Discovery of histamine H3 receptor antagonistic property of simple imidazole-free derivatives: Preliminary pharmacological investigation.

The histamine H3 receptor subtype negatively modulates the release of various neurotransmitters such as histamine, glutamate, norepinephrine, acetylcholine and many others mainly in the CNS and H3 antagonists have been developed to treat central diseases characterized by neurotransmission disturbance such as schizophrenia, memory/learning and sleep disorders. In search for non-imidazole histamine H3 receptor antagonists, currently indicated as a promising class of H3 blockers, a series of simple alkylpiperidine derivatives has been studied to attain a preliminary pharmacological profile. The compounds were characterized in vitro in terms of binding affinity, antagonistic potency and selectivity at rodent H3 receptors. The imidazole-free derivatives possessed moderate to pronounced antagonistic potency at guinea-pig ileal H3 receptor consistent with binding affinity at rat brain H3 receptors and showed a favourable receptor selectivity profile. For the compound 5, with the highest affinity at rat H3 receptors, comparable values were calculated in binding (pKi = 8.35) and functional (pA2 = 8.22) assays in SK-N-MC cells stably expressing human H3 receptors. These findings indicate to extend the investigation to pharmacokinetic property and central effects to gain deeper knowledge on the pharmacological potential of this compound.     

The effects of stimulants and inhibitors of histamine receptors on acid secretion from guinea pig gastric fundus

Two selective H₂ receptor stimulants (5-methyl-N-methylhistamine and dimaprit) so far never tested in isolated gastric preparations, were found to be strong stimulants of acid secretion from the guinea pig isolated gastric fundus. Although some differences were observed in the cumulative dose-response curves for these two agonists, the peak responses obtained were not significantly different from the maximum response to histamine. Cimetidine produced parallel displacement of the dose-response curves to the right with the maximum response unchanged, suggesting competitive antagonism on H₂ receptors. The dose-response curve for histamine was not affected by the simultaneous administration of an H₁ receptor agonist, 2(2-aminoethyl)thiazole, or of an H₁ receptor antagonist, pyrilamine. This indicates that the action of histamine on the isolated guinea pig gastric fundus is associated exclusively with H₂ receptor stimulation.     

Different role of the histamine H3-receptor in vagal-, betanechol-, pentagastrin-induced gastric acid secretion in anaesthetized rats

BACKGROUND: To date, involvement of the histamine H3-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 H3-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 microg/kg/h i.v.) or betanechol (100, 250, 500 microg/kg/h i.v.). The selective H3 ligands (R)-alpha-methylhistamine and thioperamide (100 microg/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-alpha-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 microg/kg/h) and this effect was counteracted by R-alpha-methylhistamine, which was ineffective when administered alone. Betanechol-induced hypersecretion was substantially unaffected by the H3 ligands, which were also inactive on basal acid output. CONCLUSIONS: Although this functional study confirms the presence of histamine H3-receptors in the rat stomach, they appear to have minor weight in regulation of the acid secretion in this species.     

Anomalous responses to histamine stimulation of guinea-pig oesophageal muscularis mucosae

The incomplete tachyphylaxis of the contractile response to the H₁-stimulants observed on guinea-pig oesophageal muscularis mucosae seems to be H₂-and H₃-antagonist as well as atropine- and tetrodotoxin-resistant. Lidocaine and eserine partially prevented this process probably by a mechanism independent of their main activity. The dualistic antagonism exerted by mepyramine and methysergide on reproducible histamine responses could be explained by a kinetic condition of hemi-equilibrium state together with changes of drug-receptor interaction and by non-specific properties of methysergide. On the whole, the present data indicate that the role of histamine in this tissue has still to be defined.     

Effect of dimaprit on gastric acid secretion in conscious cats

Gastric acid secretion was studied in conscious cats with gastric fistulas. Dimaprit and N,5-dimethylhistamine produced higher maximal responses than histamine. In the presence of pyrilamine, the maximal response to histamine was equal to that of dimaprit. Pyrilamine increased abmaximal but not maximal responses to pentagastrin. dimetidine decreased the potency of dimaprit but did not after the maximal response. Gastric acid secretion continued for 90 min after infusion of dimaprit was stopped. Possible mechanisms for the enhancement of acid secretion by rilamine include: (a) blocking of an inhibitory histamine H₁-receptor and (b) inhibition of histamine methyl-transferase.     

Mothers as active partners in the prevention of childhood diseases: maternal factors related to immunization status of preschool children in Italy

BACKGROUND: We examined how maternal socio-demographic factors, together with mother's education, knowledge, and perception of immunizations, can affect the uptake of optional vaccinations of preschool children in Italy. METHODS: Interviews of Italian mothers were performed using a structured questionnaire administered by trained interviewers with no specific medical competence. RESULTS: A convenience sample of 1,035 mothers were interviewed. Fifty-nine percent of the respondents reported to have had their child immunized with the MMR vaccine and 54% reported to have had their child immunized against pertussis. In logistic regression analysis, three variables were significantly associated with both the immunization outcomes: mother's positive attitude toward immunization (OR = 1.69; IC 1.13-2.52 for pertussis; OR = 1.86, IC 1. 17-2.96 for MMR); mothers' residency in the North of the country (OR = 1.74; IC 1.32-2.30 for pertussis; OR = 1.63, IC 1.18-2.24 for MMR); and mother's receipt of satisfactory information on immunization (OR = 1.67; IC 1.15-2.21 for pertussis; OR = 2.25, IC 1. 47-3.43 for MMR). An immunization performed in recent years (after 1994), probably following the widespread use of acellular vaccine, was the most significant predictor for pertussis immunization (OR = 3.21; IC 2.43-4.24). CONCLUSIONS: The findings suggest that mothers' attitudes, educational level, and socio-demographic characteristics, as well as socio-economic factors and local health policies, can influence children's immunization uptake. Health promotion, based on a partnership between parents and health professionals, should become a priority in Italian vaccination policies.     

Antipyretic activity of new compounds 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenylalkanoic acids, their esters, amides and 1,1-dioxide derivatives

Antipyretic activity of new compounds, 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenylalkanoic acids, their esters, amides and 1,1-dioxide derivatives has been studied. The acid compound of the benzoic series (I:a), tested at graded doses, exerted a noticeable antipyretic action; it had two times the "potency" of benzisothiazolone but an almost equal "efficacy". Its "potency" however was not proportional to the development of gastric lesions and to the acute toxicity. A decreased pharmacological activity has been observed in phenylalkanoic acids in the following order: R = COOH greater than CH2COOCH greater than CH(CH3)COOH greater than CH(C2H5)COOH, probably due to their increasing lipophilic character. By contrast among 1,1-dioxide derivatives the most effective in preventing pyrogen-induced fever was the ethyl ester (V:c) of benzoic series which appeared to be as active as paracetamol. The interest arising from these observations is here after discussed.