Muscle relaxants; effects on respiratory and circulatory dynamics

There are exceptions and variations to the general clinical rule that muscle relaxants depress respiration and have no effect on circulation. Variation may be attributed to differences in animal species, in individual response, in muscle affected, in drug used and in dose employed. Conclusions about muscle relaxants derived from animal experiments cannot always be assumed to apply to man. The "respiratory sparing" action of a muscle relaxant cannot be relied upon in any individual patient. Facilities for adequate artificial respiration must always be available when any dose of any muscle relaxant drug is administered. Muscle relaxants affect circulation by inhibition of parasympathetic and sympathetic ganglia, by anticholinesterase activity and by release of histamine.     

Potential benefits of gallic acid as skeletal muscle relaxant in animal experimental models

Background and ObjectiveMany natural bioactive chemicals have been shown to have functional activity, suggesting that they could be useful in the treatment and management of a wide range of chronic conditions. Flavonoids, which include gallic acid (GA), are the most abundant polyphenols found in nature. Skeletal muscle relaxants are drugs that reduce undesired spasms while maintaining awareness and reflexes unaffected. The purpose of this investigation was to determine if GA has any skeletal muscle relaxant properties in experimental animal models.Materials and MethodsThe muscle relaxant activity of three dosages of GA (5, 10, and 20 mg/kg) was compared to that of normal diazepam (5 mg/kg) utilizing climbing, chimney, and modified Kondziela''s inverted tests. An analysis of variance (ANOVA) and a post-ANOVA Tukey multiple comparisons test were used to assess the data.ResultsAnimals given 10 and 20 mg/kg of GA had a great deal of trouble climbing up the chain, presumably because their muscles were relaxed. Similarly, rats given a high dose of GA (20 mg/kg) had a significantly (P < 0.05) longer response time in the chimney test, indicating a lack of attention and slowed muscle tone, resulting in problems with motor coordination. In inverted testing, animals given a high dose of GA had a significantly (P < 0.01) reduced holding capacity on the mesh for a longer period of time. A decrease in holding time is caused by a decrease in muscular contraction. The low dose of GA, on the other hand, failed to show muscle relaxant effect in any of the three models.ConclusionsAs a conclusion, our data show that GA has a dose-dependent skeletal muscle relaxant effect when administered orally to mice.Keyword: GA, Skeletal muscle relaxant, Climbing test, Chimney test, Inverted test, Diazepam, Spasmolytics     

Anesthesia for eye operations in the aged

Aged persons appear to fear eye operations. Hence both patient and surgeon are more at ease with the use of a general anesthetic, particularly if the anesthetist has visited the patient before the operation and reassured him. Early ambulation, ordinarily so desirable in the aged, is curtailed in most eye operations because the head and eyes must be completely quiet. Since barbiturates are not well tolerated by aged patients, Dramamine is used instead preoperatively. Dramamine adequately sedates but does not cause depression or hallucinations. Morphine is contraindicated because of its pupillary action; Demerol is the drug of choice for preoperative medication. Xylocaine applied directly to the pyriform fossa and vocal cords prevents laryngospasm, coughing and straining. Then, following induction with Pentothal, a Guedel airway is introduced into the oropharynx and through it a continuous flow of oxygen is maintained throughout the procedure. Relaxation of the eyelids is aided by the use of various muscle relaxants, succinylcholine being the relaxant of choice because it is rapidly eliminated. By administering narcotics intravenously during the course of the operation the amount of Pentothal needed can be held to a minimum. To prevent any slowing of the respiration, Nalline is administered in conjunction with the narcotic. In dealing with debilitated patients, Nalline is usually given in conjunction with the preoperative narcotic. Any latent slowing of the respiration can be promptly relieved by an additional dose of Nalline.     

