The role of ketoconazole in the QTc interval prolonging effects of H1-antihistamines in a guinea-pig model of arrhythmogenicity.

We have carried out experiments to re-evaluate the influence of ketoconazole (400 mg kg-1,p.o.) on the effects of ebastine, terfenadine and loratadine on the QTc interval in conscious guinea-pigs. Following a previously described protocol of oral drug administration, but using telemetric recording of the ECG, we have found that the prolongation of the QTc interval attributed to ebastine and terfenadine is in fact entirely due to ketoconazole, and that neither terfenadine, ebastine nor loratadine produce any additional effects on subsequent administration.

Investigation into the role of phosphodiesterase IV in bronchorelaxation, including studies with human bronchus.

1. We have investigated the role of cyclic nucleotide phosphodiesterase IV (PDE IV) in the relaxation of human bronchus and guinea-pig trachea in vitro and in guinea-pigs in vivo. 2. Functional studies showed that the selective PDE IV inhibitors, rolipram and denbufylline, relaxed human and guinea-pig preparations in vitro. 3. Two clinically used xanthine non-selective PDE inhibitors, theophylline and pentoxifylline, were also effective in these preparations, but were much less potent than the selective agents used. 4. The rank order of potency for the four PDE inhibitors in both species was similar. 5. Biochemical studies indicated that PDE IV was the major PDE isoform present in the human bronchial tissue. PDEs I, II and V were also identified. 6. Theophylline and pentoxifylline were, as expected, non-selective inhibitors of the human enzymes, but there was a good correlation between PDE IV inhibitory and bronchorelaxation potencies, suggesting that PDE IV inhibition is important for the clinical bronchodilator activities of the two xanthine compounds. 7. We have confirmed the ability of selective PDE IV inhibitors to cause bronchodilatation in guinea-pigs in vivo. 8. We conclude that our study has provided further evidence that selective PDE IV inhibitors could act as bronchodilators in the clinic.

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.

Effects of H1 antihistamines on animal models of QTc prolongation.

OBJECTIVE: The clinical use of some nonsedating H1 antihistamines (histamine H1 receptor antagonists) has been associated with a rare but life-threatening type of arrhythmia, torsade de pointes, especially when these drugs are coadministered with cytochrome P450 (CYP) 3A4 enzyme inhibitors. On the basis of the latter observation and the fact that most of these H1 antihistamines undergo extensive first-pass metabolism to active metabolites apparently devoid of cardiovascular adverse effects, this arrhythmogenicity has been attributed to the parent drug. The objective of this study was to find an animal model with the ability to predict the proclivity of drugs to produce torsade de pointes. DESIGN: Two experimental approaches were used: (i) blockade of CYP3A4 metabolism by coadministration of ketoconazole to increase the plasma concentrations of the parent compound in the conscious guinea-pig, and (ii) administration of the compound directly into the coronary circulation of the anaesthetised dog in order to circumvent first-pass metabolism. RESULTS: The first approach demonstrated that terfenadine administered in the presence of ketoconazole prolongs the corrected QT (QTc) interval of the electrocardiogram, whereas ebastine does not. Similarly, when terfenadine was administered through the coronary circulation, a statistically significant increase in the QTc interval was also seen, whereas ebastine and carebastine were without effect. Thus, it is clear that ebastine was much better tolerated than terfenadine from a cardiovascular standpoint, since ebastine and its metabolite are devoid of effects on cardiac repolarisation, as measured by the QTc interval in these animal models.

Cardiotoxicity of histamine and the possible role of histamine in the arrhythmogenesis produced by certain antihistamines.

Since 1990 it has repeatedly been reported that some histamine H1 receptor antagonists (e.g. terfenadine and astemizole) are able to produce ventricular arrhythmias (e.g. torsade de pointes) when they are given at dosages above the therapeutic range and/or administered together with cytochrome P-450 3A4 inhibitors, such as ketoconazole or erythromycin. Although the mechanism by which these arrhythmias are produced remains unclear, the recently reported ability of these drugs to block outward K+ currents has been suggested as the cause of their arrhythmogenic effects. Alternatively, we have observed that some H1 antihistamines, including terfenadine and astemizole, are able to release histamine from guinea-pig cardiac mast cells. Thus, we have proposed that the liberated histamine, acting through an H2 receptor-stimulating mechanism, can prolong the action potential duration and hence induce arrhythmogenic effects. This paper describes experimental observations supporting the hypothesis that some H1 antihistamines can induce severe cardiac arrhythmias via the local release of histamine.

