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Two quinoline alkaloids, japonine (1) and eduline (2) were isolated from the methanol extract of the leaves of Orixa japonica as relaxants against rat small intestine muscle. The activity of these alkaloids was comparable to that of the typical muscle relaxant papaverine (4). This is also the first report of the isolation of eduline (2) from O. japonica.
The pharmacological properties of NK433 ((-)-(R)-2-methyl-3-(1-pyrrolidinyl)-4'-trifluoromethylpropiophenone+ ++ monohydrochloride), a novel muscle relaxant, were investigated. NK433 inhibited intercollicular decerebrate rigidity (gamma-rigidity) and anemic decerebrate rigidity (alpha-rigidity) dose dependently. NK433 was stronger in inhibiting gamma-rigidity than alpha-rigidity. NK433 inhibited the increase in muscle spindle discharges induced by pinna pinching (gamma-activity) without affecting muscle spindle discharges or neuromuscular transmission. At muscle relaxant doses in decerebrate rigidities, NK433 did not affect the muscle tone induced by morphine-HCl nor that of normal animals. These results suggest that NK433 selectively depresses the excessive muscle tone of decerebrate rigidities through its effects on the central nervous system, and inhibition of gamma-activity causes a preferential depression of gamma-rigidity in comparison to alpha-rigidity. In i.v. experiments, the effects of NK433 on decerebrate rigidities were similar to those of eperisone-HCl and tolperisone-HCl, but in p.o. experiments, NK433 was at least 3 times as potent as eperisone-HCl and tolperisone-HCl.
The use of muscle relaxants, considered until recently as common practice in current neurosurgical anaesthesia protocols, becomes increasingly more questionable today. The reasons rely on the evolution of neurosurgery including the advent of new surgical techniques, the evolution of anaesthesia having the benefit of new drugs and devices, and the rationale for using muscle relaxants balanced against their potential side-effects and possible pharmacodynamic alterations in neurosurgical patients.
BACKGROUND: Tracheal intubation in children can be achieved by deep inhalational anaesthesia or an intravenous anaesthetic and a muscle relaxant, suxamethonium being widely used despite several side-effects. Studies have shown that oral intubation can be facilitated safely and effectively in children after induction of anaesthesia with propofol and alfentanil without a muscle relaxant. Remifentanil is a new, ultra-short acting, selective mu-receptor agonist that is 20-30 times more potent than alfentanil. This clinical study was designed to assess whether combination of propofol and remifentanil could be used without a muscle relaxant to facilitate tracheal intubation in children. METHODS: Forty children (5-10 years) admitted for adenotonsillectomy were randomly allocated to one of two groups to receive remifentanil 2 microg.kg(-1) (Gp I) or remifentanil 3 microg.kg(-1) (Gp II) before the induction of anaesthesia with i.v. propofol 3 mg.kg(-1). No neuromuscular blocking agent was administered. Intubating conditions were assessed using a four-point scoring system based on ease of laryngoscopy, jaw relaxation, position of vocal cords, degree of coughing and limb movement. Mean arterial pressure (MAP) and heart rate (HR) measured noninvasively before induction of anaesthesia to 5 min after intubation (seven time points). RESULTS: Tracheal intubation was successful in all patients without requiring neuromuscular blocking agent. Intubating conditions were clinically acceptable in 10 of 20 patients (50%) in Gp I compared with 18 of 20 patients (90%) in Gp II (P < 0.05). MAP and HR decreased in both groups after induction of anaesthesia (P < 0.01). Both HR and MAP were significantly lower in Gp II compared with Gp I after tracheal intubation (P < 0.01). No patient in the present study developed bradycardia or hypotension. CONCLUSIONS: We conclude that remifentanil (3 microg.kg(-1)), administered before propofol (3 mg.kg(-1)) provides acceptable tracheal intubating conditions in children, and completely inhibited the increase in HR and MAP associated with intubation.
