Overview of the pharmacological properties, pharmacokinetics and animal safety assessment of lornoxicam.

Lornoxicam is a new, highly potent antirheumatic agent which is an oxicam derivative. Although highly potent as a cyclo-oxygenase inhibitor, the compound does not cause inhibition of 5-lipoxygenase and does not appear to shunt arachidonic acid through this cascade. This powerful inhibition of cyclo-oxygenase has manifested itself as highly potent analgesic and anti-inflammatory effects in animal studies and also prevented the bone destruction which normally occurs in the adjuvant polyarthritic rat. To explain this finding, studies have demonstrated that lornoxicam inhibits polymorphonuclear (PMN)-leukocyte migration; inhibits the release of superoxide from human PMN-leukocytes; inhibits the release of platelet derived growth factor (PDGF) from human platelets and stimulates the synthesis of proteoglycans in cartilage in tissue culture. Lornoxicam is well absorbed and has a plasma t1/2 in man of 4 hours which is distinctly different from other oxicams. It is metabolized in animals and in man to the 5'-hydroxy-metabolite which is inactive in pharmacological tests. In vitro and in vivo animal safety studies have demonstrated both subchronically and chronically that lornoxicam manifests no unusual toxicity, is not a mutagen nor is it tumorigenic and causes no fetal teratogenicity in reproduction studies.

Celiprolol, a compound which attenuates myocardial acidosis and improves regional segmental function following ischemia in dogs: a comparison with propranolol.

Celiprolol, propranolol or saline were administered to separate groups (n = 5-6) of anesthetized dogs in which a critical stenosis was applied to the circumflex coronary artery for 90 min and then reperfused for 30 min. Test drugs were administered at 30 min poststenosis and the effects on pH, regional function and endocardiogram were monitored. A reduction in coronary flow of 54 +/- 2% (n = 27) yielded marked increases in hydrogen ion concentration (H+) of 17 +/- 2 X 10(-8) and ischemic endocardial ST segment of 6 +/- 1 mV while ischemic segmental shortening decreased 75 +/- 9%. Heart rate, arterial pressure and normal regional function were not altered. Celiprolol 0.1 and 1 mg/kg, i.v., reversed the alterations in H+ and ischemic ST segment to prestenosis values while improving ischemic segmental shortening 20 and 38%, respectively, and not affecting heart rate. Propranolol 0.1 and 1 mg/kg, i.v., reversed the alterations in H+ and ischemic ST segment to prestenosis values while further decreasing ischemic segmental shortening 66 and 30%, respectively. Upon reperfusion, ischemic segmental shortening returned to prestenosis values in the group treated with celiprolol 1 mg/kg, i.v., while the propranolol- and saline-treated groups further decreased. It is concluded that celiprolol is efficacious in normalizing myocardial function and ischemia-induced electrophysiological changes following coronary artery stenosis.

Celiprolol: its profile as a potential antiarrhythmic agent.

Preliminary animal studies indicate tha celiprolol has antiarrhythmic properties. Animal and clinical electrophysiologic studies suggest that the antiarrhythmic activity is from celiprolol beta-blocking effects (class II antiarrhythmic). Studies with anesthetized dogs show that celiprolol elevates the ventricular fibrillation threshold. An unexpected finding in the canine infarct drug model is the spontaneous conversion of ventricular fibrillation to normal sinus rhythm. The beta2-agonist property of celiprolol may account for this observation. In a clinical study celiprolol has bee found to decrease ventricular rate in patients with chronic atrial fibrillation. In the same study, the compound decreased the occurrence of premature ventricular contractions by 50%. Animal and clinical studies demonstrate that celiprolol does not adversely interact wit digitalis glycosides.

Cardiopulmonary effects of celiprolol and bisoprolol in serotonin-infused cats.

