Showing papers in "Drug Development Research in 1986"

Thymosthenic effects of ritanserin (R 55667), a centrally acting serotonin‐S2 receptor blocker

Abstract: Ritanserin, characterized as a long-acting serotonin-S2 antagonist and as a pure and selective antagonist of LSD discrimination in rats, was found to be effective in the treatment of anxiety states. In these studies the observation that the patients felt less tired and more energetic with improved mood has led to study the effects of ritanserin 10 mg b.i.d. in dysthymic disorder and chronic schizophrenia, two conditions with a predominant symptomatology of anergy. The results obtained from two separate placebo-controlled studies showed significant improvement of depressive mood, early insomnia, agitation, and psychic anxiety in the dysthymic group, whereas negative and affective symptoms showed the best improvement in the schizophrenic group under concurrent decrease of extrapyramidal symptomatology. In both diagnostic groups the drug treatment was very well tolerated. Based on the results that ritanserin showed predominant improvement of anergy and depressed mood, the drug was ascribed thymosthenic properties, which are further supported by the specific property of ritanserin to increase human slow wave sleep.

Cytochrome p-450: Target for itraconazole

Abstract: The N-substituted triazole, itraconazole, has high affinity for the cytochrome P-450 (cyt. P-450) isozyme involved in the 14α-demethylation of lanosterol in Candida albicans microsomes. Fifty per cent inhibition was already observed at itraconazole concentrations ≤ 5 × 10−9 M. Higher concentrations (≥ 10−7 M) of this antifungal are needed to interfere with the 14 α-demethylation in mammalian cells. Unlike ketoconazole, itraconazole does not significantly affect in vitro androgen, gluco- and mineralocorticoid steroidogenesis. Itraconazole also does not affect the cyt. P-450-dependent 19-hydroxylation of testosterone, a step in the conversion of androgens to estrogens. The 1-hydroxylation of testosterone by pig testes microscomes is only slightly inhibited. It is hypothesized that itraconazole's selective activity on ergosterol bisosynthesis is due to its high affinity for the apoprotein of the C. albicans cyt. P-450 involved in the 14α- demethylation of lanosterol.

Oral antiallergic activity in ascaris hypersensitive dogs: A study of known antihistamines and of the new compounds ramastine (R 57 959) and levocabastine (R 50 547)

Abstract: The antiallergic effectiveness of twelve compounds was studied in ascaris hypersensitive dogs by measuring allergen-induced skin reactions before and 1, 4, 20, and 72 hr after oral treatment. The specific serotonin S2-antagonist ritanserin at 2.5 mg/kg and the selective histamine H2-antagonist cimetidine at 10 mg/kg did not reduce the allergic wheals. Chlorpheniramine and clemastine were inactive at 2.5 mg/kg. The remaining eight compounds studied over a wide dose range produced peak activity at markedly different doses and time intervals (hr). The lowest oral ED50-values in mg/kg were: levocabastine: 0.0035 (4); R 57 959: 0.048 (20); astemizole: 0.13 (20); ketotifen: 0.20 (4); cyproheptadine: 0.21 (4); azatadine: 0.32 (4); oxatomide: 1.26 (20); terfenadine: 1.26 (1). The lowest oral ED50-values in dogs and in rats (compound 48/80 lethality test) were similar, the largest difference being a fourfold potency gain of oxatomide in dogs. The short-acting compounds in rats (azatadine, cyproheptadine, ketotifen, and terfenadine) had also a duration of action of less than 12 hr in dogs. Levocabastine, R 57 959, astemizole, and oxatomide acted more than 16 hr. Maximal inhibition of the allergic wheal volumes was highest with levocabastine (90%); it reached 80% with R 57 959 and ranged from 67 to 78% with the remaining compounds. On the basis of their activity characteristics in dogs, levocabastine and R 57 959 are potentially very effective antiallergic drugs.