PURPOSE: Muscle relaxants and anesthetics are usually associated during intubation. However, their relative role to facilitate the process is not clearly defined. This study was designed to determine, during intubation: i). the relative role of anesthetics and atracurium-induced neuromuscular block and; ii). the effect of different doses of propofol in the presence of complete muscle block. METHODS: Patients were randomized to four groups and received fentanyl and a standardized anesthetic procedure. Patients from groups high (H; n = 45), medium (M; n = 48) and low (L; n = 47) received 2.5 mg x kg(-1), 2.0 mg x kg(-1), and 1.5 mg x kg(-1) of propofol respectively. Atracurium (0.5 mg x kg(-1)) was then injected and tracheal intubation performed once complete block was achieved at the orbicularis oculi. Patients from group without atracurium (WA; n = 20) received propofol as in group H. Intubation was performed at the expected onset time of action of atracurium. RESULTS: Using the same dose of propofol, the incidence of good or excellent intubating conditions was 35% without atracurium and 95% with atracurium (P < 0.0001). In patients receiving atracurium, clinically acceptable intubating conditions were more frequently achieved in groups receiving the highest propofol doses (group H or M vs group L; P < 0.03). CONCLUSION: Our study confirms the interaction between anesthesia and muscle relaxation to produce adequate intubating conditions. In the conditions described, intubating conditions were more dependent on atracurium-induced neuromuscular blockade than on anesthetics, but both atracurium and propofol improved intubating conditions.
To clarify the cortical mechanisms involved in motor inhibition, modulation of cortical rhythms around 20 Hz during voluntary muscle relaxation was compared to that during muscle contraction in ten normal volunteers, using a whole head type neuromagnetometer. Each subject relaxed or contracted the right forearm muscles, from which electromyograms were recorded. After bandpass filtering magnetoencephalographic signals into frequency bands of 6-10, 10-14, 14-18, 18-22, 22-26, and 26-30 Hz, the signals of each frequency band were rectified and averaged with respect to the onset of motor trial. The relaxation task showed movement-related 20-Hz desynchronization over bilateral central areas beginning a few seconds before the termination of muscle contraction. Twenty-hertz desynchronization was present also for the contraction task at the same location within each subject. The two tasks had a positive correlation among subjects in both the percent decrease (r2=0.76, P<0.01) and the peak time (r2=0.61, P<0.05) for the contralateral 20-Hz desynchronization. After the muscle relaxation, desynchronization was followed by conspicuous movement-related synchronization of the 20-Hz passband in the contralateral central areas, which was significantly larger than that after the contraction (P<0.001). The results suggest that the voluntary muscle relaxation involves the modulation of central rhythms starting a few seconds before the actual event, and the 20-Hz desynchronization has a similar temporal property in the muscle relaxation and contraction. The 20-Hz synchronization in the contralateral central area after the muscle relaxation may be associated with the temporally arrayed termination of the ongoing muscle contraction.
Rocuronium bromide (Org 9426) is a new, non-depolarising steroidal muscle relaxant that is currently undergoing extensive clinical trials worldwide. Since it is expected to be introduced into clinical practice in the near future, the purpose of this review is to give a summary of the currently available information on this promising new compound. The search for the so-called ideal muscle relaxant [34] in the last years was focused on a non-depolarising compound that could replace succinylcholine for rapid intubation. The currently most frequently used agents vecuronium and atracurium have an onset of action that usually does not allow intubation earlier than 3 min after its injection. Recent animal [40] and human [10] studies have shown that development of neuromuscular blockade of the vocal cords and laryngeal muscles can be faster than that of the peripheral skeletal muscles. This would mean that intubation can be performed before complete relaxation of the adductor muscle of the thumb is achieved. Rocuronium is the 2-morpholino, 16 N-allyl-pyrrolidino derivative of the 3-hydroxy metabolite of vecuronium. In initial clinical studies [13, 42] its most impressive features appeared to be rapid onset time and, more importantly, the rapid development of good intubating conditions. Thirty to 90 s after the injection of 0.6 mg/kg (2 x ED90), rocuronium provided intubating conditions that were equal to those observed after succinylcholine [9, 17, 31, 38]. Although the onset time of rocuronium at the adductor pollicis muscle is slower than that of succinylcholine, intubation with this compound can be performed faster than with any other non-depolarising agent.(ABSTRACT TRUNCATED AT 250 WORDS)