The effects of celiprolol and bisoprolol on cardiopulmonary function in serotonin-infused cats were compared. Celiprolol reversed the bronchoconstrictive effect of serotonin at doses greater than or equal to 1.0 mg/kg. Also, decreases in mean arterial pressure and heart rate were noted after administration of 3-10 and 10 mg/kg celiprolol, respectively. In contrast, bisoprolol tended to induce bronchoconstriction. Reductions in mean arterial pressure and heart rate were observed with 1 or 3 mg/kg. Bisoprolol administration at 10 mg/kg was lethal. The unique ability of celiprolol to induce bronchodilation enhances its therapeutic potential.

Celiprolol--overview of 6 years of clinical trials experience.

The results of an extensive pre-clinical and clinical research programme indicate that celiprolol is a safe and effective treatment for both hypertension and angina pectoris. Celiprolol is well absorbed, is largely unmetabolized, and is excreted equally in the urine and bile. As a result of this pharmacokinetic profile celiprolol can be safely administered to the elderly and to patients with renal or hepatic impairment. Haemodynamic studies indicate that celiprolol lowers arterial blood pressure, and decreases both renal vascular resistance and peripheral vascular resistance. Celiprolol does not depress myocardial function, neither does it induce bronchoconstriction in asthmatic patients. Weak alpha 2-adrenoceptor antagonism, combined with beta 2-adrenoceptor agonism are thought to contribute to these properties. The antihypertensive efficacy of celiprolol, 200 mg/day, is comparable to that of propranolol, atenolol and nadolol. Moreover, the actions of celiprolol last for 24 h, and are accompanied by less resting bradycardia than that seen with other beta-blockers. The anti-anginal efficacy of celiprolol is similar to that of atenolol, propranolol and metoprolol. In addition, celiprolol decreases the ventricular rate in patients with atrial tachyarrhythmias. This effect results from its ability to slow atrioventricular conduction. Celiprolol is generally very well tolerated.

REV 2871 (CHBZ): a potent antiallergic agent with a novel mechanism of action. I. Activity profile as an inhibitor of mediator release.

REV 2871 (CHBZ) and its putative metabolite REV 3579-Z (also designated in the literature as RHC 3579-Z) were shown to be potent and orally effective inhibitors of passive cutaneous anaphylaxis (PCA) in the rat (ED50 = 12 mg/kg). The activity profiles of CHBZ, REV 3579-Z and disodium cromoglycate (DSCG) were compared as inhibitors of histamine release (HR) in vitro from rat mast cells, human basophils, and guinea pig lung slices. CHBZ was a potent inhibitor of both immunologic and non-immunologic HR (I50 2-20 microM from rat mast cells). The activity profile of CHBZ as an inhibitor of HR from rat mast cells differed from that of DSCG and REV 3579-Z in the following respects: increasing inhibition of HR with increasing preincubation time; irreversibility of the inhibition; lack of tachyphylaxis and cross-tachyphylaxis to DSCG; potentiation of the inhibition of antigen-induced release of histamine (AIR) by DSCG; and inhibition of HR induced by dextran + phosphatidyl serine, compound 48/80, ionophore A23187 and platelet activating factor (PAF). In the human basophil model, CHBZ was: a potent inhibitor (I50 = 25 microM) of anti-IgE-induced release (AbIR), whereas DSCG and REV 3579-Z had no effect on AbIR; more potent as an inhibitor of AbIR than ionophore-induced release, whereas the reverse was true for proxicromil; an inhibitor of PAF-induced release, whereas proximcromil stimulated it; and potentiative with proxicromil for inhibition of AbIR. In the guinea pig lung slice model, CHBZ inhibited AIR (I50 = 800 microM) whereas DSCG and REV 3579-Z did not (I50 greater than 300 microM). We conclude that CHBZ is an orally effective antiallergic agent whose mechanism of action as an inhibitor of mediator release is different from DSCG and proxicromil.

Substituted arylmethyl phenyl ethers. 1. A novel series of 5-lipoxygenase inhibitors and leukotriene antagonists.