2-amino-7-phosphonoheptanoic acid (AP7) produces discriminative stimuli and anticonflict effects similar to diazepam

The N-methyl-D-aspartate (NMDA) receptor antagonist, AP7, was evaluated in two animal test procedures known to be sensitive to the effects of diazepam. In rats trained to discriminate diazepam from vehicle, AP7 produced dose-dependent generalization to the diazepam interoceptive stimuli. This NMDA antagonist also increased the rates of conflict responding in a chronic test procedure used to identify compounds with potential anxiolytic effects. A comparison of AP7 with diazepam and two muscle relaxants (methocarbamol and baclofen) showed that excitatory amino acid antagonists (of the receptor site stimulated by NMDA) produce a muscle relaxant effect (drug discrimination) and may represent a new class of compounds for the treatment of anxiety-related disorders (conflict test).     

Comparison of Effect of Two Induction Doses of Methohexitone on Infants Delivered by Elective Caesarean Section

Observations were made on 26 infants delivered by elective caesarean section under general anaesthesia. A standard anaesthetic technique was employed using a methohexitone, relaxant, nitrous oxide-oxygen sequence with regulated ventilation and the administration of papaveretum after clamping the umbilical cord. In 12 patients the induction dose of methohexitone was 1·4mg/kg and in 14 it was reduced to 1·0 mg/kg. There were no significant differences between the two groups in the clinical status of the mothers, in operative technique and timing, or in the value of PO₂, PCO₂, and pH in the umbilical cord venous blood.The infants whose mothers received the lower dose of methohexitone were in better condition, as assessed by the number needing assisted ventilation, the time taken to establish regular respiration, the Apgar score, and the “Apgar minus colour” score.     

Synthesis of quaternary ammonium salts of 16E-[4-(2-alkylaminoethoxy)-3-methoxybenzylidene]androstene derivatives as skeletal muscle relaxants

Synthesis of eighteen new quaternary ammonium salts of 16E-arylidene androstene derivatives as skeletal muscle relaxants is reported in the present study. The effects of possibly extended interonium distances on muscle relaxant activity are discussed. All the quaternary ammonium steroids produced reduction in the twitch responses, when screened for in vitro neuromuscular blocking activity using isolated chick biventer cervicis muscle preparation. However, the variable interonium distance, which is believed to range from 11 to 17 Å in these quaternary compounds and is associated with the built in flexibility of these structures about the single bonds on the moieties linked to ring D of the steroid skeleton, resulted in varied degrees of muscle relaxant activity. Some of the compounds also inhibited acetylcholinesterase activity in low concentrations so that they would not be directly suitable for use as muscle relaxants.     

LEG CRAMPS

Foot and leg cramps are among the most frequent complaints presented by patients of both sexes, especially older persons. Similar cramping may occur in the thighs or in other skeletal muscles of the extremities and trunk. Foot and leg cramps usually occur after unusual exertion or during sleep. “Nocturnal leg cramps” may be of sufficient intensity to prevent sleep. “Pregnancy cramps” are particularly distressing.Effective treatment of foot and leg cramps requires an understanding of the etiology, pathophysiology and diagnostic techniques. Weight reduction and improved diet are essential. Among the useful supplementary medications are calcium lactate or gluconate, vitamin-mineral supplements, sympathetic blocking agents, vasodilators, ataraxics, muscle relaxants, quinine, hydrochloride, antihistamines, and nonmercurial diuretics.Improved foot care and correction of foot imbalance is usually required. Edema and venous insufficiency are improved by elastic support, by repeated foot elevation for massages, by manipulations and exercises and by the use of diuretics. There may be need for operations on the veins and for sclerotherapy. Patients with arterial insufficiency are often benefited by lumbar sympathetic blocks with long-acting anesthetics and intra-arterial injections with relaxants, vasodilators, thrombolytic enzymes and anticoagulants. Sympathectomy, angiography and reconstructive arterial operations are indicated in only a small proportion of patients with foot and leg cramps.     

