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Seven coumaric compounds analogous to aurapten were synthesized. Their spasmolytic activity against Ba2+, acetylcholine and histamine was evaluated to investigate their structure-activity relationship. The results of the bioassay demonstrated the important roles of the cis type of double bond at C-2' and the epoxide between c-6' and 7'.
Quaternary ammonium derivatives such as cimetropium, n-butyl scopolammonium, otilonium and pinaverium bromide have been discovered and developed as potent spasmolytics of the gastrointestinal tract. Their pharmacological activity has been proven in both "in vivo" and "in vitro" studies of hypermotility. "In vitro" experiments showed that they possess antimuscarinic activity at nM level but only pinaverium and otilonium are endowed with calcium channel blocker properties. These latter compounds relaxed the gastrointestinal smooth muscle mainly through a specific inhibition of calcium ion influx through L-type voltage operated calcium channels. Molecular pharmacology trials have indicated that pinaverium and otilonium can bind specific subunits of the calcium channel in the external surface of the plasma membrane and in this way they block the machinery of the contraction. Recent evidence showed that otilonium is able to bind tachykinin NK(2) receptors and not only inhibits one of the major contractile agents but can reduce the activation of afferent nerves devoted to the passage of sensory signals from the periphery to the central nervous system. Thanks to their typical physico-chemical characteristics, they are poorly absorbed by the systemic circulation and generally remain in the gastrointestinal tract where they exert the muscle relaxant activity by a local activity. Some differences exists in the absorption among these compounds: both n-butyl scopolammonium and cimetropium are partially taken up in the bloodstream, pinaverium has a low absorption (8-10 %) but is endowed with an excellent hepato-biliary excretion and otilonium, which has the lowest absorption (3 %), is almost totally excreted by faeces. Quaternary ammonium derivatives are widely used for the treatment of irritable bowel syndrome and recent meta-analyses have supported their efficacy in this disease. Due to its therapeutic index, the use of n-butyl scopolammonium is more indicated to treat acute colics than a chronic disease such as irritable bowel syndrome. Taking into consideration the published trials carried out with validated methodology in irritable bowel syndrome, cimetropium and otilonium are the best demonstrated drugs for the improvement in global assessment, pain and abdominal distension.
Mebeverine, N-ethyl-4'-[1-methyl-2-(4-methoxyphenyl)ethylamino] butyl-3,4-dimetoxybenzoate, was studied for its inhibitory effect on the motility of the gastrointestinal tract in vivo and in vitro. In both cases its activity was more evident on the hypermotility induced by some common physiological spasmogenic agents than on basal motility. In various tests it was ascertained that mebeverine was able to inhibit the stimulant actions of all the drugs employed, both those acting on specific receptor sites such as histamine and acetylcholine, and those acting directly on the smooth muscle such as substance P, physalaemin etc. This backs up the suggestion of a nonspecific miotropic effect of mebeverine. This compound has the same spasmolytic action at different levels of the gastrointestinal tract and is decisively stronger than papaverine. The lack of remarkable side-effects in the tests which were carried out in vivo with decisively active doses on the gastrointestinal motility and the good inhibitory effect on human isolated strips of the gastrointestinal tract suggest that mebeverine may be useful in the treatment of clinical morbid conditions characterized by hypertone or hypermotility of the gastrointestinal tract.
The subject of the research was the adsorption of selected musculotropic and cholinolytic spasmolytics on a cytoprotective drug--sucralfate. Adsorption evaluation was made by a static method, in vitro, the environment reaction, the concentrations of the tested drugs and the sucralfate form being taken into account. The obtained results prove that the analysed therapeutic substances are adsorbed on the sucralfate in all pH. The highest bonding capacity was observed in tests at pH=3.6, in the presence of sucralfate, which at this pH occurs in the form of suspension. The lowest capacity was at pH=1.5 in the presence of sucralfate in the paste form. In the group of the tested drugs, scopolamine butylbromide is adsorbed best, drotaverine hydrochloride little less and papaverine hydrochloride least of all.
The para-hydroxy-benzonitrile (PHB) show spasmolytic activity of the muscular of duodenum provoked by acetylcholine or barium chloride. The results obtained on the vas deferent of the rat versus the contracture effects of norepinephrine show that PHB is an antagonist of the neuromediator on the post-synaptic alpha adrenoceptors.