A series of new substituted arylmethyl phenyl ethers has been prepared. These compounds were tested as inhibitors of 5-lipoxygenase (5-LO) in rat neutrophils, in vitro antagonists of leukotriene-induced contraction of guinea pig (GP) lung parenchymal strips, and inhibitors of slow reacting substance of anaphylaxis (SRS-A) mediated bronchospasm in the GP in vivo. Most representatives of this new class of potential antiallergic/antiinflammatory agents showed potent inhibition of 5-LO activity in rat PMNs. The most potent compound, 2-[[3-(1-hydroxyhexyl)phenoxy]-methyl]quinoline (33), had an I50 of 0.12 microM in the rat PMN 5-LO assay and an I50 of 3.6 microM in the leukotriene-induced contraction of GP lung parenchymal strips, and it also showed 91% inhibition of SRS-A-mediated bronchospasm in the GP in vivo at 10 mg/kg, administered intraduodenally. Some of the compounds in this series were also leukotriene antagonists in vitro, and several of them showed in vivo activity against SRS-A-mediated bronchospasm in the GP.

Mechanistic studies on the "bronchosparing" activity of celiprolol, a cardioselective beta-adrenoceptor antagonist.

In some animal models, celiprolol, a cardioselective beta-adrenoceptor antagonist, has been reported to relax bronchial smooth muscle, an activity unique for this class of compound. Mechanistic studies with isolated cat tracheal rings and peripheral lung strips from guinea-pigs indicated that this relaxing activity could not be explained by competitive antagonism of serotonin receptors, beta- or alpha 1-adrenergic receptors, or histamine1-, leukotriene- or prostaglandin F2 alpha-receptors. Furthermore, this activity could not be explained by stimulation of beta-adrenergic or histamine2-receptors, nor can it be explained by a nonselective relaxing activity such as via the inhibition of cyclic nucleotide phosphodiesterases. Serotonin-induced contractions of isolated tracheal rings seem to involve a secondary process which could be the unmasking of alpha 2-adrenoceptors. It is this secondary process which appears to be affected by celiprolol; i.e. celiprolol could be a weak but selective antagonist of alpha 2-adrenoceptors associated with serotonin receptors.

The antagonist and partial beta agonist properties of celiprolol in isolated rat cardiac tissue.

Celiprolol was evaluated for its antagonist and partial beta agonist effects in rat spontaneously beating right atria and in electrically stimulated left ventricular strips. Celiprolol, like propranolol, produced a parallel concentration-related rightward shift of the isoproterenol (ISO) (beta agonist) concentration-response curve without decreasing the maximum response in rat right atria. The pA2 values for celiprolol and propranolol were 7.02 +/- 0.30 and 8.45 +/- 0.29, respectively. Unlike propranolol, however, celiprolol increased the resting spontaneous rate at concentrations 3 X 10(-7) to 10(-4)M. ISO alone produced a concentration-related increase in heart rate of rat right atria (maximum 149 +/- 15 bpm at 3 X 10(-7)M). Whereas, celiprolol increased atrial rate a maximum of 49 +/- 5 bpm at 10(-6)M. ISO produced a concentration-related increase in the developed tension of rat right ventricular strips (maximum 79 +/- 4% at 10(-6)M. Celiprolol, by contrast, had no effect on developed tension in concentrations up to 10(-3)M. In separate experiments, celiprolol alone increased right atrial rate a maximum of 40 +/- 6 bpm at 10(-5)M. Pretreatment with propranolol (10(-6)M) completely blocked the increase in rate. It is concluded that celiprolol is a potent and competitive beta antagonist and a partial agonist with approximately 33% of the efficacy (comparing maximum stimulating concentrations) and 0.01 the potency of ISO in rat right atria (at ED50 concentrations). Celiprolol, however, unlike ISO, has no inotropic effect in rat ventricular strips suggesting possible differences in their agonist properties.

Celiprolol: a new beta adrenoceptor antagonist with novel ancillary properties.

