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Pharmacological studies of 1-(2,3-dimethyl-4-methoxyphenyl)-2-methyl-3-(1-pyrrolidinyl)-1- propanone hydrochloride (AD-2239), a centrally acting muscle relaxant.

Centrally acting muscle relaxant properties of AD-2239 were compared with those of tolperisone, eperisone, diazepam and baclofen. AD-2239 dose-relatedly depressed extensor reflex in urethane-chloralose anesthetized intact and spinal rats, the i.v. potencies being similar to those of tolperisone and eperisone. These effects of AD-2239 were long-lasting. When orally administered, AD-2239 was 4 times more potent than eperisone. Diazepam was without effect on the extensor reflex in spinal rats. AD-2239 depressed the flexor reflex without affecting the patellar reflex in anesthetized cats. Baclofen depressed the latter. When orally administered, AD-2239, in a dose-related manner, depressed the flexor reflex in anesthetized cats, with a potency approximately 8 times that of tolperisone or eperisone. AD-2239 produced a dose-related reduction of anemic decerebrate rigidity (alpha-rigidity) in rats. The potency, at the minimum effective i.v. dose, was 4 times greater than that of tolperisone or eperisone, equal to that of diazepam, and one-half of that of baclofen. AD-2239 neither affected spontaneous electroencephalogram (EEG) nor EEG arousal response in immobilized cats, while the other drugs, at comparatively low doses, depressed them. The results strongly suggest that AD-2239 may have advantages over the existing centrally acting muscle relaxants in the treatment of human clinical spasticity and muscle spasm syndromes.

Animals↗

Differing effect of agonist and antagonist muscle relaxants on cat jaw muscles.

Mouth closure and an increased resistance to mouth opening follow succinylcholine administration in humans. To elucidate the effects of succinylcholine on masticatory muscle function, mouth opening in the cat, produced by a constant test force, was measured during steady state halothane anesthesia. After baseline measurements, either succinylcholine (0.3 mg.kg-1 of body weight) or vecuronium (0.1 mg.kg-1 of body weight) was infused intravenously, and mouth opening measurements were repeated for up to 30 min. Concomitantly, muscle relaxant effect was quantified by measurement of the neurally-evoked tibialis anterior muscle response. All animals given succinylcholine displayed active jaw closure, which was followed by an increased resistance to mouth opening. This increased resistance was present after cessation of fasciculations and during complete twitch suppression. It lasted beyond the time at which the limb muscle twitch had fully recovered. Vecuronium administration was associated with a decreased resistance to mouth opening without a closing action. The initial jaw closure and the subsequently increased resistance to mouth opening after succinylcholine administration during halothane anesthesia in the cat are comparable with mouth opening changes after succinylcholine administration during inhalation anesthesia in humans. The cat may serve as an animal model for study of the mechanisms involved in responses of jaw muscles to succinylcholine with use of techniques inappropriate in humans.

Animals↗

Recurrent tension headache in adolescents treated with self-help relaxation training and a muscle relaxant drug.

Forty-eight adolescents suffering from recurrent tension headache participated in a controlled trial conducted in a high school setting. During the first treatment phase self-help relaxation training was compared with a waiting-list group. Following this phase a pharmacological regimen consisting of a muscle relaxant (chlormezanone) and placebo was superimposed on relaxation therapy in a double-blind crossover design. Each treatment phase encompassed a 5-week period. In addition to the evaluation of headache complaints, psychological distress among students was measured with respect to their experience of somatic complaints, depressive, anxiety and stress symptoms. Although self-help relaxation training significantly decreased the severity and annoyance of adolescents' headache besides their somatic complaints, the clinical improvement of headache was modest. The addition of chlormezanone did not help those who were nonresponders to self-help relaxation training. Finally, a set of pretreatment variables consisting of baseline headache severity and annoyance, experience of anxiety and daily life stress among adolescents could predict outcome of self-help relaxation therapy.

