Synthesis and antiarrhythmic activity of new 3-[2-(omega-aminoalkoxy)phenoxy]-4-phenyl-3-buten-2-ones and related compounds.

A number of the title compounds (1) and a few related hydroquinone derivatives (2) have been synthesized and tested for antiarrhythmic activity in vivo (protection against CaCl2-induced ventricular fibrillation in anesthetized rat) and in vitro (ability to reduce the maximum driven frequency of an electrical stimulus in isolated rabbit atria). The effects induced by modification of the enol ether moiety in the parent compound 1a were also examined. Many of the compounds exhibited antiarrhythmic properties stronger than quinidine and procainamide, associated with a more favorable LD50/ED50 ratio. Compounds 1a (LR-18,460, 3-[2-[2-(diethylamino)ethoxy]phenoxy]-4-phenyl-3-buten-2-one) and 1h (LR-18,795, 3-[2-[3-(dimethylamino)propoxy]phenoxy]-4-phenyl-3-buten-2-one) were submitted to further antiarrhythmic testing, which confirmed their effectiveness and superiority to quinidine in all the experiments. After safety evaluation studies, both were selected for clinical investigation.

Therapeutic properties of dihydroxy-dibutylether on sub-acute liver damage induced by several hepatotoxic agents in rats.

The data presently reported show that repeated exposure of rats to allyl alcohol, ethionine or alpha-naphthyl isothiocyanate (ANIT) impaired some plasmatic parameters mainly by means of different mechanisms which involve the liver function. In particular, four administrations of allyl alcohol, given every other day, increased glutamate oxaloacetate transaminase (GOT) for at least 48 hours from the last dose; ethionine reduced the bromsulphthalein (BSP) clearance even after 48 hours from the 1st, 2nd, or 3rd administration given on the 1st, 5th, or 12th day; ANIT, administered daily for seven days, increased glutamate pyruvate transaminase (GPT), alkaline phosphatase (AP), bilirubin, triglycerides (TG) and cholesterol (CH) while it decreased the body-weight and retarded growth for at least six to seven days after intoxication. Twice daily administrations of dihydroxy-dibutylether (DHBE), a strong choleretic agent, brought to normality the parameters impaired by the three hepatointoxicating agents even when the intoxication was already established. In fact, DHBE reduced the plasma GOT levels increased by allyl alcohol, improved the BSP clearance impaired by ethionine and tended to normalize the parameters modified by ANIT by lowering GPT, AP, CH, TG and bilirubin plasma levels and by enhancing body growth. The curative activity of DHBE does not seem to be related only to a membrane stabilizing action since silymarin, a known cell membrane stabilizer, does not significantly influence the parameters described above in all the experimental conditions. Even the choleretic activity of DHBE alone might not be sufficient to explain its hepatoprotective action since fenipentol (a known choleretic agent) is inactive at least after ANIT intoxication.

Synthesis and free radical scavenging properties of the enantiomers of erdosteine.

The synthesis of enantiomers R and S of erdosteine, a derivative of homocysteine-gamma-thiolactone, and the NMR studies for the determination of the enantiomeric excess with chiral shift reagent on the more soluble ethyl esters, are described. Pharmacological data relative to the free radical scavenging properties of the R and S enantiomers are reported. In particular, it has been documented that the S isomer is more effective than R isomer in protecting mice against lethal doses of paraquat (substance able to form free radicals when administered by i.p. route).

Pharmacokinetics of dipyridamole-beta-cyclodextrin complex in healthy volunteers after single and multiple doses.