The human pS2 gene, isolated from the breast carcinoma cell line MCF-7 and shown to be under estrogen transcriptional control in a subclass of breast cancer cells was reported to be secreted in normal stomach surface epithelial cells, whereas additional gastrointestinal tissues like pancreas and colon do not secrete pS2 at all. In porcine pancreas, a spasmolytic polypeptide (sharing domains of homology with pS2) was observed; a corresponding human gene (hSP) was shown to be active in normal stomach mucosa. hSP and pS2 gene activity in normal and neoplastic pancreas tissues was then compared. Whereas both genes are inactive in normal pancreatic cells, activation of the pS2 sequence in a primary pancreatic carcinoma cell culture and in 23 tumor tissues was noted when investigated by immunostaining. In all cases when pS2 showed a regular 0.6 kb transcript, hSP displayed a transcript of 0.7 kb. Six of these tumors showed a reduced pS2 immunoreactivity and, at the same time, aberrant pS2 mRNA bands and a complete shut-down of the hSP gene were noted. In one case, whereas normal pancreas remained negative, the corresponding tumor and its metastasis displayed regular transcripts of pS2 and hSP. This remarkably high correlation suggests that pS2 and hSP expression in the pancreatic tumors, but not in their corresponding healthy tissue is significantly linked to molecular steps leading to tumorigenesis.
Pitofenone, a spasmolytic compound, inhibited the acetylcholinesterase activity from bovine erythrocytes and from electric eel. It is a potent inhibitor of this enzyme from the two sources, with Ki values of 36 and 45 microM, respectively. Of the five compounds structurally related to pitofenone, only those containing a piperidine moiety show acetylcholinesterase inhibition. All these inhibitions are reversible, linear, and noncompetitive in nature. A qualitative correlation between the anticholinesterase and the corresponding antimuscarinic activity for some of these compounds was apparent. Good separation of these two effects would be a desirable feature for newer muscarinic antagonists.
We treated 38 consecutive outpatients with ureter colic with a new anticholinergic spasmolytic agent, cimetropium bromide, in order to evaluate its efficacy in this condition. After assessing pain intensity by means of a visual analogic scale, we administered 5 mg i.v. Already after 30 minutes, 4 patients (11%) reported complete subsidence of pain. In 21 patients (55%) pain subsided almost completely within one hour. Eighteen patients required a second 5 mg i.v. injection after one hour; of these, 13 (72%) had complete regression or marked reduction of pain. Apart from dryness of the mouth which appeared in two cases after the second injection and was of moderate intensity, no side effects were observed.
An in vivo model for evaluating spasmolytic activity in the anaesthetized rat has been developed. A peculiarity of this model is the injection of parasympathetic agonists directly into the abdominal aorta. Acetylcholine and carbachol produced constant contractions of the ascending colon, while the cardiovascular system was affected only to a small extent. The contractions could be selectively antagonized by antimuscarinic drugs administered by either intravenous or intraduodenal route. Antagonists at other receptor systems were ineffective. The present procedure provides a reliable test model which mimics, in the rat, the technique of close intra-arterial injection of spasmogen feasible only in bigger animals.
Vasodilating action of a new calmodulin antagonist, 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-[( 4-(2- methoxyphenyl)-1-piperazinyl] methyl) isoquinoline (Ro 22-4849) was examined in various isolated canine vessels. Ro 22-4839 was found to dilate basilar and middle cerebral arteries and to non-selectively antagonize submaximal contraction of these arteries under the treatment of various constrictors (K+, Ca2+, PGF2 alpha (dinoprost), serotonin and incubated blood) with IC50 values ranging from 0.043 to 1.69 mumol/l. Vasospasmolytic action of the compound in these cerebral arteries was 9 and 20 times greater than those in coronary and femoral arteries, respectively. The arterial relaxation by Ro 22-4839 was hardly overcome by addition of extra calcium and Ro 22-4839 did not alter calcium channels in the guinea-pig papillary muscle, although the compound inhibited the tension development, confirming its calmodulin antagonistic properties. Ro 22-4839 inhibited norepinephrine (NE)-induced contraction of femoral arterial strips concentration-dependently, and prevented NE-induced lethal extravasation in mice with an ED50 value of 1.96 mg/kg p.o. In in vitro [3H]-dihydroergocryptine binding assay and ex vivo [3H]-WB-4101 (2-[(2',6'-dimethoxy)phenoxyethylamino] methylbenzodioxan) binding assay, the compound showed a potent inhibitory action on alpha 1-adrenoceptor. These findings indicate that Ro 22-4839 exerts the spasmolytic effects on cerebral vessels through calmodulin antagonistic properties combined with alpha 1-adrenoceptor blocking action.