Social Network Analysis Shows Direct Evidence for Social Transmission of Tool Use in Wild Chimpanzees

Social network analysis methods have made it possible to test whether novel behaviors in animals spread through individual or social learning. To date, however, social network analysis of wild populations has been limited to static models that cannot precisely reflect the dynamics of learning, for instance, the impact of multiple observations across time. Here, we present a novel dynamic version of network analysis that is capable of capturing temporal aspects of acquisition—that is, how successive observations by an individual influence its acquisition of the novel behavior. We apply this model to studying the spread of two novel tool-use variants, “moss-sponging” and “leaf-sponge re-use,” in the Sonso chimpanzee community of Budongo Forest, Uganda. Chimpanzees are widely considered the most “cultural” of all animal species, with 39 behaviors suspected as socially acquired, most of them in the domain of tool-use. The cultural hypothesis is supported by experimental data from captive chimpanzees and a range of observational data. However, for wild groups, there is still no direct experimental evidence for social learning, nor has there been any direct observation of social diffusion of behavioral innovations. Here, we tested both a static and a dynamic network model and found strong evidence that diffusion patterns of moss-sponging, but not leaf-sponge re-use, were significantly better explained by social than individual learning. The most conservative estimate of social transmission accounted for 85% of observed events, with an estimated 15-fold increase in learning rate for each time a novice observed an informed individual moss-sponging. We conclude that group-specific behavioral variants in wild chimpanzees can be socially learned, adding to the evidence that this prerequisite for culture originated in a common ancestor of great apes and humans, long before the advent of modern humans.     

Endotoxin and Acute Renal Failure Associated with Obstructive Jaundice

A single dose of endotoxin given to rats with obstructive jaundice produced death with intravascular coagulation. This action was apparently due to delayed clearance of endotoxin from the circulation. The finding is relevant to “hepatorenal failure,” which can be caused by bacteraemia after biliary tract operations.     

Sound Symbolism in the Languages of Australia

The notion that linguistic forms and meanings are related only by convention and not by any direct relationship between sounds and semantic concepts is a foundational principle of modern linguistics. Though the principle generally holds across the lexicon, systematic exceptions have been identified. These “sound symbolic” forms have been identified in lexical items and linguistic processes in many individual languages. This paper examines sound symbolism in the languages of Australia. We conduct a statistical investigation of the evidence for several common patterns of sound symbolism, using data from a sample of 120 languages. The patterns examined here include the association of meanings denoting “smallness” or “nearness” with front vowels or palatal consonants, and the association of meanings denoting “largeness” or “distance” with back vowels or velar consonants. Our results provide evidence for the expected associations of vowels and consonants with meanings of “smallness” and “proximity” in Australian languages. However, the patterns uncovered in this region are more complicated than predicted. Several sound-meaning relationships are only significant for segments in prominent positions in the word, and the prevailing mapping between vowel quality and magnitude meaning cannot be characterized by a simple link between gradients of magnitude and vowel F2, contrary to the claims of previous studies.     

PROBLEMS IN VENTILATION IN THE IMMEDIATE POSTOPERATIVE PERIOD

In the present day practice of surgical anesthesia, drugs and techniques are used which require or lead to cessation of voluntary respiration by the patient. Respiration is then controlled by the anesthesiologist. At the termination of operation many patients do not breathe adequately for variable periods of time. The causes include obstruction, excessive sedation, muscle relaxants, the effect of controlled respiration itself and various miscellaneous factors. A diagnosis is made by taking into consideration the drugs and techniques which have been used and the character of the patient''s respiratory efforts, if any. The cause may then be treated. In some cases antidotes are available. However, until truly adequate spontaneous respiration is observed for some time the patient must have his efforts assisted. High oxygen concentrations must not be substituted for adequate ventilation.     