Adolescent↗

Pretreatment with sedative-hypnotics, but not with nondepolarizing muscle relaxants, attenuates alfentanil-induced muscle rigidity.

STUDY OBJECTIVE: To evaluate and compare the efficacy of various pretreatment agents to attenuate or prevent opioid-induced muscle rigidity using a well-established, previously described clinical protocol. DESIGN: Prospective, controlled, single-blind, partially randomized study. SETTING: Large medical center. PATIENTS: ASA physical status I-III patients undergoing elective surgical procedures of at least 3 hours' duration. INTERVENTIONS: The effect of pretreatment with nondepolarizing muscle relaxants (atracurium 40 micrograms/kg or metocurine 50 micrograms/kg), benzodiazepine agonists (diazepam 5 mg or midazolam 2.5 mg), or thiopental sodium 1 mg/kg on the increased muscle tone produced by alfentanil 175 micrograms/kg was compared with a control group (given no pretreatment). MEASUREMENTS AND MAIN RESULTS: Rigidity was assessed quantitatively by measuring the electromyographic activity of five muscle groups (biceps, intercostals, abdominals, quadriceps, and gastrocnemius). Rigidity also was rated qualitatively by attempts to initiate and maintain mask ventilation, attempts to flex an extremity, and the occurrence of myoclonic movements. Pretreatment with the two nondepolarizing muscle relaxants had no effect on the severe muscle rigidity produced by high-dose alfentanil. Whereas thiopental was only mildly effective, the benzodiazepines midazolam and diazepam significantly attenuated alfentanil rigidity (p < 0.05). CONCLUSION: This study suggests that benzodiazepine pretreatment is frequently, but not always, effective in preventing opioid-induced muscle rigidity.

Abdominal Muscles↗

Diagnosing erectile dysfunction: instruments for the study of smooth muscle relaxation.

Complete cavernosal smooth muscle relaxation is the pre-requisite for the reliability of every evaluation of the integrity of the corporal veno-occlusive system. Such evaluation is needed whenever reaching a diagnostic conclusion on the haemodynamic status of a given patient is clinically relevant. Clinical challenges that a laboratory evaluation of veno-occlusive integrity face comprise both the induction of complete smooth muscle relaxation, and the possibility to monitor it. This article will review the relevant aspects of normal range values of veno-occlusive function, existing strategies aimed to promote complete smooth muscle relaxation, and available techniques to monitor the cavernosal smooth muscle status.

Erectile Dysfunction↗

Molecular mechanism of cGMP-mediated smooth muscle relaxation.

Contraction and relaxation of smooth muscle is a tightly regulated process involving numerous endogenous substances and their intracellular second messengers. We examine the key role of cyclic guanosine monophosphate (cGMP) in mediating smooth muscle relaxation. We briefly review the current art regarding cGMP generation and degradation, while focusing on the recent identification of the molecular mechanisms underlying cGMP-mediated smooth muscle relaxation. cGMP-induced SM relaxation is mediated mainly by cGMP-dependent protein kinase activation. It involves several molecular events culminating in a reduction in intracellular Ca(2+) concentration and a decrease in the sensitivity of the contractile system to Ca(2+). We propose that the cGMP-induced decrease in Ca(2+) sensitivity is a strategic way to achieve "active relaxation" of the smooth muscle. In summary, we present compelling evidence supporting a key role for cGMP as a mediator of smooth muscle relaxation in physiological and pharmacological settings.

Animals↗

Effect of muscle relaxants on experimental jaw-muscle pain and jaw-stretch reflexes: a double-blind and placebo-controlled trial.

