Neuromuscular blocking effects of the aminoglycoside antibiotics arbekacin, astromicin, isepamicin and netilmicin on the diaphragm and limb muscles in the rabbit

Aminoglycoside antibiotics are known to produce a depression of neuromuscular function which may cause prolonged paralysis of respiratory muscles. However, differences in the effects of aminoglycoside antibiotics on diaphragm and limb muscles have not been investigated. We determined the neuromuscular blocking effects of the aminoglycoside antibiotics arbekacin sulfate, astromicin sulfate, isepamicin sulfate and netilmicin sulfate on the diaphragm, tibialis anterior and soleus muscles in anesthetized rabbit nerve-muscle preparations. Neuromuscular block was assessed by mechanical response with single twitch stimulation. Cumulative drug dose-response curves were obtained for three different muscles in 24 rabbits. The mean ED(50) and ED(95) of the antibiotics in diaphragm, tibialis anterior and soleus muscles were calculated. The neuromuscular blocking effects of all the aminoglycosides on ED(50) and ED(95) values were in the order of soleus > tibialis anterior > diaphragm, and soleus > diaphragm > tibialis anterior, respectively. The ED(50) ratios for the tibialis anterior and soleus muscles were approximately 1.5 and 2.7 times greater than that for the diaphragm.     

Neuromuscular blocking properties of some bistropinium esters

The neuromuscular blocking, anti-acetylcholine and ganglion blocking properties of two series of bistropinium esters were examined. The neuromuscular blocking activities of the mandelic acid esters of NN'-polymethylenebis(tropinium halides) were found to depend upon the number of carbon atoms (n) in the linking chain. Potency was enhanced more than 50 times as n was increased from 2 to 7. Compounds in which n equalled 7, 8, 9, 10 and 12 differed little in activity, but were generally more potent than tubocurarine in cats and rabbits. A peak of ganglion blocking action was obtained at the pentamethylene member. Esterification enhanced the feeble neuromuscular blocking properties of NN'-decamethylenebis(tropinium halide), the mandelic acid ester being more effective than the tropic, benzoic or phenylacetic acid esters in cats and rabbits. When two benzoic or mandelic acid esters of tropine were linked through their nitrogen atoms by a phenylenedimethyl grouping (-CH₂.C₆H₄.CH₂-), meta substitution was more effective than was ortho or para in producing neuromuscular block. The effectiveness of esterifying acids in m-phenylenedimethyl derivatives decreased in the following order, phenylacetic> tropic or mandelic>benzoic>acetic and diphenylacetic.     

Neuromuscular blocking and ganglion blocking activities of some acetylcholine antagonists in the cat

The potencies of tubocurarine, gallamine, pancuronium, benzoquinonium, hexamethonium and mecamylamine in blocking neuromuscular transmission in the soleus muscle, and in blocking contractions of the nictitating membrane evoked by preganglionic sympathetic stimulation have been compared in cats under chloralose anaesthesia. On a molar basis, pancuronium was about 8 times and benzoquinonium about 2·5 times more potent than tubocurarine in blocking the soleus muscle; gallamine was less than half as potent, mecamylamine about 128 times and hexamethonium about 380 times less potent. In blocking the superior cervical ganglion, mecamylamine was about 17 times more, tubocurarine was about 5 times more and pancuronium about twice as potent as hexamethonium. Benzoquinonium was about half as potent as hexamethonium, and gallamine about 5 times less potent. The results emphasize that the shorter distance between charged centres, as in hexamethonium, reduces affinity for muscle receptors but does not necessarily enhance affinity for ganglion receptors, and from the point of view of deductions concerning the configuration of the ganglionic receptor, the ganglion blocking potencies of some neuromuscular blocking drugs should be taken into account.     

Neuromuscular blocking activity of aminoglycoside antibiotics

The aminoglycoside antibiotics possess neuromuscular blocking activity; the potency of those antibiotics tested appears to be as follows: gentamicin greater than streptomycin greater than amikacin greater than sisomicin greater than kanamycin = tobramycin greater than kanendomycin = dibekacin. The neuromuscular blockade produced by these antibiotics is not reversed by neostigmine, whereas it is reversed by calcium. Calcium not only has the ability to restore the neuromuscular transmission but also to exert protective action against the neuromuscular blocking activity of aminoglycoside antibiotics; these antibiotics are also potentially capable of interacting with non-depolarizing muscle relaxant drugs (d-tubocurarine, pancuronium) or propranolol, a beta-adrenergic receptor blocking agent. This interaction results in respiratory depression and/or prolonged apnoea. Our findings lead to the assumption that amino-glycoside antibiotics are involved in the process of acetylcholine release by nerve impulses, antagonizing calcium ions.     

