New insights into the pharmacological properties of potent antiplatelet 2-amino-benzo[d]isothiazol-3-one derivatives.

A series of 2-amino-benzo[d]isothiazol-3-one derivatives (1-8), previously described as in vitro potent antiaggregatory agents endowed with spasmolytic properties, was evaluated for in vitro antiplatelet activity in guinea-pig platelet rich plasma and for in vivo effects on experimental thrombosis and bleeding time in mice. All the 2-amino-benzo[d]isothiazol-3-one derivatives 1-8 were more potent antiplatelets against collagen than acetylsalicylic acid and, unlike this drug, strongly inhibited thromboxane agonist U46619-induced aggregation. Subacutely administered (5mgkg(-1) day i.p. for 5 days), compounds 6 and 7 protected mice from collagen/epinephrine induced pulmonary thromboembolism at about 20-fold lower doses than acetylsalicylic acid and they prolonged bleeding time like the most part of the other derivatives. The potent antithrombotic activity was coupled with the absence of any lethal and ulcerogenic effect up to 200mgkg(-1) os.     

Effects of antimuscarinic agents, H2-blockers and omeprazole on rat chronic gastric ulcer after long- and short-term administration

Two series of experiments were performed on rat chronic ulcer in order to assess the possible curative and mucosal protective properties of 2 week treatments, or the preventive properties of 4 week treatments with antisecretory agents, acting with different mechanisms of action. At the end of the treatments the gastric secretory and motor responsiveness to a gastrin-like stimulus was simultaneously evaluated. The results support the view that antimuscarinic agents as well as H2-blockers cannot be defined as protective and that after a 4 week treatment they can induce modifications of gastric functions.     

Synthesis and binding assays of H3-receptor ligands.

The preparation of a representative group of derivatives of the known H3-antagonist thioperamide is described. Binding affinity for histamine H3-receptors of thioperamide and its derivatives, which were obtained by substitution on the imidazole ring, was measured on rat brain cortex synaptosomes. Competitive binding assays were performed with two different labelled ligands, the physiological agonist [3H]histamine ([3H]HA) and the potent H3-agonist N alpha-[3H]methyl-histamine ([3]NAMHA). We observed a remarkable difference in Ki values obtained versus the two labelled ligands, both for thioperamide and its derivatives. In particular, 5-methylthioperamide showed a considerable selectivity for the system recognized by [3H]NAMHA, being about 100 times more potent versus this system than versus the system recognized by [3H]HA. On the basis of these observations, we suggest that it is necessary to consider this difference in evaluating the affinity of new compounds for the H3-receptors.     

Spasmolytic effect of mebeverine on the gastrointestinal motility]

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.     

Isolated rabbit colon preparation: a sensitive method for the bioassay of caerulein and related substances

Summary An isolated preparation of the rabbit colon with a very high sensitivity to caerulein is described. The threshold dose of caerulein was 0.1–0.5 ng/ml; the heptapeptide of cholecystokinin pancreozymin behaved like caerulein, and pentagastrin was almost ineffective.The mode of action of the peptide in this preparation is briefly discussed.This work was supported by a grant from the C.N.R., Rome.     

Ovulation inducing agents and cancer risk: review of literature

Over the past decades, the use of ovulation inducing drugs has been increasing. A possible causal link between fertility treatments (especially clomiphene citrate and gonadotrophins) and various types of malignancies, including cancers of female reproductive system, thyroid cancer and melanoma, has been postulated. The majority of the available studies on this subject suffers from methodological limitations, including the small number of outcomes, short and incomplete follow-up, and inability to control for potential confounders. Concerning ovarian cancer, while early studies led to the suggestion of an association between ovulation inducing agents and increased risk of malignancies, the majority of data do not support a causal link. An increased risk was recently observed in women giving birth after in vitro fertilization (IVF), but it appeared to be consequential to the infertile status rather than the effect of fertility drugs. More controversial are the results concerning breast cancer with some investigations suggesting an increased risk after exposure to ovulation inducing agents, especially clomiphene citrate, whereas others not supporting this concept. A possible trend towards an increased risk has been reported by some authors for endometrial cancer. Altogether, current data should be thus regarded as a signal for the need of further studies rather than being definitive in them.     

Different Role of the Histamine H 3 -Receptor in Vagal-, Betanechol-, Pentagastrin-induced Gastric Acid Secretion in Anaesthetized Rats

Background : To date, involvement of the histamine H 3 -receptor in the control of gastric acid secretion in rats is not conclusively defined because of the variability of experimental results. This study was therefore aimed at investigating the role of H 3 -receptors in acid secretion produced by nervous or pharmacological stimulation in anaesthetized rats. Methods : Gastric acid output was measured by flushing the rat stomach lumen with 5 ml saline and titrating the flushed perfusate. Hypersecretory responses were evoked through direct vagal stimulation (0.5 msec, 10 Hz, 50 V for 30 min every 30 min) or by stimulation with pentagastrin (20, 40, 100, 250 μg/kg/h i.v.) or betanechol (100, 250, 500 μg/kg/h i.v.). The selective H 3 ligands (R)- α -methylhistamine and thioperamide (100 μg/kg i.v.) were tested alone or in combination on both basal and electrically/pharmacologically induced secretion. Results : Vagally-induced response was significantly reduced by the agonist R- α -methylhistamine and this effect was antagonized by the antagonist thioperamide at a dose unable by itself to modify vagal response. Thioperamide significantly increased acid response only on pentagastrin low dose (20 μg/kg/h) and this effect was counteracted by R- α methylhistamine, which was ineffective when administered alone. Betanechol-induced hypersecretion was substantially unaffected by the H 3 ligands, which were also inactive on basal acid output. Conclusions : Although this functional study confirms the presence of histamine H 3 -receptors in the rat stomach, they appear to have minor weight in regulation of the acid secretion in this species.     

Effects of alkyl analogs of histamine and metiamide on gastric acid secretion.

Histamine and metiamide analogs with alkyl, methyl, ethyl or isopropyl groups on the imidazole ring in position 5, not previously tested on an in vivo preparation, were studied for their effects on gastric acid secretion in cats with gastric fistulas. Our findings confirmed that the methyl group appears to be optimal for an effect on gastric acid secretion as regards both agonism and antagonism. Ethyl substitution apparently did not change the pharmacological activity of histamine but modified the inhibitory effect of metiamide from competitive to non-competitive kinetics. Isopropyl analogs were inactive on gastric secretion under our experimental conditions.