Drug‐receptor dissociation time, new tool for drug research: Receptor binding affinity and drug‐receptor dissociation profiles of serotonin‐S2, Dopamine‐D2, histamine‐H1 antagonists, and opiates

Abstract: A new filter technique for in vitro measurement of the drug-receptor dissocation time of unlabeled compounds was applied. The receptor binding affinity and drug-receptor dissociation profiles were obtained for new and reference compounds belonging to the classes of serotonin-S2, dopamine-D2, and histamine-H1 antagonists and of opiates. In vitro binding to the serotonin-S2, dopamine-D2, histamine-H1, adrenergic-α1 and -α2, cholinergic muscarinic and μ-opiate receptors was studied. The binding affinity profiles provide indications about the specificity of the drugs; in each pharmacological class more selective drugs were found, whereas others cross-reacted with various receptor sites. The drug-receptor dissociation profiles revealed substantial differences amongst drugs in drug-receptor dissociation times. For a particular receptor, drugs showed differences in dissociation time from half-times of less than 1 min (e.g., alfentanil from opiate receptors) to several hours (e.g., lofentanil). In addition, drugs were found that dissociated very slowly from one receptor site and very rapidly from another receptor site (e.g., ritanserin: slow from serotonin-S2, rapid from dopamine-D2; spiperone: slow from dopamine-D2, rapid from serotonin-S2; astemizole: slow from histamine-H1, rapid from serotonin-S2 and adrenergic-α1). Nevertheless, apparent binding affinities of these drugs for the receptor sites respectively were often found to be similar. Information on the drug-receptor dissociation time allows re-evaluation of apparent binding affinity data and gives better insight into the specificity of action of drugs. It can be applied at various levels of drug research: e.g., for interpretation of receptor binding data, drug effects on receptor regulation, functional effects of drugs, antagonizability of drug effects, and factors contributing to the in vivo duration of action of drugs. Finally, the information on drug-receptor dissociation time may be an important factor for drug design and receptor modeling.

Haemodynamic effects in man during exercise of a single oral dose of narbivolol (R 67555), a new beta-1-adrenoceptor blocking agent: A comparative study with atenolol, pindolol, and propranolol

Abstract: In eight normal volunteers R 67555 at 5 mg and 10 mg significantly lowered the exercise-induced increase of systolic blood pressure by 20 and 25%, and the exercise-induced increase of heart rate by 20 and 21% respectively. The blood pressure lowering effect of R 67555 6 hr after intake was comparable to that observed after atenolol, pindolol, and propranolol. In contrast, the lowering of exercise-induced increase of heart rate was significantly less with R 67555 than with the other beta-blockers tested. The ratio of PEPc/LVETc, a measure of left ventricular performance, significantly increased 3 hr after intake aof atenolol, propranolol, and 10 mg of R 67555 but not after pindolol and 5 mg of R 67555. Six hr after administration of pindolol and of 5 mg of R 67555, the ratio PEPC/LVETc was significantly lowered as compared with control values. The post-exercise left ventricular ejection time (LVETc) significantly shortened 3 hr and 6 hr after intake of 5 mg and 10 mg of R 67555, whereas a trend to prolongation was observed after administration of atenolol, pindolol, and propranolol.

Structural damage of the ischemic brain: Involvement of calcium and effects of postischemic treatment with calcium entry blockers

Abstract: The consequences of acute cerebral ischemia and the protective effects of post-treatment with flunarizine and nimodipine were morphologically studied in an experimental rat model allowing simple quantification of delayed neuronal damage. Global incomplete ischemia was induced by temporary clamping of both carotid arteries combined with severe hypotension. Selective damage to CA1 hippocampal neurons was quantified 7 days later. Cytochemical visualization of subcellular Ca2+ in this model revealed a correlation between irreversible cell necrosis and toxic cytosolic Ca2+-overload, the latter being a relatively slow process originating late in the reoxygenation period. Treatment with Ca2+-entry blockers started at 5 min after restoration of cerebral blood flow. Flunarizine significantly protected against ischemic hippocampal damage, whereas nimodipine had no effect.