Development of a Novel Model for the Assessment of Dead-Space Management in Soft Tissue

Following extensive surgical debridement in the treatment of infection, a “dead space” can result following surgical closure that can fill with hematoma, an environment conducive to bacterial growth. The eradication of dead space is essential in order to prevent recurrent infection. This study describes a novel small animal model to investigate dead-space management in muscle tissue. Two absorbable test materials were implanted in each animal; beads of calcium sulfate alone, and beads loaded with vancomycin and tobramycin. In-life blood samples and radiographs were taken from each animal following implantation. Animals were sacrificed at 1, 7, 21, 42, and 63 days post-operatively (n = 4), and implant sites were analysed by micro-computed tomography, histology and immunohistochemistry. Complete resorption was confirmed radiographically at 3 weeks post-implantation. Histologically, the host tissue response to both materials was identical, and subsequent healing at the implant sites was observed with no dead space remaining. Vancomycin was not detected in blood serum. However, peak tobramycin levels were detected in all animals at 6 hours post-implantation with no detectable levels in any animals at 72 hours post implantation. Serological inflammatory cytokine expression for IL-6, TNF-α and IL-1β indicated no unusual inflammatory response to the implanted materials or surgical procedure. The model was found to be convenient and effective for the assessment of implant materials for management of dead space in muscle tissue. The two materials tested were effective in resolving the surgically created dead space, and did not elicit any unexpected adverse host response.     

高龄患者腹腔镜直肠癌根治术不同麻醉方法的比较

目的观察比较3种麻醉方法对高龄腹腔镜直肠癌根治术患者的呼吸循环功能和麻醉效果的影响。方法将45例高龄腹腔镜直肠癌根治术患者随机分成3组,每组15例。EA组,连续硬膜外阻滞麻醉组;GA组,静吸复合全身麻醉组;EGA组,小剂量硬膜外阻滞复合静吸全身麻醉组。观察3组麻醉开始前(T0)、麻醉诱导期(T1)、气管插管时(T2)、拔除气管导管时(T3)的HR、SBP、DBP、MAP、PETCO2、ECG,GA组与EGA组同时监测异氟醚MAC、气道压、手术结束自主呼吸恢复时间、自主呼吸潮气量达标、拔管时间、肌松情况及患者麻醉苏醒时间。结果 EA组有13例麻醉效果优良,SpO295%,PETCO2维持在正常范围;EGA组术毕自主呼吸恢复时间、潮气量达标、拔管时间均明显短于GA组(P0.01)。EA组在麻醉10～15 min后血压下降程度与GA组、EGA组麻醉诱导期血压下降相似(P0.05),EGA组在气管插管/拔管期血压波动不明显,而GA组血压显著升高(P0.01);EA组与GA组麻醉效果相似,EGA组麻醉效果优于GA组(P0.05)。结论 EGA组椎管内局麻药用量、全麻维持药用量、肌松药用量等均相应减少,呼吸循环功能较为稳定,术毕麻醉苏醒快,自主呼吸恢复和潮气量达标迅速,多数患者术毕即可拔除气管导管,是高龄腹腔镜直肠癌根治术患者理想的麻醉方法。     

A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness

Intratumor cellular heterogeneity and non-genetic cell plasticity in tumors pose a recently recognized challenge to cancer treatment. Because of the dispersion of initial cell states within a clonal tumor cell population, a perturbation imparted by a cytocidal drug only kills a fraction of cells. Due to dynamic instability of cellular states the cells not killed are pushed by the treatment into a variety of functional states, including a “stem-like state” that confers resistance to treatment and regenerative capacity. This immanent stress-induced stemness competes against cell death in response to the same perturbation and may explain the near-inevitable recurrence after any treatment. This double-edged-sword mechanism of treatment complements the selection of preexisting resistant cells in explaining post-treatment progression. Unlike selection, the induction of a resistant state has not been systematically analyzed as an immanent cause of relapse. Here, we present a generic elementary model and analytical examination of this intrinsic limitation to therapy. We show how the relative proclivity towards cell death versus transition into a stem-like state, as a function of drug dose, establishes either a window of opportunity for containing tumors or the inevitability of progression following therapy. The model considers measurable cell behaviors independent of specific molecular pathways and provides a new theoretical framework for optimizing therapy dosing and scheduling as cancer treatment paradigms move from “maximal tolerated dose,” which may promote therapy induced-stemness, to repeated “minimally effective doses” (as in adaptive therapies), which contain the tumor and avoid therapy-induced progression.     

