Studies on the cardiac actions of flosequinan in vitro.

1. We have investigated the in vitro cardiac actions of flosequinan and of its major metabolite in man, BTS 53554. 2. Positive inotropic activity was seen with flosequinan in guinea-pig isolated ventricles, the threshold concentration for effect being less than 1 x 10(-5) M. BTS 53554 was approximately half as potent as the parent compound. 3. In guinea-pig working whole hearts flosequinan increased left ventricular dp/dtmax, indicating a positive inotropic action. This effect was accompanied by increases in heart rate, cardiac output and stroke volume. 4. The virtual complete inhibition of inotropic responses to flosequinan and BTS 53554 by carbachol suggests that these responses are adenosine 3':5'-cyclic monophosphate (cyclic AMP)-mediated. 5. Flosequinan was shown to increase calcium inward current in guinea-pig ventricle, an action consistent with a cyclic AMP involvement in the response. 6. The inotropic activity of flosequinan was not potentiated by the selective phosphodiesterase (PDE) III inhibitor SK&F 94120, a result which indicates that flosequinan does not increase cyclic AMP concentrations via stimulation of adenylate cyclase. 7. Flosequinan inotropic responses were potentiated by rolipram, a selective PDE IV inhibitor, a result consistent with flosequinan being itself a PDE III inhibitor. 8. Biochemical studies with purified enzymes confirmed that flosequinan and BTS 53554 are relatively selective inhibitors of PDE III. 9. A comparison of pharmacological and biochemical data for both flosequinan and BTS 53554 indicates that their PDE III inhibitory potency is sufficient to account for their inotropic activity.

Pancopride, a potent and long-acting 5-HT3 receptor antagonist, is orally effective against anticancer drug-evoked emesis.

Pancopride ((+-)N-(1-azabicyclo-[2,2,2]-oct-3-yl)-2-cyclopropylmethoxy-4-ami no-5-chlorobenzamide) is a new potent and selective 5-HT3 receptor antagonist, orally and parenterally effective against cytotoxic drug-induced emesis. In vitro, pancopride displayed high affinity (Ki = 0.40 nM) for [3H]GR65630-labelled 5-HT3 recognition sites in membranes from the cortex of rat brains. In vivo, pancopride antagonized 5-HT-induced bradycardia in anaesthetized rats when administered i.v. 5 min (ID50 = 0.56 microgram/kg) or p.o. 60 min (ID50 = 8.7 micrograms/kg) before 5-HT challenge. A single oral dose (10 micrograms/kg) of pancopride produced a significant inhibition of the bradycardic reflex over an 8-h period. Pancopride dose dependently inhibited the number of vomiting episodes and delayed the onset of vomiting induced by cisplatin in dogs (ID50 = 3.6 micrograms/kg i.v. and 7.1 micrograms/kg p.o.). Pancopride was also effective in blocking mechlorethamine- and dacarbazine-induced emesis. Unlike metoclopramide, pancopride was shown to lack any measurable antidopaminergic activity both in vitro and in vivo. These results support clinical data, indicating that pancopride will be a useful drug for treating cytostatic-induced emesis in humans.

Cardiovascular effects of LAS 30538, a new vascular selective Ca(2+)-channel blocker.

A new compound, 1-[2-(2,6-dimethylphenoxy)ethyl]-alpha,alpha-bis-(p-fluorphenyl)-4 -piperidine methanol (LAS 30538), was found to have potent vasodilator effects. Its vasorelaxant activity was demonstrated in rat perfused hindlimbs contracted with 80 mM K+, having an IC50 value of 40 nM. In conscious spontaneously hypertensive rats, LAS 30538 administered orally, caused dose-dependent sustained falls in systolic blood pressure with an ED30 value of 11 mg kg-1. In pithed rats, LAS 30538, strongly inhibited vasoconstriction induced by the alpha 2-adrenoceptor agonist B-HT 933 and the calcium agonist compound Bay K8644 with ED50 values of 4 mg kg-1 p.o. and 1.3 mg kg-1 i.v., respectively. Results from electrophysiological studies carried out using guinea-pig papillary muscles partially depolarized by 22 mM K+ are consistent with LAS 30538 acting as a Ca(2+)-channel blocker. When compared with verapamil, in guinea-pig and rabbit isolated heart preparations, LAS 30538 caused less cardiodepression and bradycardia. The results suggest that LAS 30538 may have some advantages over other Ca(2+)-channel blockers such as verapamil in causing less myocardial depression for a given level of vasodilatation.