Adenosine A1 receptors in mammalian brain: Species differences in their interactions with agonists and antagonists

Abstract: The binding of the selective ligand [3H]cyclohexyladenosine (CHA) to adenosine A1 receptors was studied in brain membrane from six species; cow, rabbit, rat mouse, human, and guinea pig. Saturation analysis gave evidence for a single binding site in each species. The number of binding sites (2.6–4.7 pmol/mg protein), based on saturation analysis, was virtually identical in each species. The Kd values were, however, different; whereas rat, rabbit, and mouse A1 receptors had similar affinities (Kd=1–2 nM), the binding site in bovine tissue had three to four times greater affinity (Kd=0.59 nM). Adenosine binding sites in human and guinea pig brain had two to three times less affinity, with Kd values 3.7 and 6.6 nM, respectively, than those in rat, rabbit, and mouse brain. Examination of the binding of five agonists, the R and S diastereomers of N6-phenylisopropropyladenosine (PIA), CHA, 5′N-ethylcarboxamido adenosine (NECA), and 2-chloroadenosine, and of five xanthine antagonists, PACPX [1,3,dipropyl-8-(2-amino-4-chloro)phenylxanthine], 1,3 diethyl-8-phenylxanthine (DPX), 8-phenyltheophylline (8PT), 8-parasulfophenyl-theophylline (8PST), and theophylline, showed that across the species N6-substituted adenosine analogs showed consistent differences in rank order activity. R-PIA ≥ CHA >S-PIA, with the compounds being most active in bovine tissue and least active in guinea pig, showing an 18-fold difference. In contrast, the 2-substituted analog, 2-chloroadenosine was most active in guinea pig and human brain membranes, and least active in rat and bovine brain. The 5′-substituted analog NECA had similar activity in all species studied. PACPX was the most potent of the xanthines studied, being most active in bovine brain tissue and least active in guinea pig; the difference in activities was 393-fold. The interaction of the remainder of the xanthines studied was complex. In general, the rank order of potency was PACPX > DPX=8 phenyltheophylline > 8PST >> theophylline. However, in human and rabbit brain 8PT was more active than DPX, and in guinea pig 8PT was twofold less active than DPX. In addition, in human and guinea pig brain, 8PST had comparable activities. These differences in pharmacological profiles may be attributable to differences in the adenosine systems studied as previously noted by Murphy and Snyder [Mol. Pharmacol. 22:250–257, 1982], which may in turn reflect distinct differences in A1 receptors or the presence of different subtypes of adenosine receptor in the various species. While these interspecies studies need to be extended to both A2 receptors and to coupled, i.e., adenylate cyclase, systems, they underline the need for care in choosing the mammalian species in which structure activity relationships are generated. Some caution is necessary in the use of bovine brain tissue in development programs targeted towards therapeutic entities in the adenosine A1 antagonist area.

Synthesis of cisapride, a gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine

Abstract: A novel synthon, 3-hydroxy-4,4-dimethoxy-N-phenylmethylpiperidine, is reported on for the preparation of 3-oxygenated-4-substituted piperidines. Different synthetic approaches are described for the synthesis of cis and trans 3-hydroxy- or 3-methoxy-1-substituted-4-piperidinamines. The pharmacological properties of benzamides derived from these piperidinamines were evaluated. Several compounds showed a marked activity in tests indicative of potential gastrokinetic activity and were found to be free of dopamine (DA) antagonism. Compounds 31 (cisapride) and 35 were selected for further detailed pharmacological studies.

The serotonin‐S2 Receptor: A receptor‐transducer coupling model to explain insurmountable antagonist effects

Abstract: Five serotonin-S2 antagonists, ketanserin, pipamperone, methysergide, ritanserin, and LSD, were tested for their ability to inhibit signal transduction coupled to the serotonin-S2 receptor by measuring the serotonin-induced [32P] phosphatidic acid formation. The five drugs inhibited the response in a non-competitive manner. Since drugs such as ketanserin and pipamperone were found to dissociate rapidly from serotonin-S2 receptor sites in binding studies, slowly reversible binding can hardly explain the apparent non-competitive inhibition of the biochemical effect. The authors, therefore, propose a new model of interaction between the serotonin-S2 receptor macromolecule and the signal transducing system that is compatible with the present and previous experimental observations.

