Muscle Relaxant Agent Research Articles

On-line Analysis of AEP and EEG for Monitoring Depth of Anaesthesia

Achieving and monitoring adequate depth of anaesthesia is a challenge to the anaesthetist. With the introduction of muscle relaxing agents, the traditional signs of awareness are often obscured or difficult to interpret. These signs include blood pressure, heart rate, pupil size, etc. However, these factors do not describe the depth of anaesthesia, (DA), in a cerebral activity sense, hence there is a desire to achieve a better measure of the DA. Auditory Evoked Potentials (AEP) provide two aspects relevant to anaesthesia: (1) they have identifiable anatomical significance and, (2) their characteristics reflect the way in which the brain reacts to a stimulus. However, AEP is embedded in noise from the ongoing EEG background activity. Hence, processing is needed to improve the signal to noise ratio. The methods applied were moving time averaging (MTA) and ARX-modeling. The EEG was collected from the left hemisphere and analysed by FFT to 1 sec epochs and the spectral edge frequency was calculated. Both the changes in ARX extracted AEP and the spectral edge frequency of the EEG correlated well with the time interval between propofol induction and onset of anaesthesia measured by clinical signs (i.e., cessation of eye-lash reflex). The MTA extracted AEP was significantly slower in tracing the transition from consciousness to unconsciousness.

Automated On-Line Hydrolysis of Benzodiazepines Improves Sensitivity of Urine Screening by a Homogeneous Enzyme Immunoassay

Benzodiazepines are used therapeutically as antidepressant, anxiolytic, anticonvulsant, hypnotic, muscle relaxant, and preanesthetic agents. Moreover, benzodiazepines are often abused for their euphoric effects. Consequently, benzodiazepines are commonly detected in toxicological analyses. Immunoassays of benzodiazepines are plagued by several factors that make reliable detection difficult. Complicated metabolic pathways, including N -dealkylation, C -hydroxylation, and glucuronidation, effectively reduce the parent compound to more polar, and thus easily excreted, metabolites. Some of these metabolites are pharmacologically active; in some cases, they are present in higher concentrations and have a longer elimination half-life than the parent compound (1)(2). Many, especially the glucuronide conjugates, which appear at high concentrations in the urine, do not readily cross-react with commercial immunoassays. In contrast, other benzodiazepine metabolites demonstrate high cross-reactivity, depending on the immunoassay utilized (3). In the US, 13 benzodiazepines of various potencies are commonly prescribed. Therapeutic daily doses have substantially decreased with the newer generation of benzodiazepines (2). Variations in dosage and in ultimate excretion patterns complicate the ability to accurately detect benzodiazepine use (4). Accumulated research findings indicate pretreating urine specimens with β-glucuronidase (EC 3.2.1.31) increases the diagnostic …

New muscle relaxants for anesthesia during 1-day surgery

In the last few years, the growth of 1-day surgery and the introduction of new techniques have increased the need for general anesthesia with endotracheal intubation and mechanical ventilation. The end point of 1-day anesthesia is early patient discharge home. Therefore, new muscle relaxant agents have been propounded to anesthetists to achieve this. In this paper, we analyze pharmacological and clinical characteristics of available newer muscle relaxants and evaluate their possible use in 1-day surgery.

Anesthesiologic management of ankle joint osteosynthesis in the 35th week of pregnancy in a patient with Charcot-Marie-Tooth syndrome

We describe the case of an extremely overweight woman in her 35 th week of pregnancy with a manifest Charcot-Marie-Tooth syndrome (CMT), on whom a tibial fracture was operated under general anaesthesia. Anaesthesia was induced with thiopental, droperidol, fentanyl and maintained with nitrous oxide and isoflurane. Atracurium was administered as a muscle relaxant agent. Depolarizing muscle relaxants have not been used because of a significantly increased risk of hyperkalemia. The immediate intubation using the principle of a so-called "priming dose" was within normal limits. CMT syndrome is a very rare hereditary autosomal dominant degenerative disease of the peripheral nervous system. The main site of manifestation is the peroneus muscle. In case of affection of the respiratory muscular system, which acutely can occur postoperatively even without any suspicious findings in the preoperatively performed lung function tests, an insufficiency of the respiratory tract is predominant and may require a postoperative intensive care with a prolonged artificial respiration. With the application of non-depolarizing muscle relaxants significant prolongations of the half-life period have occasionally been observed. Therefore we recommend the monitoring of the neuromuscular blockade perioperatively using the train-of-four ratio. An extraordinary progression of the disease frequently occurs during pregnancy.