Elevations in cyclic nucleotide levels can decrease myoplasmic [Ca2+] ([Ca2+]i) and thereby induce arterial smooth muscle relaxation. We evaluated whether cyclic nucleotide-induced reductions in [Ca2+]i are caused by 1) decreased Ca2+ influx or 2) increased Ca2+ sequestration or efflux. Swine carotid medial tissues were loaded with fura-2, and Ca2+ influx was estimated from the quenching rate of 360-nm fluorescence after addition of extracellular Mn2+. Histamine stimulation or high KCl depolarization increased Mn2+ influx, [Ca2+]i, and contractile force. The Ca2+ channel blocker diltiazem attenuated histamine- or KCl-induced increases in Mn2+ influx, [Ca2+]i, and force. Addition of forskolin (which increases cAMP) or nitroglycerin (which increases cGMP) attenuated histamine-induced increases in Mn2+ influx, [Ca2+]i, and force. Addition of forskolin or nitroglycerin also relaxed KCl depolarized tissues; however, Mn2+ influx and [Ca2+]i remained high. These results suggest that Mn(2+)-induced quenching of 360-nm fluorescence is an estimate of Ca2+ influx in the intact swine carotid artery. These results also suggest that cyclic nucleotides can relax swine arterial smooth muscle by at least two mechanisms: 1) reduction of [Ca2+]i primarily induced by decreases in Ca2+ influx and 2) uncoupling force from [Ca2+]i without changing Ca2+ influx or [Ca2+]i.
BACKGROUND: Lightwand tracheal intubation is a suitable technique for patients who are difficult to intubate but who are receiving effective ventilation. The effect of muscle relaxants on the efficacy of lightwand intubation has not yet been evaluated. The authors conducted a prospective, double-blind, placebo-controlled study to assess the effectiveness and incidence of complications of lightwand tracheal intubation performed during general anesthesia with and without the use of a muscle relaxant in patients with apparently normal airway anatomy. METHODS: One hundred seventy-six patients who required orotracheal intubation were prospectively included. Anesthesia was administered using propofol (2 mg/kg, then 3 mg . kg (-1). h(-1)) and remifentanil (1 microg/kg, then 0.3 microg . kg(-1) . min(-1)). Patients were randomly assigned to one of two groups (n = 88 for each) to receive rocuronium 0.6 mg/kg or saline intravenously. Lightwand orotracheal intubation (Trachlight; Laerdal Medical Inc., Armonk, NY) was attempted after 3 min. The authors recorded the number of successful intubations, the number of attempts and their duration, and events during the procedure. RESULTS: The failure rate of lightwand intubation was 12% in the placebo group and 2% in the rocuronium group (P = 0.021). Patients in the placebo group received more multiple intubation attempts (P < 0.001), required a greater intubation time (77 +/- 65 vs. 52 +/- 31 s; P = 0.002) and experienced a greater incidence of events during intubation (61 vs. 0%; P < 0.001) than patients in the rocuronium group. CONCLUSIONS: The use of muscle relaxants in patients with apparently normal airways is associated with a lower failure rate, decreased intubation time, and fewer attempts when performing lightwand orotracheal intubation.
Dantrolene sodium (Dantrium) is a skeletal muscle relaxant, unique in that it acts on the muscle itself. It should be considered for use in patients with skeletal muscle spasticity who are in a stable neurological state. After careful adjustment of the dose, a substantial number of such patients will experience one or more of the following benefits: (1) a reduction in pain, (2) an increased ability to make use of residual motor function, (3) a reduction in the level of nursing care required, (4) an increased ability to utilize devices, and (5) an increased ability to participate in rehabilitation. The drug should not be used when reduced spasticity will decrease functional ability. The adverse effects generally are transient; some are the result of central nervous system depression.
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Flavoxate hydrochloride is a flavone derivative with smooth muscle relaxing activity. The product has a broad range of indications and has found one major application in the treatment of urge incontinence. Information on different forms of incontinence and epidemiologic data are summarized. Differences between the myolytic agent flavoxate and anticholinergics are highlighted. The vast amount of information deriving from some 20 years of clinical experience is analysed and major conclusions are drawn. The compound has valid therapeutic efficacy and excellent tolerability. By this token flavoxate is the agent of choice for therapy of disorders caused by smooth muscle spasms.