A comparison of the effects of verapamil and cinnarizine upon responses elicited by selective alpha 1- and alpha 2-adrenoceptor agonists in the autoperfused canine hindlimb.

In an attempt to extend the hypothesis that activation of vascular postsynaptic alpha 2-adrenoceptors requires an influx of Ca2+ ions, the effects of 2 calcium entry blocking drugs verapamil and cinnarizine have been examined as inhibitors of the pressor responses to methoxamine and B-HT 920 in autoperfused dog hindlimb preparations. Verapamil (0.1-1 mg i.a.) selectively antagonized responses to B-HT 920 and had little or no effect upon responses to methoxamine, thus supporting this hypothesis. However cinnarizine, over the dose range studied (0.1-1 mg/kg i.a.) produced quantitatively similar inhibitions of the hindlimb responses to B-HT 920 and methoxamine. These results suggest that cinnarizine may have a different site of action to verapamil in resistance vessels of the dog hindlimb.

Inhibition of lipopolysaccharide-induced bowel erythrocyte extravasation in rats, and of mesenteric hypoperfusion in dogs, by phosphodiesterase inhibitors.

Sepsis is intricately associated with mesenteric ischemia. The remote complications of mesenteric ischemia are essentially those of sepsis, whether as a cause or as a consequence. Experimental endotoxic shock induces bowel hypoperfusion, erythrocyte extravasation and intestinal necrosis. The effects of pentoxifylline, rolipram and denbufylline, three phosphodiesterase inhibitors, were studied on endotoxin-induced bowel erythrocyte extravasation and intestinal and renal hypoperfusion, in conscious rats and anaesthetized dogs, respectively. Two hours after lipopolysaccharide i.v. injection in rats, erythrocyte extravasation was evident throughout the intestinal musculature and mucosa, apparently without affecting lungs, heart, kidneys, liver or pancreas. Pretreatment with the non-selective phosphodiesterase inhibitor, pentoxifylline, or selective phosphodiesterase IV inhibitors such as denbufylline or rolipram reduced intestinal haemoconcentration. In the anaesthetized dog, pentoxifylline and denbufylline both inhibited the E. coli lipopolysaccharide-induced mesenteric blood flow fall, without affecting renal blood flow or cardiac index. In conclusion, phosphodiesterase inhibitors protected from intestinal damage and bowel hypoperfusion after lipopolysaccharide challenge. This action may thus play a role in the protective effects against endotoxin-induced lethal toxicity previously described for phosphodiesterase inhibitors.

Cardiovascular safety profile of almotriptan, a new indolic derivative for the treatment of migraine.

Almotriptan is a new 5-HT(1B/1D) receptor agonist effective for treating acute migraine attacks with or without aura. As 3-5% of patients treated with sumatriptan experience chest symptoms thought to be of cardiac origin, we investigated the cardiovascular safety profile of almotriptan in comparison with that of sumatriptan in six animal models. Almotriptan did not modify blood pressure or heart rate in conscious telemetered normotensive Wistar rats (p.o.), in anaesthetised beagle dogs (i.v.), or in conscious beagle dogs (i.v.), and only produced transient increases when administered (s.c.) to telemetered cynomolgus monkeys. Almotriptan did not consistently affect the duration of the electrocardiogram (ECG) intervals in anaesthetised beagle dogs even when the drug was administered into the coronary artery, nor was ECG morphology altered in telemetered cynomolgus monkeys. In contrast, sumatriptan i.v. consistently increased mean blood pressure and heart rate in conscious beagle dogs. Finally, almotriptan did not modify coronary blood flow at a dose of up to 0.3 mg/kg i.v. in conscious beagle dogs. Thus, almotriptan has a favourable cardiovascular safety profile.

Functional profile of almotriptan in animal models predictive of antimigraine activity.

Almotriptan is a new 5-HT(1B/1D) receptor agonist whose clinical efficacy for the treatment of migraine attacks has been demonstrated in Phase III clinical trials. We now compare the functional profile of almotriptan (assessed using animal models) with that of sumatriptan. Almotriptan selectively increased carotid vascular resistance in anaesthetised cats after intravenous or intraduodenal administration (ED(100)=11 microg/kg, i.v.; ED(50)=339 microg/kg, i. d.) and in anaesthetised beagle dogs following intravenous administration (ED(50)=116 microg/kg). A study in anaesthetised cats also demonstrated that almotriptan acts by selectively increasing the resistance of the carotid arteriovenous anastomoses without adversely affecting brain irrigation. In addition, almotriptan inhibited meningeal extravasation produced by electrical stimulation of the trigeminal ganglion in anaesthetised guinea pigs in the dose range of 0.3-3 mg/kg, i.v. In conclusion, almotriptan is both a selective constrictor affecting intracranial blood vessels and an inhibitor of neurogenically evoked plasma protein extravasation of the dura mater.

