the nonalcoholics (0.28 +/- .09 vs. 0.38 +/- .17, respectively, P = .03). The maximum serum concentration after oral midazolam dosing was significantly different between the 2 groups. CHZ CL was significantly higher in alcoholics than in nonalcoholics (31.5 +/- 11.9 vs. 23.4 +/- 8.7 L/hr, P < 0.05). CYP3A4 and CYP2E1 mRNA levels were not significantly different between the groups, and no correlation was observed between lymphocyte CYP mRNA and in vivo CYP activity. In conclusion, in individuals with moderate alcohol consumption, there was no alteration in the hepatic CYP3A activity, but the reduced midazolam oral bioavailability suggests that moderate alcohol consumption may cause intestinal CYP3A induction. Lymphocyte CYP2E1 and CYP3A4 mRNA levels did not correlate with CYP2E1 and CYP3A activities.


Synthesis and biological activity of novel substituted benzanilides as potassium channel activators. V.

As part of our program toward designing potassium channel openers, the synthesis of a novel series of substituted benzanilides and their vasodilating activity are presented. The facile synthetic pathway generally involves coupling between the appropriate benzoyl chloride and commercial available anilines, followed by the selective or non-selective cleavage of methyl ether substituent(s), affording the corresponding phenol or bisphenol derivatives. The pharmacological evaluation of these structurally novel potential BK-openers on vascular contractile activity was studied in vitro, using isolated rat aortic rings pre-contracted with KCl 20 mM. Some derivatives were found to be potent smooth muscle relaxants / relaxant and the vasodilation effects of these compounds were inhibited by tetraethylammonium (TEA) and iberiotoxin (IbTX), suggesting that the opening of BK channels is prevalent in the mechanism of action of these compounds. The best compound of the series was N-(2-hydroxy-5-phenyl)-(2-methoxy-5-chloro)-benzamide (16b) showing a full vasorelaxant efficacy and almost nanomolar potency index.

Retrospective review of Tizanidine ( Zanaflex ) ( Zanaflex ) overdose.

BACKGROUND: Tizanidine ( Zanaflex ) is a centrally acting muscle relaxant / relaxants with a novel mechanism of action and structurally related to clonidine. There are no large case series of Tizanidine ( Zanaflex ) exposure. METHODS: Retrospective review of all ingestions involving Tizanidine ( Zanaflex ) reported to a poison control center from January 2000 through February 2003. Exclusion criteria were polydrug ingestion, no follow-up or lost to follow-up. RESULTS: There were 121 cases of which 45 patients met entrance criteria. Mean age was 32 years (range 1 to 80). Thirty-seven patients were evaluated in a health care facility of which 27 were admitted for medical care. Clinical effects included lethargy (n = 38), bradycardia (n = 14), hypotension (n = 8), agitation (n = 7), confusion (n = 5), vomiting (n = 3), and coma (n = 2). Mean dose ingested by history was 72 mg (S.D. + 86). The lowest dose associated with hypotension was 28mg, which occurred in a 63-year-old female with a BP of 88/52 and a HR of 54. The lowest dose associated with coma was between 60 mg and 120 mg, which occurred in a 30-year-old female with a HR of 30 and BP of 81/48. There were 6 patients < 6 yrs. The lowest dose with bradycardia and drowsiness in a small child was 16 mg in a 2 YO (weight unknown). All other cases in children < 6 yrs involved ingestion of a single tablet (2 or 4 mg) with only mild drowsiness reported. Therapy in this series was primarily supportive and included pressors in 3 cases and intubation in 3 cases. Naloxone was administered to 7 patients. There was no response to naloxone in 5 patients, poor documentation of response in one, and arousal in one patient. All patients recovered without residual complications. CONCLUSION: Clinical manifestations of Tizanidine ( Zanaflex ) overdose include alterations of mental status, bradycardia, and hypotension. In this series, outcome was good with supportive therapy.

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.


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