A randomised, double-blind, placebo-controlled three-way cross-over study was performed to investigate the effect of two muscle relaxants (tolperisone hydrochloride and pridinol mesilate) on experimental jaw-muscle pain and jaw-stretch reflexes. Fifteen healthy men participated in three randomised sessions separated by at least 1 week. In each session 300 mg tolperisone, 8 mg pridinol mesilate or placebo was administered orally as a single dose. One hour after drug administration 0.3 ml hypertonic saline (5.8%) was injected into the right masseter to produce muscle pain. Subjects continuously rated their perceived pain intensity on an electronic 10-cm visual analogue scale (VAS). The pressure pain threshold (PPT) was measured and short-latency reflex responses were evoked in the pre-contracted (15% maximal voluntary contraction) masseter and temporalis muscles by a standardised stretch device (1 mm displacement, 10 ms ramp time) before (baseline), 1 h after medication (post-drug), during ongoing experimental muscle pain (pain-post-drug), and 15 min after pain had vanished (post-pain). Analysis of variance demonstrated significantly lower VAS peak pain scores (5.9 +/- 0.4 cm) after administration of tolperisone hydrochloride compared with pridinol mesilate (6.8 +/- 0.4 cm) and placebo (6.6 +/- 0.4 cm) (P=0.020). Administration of pridinol mesilate was associated with a significant decrease in PPTs compared with tolperisone hydrochloride and placebo (P=0.002) after medication, but not after experimental jaw-muscle pain. The normalised peak-to-peak amplitude of the stretch reflexes were not significantly influenced by the test medication (P=0.762), but were in all sessions significantly facilitated during ongoing experimental jaw-muscle pain (P=0.034). In conclusion, tolperisone hydrochloride provides a small, albeit significant reduction in the perceived intensity of experimental jaw-muscle pain whereas the present dose had no effect on the short-latency jaw-stretch reflex.

Adult↗

Abuse of skeletal muscle relaxants.

Centrally acting skeletal muscle relaxants are potential drugs of abuse. Although skeletal muscle relaxants are occasionally the primary drug of abuse, they are often used along with other central nervous system depressants, such as narcotics or alcohol. The major toxic effects are respiratory depression and coma. For the most part, the abuse problem is initiated and sustained iatrogenically. Physicians should be aware of the abuse potential of skeletal muscle relaxants.

Adult↗

Sites of action of CS-722, a newly synthesized centrally acting muscle relaxant.

Sites of the muscle relaxant action of CS-722 were investigated in rats. Doses injected intra-4th ventricularly (i.c.v.) or intrathecally (i.t.) were determined according to measurements of CS-722 concentration in the brain stem and the spinal cord after systemic administration. When administered i.c.v. (50 and 100 micrograms) or i.t. (200 and 400 micrograms), CS-722 reduced the radio frequency decerebrate rigidity, although the effect after i.c.v. injection was transient. These results indicate that CS-722 exerts its muscle relaxant action by affecting both the supraspinal structure and the spinal cord. Spinal reflexes were not affected by CS-722 injected i.c.v. It seems that muscle relaxation is not always accompanied by impairment of the spinal reflex.

Animals↗

Comparison of effects of smooth muscle relaxing drugs in intestinal smooth muscle of guinea pig.

Effects of smooth muscle relaxants on histamine-, Ba2+- and Ca2+-induced contractions, or on electrical activities were examined in the longitudinal smooth muscle of guinea-pig ileum or taenia coli, respectively. Papaverine, D-600 and diltiazem effectively inhibited the Ca2+ responses and the tonic components of the histamine and Ba2+ responses. Especially, D-600 and diltiazem depressed the Ca2+ responses in much lower concentrations than papaverine and theophylline. In contrast, benactyzine and etomidoline were not specific antagonists against the Ca2+ responses, and they were effective inhibitory agents on the phasic responses to histamine and Ba2+. Nitroprusside failed to reduce the three types of contractions effectively. These results suggest that these seven relaxants can be divided into four types. Influence of those relaxants on spontaneously- and Ba2+-evoked electrical activities are compatible with the above differentiation. The four types of relaxants used in this study seem to exert their actions on smooth muscle in different way. Nitroprusside, however, is not a potent relaxant against contractions of the intestinal smooth muscles.

Animals↗