Conformational analysis of five novel smooth muscle relaxant agents

Conformational analysis of five novel smooth muscle relaxant agents

Autoregressive Modeling with Exogenous Input of Middle-Latency Auditory-Evoked Potentials to Measure Rapid Changes in Depth of Anesthesia

Obtaining an adequate depth of anesthesia is a continuous challenge to the anesthetist. With the introduction of muscle-relaxing agents the traditional signs of awareness are often obscured, or difficult to interpret. These signs include blood pressure, heart rate, pupil size, etc. However, these factors do not describe the depth of anesthesia (DA) in a cerebral activity sense. Hence, a better measure of the DA is required. It has been suggested that Auditory-Evoked Potentials (AEP) can provide additional information about the DA. The general method of extracting AEP is by use of a Moving Time Average (MTA). However, the MTA is time consuming because a large number of repetitions is needed to produce an estimate of the AEP. Hence, changes occurring over a small number of sweeps will not be detected by the MTA average. We describe a system-identification method, an autoregressive model with exogeneous input (ARX) model, to produce a sweep-by-sweep estimate of the AEP. The method was clinically evaluated in 10 patients anesthetized with alfentanil and propofol. The time interval between propofol induction and the time when the Na-Pa amplitude was decreased to 25% of the initial amplitude was measured. These measurements showed that ARX-estimated compared to MTA-estimated AEP was significantly faster in tracing transition from consciousness to unconsciousness during propofol induction (p < 0.05).

Functional maturation of hypothalamic GABAergic neurones; evidence for the emergence of a GABA A-receptor mediated inhibition of GABA secretion

Thiocolchicoside, a muscle-relaxant agent, is administered by the oral, intra-muscular and topical route. After oral administration the extent of bioavailability compared with intra-muscular administration is low, due to a first pass effect. In this paper, the delivery of thiocolchicoside through oral mucosa is studied to improve the bioavailability. Thiocolchicoside in vitro permeation through porcine oral mucosa and in vivo buccal transport in humans were investigated. Two dosage forms, a bioadhesive disc and a fast dissolving disc for buccal and sublingual administration of thiocolchicoside, respectively, were designed. The in vitro permeation of thiocolchicoside through porcine buccal mucosa from these dosage forms was evaluated and compared with in vivo absorption. Results from in vitro studies demonstrated that thiocolchicoside is quite permeable across porcine buccal mucosa and that permeation enhancers, such as sodium taurocholate and sodium taurodeoxycholate, were not able to increase its flux. The in vivo thiocolchicoside absorption experiments, in which the drug loss from oral cavity was measured, indicated that both formulations could be useful for therapeutic application. The fast dissolving (sublingual) form resulted in a quick uptake of 0.5 mg of thiocolchicoside within 15 min whereas with the adhesive buccal form the same dose can be absorbed over an extended period of time.

K+ Channels and Guinea-pig Trachea: a Possible Functional Modulation by GABAB Receptors