国产维库溴铵神经肌肉阻滞效应及对心血管的影响

目的：评价国产维库溴铵的神经肌肉阻滞效应及对心血管的影响。方法：选择择期手术病人２０例，随机分为国产维库溴铵组（１０例）和进口维库溴铵组（１０例）。每组均注射维库溴铵０．１ｍｇ／ｋｇ后测定肌松药的起效时间和维持时间，并观察心血管反应。结果：国产维库溴铵和进口维库溴胺在神经肌肉阻滞效应的各项指标和对心血管的影响方面均无明显差异。结论：国产维库溴铵的肌松效果满意且不明显影响心血管系统。     

Immunological properties of isepamicin (HAPA-B)

Immunological properties of isepamicin (HAPA-B), a new semisynthetic aminoglycoside, were compared with those of gentamicin (GM). The results are summarized as follows. Rabbits were immunized by HAPA-B or GM with a strong adjuvant, Freund's complete adjuvant, and specific IgG antibodies were found in sera when assayed using PHA and PCA reactions. In sera from guinea pigs and mice immunized by HAPA-B or GM with aluminum hydroxide gel, no specific IgG nor IgE antibody was detected when assayed using PCA reactions. Specific antibodies (IgG, IgE) produced against HAPA-B and GM were confirmed in different animals immunized by chemically introduced antigens of HAPA-B-carrier protein conjugate and GM-carrier protein conjugate, respectively. Guinea pigs immunized by HAPA-B or HAPA-B-carrier protein conjugate with aluminum hydroxide gel did not exhibit typical systemic anaphylactic reactions when elicited with HAPA-B alone. HAPA-B had some immunocross-reactivity with GM. These results suggested that the antibody-producing activity of HAPA-B was similar to that of GM.     

A clinical trial of astromicin, a new aminoglycoside antibiotic, in thoracotomized patients and astromicin concentrations in the lung tissue

There have been no report on concentrations in human lung tissue of aminoglycoside antibiotics which are frequently used in combination with cephem antibiotics in the treatment of severe respiratory infections. The authors examined lung tissue concentration of astromicin (ASTM) during clinical trials in thoracotomized patients using intravenous drip infusion just before operation. And the following conclusions have been obtained: 1. The average peak serum level obtained upon intravenous drip infusion of ASTM 200 mg for 1 hour just before operation was 11.2 micrograms/ml at 1 hour after starting the administration and half-life of ASTM in beta phase was 2.90 hours. 2. ASTM concentrations in the lung tissue upon 1 hour intravenous drip infusion just before operation at a dose level of 200 mg reached a maximum at 2 hours after the start of the administration averaging 7.7 micrograms/ml and were 27.7-68.8% of serum peak level. 3. Bronchiolar concentrations of ASTM 200 mg upon 1 hour intravenous drip infusion just before operation were 33.0-72.3% of peak serum level. These concentrations appear to be sufficient for the treatment of target infections. 4. The 1 hour intravenous drip infusion of ASTM 200 mg appeared to be clinically safety and useful as was the intramuscular injection of ASTM 200 mg.     

Neuromuscular blocking action of two hemicholinium-3 analogs

Two hemicholinium-3 (HC-3) analogs (NAM-204 and NAM-224) in which the C = O moiety was reduced to -CH2 and 2- or 3-CH3 substitution on the piperidine ring were demonstrated to produce a different type of neuromuscular inhibition than that induced by HC-3. The neuromuscular blocking activity was tested in several different preparations and it was shown that these compounds are potent, short-acting, and was reversed by neostigmine but not by choline. Although these compounds possess weak anticholinesterase activity, significant alterations of blood pressure and heart rate are absent. Miniature end-plate potentials' amplitude were found to be diminished by these compounds with some alteration of frequency. In voltage-clamped frog sartorius muscle NAM-224 and NAM-204 decreased amplitude of miniature end-plate current (mepcs) and accelerated the time constant of mepc decay in a concentration-dependent manner, without altering the single exponential nature of mepc decay. NAM-204 and NAM-224 at high concentrations also produced a voltage- and concentration-dependent non-linearity in current/voltage relationships, especially at more negative membrane potentials. Hence, these pharmacological and electrophysiological studies indicate NAM-224 and NAM-204 have significant activity at both pre- and post-junctional sites and their post-junctional blocking activity results from blocking ACh receptor/ion channel complex.     