Celiprolol HC1 is a new cardioselective beta-blocker with properties which may make it the next advance in the evolution of this class of compounds. Its cardioselectivity has been demonstrated both in vitro and in vivo, with an intravenous potency equivalent to atenolol. The compound is devoid of a membrane stabilizing effect which is reflected in anesthetized dogs by a lack of myocardial electrophysiological effects. The compound induces a vasodilator effect in anesthetized dogs which is partially attenuated by propranolol, suggesting a weak beta 2-agonist activity. This beta 2-agonist property is also manifested in other peripheral tissues and undergoes down-regulation with repeat exposure. In contrast to other beta-blockers, celiprolol produces a bronchodilation in anesthetized cats which is propranolol-resistant. Isolated tissue studies suggest that a weak alpha 2-blocking effect contributes to this bronchodilation, although another unknown mechanism participates as well. Celiprolol induces a cardiac stimulation in anesthetized dogs which is inhibited by propranolol. The mechanism for this effect appears to be due to adrenergic interaction. These unique properties of celiprolol convey salutary effects in the clinical use of celiprolol.

Effects of celiprolol in anesthetized dogs with reduced myocardial function.

Celiprolol HCl is a new cardioselective beta adrenoceptor antagonist with both mild propranolol-sensitive partial agonist activity and propranolol-insensitive cardiostimulatory properties. The purpose of the present investigation was to assess the significance of this unique pharmacological profile in a study of the effects of celiprolol in anesthetized dogs with depressed myocardial function. Dogs were acutely instrumented to directly monitor myocardial contractile force (CF), arterial pressure (AP), heart rate (HR), and ECG limb lead II. Mecamylamine 1 mg/kg i.v., and verapamil, 0.5 mg/kg i.v., reduced CF (80 +/- 6 g), HR (76 +/- 4 beats/min), and AP (59 +/- 8 mm Hg). Celiprolol (3 mg/kg i.v.) did not produce any further decrement in myocardial function. There were no appreciable ECG changes. These data suggest that celiprolol may be the drug of choice in patients receiving verapamil, since it should not further compromise myocardial function.

Celiprolol, a potent cardioselective beta 1-adrenoceptor antagonist with mild alpha 2-adrenoceptor antagonist properties.

Celiprolol is a cardioselective beta-adrenoceptor antagonist, with interesting propranolol-insensitive cardiostimulatory, vasodilatory and bronchodilatory effects. Recent reports suggest that mild alpha 2-adrenoceptor antagonism may contribute to these effects. The present investigation further explored the alpha 2 effects of celiprolol. In isolated electrically-stimulated rat atria celiprolol (1.0 and 10 mumol/l) significantly increased the release of [3H]-norepinephrine, consistent with the blockade of pre-junctional alpha 2-adrenoceptors. Evidence for post-synaptic alpha 2-adrenoceptor antagonist activity was obtained in studies of the effects of celiprolol on the pressor response to clonidine and either phenylephrine or methoxamine in perfused hind-limbs of dogs (pretreated with mecamylamine and propranolol) and pithed rats. In the dog, celiprolol (10 mg/kg) significantly inhibited the vasoconstrictor response of clonidine while in the rat higher doses were required (> or = 12.5 mg/kg). Celiprolol did not affect the pressor response induced by alpha 1-agonists. We conclude that celiprolol possesses a mild alpha 2-adrenoceptor blocking action which may contribute to its unconventional profile.

Effects of celiprolol (REV 5320), a new cardioselective beta-adrenoceptor antagonist, on in vitro adenylate cyclase, alpha- and beta-adrenergic receptor binding and lipolysis.