Summary: K+ channel activators represent a novel class of smooth muscle relaxant agents. There is now much evidence demonstrating that K+ channels, localized to prejunctional neurones and post-junctional smooth muscle membranes, can regulate airway smooth muscle activity, inducing smooth muscle cell membrane hyperpolarization. K+ channel activity may be influenced by some neurotransmitters, such as adenosine, serotonin and noradrenaline. More recently, it has been observed that the stimulation of GABAB receptors influences K+ channels in the hippocampus, dorsal rafe and spinal cord neurons. The aim of this study was to investigate the effects of levcromakalim in guinea-pig trachea at pre- and post-junctional sites and to evaluate whether GABAB receptors may modulate K+ channel activation. Levcromakalim (from 1 nM to 1 μM) relaxed guinea-pig trachea (IC50 10±0.9 nM) previously contracted by KCl (30 mM). This effect was reversed by a pretreatment with tetraethylammonium (10 mM) (IC50 120±0.7 nM). A 30-min pretreatment with baclofen (1 μM) or phaclofen (1 μM) failed to modify the effects of levcromakalim (IC50 18±1.0 nM and 14±0.6 nM, respectively). The contractile responses to electrical field stimulation (71.20±5.12% of acetylcholine -100 μM-contraction) was significantly (P<0.05) reduced by a pretreatment with levcromakalim (10 nM) (54.00±6.68%). This reduction was antagonized by tetraethylammonium (10 nM) (72.20±14.27%). A 30-min pretreatment with baclofen (1 μM) significantly (P<0.05) enhanced the effect of levcromakalim on electrical field stimulation, whereas phaclofen (1 μM) significantly (P<0.05) antagonized these responses. These data demonstrate that K+ channels may be localized both to prejunctional and post-junctional post-ganglionic sites, and may play an important role in modulating airway responsiveness. In fact, they may act at the prejunctional neurones, inhibiting the release of contractile neurotransmitter, or at the post-junctional sites, hyperpolarizing smooth muscle airway membranes. Moreover, the present study seems to demonstrate that K+ channels localized on the prejunctional post-ganglionic nerves may be influenced by GABAB receptors.

The Risk of In Utero Exposure to Lithium

To the Editor. —The excellent article by Cohen et al1does much to dispel fears about the risks of lithium carbonate during pregnancy. We would like to point out that in addition to carbamazepine, valproate sodium, and neuroleptics, electroconvulsive therapy (ECT) should be considered as an antimanic and antidepressant treatment during pregnancy. In fact, most experts consider ECT to be safer for the fetus than many psychotropic medications,2and there is an extensive literature documenting the safe and effective use of ECT in all three trimesters.3The brief exposure to the anesthetic and muscle relaxant agents during ECT is likely to be more benign than constant exposure to (even slightly) teratogenic psychotropic medications. For severely depressed or manic pregnant women, ECT should be considered seriously.

Characterization of Calcium Channel Blocker Induced Smooth Muscle Relaxation Using a Model of Isolated Corpus Cavernosum

Several classes of smooth muscle relaxing agents have proven effective in relaxing cavernosal smooth muscle and useful in the pharmacotherapy of erectile dysfunction. The purpose of this investigation was to determine whether the calcium channel blockers (CCB) relax cavernosal smooth muscle. Thirty-two rabbit cavernosal strips were contracted by electrical field stimulation, and contraction inhibition was tested in response to cumulative doses (10−8M. to 10−4M.) of verapamil (V), diltiazem (D), isradipine (I), nicardipine (Nc) and nifedipine (Nf). All of the calcium channel blockers were effective at inhibiting electrically induced contractions (p <0.0001 when CCB was compared with control; p <0.05 when V or D was compared with I, Nc or Nf). Sixteen cavernosal strips were precontracted with 10−5M. norepinephrine. Relaxation in response to cumulative doses of each CCB was determined. Verapamil and the dihydropyridines (isradipine, nicardipine and nifedipine), but not diltiazem, were effective at relaxing norepinephrine induced contractions at 10−5 and 10−4M. with verapamil most effective at 10−4M. concentration (p < 0.0001 by ANOVA at both concentrations when V, I, Nc, or Nf was compared with control). Sixteen cavernosal strips were incubated in solutions of 10−5 and 10−4M. of each CCB followed by cumulative addition of norepinephrine (concentration range 10−8 to 10−4M.). Preincubation with CCB did not affect the concentration of norepinephrine at which 50% of maximal cavernosal contractile response occurred (ED50). Maximum active tension of norepinephrine induced contractions was moderately decreased after CCB preincubation with 10−4M. of each dihydropyridine.It is concluded that the calcium channel blockers are effective in relaxing cavernosal smooth muscle and therefore possess potential as intracavernous pharmacotherapeutic agents for the treatment of erectile dysfunction. Verapamil appears to be the best candidate for further testing and clinical trial.