Neuromuscular blocking activity of snake (Naja melanoleuca, Hallowel) venom

Naja melanoleuca venom had potent neuromuscular blocking activity interrupting transmission mainly by a post-junctional non-depolarizing mechanism. The venom did not appear to act on the choline transport mechanism or the neurotransmitter release mechanism. The blocking effect of N. melanoleuca venom was significantly antagonized by elevated magnesium levels and perhaps somewhat potentiated by lowered levels. The neuromuscular blocking effect of N. melanoleuca venom appears similar to that of the neurotoxin from N. naja venom and unlike that of the whole venom, in that it causes neither contraction of the diaphragm nor inhibition of the muscle response to direct stimulation, and its effects are partially reversed by neostigmine.     

Neuromuscular blocking profile of the vecuronium analogue, Org-9487, in the rat isolated hemidiaphragm preparation.

1. The neuromuscular effects of the short-acting aminosteroid muscle relaxant Org-9487 have been studied in the in vitro rat phrenic nerve/hemidiaphragm preparation by use of twitch tension and electrophysiological recording techniques. 2. Org-9487 (5-100 microM) produced a concentration-dependent decrease in the amplitude of twitches (0.1 Hz) and tetanic contractions (50 Hz) evoked by motor nerve stimulation. The compound produced fade of force during both 50 Hz stimulation and train-of-four stimulation at 2 Hz, indicating a prejunctional component of action. 3. Anticholinesterases only partially reversed the effect of Org-9487 on twitch responses. This was possibly because, at the concentrations required to block twitches in the rat, Org-9487 itself was found to possess significant anticholinesterase activity. 4. Org-9487 (3 microM) increased the rundown of endplate current amplitudes during a 2 s train of 50 Hz nerve stimulation. This was because Org-9487 increased the quantal content of the first endplate current in the train without affecting acetylcholine release towards the latter part of the train. 5. Org-9487 (10 microM) produced a voltage-dependent decrease in the time constant of decay of endplate currents at 32 degrees C and 0.5 Hz, indicative of a block of endplate ion channels. The blocking rate constant increased with membrane hyperpolarization.     

Neuromuscular blocking effect of fluoxetine and its interaction with rocuronium

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Comparison of beta-adrenoceptor blocking properties of sotalol, oxprenolol, propranolol and pindolol on rabbit intestinal smooth muscle.

Adrenergic agonists produced a characteristic and definite decrease in the amplitude of spontaneous contractions and tone of the isolated rabbit jejunum. Effect of phenylephrine was abolished either by phenoxybenzamine or phentolamine. Relaxation induced by epinephrine and by norepinephrine was inhibited after combined treatment with phentolamine and propranolol. Phentolamine alone diminished the response to epinephrine and to norepinephrine, but the diminution for epinephrine was greater, indicating that epinephrine has a greater affinity for alpha- than for beta-receptors in the rabbit jejunum. Stimulation of the beta-receptors by isoproterenol was inhibited by propranolol, oxprenolol, sotalol and pindolol, but the block was incomplete. The activity of these four beta-blockers in preventing the inhibitory response to isoproterenol was as follows: inidolol greater than or equal to oxprenolol greater than propranolol greater than sotalol. This demonstrates the fact that not all beta-adrenergic blocking agents possess an identical pharmacologic spectrum of activity. Also it can be suggested that the beta-receptors of jejunum differ in specificity from those of other organs.     

Neuromuscular blocking activity of two fractions isolated from the venom of the seasnake, Laticauda semifasciata

Two components (0·06 M and 0·09 M fractions) have been isolated from the venom of the seasnake, Laticauda semifasciata. Both are similar polypeptides, each with about 100 amino acids and a mol. wt of approximately 10,000. When tested on the isolated chick biventer cervicis nerve-muscle preparation, both fractions were post-junctional cholinoceptor antagonists, although about 100 times less active than erabutoxin b from the same venom. The fractions chemically resemble venom phospholipase A, but they differed from the enzyme in some effects at the neuromuscular junction. The fractions were very slowly and only partially reversible, whereas the effects of phospholipase A were reversed rapidly on washing.     