Synthesis and pharmacological evaluation of 2, 3-dihydro-3-oxo-4H-thieno[3,4-e][1,2,4]thiadiazine 1,1-dioxides as voltage-dependent calcium channel blockers.

The synthesis of a novel series of 2,3-dihydro-3-oxo-4H-thieno[3, 4-e][1,2,4]thiadiazine 1,1-dioxides and their pharmacological evaluation as drugs with effects on the rat cardiovascular system are described. The compounds under study were synthesized via Curtius rearrangement of appropriate sulfamoylacylazides which, in turn, were prepared from known starting materials. In isolated rat portal vein, these thienothiadiazines, like verapamil and diazoxide, inhibited the spontaneous motility produced by KCl (20 mM). In addition, the new compounds, like verapamil and unlike diazoxide, also exhibited inhibitory effects in the same preparation when the cell membrane was depolarized by an increased extracellular KCl concentration (80 mM) and, consequently, the membrane potential approached a level close to the K(+) equilibrium potential. Further characterization of this inhibitory activity led to the identification of a selective inhibitory effect of the new compounds on KCl (80 mM)-induced 45Ca(2+) uptake in the same vascular tissue. When tested in vivo (anaesthetized normotensive rats), acute administration of verapamil, diazoxide and some of the most in vitro potent compounds in 45Ca(2+) uptake experiments produced a gradual, dose-dependent and sustained decrease in diastolic arterial blood pressure, devoid of cardiac effects. These results suggest that, like verapamil, the cardiovascular effects produced by the new thienothiadiazines seem to be due, at least in part, to a blockade of transmembrane voltage-dependent calcium channels present in vascular smooth muscle cells and not to an activation of ATP-sensitive K(+) channels. Compounds 5b, 5e and 5i have been selected for further studies as antihypertensive agents.

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.

Clinical anti-inflammatory efficacy of arofylline, a new selective phosphodiesterase-4 inhibitor, in dogs with atopic dermatitis.

Forty atopic dogs were studied for 28 days after the oral administration of four randomised treatments: (A) arofylline (1 mg/kg) twice daily for four weeks; (B) prednisone (0.5 mg/kg) twice daily for the first week, once a day during the second week and every 48 hours for the remaining two weeks; (C) prednisone following the same protocol but at a dose of 0.25 mg/kg; or (D) arofylline (1 mg/kg) twice daily for four weeks plus prednisone (0.25 mg/kg) following the same protocol as in (B) and (C). The degree of pruritus and skin lesions and the side effects were evaluated and graded from 0 to 3 before and weekly during the treatments. In all cases there was a progressive clinical improvement in the clinical signs, with no statistical differences among the four treatments. However, many of the dogs treated with arofylline vomited and had adverse gastrointestinal signs.

[Historical review of the most outstanding neurological institutions]. / Reseña histórica de las instituciones neurológicas más destacadas.

OBJECTIVE: To present a historical review of the main Institutions of Neurological Sciences which have existed from the mid XIX century to the present day. DEVELOPMENT: We remember the founders and collaborators of these Institutions who with dedication contributed to the maintenance of their prestige and the advance of the neurosciences. These names are no doubt well known to those of us who have worked in any of the branches of the neurosciences. Unfortunately, some of the Institutions described no longer exist. Others, although somewhat overlooked continue their scientific work while some still maintain the prestige which was always theirs. The description follows the chronological order of their foundation. We have given a more extensive description of those which we consider of greater importance due to their contribution to advances in the neurosciences, and which we have had the opportunity to visit and study their function and organization at first hand. We state the site of an institution of a given neurological speciality, independently of whether or not it forms part of a general hospital complex, but maintaining its own autonomy under the direction of a neuroscientist, contributing to establish closer collaboration with neurologists, neurosurgeons, neuropathologists etc., which undoubtedly helps to raise the level of teaching and investigation in the neurosciences.

[Neuroradiology, a specialty among the neurosciences]. / La Neurorradiología, una especialidad de las Neurociencias.

Neuroradiology as a Neuroscience speciality has to keep undoubtedly a narrow relationship with the rest of the branches of Neurological Diagnostic, but mainly with Clinical Neurology, Neurosurgery and Neuropathology. It is specially remarked that cooperation with Neurosurgery has to be very narrow not only in diagnostic field as in evaluation of Neuroradiology operation techniques (endovascular therapy) as in the field of Stereotaxis and Radiosurgery.