A cDNA sequence has been used to derive the precursor structure of a highly repetitive protein in Xenopus laevis skin. From the sequence of a whole family of secretory proteins can be predicted containing a classical hydrophobic signal sequence at the NH2-terminal end of the precursor. The proteins contain four domains with high homology to porcine pancreatic spasmolytic polypeptide. These four cysteine-rich, presumably physiologically active domains are separated in the molecule by a repetitive element, locating two such domains to the NH2 terminus of the precursor protein and the remaining two to the COOH-terminal end. The separating spacer consists of very unusual, precise, threonine and proline-rich repeats containing 9 residues which could be targets for extensive O-glycosylation. Additionally, processing at two pairs of basic residues is suggested to liberate two polypeptides ("spasmolysins") and "spasmolysin-glycoprotein."
The bladder spasmolytic propiverine hydrochloride is subject of an extensive metabolism in the animal and human body. Various consequent products could be detected. The synthesis and characterization of some compounds are reported.
The effects of intravenously administered glycopyrrolate 0.2 mg (n = 10, Group I) or one orally given analgesic-spasmolytic combination preparation tablet (n = 10, Group II) on the contraction of human gallbladder during control oral cholecystography were compared with patients without any medication (n = 10, Group III). Neither drug had any effect on the gallbladder contraction and, hence, their usefulness in a patient with pain caused by gallstones is questionable. Heart rates and blood pressures were constant in Groups II and III but in Group I glycopyrrolate occasionally caused slight tachycardia and elevated blood pressure. Only in Group I 2 patients had mild side-effects (anticholinergic).
A report is given on the spasmolytic effect of two benzisothiazolcarboxyamides (compound A and compound B). These drugs were able to inhibit the stimulant action of histamine on human isolated myometrium. The potency of the two compounds exceeded by ten times that of ritodrine (a beta adrenergic stimulant), the efficacy was slightly higher (20-30%) than that of papaverine. This pharmacological effect is discussed on the light of the spectrum of activites of the benzisothiazolcarboxyamidic compounds.
Correlation was found between the hydrolysis constant and spasmolytic potency of some isoquinoline derivatives measured on isolated guinea-pig's ileum: the greater the hydrolysis constant the greater was the antispasmodic activity. On the basis of the results obrained the influence of pH on the pharmacologic activity of these compounds may be explained.
Experiments with isolated ring-like strips of pig heart veins and arteries and those with rat small intestinal strips made in the presence of hyperpotassium contracture have demonstrated that spasmolytic activity of papaverine, nospa, nonachlazine, and ethmozine is a consequence of the reduced respiratory intensity and phosphorylation in smooth muscle mitochondria. No changes in the anaerobic glycolysis rate have been found after drug administrations.
The objective of this work was to thoroughly examine the smooth muscle relaxing properties of cinnamedrine, compared with papaverine, in vitro, using rat uterus. Cinnamedrine and papaverine both exhibited dose-related spasmolytic activity in the isolated spontaneously contracting rat uterus and in uterine tissue pretreated with oxytocin to augment spasms. The IC50's for cinnamedrine and papaverine were 36.2 and 7.7 microM respectively; the IC50's after oxytocin pretreatment were 25.7 microM for cinnamedrine and 10.0 microM for papaverine. Neither hormonal status of the rats, with respect to their estrus cycle, nor oxytocin pretreatment of the isolated tissues noticeably affected the activity of either cinnamedrine or papaverine.
The influence of smooth muscle contractility of (3,4-dichloranilino)phenyl-acetonitrile (H 74) was studied in comparison with the analogs (4-chloranilino)phenyl-acetonitrile (H 47) and (3,4,5-trichloranilino)phenyl-acetonitrile (H 84) and several standard pharmaca. H 74 and H 84 showed a spasmolytic action that was almost equal to that of methphenethamine and papaverine. Other investigations have revealed that H 74 was free from any side effect. It is concluded that chloranilino-phenyl-acetonitriles cause a nonspecific inhibition of smooth muscle contractility.