Dipyridamole is a well known anti-aggregating agent characterized by poor water solubility as well as scant and variable bioavailability. Recently, the compound was complexed with beta-cyclodextrin forming a molecular encapsulation resulting in better oral absorption and stronger biological activities in animals. In the present study, a randomized double blind cross-over comparison between dipyridamole-beta-cyclodextrin complex (dip-beta-CD) and dipyridamole was performed in 12 healthy subjects after single (75mg) and multiple oral treatments (75mg TID). Dip-beta-CD showed better bioavailability and less interindividual variability than dipyridamole either after single or multiple doses. In particular, dip-beta-CD had a greater AUC and Cmax, and a smaller Tmax even at the steady state. In addition, 100% of the subjects receiving a single dose of dip-beta-CD, as compared to 66.7% of those treated with dipyridamole, had plasma levels superior to 1 microgram/ml (which is the supposed anti-aggregating threshold level). In contrast, 0 and 33.03% of the subjects showed plasma levels superior to 2.5 micrograms/ml (which might cause the appearance of side-effects) on the 7th day of the multiple treatment with dip-beta-CD and dipyridamole, respectively. In fact, the subjects presenting higher levels after uncomplexed dipyridamole also complained of headache and/or dizziness on occasion. No adverse side effects were reported for dip-beta-CD.

A comparison between some biochemical and behavioural effects produced by neuroleptics.

Acute administration of five neuroleptics to rats produced a dose-dependent increase in brain homovanillic acid (HVA) which was of greater magnitude and of longer duration in the corpus striatum than in the tuberculum olfactorium. 4-p-Fluorophenyl-5-N(N'-o-methoxy-phenyl) piperazinoethyl-4-oxazolin-2-one (LR 511) appeared to be 5--10 times more potent than fluanisone and clozapine, as active as chlorpromazine (CPZ) but at least twentyfold less active than haloperidol. Time-course studies on dopamine turnover have indicated that LR 511 at a moderate pharmacological dose has some similarities with clozapine, e.g., a lower difference between striatal and limbic tissues. All the neuroleptics caused inhibition of the conditioned avoidance response and at their ED50S on this parameter (with the exception of clozapine) caused also an equal increment of the cerebral HVA level. At their ED50S on catalepsy, the neuroleptics evoked HVA changes which varied according to the drug tested. Thus, potent cataleptogenic agents caused either strong stimulation of the DA turnover in both brain structures (haloperidol and CPZ) or weak stimulation only in corpus striatum (fluanisone). On the other hand a poor cataleptogenic agent, such as LR 511, was accompanied by the highest HVA levels and also the non-cataleptogenic clozapine at the dose of 40 mg/kg increased the cerebral HVA levels. It is suggested that the acceleration of DA turnover in animals is not an essential prerequisite for predicting the antipsychotic activity in man and that the preferential reactivity of dopaminergic limbic receptors is not necessarily linked to a better ratio of antipsychotic versus extrapyramidal effects in man.

Pharmacology of dihydroxy-dibutylether, a specific choleretic drug.

The choleretic and the general pharmacological properties of dihydroxy-dibutyl ether (Discinil) were investigated in several animal species. Discinil (DHBE) increased the bile flow in conscious rats and dogs, after both oral and i.v. administration. A choleretic effect was also observed after i.v. injection into anaesthetized rats and guinea pigs. A dose-response relationship was always obtained, the threshold dose being 25--100 mg/kg. No evidence of tachyphylaxis was observed in rats after repeated treatments. The bile hyperflow was generally accompanied by an increased excretion of the total dry residue in guinea pigs and dogs. The choleretic effect in rats was still present after pretreatment with either DL-ethionine (causing parenchymal liver damage) or atropine (blocking the cholinergic control of bile production). At low doses (25--100 mg/kg i.v.) eliciting a definite choleretic response, DHBE did not show spasmogenic and spasmolytic effects in vivo on the smooth muscles of the gallbladder of guinea pigs and dogs, neither on the stomach and intestine of mice and dogs; while it constricted the pylorus sphincter of rats. At larger doses (200--400 mg/kg i.v.) the compound showed a mild relaxing activity on Oddi's sphincter of guinea pigs and a weak spasmogenic activity either on gall bladder or on small intestine. In vitro, it caused an unspecific antagonism against the spasm induced by acetylcholine, barium chloride, histamine, 5-hydroxytryptamine and norepinephrine. In anaesthetized rats, rabbits and dogs, DHBE caused a moderate and short-lasting hypotension, and tachycardia. The threshold doses for these effects were 2--4 times superior to those being choleretic. In conscious dogs, the compound was slightly hypertensive. DHBE did not provoke important respiratory and ECG changes, neither showed diuretic nor antiphlogistic effects.