Body composition adaptations to lower-body plyometric training: a systematic review and meta-analysis

The aim of this meta-analysis was to explore the effects of plyometric jump training (PJT) on body composition parameters among males. Relevant articles were searched in the electronic databases PubMed, MEDLINE, WOS, and SCOPUS, using the key words “ballistic”, “complex”, “explosive”, “force-velocity”, “plyometric”, “stretch-shortening cycle”, “jump”, “training”, and “body composition”. We included randomized controlled trials (RCTs) that investigating the effects of PJT in healthy male’s body composition (e.g., muscle mass; body fat), irrespective of age. From database searching 21 RCTs were included (separate experimental groups = 28; pooled number of participants = 594). Compared to control, PJT produced significant increases in total leg muscle volume (small ES = 0.55, p = 0.009), thigh muscle volume (small ES = 0.38, p = 0.043), thigh girth (large ES = 1.78, p = 0.011), calf girth (large ES = 1.89, p = 0.022), and muscle pennation angle (small ES = 0.53, p = 0.040). However, we did not find significant difference between PJT and control for muscle cross-sectional area, body fat, and skinfold thickness. Heterogeneity remained low-to-moderate for most analyses, and using the Egger’s test publication bias was not found in any of the analyses (p = 0.300–0.900). No injuries were reported among the included studies. PJT seems to be an effective and safe mode of exercise for increasing leg muscle volume, thigh muscle volume, thigh and calf girth, and muscle pennation angle. Therefore, PJT may be effective to improve muscle size and architecture, with potential implications in several clinical and sport-related contexts.     

Histamine release by some new skeletal muscle relaxants studied at the rat ileum

The effects of 6 non-depolarizing muscle relaxants on histamine release were investigated, pharmacologically, using histamine and histamine antagonists, e.g. mepyramine, clemastine, dimotane. The results showed that gallamine, pancuronium, vecuronium, atracurium, tubocurarine and alcuronium produced concentration-dependent contractions in the rat ileum, gallamine and pancuronium being the most effective agents in producing muscle contraction. The H1 blocker, mepyramine, reduced the contractions produced by the muscle relaxants, as well as that produced by histamine. However, there was always some residual contraction, not blocked by high concentrations of mepyramine in the case of the muscle relaxants, but not in the case of histamine, the contraction of which was totally blocked by high concentrations of mepyramine. These results also suggested that, in part, the contraction produced by muscle relaxants, may be due to a mechanism other than histamine release, e.g. release of other mediators and/or an effect on intracellular calcium ions. Since very high concentrations of atracurium and vecuronium (40-50 times higher than clinical concentrations) were used in this study to produce marked contractions, the implication is that in clinical concentrations, they have little effect on histamine release. In contrast, gallamine and pancuronium can release histamine even at low concentrations, i.e. at or near their clinical concentrations in man. These, therefore, are the cause of the adverse reactions seen after drug administration.     

Hemorrhage During Long-Term Anticoagulant Drug Therapy—Part IV: Selection and Management of Patients

Most serious hemorrhages that occur during long-term anticoagulant drug therapy are due either to poor patient selection or to poor management of the patient, or both.In each patient being considered for treatment, the risk of bleeding must be evaluated and classified as high, moderate or low.The clinician must especially assess the risk of intracranial hemorrhage in hypertensive patients, and must screen all patients for potential sources of gastrointestinal bleeding. There is ample time for such investigations, since initiating long-term anticoagulant therapy is not an emergency procedure.The desired level of prothrombin activity must be adjusted to the risks determined for each individual patient. There is no single “therapeutic range” applicable to all patients with their varying hemorrhagenic risks.Proper management includes sufficient laboratory testing to maintain the desired prothrombin level, and continued vigilance to detect signs of early bleeding.Preventable hemorrhage cannot be cited as evidence against the value of anticoagulant drug therapy.     