Microinjection of tizanidine into the substantia nigra pars reticulata or entopeduncular nucleus reduces muscle tone in genetically spastic rats. The effect of tizanidine is related to alpha 2-adrenergic mechanism since yohimbine, an alpha 2-adrenergic antagonist, and not prazosin, an alpha 1-adrenergic antagonist, attenuates the muscle relaxation produced by the drug. These results signify basal ganglia output stations as possible sites whereby tizanidine acting via alpha 2-adrenergic mechanism exerts its muscle relaxant action.
The pharmacological properties of 4'-ethyl-2-methyl-3-pyrrolidinopropiophenone hydrochloride (HSR-770), a new centrally acting muscle relaxant, were investigated in experimental animals. HSR-770, within a dose range of 1-10 mg/kg i.v., relaxed alpha- and gamma-rigidities in rats, the dose required to relax gamma-rigidity being lower than the dose required to relax alpha-rigidity. When HSR-770 was intraduodenally (i.d.) administered within a dose range of 25-50 mg/kg, the relaxant activity on alpha-rigidity was potent and long-lasting in comparison with eperisone or tolperisone. HSR-770 inhibited flexor reflex more strongly than patellar reflex in a dose-dependent manner within a dose range of 2.5-10 mg/kg i.v. or 25 and 50 mg/kg i.d. in anesthetized cats. In spinal cts, HSR-770 (5 and 10 mg/kg i.v.) inhibited flexor reflex but this potency was weaker than that in anesthetized cats. HSR-770 (12.5-50 mg/kg i.d.) inhibited he crossed extensor reflex in anesthetized rats. In spinal cats, HSR-770 inhibited mono- and polysynaptic reflex potentials to the same extent and also depressed dorsal root reflex potential at 5 and 10 mg/kg i.v. HSR-770 at a dose (50 mg/kg p.o.) which exerted muscle relaxant activity on both rigidity and flexor reflex, had little effect on spontaneous motor activity (mice), hexobarbital-induced sleeping time (mice) and conditioned avoidance response (rats). These results indicate that HSR-770 is a potent centrally acting muscle relaxant and that its central nervous system depressant activity is relatively weak.
The ability of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (E)-O-(aminocarbonyl) oxime) (WAY-PDA-641) to inhibit cyclic AMP-metabolizing phosphodiesterases (PDEs) and to relax respiratory muscle was explored as part of a program to identify a PDE-IV inhibitor for potential use in the treatment of asthma. WAY-PDA-641 was identified as a preferential inhibitor of PDE-IV, possessing 36 times greater potency versus canine trachealis PDE-IV than PDE-III (IC50, 4.2 x 10(-7) M and 1.5 x 10(-5) M, respectively). The classification of WAY-PDA-641 as a preferential PDE-IV inhibitor was supported in radioligand binding studies, which demonstrated that 10 microM WAY-PDA-641 did not displace ligands from a large number of receptors, and in functional studies, which used isolated guinea pig tracheal rings. Under conditions in which tracheal rings were made sensitive to the relaxant effects of PDE-IV or PDE-III inhibitors, WAY-PDA-641 induced relaxation with IC50S of 2.6 x 10(-8) M (PDE-IV) and 3.2 x 10(-5) M (PDE-III). Moreover, PDE-IV inhibitory concentrations of WAY-PDA-641 significantly potentiated the relaxant effects of albuterol. WAY-PDA-641 reversed tracheal contractions induced by prostaglandin F2 alpha, leukotriene D4 or histamine in a biphasic manner consistent with its activity as a preferential PDE-IV inhibitor. The IC50S for reversal of each spasmogen were similar, which confirmed that WAY-PDA-641 is a functional antagonist of respiratory muscle contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: The results from studies of muscle relaxants show wide variations among institutions. The authors hypothesized that some of this variability could be explained by differences in duration of nerve stimulation before drug administration (stabilization period). METHODS: Train-of-four stimulation was applied every 12 s to both ulnar nerves and adductor pollicis twitch tension was measured in anesthetized participants given 30 micrograms/kg vecuronium. In phase 1, the stabilization period was > 30 min