Celiprolol has been previously shown in vivo to be an effective beta-adrenergic antagonist with cardio-selectivity and weak intrinsic sympathomimetic activity but no membrane stabilizing or "quinidine-like" effects. With in vitro systems reported here, the following was observed. Against the stimulation of adenylate cyclase from dog ventricular muscle by isoproterenol, celiprolol had a Ki of 2.6 X 10(-7) M which was about 1/20 the potency of propranolol. At 100 microM, celiprolol did not affect histamine or dopamine concentration-response curves for the stimulation of adenylate cyclase from guinea-pig cerebral cortex. By itself, up to 1 mM, celiprolol did not affect basal adenylate cyclase activity from either preparation. With in vitro radioligand binding assays to directly measure beta-adrenergic receptor interactions, celiprolol had Ki values of 1.4 X 10(-7) to 8.3 X 10(-6) M. A 35-fold beta selectivity was noted with membranes from rat heart vs. rat reticulocytes, which supports previously reported in vivo data on cardioselectivity. No difference in affinity to beta-receptors was noted with frog vs. turkey erythrocyte membranes which supports the contention that these two non-mammalian systems are not predictive of beta1/beta2 specificity with mammalian systems. Celiprolol also showed some selective alpha2-adrenoceptor antagonism against (3H)-yohimbine binding vs. (3H)-prazosin binding to membranes from rat cerebral cortex. With rat adipocytes, up to 300 microM celiprolol did not stimulate basal lipolysis in the presence or absence of 10 microM 1-methyl-3-isobutyl-xanthine. Celiprolol inhibited isoproterenol-induced lipolysis with a potency about 2 times greater than practolol. Unlike propranolol, celiprolol at very high concentrations did not show non-specific inhibition of lipolysis induced with cyclic nucleotides. These and other published data would suggest the following: in vitro beta adrenergic receptor antagonist activity can be demonstrated for celiprolol, cardioselectivity is due to a combination of many factors including stereochemistry of the molecule and in vivo distribution and metabolism, celiprolol does not possess "non-specific" membrane activity, the "intrinsic-sympathomimetic activity" of celiprolol is selectively observed in some but not all in vitro test models, celiprolol has about a 10-fold selectivity for alpha 2-vs. alpha 1-receptors which is relatively unique to beta-antagonists and needs further investigations as to the potential physiological significance.

Preclinical studies of indapamide, a new 2-methylindoline antihypertensive diuretic.

Indapamide is a new indoline antihypertensive diuretic agent whose chemical structure differs substantially from those of the thiazides. The hydrophobic indoline moiety of indapamide confers a lipid solubility to the molecule that is 5 to 80 times greater than that of the thiazide diuretics. Thus indapamide accumulates in vascular smooth muscle at a concentration 10 times higher than that of protein-free perfusate. The affinity of indapamide for vascular smooth muscle manifests itself in vitro and in vivo as a decrease in reactivity following various pharmacologic interventions. Moreover, in vitro studies have demonstrated that indapamide decreases the inward calcium current and the transmembrane influx of calcium. The diuretic effect of indapamide is predominantly due to inhibition of sodium reabsorption at the cortical diluting segment of the distal convoluted tubule. In animal studies, intravenous indapamide has no effect on glomerular filtration rate or renal blood flow. Indapamide is well absorbed and extensively metabolized in animals and humans, with biliary excretion being the predominant route of elimination in animals. Most important, repeat administration of indapamide to dogs with both kidneys removed produces no accumulation of intact indapamide or its metabolites. Extensive drug safety studies in animals indicate that indapamide produces no overt toxicity and exhibits a good margin of safety.

Evaluation of the analgesic properties of zomepirac.

Zomepirac, an inhibitor of prostaglandin biosynthesis, was evaluated for analgesic activity in a number of pharmacological screens. In the acetylcholine writhing test, zomepirac was found to be more potent than codeine, pentazocine, aspirin, and acetaminophen and equivalent in potency to morphine. Zomepirac was inactive in a number of tests that detect narcotic agents, suggesting that the drug will not induce physical dependence. The possibility of a central nonnarcotic as well as a peripheral analgesic mechanism merits consideration.

A comparison of the cardiovascular effects of haloperidol, thioridazine and chlorpromazine HCl.