High-Performance Liquid Chromatographic Method for Assay of Otilonium Bromide, Diazepam, and Related Compounds in Finished Pharmaceutical Forms

A rapid, simple, stability-indicating assay procedure for otilonium bromide, a smooth muscle relaxant agent, and diazepam in composite tablet analysis was developed with high-performance liquid chromatography. The tablet matrix was dissolved with water, and drugs were extracted with acetonitrile containing an internal standard. An aliquot was centrifuged and chromatographed on a 5μm, reversed- phase column with 0.5M sodium acetate trihydrate buffer containing 5mM 1-heptanesulfonic acid monohydrate sodium salt:methanol (30:70; v/v; adjusted to pH 6.0 with glacial acetic acid) as the mobile phase. The selectivity of the chromatographic system was demonstrated by resolving both compounds from various potential degradation products of each compound. The method is linear, quantitative, and reproducible.

Inhibition of contraction of isolated lymphatic ducts by atrial natriuretic peptide

Atrial natriuretic peptide (ANP) potently relaxes blood vessels but its effect on lymphatic motility is unreported. We studied the effect of ANP, and the smooth muscle relaxing agent nitroprusside (NP), on isolated ovine mesenteric lymphatic ducts. Duct segments were mounted on a myograph, and noncumulative dose-response curves were obtained for the effect of ANP and NP on the rate and force of spontaneous (and norepinephrine-induced) duct contraction. Both ANP (threshold approximately 1 nM) and NP (threshold approximately 10 nM) in a dose-related fashion reduced the frequency and force of contraction of both spontaneously contracting and norepinephrine-stimulated duct segments. ANP may therefore affect interstitial fluid balance through its effect on lymphatic motility.

The presence of prostacyclin binding sites in nonpregnant bovine uterine tissue

Myometrium of various animal species makes a considerable amount of prostacyclin (PGI 2) which is a potent myometrial and uterine vascular smooth muscle relaxing agent. This action of PGI 2 is perhaps mediated by binding to specific receptors, which have never been demonstrated in uterine tissue of any animal species until very recently. The quantitative light microscopic autoradiographic approach used in the present studies demonstrated that while bovine myometrial smooth muscle and uterine vascular smooth muscle contained PGI 2 specific binding sites, endometrial and perimetrial cells contained few or no binding sites. The number of binding sites in circular and elongated myometrial smooth muscle and in arteriolar smooth muscle were similar (P>0.05). The PGI 2 binding to the uterine cells was greatly reduced (P<0.001) following coincubation with excess unlabeled PGI 2, but not with its stable metabolite, 6-keto PGF 1α. PGE 2, PGF 2α and leukotriene C 4 which bind to nonpregnant bovine uterine tissue, also had no effect of PGI 2 binding. In conclusion, nonpregnant bovine uterine tissue contain specific PGI 2 binding sites which may mediate its potent relaxing effect on myometrium and uterine vasculature.

Degradation kinetics of (+/-)-4'-ethyl-2-methyl-3-(1-pyrrolidinyl)propiophenone hydrochloride (HY-770) and structure-stability relationship among its analogues in aqueous solution.

The kinetics and pathways for degradation of (+/-)-4'-ethyl-2-methyl-3-(1-pyrrolidinyl)propiophenone hydrochloride (HY-770; 1), a newly developed muscle-relaxing agent, and its analogues were studied in aqueous solution at 50 degrees C, ionic strength 0.5 M, and pH 8.0-12.0. Compound 1 and its four analogues followed pseudo-first-order degradation kinetics at constant pH and temperature. From the analysis of the pH degradation-rate profiles, it is evident that specific hydroxide ion-catalyzed degradations of ionized and un-ionized species occur for 1 and its structural analogue, 3'-fluoro-2-methyl-3-(1-pyrrolidinyl)propiophenone hydrochloride (HN-961; 5). The hydroxide ion-catalyzed degradation of the ionized species was found to be 100 times faster than that of the un-ionized species and to be the major process at pH less than 9.0. On the contrary, 1 was extremely stable in 0.5 M HCl at 50 degrees C, suggesting that the hydronium ion-catalyzed degradation and the spontaneous degradation of the ionized species is negligible. The Arrhenius plot for the degradation of 1 at 35-50 degrees C and pH 9.0 showed that the apparent energy of activation was 22.0 kcal/mol. The degradation rates of the five structural analogues were significantly dependent on the electron withdrawing effect of the benzene substituents of the molecule.

Renal effects of d-tubocurarine and pancuronium in the newborn rabbit.