The calcium channel blocker LAS 30538, unlike nifedipine, verapamil, diltiazem or flunarizine, potently inhibits insulin secretion in-vivo in rats and dogs.

The effects of a novel calcium channel blocker, LAS 30538 (1-[2-(2,6-dimethylphenoxy)ethyl]-alpha,alpha-bis-(p-fluorophenyl)-4- piperidine methanol), were studied on glucose tolerance and insulin secretion in rats and dogs in-vitro and in-vivo. Some comparisons were made with nifedipine, verapamil, diltiazem, flunarizine, diazoxide, cromakalim and minoxidil. LAS 30538, like a number of calcium channel blockers, was found to inhibit insulin secretion in-vitro, but was 1000-fold more potent than verapamil or diltiazem in this respect. LAS 30538 differed from the other calcium channel blockers studied in that it also potently inhibited insulin secretion and impaired glucose tolerance in-vivo. The evidence that LAS 30538 is more potent than diazoxide as a hyperglycaemic agent in-vivo suggests that this could be a useful drug for the treatment of hyperinsulinaemia in man.

Effects of prednisolone, salbutamol and theophylline on bronchial hyperreactivity and leucocyte chemokinesis in guinea pigs.

The effects of prednisolone, salbutamol or theophylline treatment were studied in guinea pigs on bronchial hyperreactivity induced by chronic administration of PAF, (subsequently measuring respiratory flow after an intravenous injection of histamine) and the chemokinesis of leucocytes in vitro. Prednisolone (10 mg/kg p.o.) was active in the bronchial hyperreactivity test, as was salbutamol, but its effect appeared to be more related to its bronchodilator activity per se, while theophylline had little activity in this test. Regarding leucocyte chemokinetic activity, prednisolone and theophylline inhibited this at nM and microM concentrations respectively, whereas salbutamol was weakly active in this test.

Synergistic interactions between piracetam and dihydroergocristine in some animal models of cerebral hypoxia and ischaemia.

In pharmacological screening tests for activity against the cerebral insults of hypoxia and ischaemia induced by MgCl2 or decapitation in mice, the combination of piracetam and dihydroergocristine has been shown to produce synergistic effects in prolonging the survival time. This was not the case in the model of histiocytic anoxia induced by KCN. Using an optimal combination of piracetam and dihydroergocristine (533:1, Diemil) significant increases in cerebral resistance to hypercapnic anoxia and reductions in the duration of the ensuing electrical silence on the electrocorticogram have been demonstrated in the rat. The same combination was also effective in antagonizing the memory ablating effects of anoxia in rats subjected to electric footshocks during a standard passive avoidance response. The absence of clear effects on gross cerebral blood flow and metabolism, together with considerations of the known pharmacological properties of the two components of the combination and the effects of standard drugs in the models used, lead to the conclusion that the explanation of the observed synergism probably lies in complimentary actions at the level of the cerebral neurones and is independent of simple vasodilation.

Effects of theophylline compared with prednisolone on late phase airway leukocyte infiltration in guinea pigs.

The effects of prednisolone, theophylline or salbutamol treatment were studied on leukocyte numbers in bronchoalveolar lavage (BAL) fluid taken 72 h after ovalbumin challenge in sensitized guinea pigs. Ovalbumin challenge resulted in an approximate 3-fold increase in the number of eosinophils in BAL fluid. This increase was significantly reduced by oral administration of prednisolone (59% inhibition with 10 mg/kg x 2) theophylline (56% with 50 mg/kg x 2) but not by salbutamol (10 mg/kg x 2). A comparison with the bronchodilator potency of the above drugs indicated that in guinea pigs salbutamol appears relatively selective as a bronchodilator, prednisolone is selective as an inhibitor of eosinophilia whilst theophylline displays a balance of both activities.