N-Alkyl-2-(5-methyl-4-imidazolyl)ethylamines. Synthesis and effect on gastric secretion

Synthesis of some 5-methylhistamines alkylated on the amino group (form. I) together with a new method (C) of obtaining them via 5-methylhistaminol, are described. Both the agonistic and antagonistic pharmacological activities of these methylhistamines were studied in vivo on gastric secretion of different animal species (conscious dogs and cats and anaesthetized rats). The potency of the compounds, as far as the H2-receptor stimulant effect is concerned, was very remarkable in the first members of the series and decreased by increasing the degree of substitution. Independently from their "potency" some members of the series showed an "efficacy" which was actually greater than that of histamine. All the compounds tested were completely devoid of any antagonistic activity against gastric hypersecretion induced by histamine.     

The effect of long-term treatment with antisecretory and antiulcer drugs on gastric secretory and motor responsiveness to caerulein in rats with chronic ulcers

In the present paper the gastric secretory and motor responsiveness to a gastrin-like peptide, caerulein, was assessed in rats with a chronic gastric ulcer induced by 'isolation', 48 h after completing prolonged treatments (30 and 60 days) with cimetidine (80 and 160 mg/kg), pirenzepine (8 and 16 mg/kg) and sulglycotide (160 mg/kg) administered orally as a single daily dose. After a 30 day pretreatment with both doses of cimetidine, gastric acid secretion was inhibited and the pylorus spasmogenic activity induced by caerulein was enhanced. The gastric effects of the peptide were not modified by pirenzepine pretreatment while an antisecretory action was shown by sulglycotide after the completion of prolonged treatment (60 days). The ulcers were significantly reduced by cimetidine (low dose) and sulglycotide after 30 day pretreatment. The effects are more likely to be related to the treatment than to the presence of the drugs on gastric receptors.     

Comparison of the effects of of structurally different H2-antagonists on acid and pepsin activity stimulated by dimaprit in conscious cats

In the present study the effects of three structurally different H₂-receptor antagonists (cimetidine, ranitidine and oxmetidine) have been investigated on gastric acid and pepsin secretion of eight cats provided with cannulated gastric fistulas. The maximum pepsin output obtained from a set of complete dose-response curves of dimaprit was not statistically different from basal vaules.In the presence of the H₂-antagonists, while the gastric acid secretion indeced by diparit was competitively antagonized, the pepsin secretion was differently affected. The data obtained on pepsin activity with cimetidine and ranitidine were quite similar to the control values. By contrast, oxemtidine induced a significant increase. The results suggest a very weak involvement of the H₂-receptors in pepsin activity and that oxmetidine performance could not be attributable to an H₂-receptor block.     

意大利母亲对学前儿童发热的知识、态度和处置方式

发热是儿童最常见的医学问题之一。学前儿童的发热常常是由相对无害的自限性的病毒感染引起 ,包括流感样疾病和急性上呼吸道感染 ,这是人体防御机制抵御感染的有益作用。如果孩子只是发热而没有严重的疾病征象 ,家长应该放心。儿科医生使用药物降温 ,并不是要加快痊愈 ,只不过是要减少患儿的不适。但家长经常为孩子的发热忧虑 ,他们对发热存在错误认识 ,常常不必要地过于积极地给孩子退热。1 995年 2～ 3月 ,意大利米兰“ＭａｒｉｏＮｅｇｒｉ”药理学研究所妇幼卫生研究室在意大利北部的米兰市区及南部的两个半农村地区 ,于公共场所 (如购…     

Extrapituitary actions of GnRH antagonists: prospects for in vitro fertilization programs

Gonadotropin-releasing hormone antagonists (GnRH-ant) are routinely used to prevent premature luteinizing hormone (LH) surges in women undergoing in vitro fertilization (IVF) programs. GnRH-ant act by competitively binding GnRH receptors (GnRHr), leading to rapid pituitary suppression. GnRH-ant can also block extrapituitary GnRHr, including those present in ovary, placenta, and endometrium. A full understanding of the functional roles played by extrapitutary GnRHr, along with a better characterization of the possible reproductive consequences of their blockage may aid the refinement of controlled ovarian stimulation (COS) protocols using GnRHant. This review summarizes current research in the area, especially focusing on the possible impact of GnRH-ant on steroidogenesis, folliculogenesis and endometrial receptivity.     