The neuromuscular blocking activity of isepamicin sulfate (HAPA-B) compared with other aminoglycoside antibiotics

Effects of isepamicin sulfate (HAPA-B), a new aminoglycoside antibiotic, on the neuromuscular transmission were studied in rats and compared with those of amikacin (AMK) or other aminoglycoside antibiotics. The HAPA-B, as well as other aminoglycoside antibiotics, depressed the twitch response of diaphragm to phrenic nerve stimulation in vitro. The depression effects of different drugs were compared and graded in the order of strengths of blocking action as: netilmicin (NTL) greater than gentamicin (GM) greater than streptomycin (SM) greater than kanamycin (KM) greater than AMK greater than HAPA-B. The IC50 (concentration which inhibited the response by 50%) of HAPA-B was 3.6 X 10(-3) g/ml. The neuromuscular blockade produced by HAPA-B was reversed by CaCl2, KCl or caffeine but not by neostigmine. D-Tubocurarine or MgCl2 augmented the neuromuscular effects of HAPA-B. Intramuscular (400 mg/kg) and intravenous (100 mg/kg) injections of HAPA-B did not affect the twitch response of gastrocnemius muscle to sciatic nerve stimulation in situ. Intravenous injection of 200 mg/kg caused death in some rats and depression of the twitch response in others. Intravenous AMK produced no significant effect on the twitch response at 50 mg/kg and caused death at 100 mg/kg. GM and SM caused death or significant degree of depression of the twitch response at intravenous doses of 50 mg/kg. In experiments of intravenous drug infusion for 60 minutes, the twitch response was depressed by HAPA-B at 400 mg/kg/hr and by AMK at 200 and 400 mg/kg/hr. In conclusion, HAPA-B has a neuromuscular blocking action presumably at the nerve terminal. However, its action was the weakest among the aminoglycoside antibiotics tested.     

Neuromuscular blocking activity of a glycosidic extract of the plant Sarcolobus globosus

Crude glycoside extracts from the plant, Sarcolobus globosus, were tested on the rat phrenic nerve-diaphragm, chick biventer cervicis and frog rectus abdominis preparations. Nerve-stimulated twitches were inhibited by the extract. The muscle paralysis was not similar to that by curare-like blockers as it was not reversed by neostigmine or by a tetanus. Although contractures to acetylcholine or carbachol were not affected by 0.6 mg/ml of the extract, higher concentration of the extracts (3 mg/ml) depressed the log dose-response curve of acetylcholine and carbachol. The results suggest that the neuromuscular blocking effect of the extracts is either dose-dependent or due to a mixture of toxins with presynaptic or postsynaptic actions.     

Neuromuscular blocking action of cadmium and manganese in isolated frog striated muscles.

In isolated frog sciatic nerve--gastrocnemius muscle preparations, exposure for 60 min to Cd2+ (0.1-2 mM) caused a marked attenuation of the twitch tension developed by stimulation of nerves but no or only a slight inhibition of the tension produced by direct stimulation at maximum twitch height. The inhibitory effect was partially reversed by 1 mM cysteine. In frog sartorius muscles, the addition of Cd2+ (0.1 mM) alos abolished the end-plate potential evoked by nerve stimulation but did not suppress potential changes induced by iontophoretically applied acetylcholine. The addition of Mn2+ (2 and 5 mM) attenuated the response of muscles to both direct and indirect stimulation; a greater attenuation of the latter was observed. The inhibition was not reserved by cysteine but was partially reversed by excess Ca2+. Contractile responses of frog rectus abdominis muscles to acetylcholine were not significantly affected by Cd2+ and Mn2+ but were attenuated by d-tubocurarine in a dose-dependent manner. Impulse conduction along sciatic nerves was not impaired by Cd2+ and Mn2+ but was by procaine. It appears that Cd2+ interferes with the release of acetylcholine from motor nerve terminals by reducing the transmembrane influxes of Ca2+, the influx possibly relating to SH groups of membrane constituents.