Transient hypotension, electrocardiographic conduction changes and cardiac arrhythmias have been reported with the use of certain anti-psychotic agents. To assess these observations, we compared the effects of haloperidol, thioridazine and chlorpromazine HCl on alpha-adrenergic receptors, mean aortic pressure, myocardial contractile force and myocardial electrophysiology in anesthetized dogs. The results from these studies indicated that, on a milligram basis, chlorpromazine HCl was equipotent to haloperidol, and thioridazine was 0.5 times as potent as haloperidol as an alpha-adrenergic receptor blocker and as a myocardial depressant. Each compound induced conduction nonhomogeneity in myocardial conducting tissue. However, as a neuroleptic, when tested in dogs, haloperidol was 50 times more potent than chlorpromazine HCl and 180 times more potent than thioridazine. The therapeutic safety indices (cardiovascular effect dose/neuroleptic dose) for haloperidol regarding alpha-adrenergic blockade, hypotension, myocardial depression and ventricular conduction delay were 4, 145, 235 and 125, respectively, whereas these indices for chlorpromazine and for thioridazine were 0.06, 2, 4, 6 and 0.05, 1, 3 and 1, respectively. Therefore, because of differences in neuroleptic potency, therapeutic doses of haloperidol are less likely to cause adverse cardiovascular effects than are those of either chlorpromazine HCl or thioridazine.

Cardiovascular profile of mixidine fumarate, a compound which attenuates myocardial chronotropic responses.

The effect of mixidine fumarate on myocardial chronotropic responses to various stimulants was examined. Mixidine decreased elevated heart rate in the anesthetized dog to basal levels. It produced a dose-related decrease in heart rate elevated reflexly by aminophylline, by beta adrenergic stimulation induced by isoproterenol, by sympathetic nerve stimulation and by intravenous infusion of glucagon. Mixidine attenuated the increase in contractile force produced by sympathetic nerve stimulation but not that induced by isoproterenol. The compound antagonized the increase in rate of isolated guinea-pig atria induced by both isoproterenol and histamine. In the conscious dog, mixidine caused no decrease in resting heart rate, mean arterial pressure and cardiac output. It reduced atropine-induced sinus tachycardia as well as that induced by treadmill exercise. Experiments in the dog heart-lung preparation indicated that attenuation of an epinephrine-induced sinus tachycardia led to a decrease in myocardial oxygen consumption and an increase in myocardial efficiency. These studies suggest that mixidine fumarate induces an antichronotropic activity by a direct effect on the sinoatrial node and by attenuating sympathetic nervous system input to the heart.

Cardiovascular profile of 2-(3,4-diethyoxy-beta-methoxyphenethyl) imino-1-methylpyrrolidine fumarate (McN-2840-46), a preferential atrial anti-arrhythmic agent.

McN-2840-46, 2.5 mg/kg, i.v., protected against atrial tachyarrhythmias induced by three different methods in dogs and monkeys. The compound was inactive against ventricular arrhythmias produced by ouabain and by chloroform-epinephrine interaction at a four-fold higher dose. Significant reversal of ventricular arrhythmias produced by occlusion of the left anterior descending coronary artery in dogs was achieved by infusion of 8.8 +/- 2.4 mg/kg, i.v. of McN-2840-46. Myocardial electrogram studies confirm that the atrium is preferentially affected. McN-2840-46 does not possess beta 1- or beta 2-adrenergic blocking activity when evaluated on isolated rabbit atrial and guinea-pit tracheal chain preparations. McN-2840-46 is vagolytic but not anticholinergic. The vagolytic activity is attributed to its local anesthetic effect. Depression of myocardial function was observed in anesthetized dogs and in the heart-lung preparation. However, the isolated cat papillary muscle was stimulated by McN-2840-46 and doses considerably above the effective anti-arrhythmic dose did not significantly decrease cardiac output in the non-anesthetized dog. The results of these experiments suggest that McN-2840-46 is a potent "preferential" atrial anti-arrhythmic agent.