Motor responses of rat hypertrophic intestine following chronic obstruction

The present work aims at investigating the changes in motor responsiveness of rat intestine hypertrophied by chronic mechanical obstruction. Motor responses to pharmacological agents and electrical field stimulation (EFS) were studied in hypertrophic ileal segments excised from rats subjected to experimental stenosis (n = 20) and compared with responses of control tissues from sham-operated animals (n = 20). Spontaneous motility and contractile responses to exogenous agents (KCl, acetylcholine and substance P) and EFS (10-s trains every minute, 120 mA, 0.5 ms, 1-10 Hz) were increased in hypertrophic longitudinal segments; however, normalization of motor responses to tissue wet weight revealed a remarkable reduction of contractile efficiency in hypertrophied tissues coupled with a loss of sensitivity to nitric oxide-mediated relaxation. Furthermore, EFS under non-adrenergic non-cholinergic (NANC) conditions unveiled a major role of the cholinergic component over the peptidergic one in the neurogenic contraction of hypertrophic intestine. On the whole, hypertrophic intestinal growth emerges as a dynamic process entailing adaptation of smooth muscle and neuronal structures to the increased functional load imposed by lumen obstruction.     

The action of caerulein on pancreatic secretion of the dog and biliary secretion of the dog and the rat

1. Caerulein displayed a potent stimulant action on pancreatic secretion in the dog. Threshold doses were 1-5 ng/kg by rapid intravenous injection, 0.25-1 ng/kg per min by intravenous infusion and 50-100 ng/kg by subcutaneous injection. There was a conspicuous increase not only in the volume flow of pancreatic juice but also in the output of solid constituents of the juice and of amylase. However, continuous stimulation of pancreatic secretion by intravenous infusion of caerulein resulted in a progressive reduction of the amylase concentration and still more of the dry residue content of pancreatic juice. The bicarbonate concentration in pancreatic juice produced by caerulein was similar to that observed in juice secreted following pancreozymin administration or following other stimuli causing the same rate of flow of pancreatic juice.2. On a molar basis, caerulein was 25-30 times as active as human gastrin I and 3-6 times as active as cholecystokinin-pancreozymin. The presence in the molecule of caerulein of a sulphated tyrosyl residue at position 4 of the decapeptide (position 7 starting from the C-terminus) was a necessary prerequisite for the manifestation of the cholecystokinin-pancreozymin-like actions of caerulein. The C-terminal heptapeptide of caerulein retained much of the activity of the intact caerulein molecule.3. At high dose levels (50-200 ng/kg in the dog, 1 mug/kg in the rat, by rapid intravenous injection) caerulein stimulated the flow of hepatic bile in the dog and the rat. The dry residue of the bile and the cholesterol concentration were appreciably greater in rats treated with caerulein than in control rats.4. The activity spectrum of caerulein was identical with that of cholecystokinin-pancreozymin. This is readily explained on the basis of the almost identical structure of the C-terminal octapeptide of the two peptides.5. Caerulein and some caerulein-like peptides may be considered as model peptides, capable of being substituted for cholecystokinin-pancreozymin in all the possible experimental and clinical uses of the duodenal hormone, with the important advantage that they are more easily available.6. The question is raised whether cholecystokinin-pancreozymin obtained from the duodenum by acid extraction is the authentic hormone or rather a carrier polypeptide from which a smaller active peptide may be set free, when needed, into the circulation.     

Thiazolylalkylamines: synthesis of analogs of imidazolylethylamines and their effect on gastric secretion

As a part of a study on H2-agonists, the preparations and properties are reported for a representative group of 2-aminothiazolethylamine derivatives which contain the gastric secretion stimulating S-aminoalkylisothiourea moiety. The test compounds were obtained by known methods or from 2-(2-amino-5-thiazolyl)ethyl chloride and were tested for their possible histamine-like activities on different biological substrates. From the biological results it appears that the behaviour of the substances is rather complex, but the following general observations can be pointed out: the contracturant properties, sometimes quite marked, do not derive from direct H1-specific activities; the effects, particularly evident in stimulating in vitro or in vivo gastric secretion, in relaxing gall-bladder smooth muscle, on auriculae and/or on blood pressure, are not competitively antagonized by cimetidine; none of the tested compounds proved to be an antagonist of histamine H2-receptors, while one of them is found to inhibit competitively the H1-receptors. On the basis of structure-activity relationships it can be excluded that the iuxta-nuclear NH2 group of 2-aminothiazolethylamines reacts, in some way, with the H2-receptors, since, in this case, the 2-aminothiazole group is not a pharmacophore like the 2-aminoimidazole or isothiurea group. Consequently the hypotheses, that the flexibility of the molecule is a fundamental requirement for the H2-stimulating properties of S-(3-dimethylaminopropyl)isothiurea and that the different activities of 2-aminohistamine, in comparison with those of 2-methylhistamine, are due to the existence of a hydrophilic area suitable for the allocation of the iuxta-nuclear NH2 group in the H2-receptor, are strengthened.