The acute renal effects of d-tubocurarine and pancuronium were assessed in 14 anesthetized newborn rabbits. Glomerular filtration rate (GFR) and renal blood flow (RBF) were calculated from the inulin and p-aminohippuric acid clearances, respectively. Each animal acted as its own control. At doses used in human neonates, d-tubocurarine administration (0.80 mg/kg) produced a marked increase in renal vascular resistance (+123 +/- 62%) with a concomitant significant decrease in GFR (-35.4 +/- 12%) and RBF (-39 +/- 13%). Pancuronium administration (0.25 mg/kg) was associated with a nonsignificant decrease in GFR (-19 +/- 17%) and RBF (-20 +/- 12%) and an increase in renal vascular resistance (+66 +/- 52%). These results stress the need for careful monitoring of renal function in neonates receiving nondepolarizing muscle-relaxant agents.

4628056 Novel oxopyrimidine derivatives, pharmaceutical compositions containing them and their use as anticonvulsant, antianxiety and muscle relaxant agents: Barrie Levitt, Morris Stolar, Haifa, Israel assigned to Taro Pharmaceutical Industries Ltd

4628056 Novel oxopyrimidine derivatives, pharmaceutical compositions containing them and their use as anticonvulsant, antianxiety and muscle relaxant agents: Barrie Levitt, Morris Stolar, Haifa, Israel assigned to Taro Pharmaceutical Industries Ltd

Motional and conformational dynamics in a homologous series of smooth muscle relaxing agents

Dynamic features were investigated in a homologous series of synthesized drugs having pharmacologic activity, with particular emphasis on relative motions of the two side chains anchored to a backbone of two aromatic rings linked by an amide bridge. A general and deep insight was reached by using a model-free approach. Conformational and motional dynamics within the compound exhibiting maximum activity were delineated and the most relevant parameters for pharmacologic action were defined.

Nuclear magnetic resonance study of conformation and dynamics in solution of p-(o-propyloxybenzamido)benzoate diethyl(2-hydroxyethyl)methylammonium bromide: a smooth muscle relaxant agent

The relative conformation of the aromatic rings and the amide bridge as well as important details of the two side chains of the title compound in a DMSO-d6 solution have been established by use of non-selective and selective proton spin-lattice relaxation times coupled with nOe experiments. The complete analysis of 13C spin-lattice relaxation times has shown the main features of the dynamic behavior of the title compound.

TRANSIENT PSEUDOCHOLINESTERASE (PChE) DEFICIENCY IN PREMATURE INFANTS

Approximately 3% of the adult population have a genetic basis for decreased PChE enzyme activity. Levels of PChE activity in healthy term newborns and infants up to 4 months of age have been reported to range from 22-86% of normal adult values. The degree of decreased enzyme activity in premature infants is unknown. Levels of PChE were measured in 39 healthy premature infants (single determinations in 12 and serial weekly determinations in 27).Birth weight ranged from 1430-2070g and GA ranged from 28-37 wks. Ten adult donor and 20 term newborn blood samples were analyzed for comparison purposes. Levels of PChE were measured in duplicate by a kit dye reduction method (normal adult reference value 7-19U/ml). Abnormally low PChE levels were found in 10% of adult, 15% of term newborn and 20% of premature infant blood samples(NS). This incidence of low PChE activity is 3-5 times that reported for adults using a different method. In 6 premature infants with initially low PChE levels, the enzyme activity rose to normal adult range within 2 weeks. In 2 other premature infants PChE levels remained low and most likely represented congenital PChE deficiency. There was no difference in PChE activity on the basis of sex, race or GA. Hospitalized premature infants exhibit similar rates of quantitative PChE deficiency when compared to adults and term infants and are at potential risk for significant complications when exposed to depolarizing muscle relaxant agents. When succinylcholine use is considered in premature infants, measurement of PChE levels or use of alternative drugs may be indicated on the basis of transient PChE deficiency.

Skeletal muscle relaxing agents as probes of a monovalent cation selective channel of cardiac muscle sarcoplasmic reticulum (SR)

Skeletal muscle relaxing agents as probes of a monovalent cation selective channel of cardiac muscle sarcoplasmic reticulum (SR)