for both extremities. In phase 2-4, stabilization period was 20 min for one extremity and 2 min for the other. In addition, in phase 3, a 2-s 50-Hz tetanus initiated the 2-min stimulation period; in phase 4, duration of tetanus was 5 s. Twitch recovery was recorded until stable for more than 15 min. Time to 25% recovery (clinical duration) was calculated based on two indices: predrug and final (recovery) twitch tension. Values for onset and clinical duration were compared by paired parametric and nonparametric tests. RESULTS: In phase 1, predrug and recovery twitch tension were similar in each extremity, and onset and clinical duration did not differ between extremities, permitting paired comparisons in remaining studies. In phase 2, onset was more rapid with 20-min of prestimulation. With 20-min prestimulation, predrug and recovery twitch tension were similar; with 2-min prestimulation, recovery twitch tension exceeded predrug values. When referenced to predrug twitch tension, clinical duration was shorter with 2-min, that with 20-min prestimulation. Initiating stimulation with 2-s or 5-s 50-Hz tetani (phases 3, 4) abolished differences between extremities in onset and recovery. CONCLUSIONS: With only train-of-four stimulation (no tetani), onset and clinical duration vary with duration of prestimulation, suggesting that a brief period of predrug stimulation is inadequate. However, lengthy prestimulation may be impractical in clinical studies. Tetanic stimulation for 2 or 5 s obviates the need for prolonged stabilization during studies of muscle relaxants.
BACKGROUND: The influence of muscle relaxation on the intra-operative neuromonitoring of the recurrent laryngeal nerve during thyroid surgery is unclear. METHODS: In a prospective study involving 200 patients undergoing elective thyroid surgery, the influence of muscle relaxation on neuromonitoring of the recurrent laryngeal nerve was investigated. The patients received balanced anaesthesia with oxygen-nitrous oxide-isoflurane, and rocuronium bromide was used as the non-depolarizing neuromuscular blocking agent. The degree of relaxation was monitored continuously by accelerometry [twitch (% TW)]. Summed action potentials (SAcP) obtained from the vocalis muscle were characterized by the area under the electromyographic curve expressed in millivolt seconds. RESULTS: Evoked potentials were obtainable in all patients and at all time points. With decreasing neuromuscular blockade a significant increase in the potentials evoked at the vocalis muscle was observed. At 0% TW SAcP was 1.27 (SD 1.02) mV s. An increase in TW to 10% was accompanied by an increase in SAcP to 2.68 (2.01) mV s (P<0.01). At a TW of 25%, mean SAcPs of 5.08 mV s were recorded. CONCLUSIONS: There was a significant difference in the degree of relaxation of the adductor pollicis muscle and the vocalis muscle. The laryngeal muscles exhibited a shorter response time than the adductor pollicis and recovered more quickly. These results confirm the feasibility of intra-operative neuromonitoring of the recurrent laryngeal nerve during neuromuscular blockade.
We evaluated the neuromuscular blocking effect of ORG9426, a new non-depolarizing muscle relaxant, and its recovery by means of washout or by antagonists in vitro, using phrenic nerve-hemidiaphragm preparations of rats. IC50 and IC90 of ORG9426 in single twitch were 10.62 +/- 0.58 microM and 15.75 +/- 0.95 microM; and those in train of four ratio were 9.04 +/- 0.38 microM and 11.87 +/- 0.42 microM, respectively. The potency of ORG9426 in vitro was compared with those of other non-depolarizing muscle relaxants. The order of potency among the non-depolarizing muscle relaxants was the following: d-tubocurarine greater than pipecuronium greater than pancuronium greater than vecuronium greater than ORG9426. There was no difference between ORG9426 and vecuronium in the recovery from block with washout, neostigmine, 4-aminopyridine, 3, 4-diaminopyridine, and edrophonium. In conclusion, the potency of ORG9426 is relatively low, and it can be easily antagonized by anti-cholinesterases and aminopyridines.