THE EFFECT OF SMOOTH MUSCLE ON THE INTERCELLULAR SPACES IN TOAD URINARY BLADDER

Phase microscopy of toad urinary bladder has demonstrated that vasopressin can cause an enlargement of the epithelial intercellular spaces under conditions of no net transfer of water or sodium. The suggestion that this phenomenon is linked to the hormone's action as a smooth muscle relaxant has been tested and verified with the use of other agents effecting smooth muscle: atropine and adenine compounds (relaxants), K⁺ and acetylcholine (contractants). Furthermore, it was possible to reduce the size and number of intercellular spaces, relative to a control, while increasing the rate of osmotic water flow. A method for quantifying these results has been developed and shows that they are, indeed, significant. It is concluded, therefore, that the configuration of intercellular spaces is not a reliable index of water flow across this epithelium and that such a morphologic-physiologic relationship is tenuous in any epithelium supported by a submucosa rich in smooth muscle.     

Soluble guanylate cyclase-dependent relaxation is reduced in the adult rat bronchial smooth muscle

Cyclic nucleotides are relaxants of the airway smooth muscle, yet most of the available data were obtained in adult animals. The expression and activity of cyclases have been reported to be developmentally regulated in the lung, and little is known about the age-related changes in their bronchial muscle relaxation potential. We evaluated and compared the newborn and adult rat bronchial smooth muscle response to cyclic AMP- and GMP-dependent agonists in isometric mounted bronchial rings. In acetylcholine-precontracted bronchial muscle, the relaxant response to the cAMP agonist forskolin was not age dependent, but the relaxant response to the nitric oxide (NO) donor sodium nitroprusside (SNP) was significantly greater (P<0.01) in the newborn. To further evaluate the cGMP pathway, we stimulated the soluble guanylate cyclase (sGC) with the specific agonists BAY 41-2272 and YC-1. In keeping with the SNP dose-response curves, the sGC agonists significantly relaxed the newborn, but not the adult bronchial muscle. Protein expression of the sGC alpha1- and beta1-subunits were significantly lower (P<0.01) in the adult compared with the newborn bronchial tissue. Consistent with these results, the NO-stimulated sGC activity was significantly greater in the newborn compared with the adult (P<0.01). In conclusion, the bronchial smooth muscle cGMP-, but not cAMP-dependent, relaxant response is developmentally regulated and significantly reduced in the adult rat.     

An Examination of Resveratrol's Mechanisms of Action in Human Tissue: Impact of a Single Dose In Vivo and Dose Responses in Skeletal Muscle Ex Vivo

The current study tested the hypothesis that a single, moderate dose of RSV would activate the AMPK/SIRT1 axis in human skeletal muscle and adipose tissue. Additionally, the effects of RSV on mitochondrial respiration in PmFBs were examined. Eight sedentary men (23.8±2.4 yrs; BMI: 32.7±7.1) reported to the lab on two occasions where they were provided a meal supplemented with 300 mg of RSV or a placebo. Blood samples, and a muscle biopsy were obtained in the fasted state and again, with the addition of an adipose tissue biopsy, two hours post-prandial. The effect of RSV on mitochondrial respiration was examined in PmFBs taken from muscle biopsies from an additional eight men (23.4±5.4 yrs; BMI: 24.4±2.8). No effect of RSV was observed on nuclear SIRT1 activity, acetylation of p53, or phosphorylation of AMPK, ACC or PKA in either skeletal muscle or adipose tissue. A decrease in post absorptive insulin levels was accompanied by elevated skeletal muscle phosphorylation of p38 MAPK, but no change in either skeletal muscle or adipose tissue insulin signalling. Mitochondrial respiration in PmFBs was rapidly inhibited by RSV at 100–300 uM depending on the substrate examined. These results question the efficacy of a single dose of RSV at altering skeletal muscle and adipose tissue AMPK/SIRT1 activity in humans and suggest that RSV mechanisms of action in humans may be associated with altered cellular energetics resulting from impaired mitochondrial ATP production.