Enhancement of specific biological activity of dipyridamole by complexation with beta-cyclodextrin.

Dipyridamole forms an inclusion complex with beta-cyclodextrin (dip-beta-CD) which shows better solubility and bioavailability than the uncomplexed compound. The present studies have demonstrated that dip-beta-CD is more effective than dipyridamole either as base or HCl (dispersed or not in lactose) on some important cardiovascular parameters when orally administered to conscious animals. In particular, dip-beta-CD causes a stronger and prompter coronary and carotid vasodilatation in dogs, at doses which weakly influence the systemic arterial pressure and the heart rate. In addition, platelets collected from treated rabbits at various intervals appear to be protected from sodium adenosine diphosphate-induced aggregation in vitro more effectively and rapidly by dip-beta-CD than by dipyridamole. Studies on tail bleeding time have confirmed that dip-beta-CD is more active than dipyridamole when given orally to mice. These biological findings are fully in agreement with other oral bioavailability studies in dogs and men indicating that dip-beta-CD gives quicker and higher blood levels with smaller interindividual variability than dipyridamole.

Cardiovascular pharmacology of bombesin, a new polypeptide from amphibian skin.

Bombesin is a tetradecapeptide extracted from the side of discoglossid frogs Bombina bombina and Bombina variegata variegata. In anaesthetized dogs bombesin causes mainly systemic hypertension, bradycardia and constriction of the renal, mesenteric and coeliac arterial vessels. The other vascular beds studied (carotid, femoral and coronaric) passively follow the blood pressure. Tachyphylaxis may occur. Dibenzyline and hexamethonium do not antagonize the hypertensive property of bombesin, while the occlusion either of the renal vessels or of the mesenteric, coeliac arteries and portal vein reduces the intensity and the duration of the hypertensive response. The simultaneous occlusion of all the above mentioned vessels further reduces the duration of the hypertensive response evoked by bombesin and reverses its effect on the heart from mainly bradycardic to pure tachycardic. In these condition bombesin causes carotid and peripheral vasoconstriction. The increase of heart rate and of blood pressure, while occurs after ligation of aplanchnic vessels, is completely or partly antagonized by propranolol. In normal conscious dogs bombesin is at least 10 times more potent and less tachyphylactic than in anesthetized dogs.

Classical neuroleptics and deconditioning activity after single or repeated treatment. Role of different cerebral neurotransmitters.

A dose-dependent inhibition of conditioned avoidance response (CAR) was documented in trained rats after acute treatment with several neuroleptics: haloperidol, chlorpromazine (CPZ), fluanisone and 4-p-fluorophenyl-5-N(N'-o-methoxyphenyl)piperazinoethyl-4-oxazolin-2-one (zoloperone, LR 511). The compounds differently affected the unconditioned escape response (UER), haloperidol and LR 511 being almost inactive. Daily treatment with LR 511 or haloperidol for 7-16 days did not cause the appearance of tolerance in young and adult rats, on the contrary, made in evidence a stronger effect on CAR and on UER. This supersensitive state towards the neuroleptics did not disappear even after 30 days' treatment interruption. The acute administration of some neuroleptics in combination with other centrally active drugs, endowed with different mechanism of action, yielded the following results on CAR: amphetamine (a dopaminergic stimulant) readily antagonized the effect of LR 511 and haloperidol; chlorpheniramine and diphenhydramine (antihistaminics) minimized the effect of small doses of LR 511 and haloperidol while they did not alter that of larger doses; atropine (an anti-cholinergic), metergoline (an anti-5-hydroxytryptaminic (5-HT) and cyproheptadine (an anti-5-HT possessing antihistaminic and anticholinergic properties) protentiated the effect of LR 511 while in part reduced that of haloperidol. CPZ, which was associated only with atropine, behaved like LR 511. The role of various brain neurotransmitters is discussed.