Levocabastine (R 50547): The prototype of a chemical series of compounds with specific H1-antihistaminic activity

Abstract: The synthesis and the histamine H1 antagonism of four racemates of 1-[cyano-4-(4- fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid, termed R 48756, R 49389, R 49429, and R 49549, are described. R48756 (cabastine) was found to be the most potent compound, with oral ED50 values of 0.002–0.003 mg/kg in both the histamineinduced lethality test (guinea pigs) and the compound 48/80 assay (rats). Upon resolution of cabastine into its two optical isomers, levocabastine (R 50547) after oral administration in guinea pigs was about four times (1 hr) to 90 times (24 hr) more potent than dextrocabastine (R 50554). Protection from dyspnea, induced by histamine aerosols, was obtained with 0.005 mg/kg of levocabastine, whereas a dose of 2.5 mg/kg, failed to protect guinea pigs from dyspnea induced by serotonin or acetylcholine aerosols.

Dose-proportionality, bioavailability, and steady-state kinetics of astemizole in man

Abstract: The pharmacokinetics and dose-proportionality of astemizole (AST) (10, 20, and 30 mg given orally) were studied in 12 healthy male subjects by radioimmunoassay after selective extraction, enabling the determination of the plasma levels of AST and its major metabolite desmethylastemizole (DES-AST). Peak levels of AST were reached within 1 hr. Plasma levels decayed biphasically with terminal half-lives of about 1 day for AST and about 10 days for DES-AST. Areas under the curve of parent drug accounted for 5% of those of DES-AST. The bioavailability/bioequivalence of AST was studied in 21 healthy subjects according to a three-way cross-over design. Subjects received orally 30-mg doses as a tablet, suspension, or solution. The study demonstrated an equal bioavailability of the drug from the three formulations since rate and extent of absorption were not significantly different. In patients with perennial allergic rhinitis, treated for 20 weeks with AST 10 mg/day, steady-state was reached within 1 week for AST and within 4 weeks for DES-AST. Elimination half-lives after chronic treatment were similar to those after single dosing. Steady-state plasma levels were in close agreement with predicted levels, indicative of linear pharmacokinetics of AST in man.

Comparative pharmacological profile of ritanserin and ketanserin

Abstract: The effect of ritanserin was determined on a variety of isolated smooth muscle tissues. The compound is a potent antagonist of serotonin-induced contractions of isolated blood vessels (IC50-, Ah- or A2−value between 5.6 × 10−11 and 3.3 × 10−10M) and trachea (IC50 = 1.6 × 10−8M) and of serotonin−induced bronchospasms in anaesthetised guineapigs (ED50 = 0.026 mg/kg i.p.). In most tests ritanserin was more potent than ketanserin (IC50- or A2-value between 5.1 × 10−10 and 2.6 × 10−9M) as a serotonergic antagonist. In these vascular and tracheal preparations, serotonin induced contractions via S2-serotonergic receptor sites. Ketanserin acted as a competitive antagonist. In contrast, ritanserin was un unsurmountable, apparently non-competitive S2-serotonergic antagonist, except at the rabbit femoral artery where the serotonergic antagonism was of the competitive type. Its resistance to wash-out suggests a long duration of action. Both compounds had little or no effect on serotonergic responses mediated through M- or D-receptors in gastrointestinal tissues. In the femoral artery of the rabbit, ritanserin and ketanserin inhibited H1-histaminergic responses at concentrations 20 times and 4 times higher, respectively, than those required for S2-serotonergic antagonism. No other effects of ritanserin were observed unless at much higher concentrations. For instance, in the femoral artery of the rabbit, concentrations approximately 200 times higher (A2-value = 2.8 × 10−8M) were needed for alpha1-adrenergic antagonism than were required for S2-serotonergic antagonism (A2- value = 1.3 × 10-10M), while this ratio was 9 for ketanserin for the same preparation. In the rat tail artery, these ratios, based on IC50-values, were 666 and 39 for ritanserin and ketanserin respectively. In conclusion, as an S2-serotonergic antagonist, ritanserin is more potent and more specific than ketanserin. The mode of interaction with the S2-serotonergic receptor and the relation between time and antiserotonergic activity are different for the two compounds.

The chemical development of selective and specific serotonin S2-antagonists

Abstract: Four types of chemical intermediates were prepared to synthesize novel piperidine derivatives inspired by the butyrophenones benperidol and lenperone and by the diphenylbutyl neuroleptic pimozide. The fist type, comprising benzimidazolone alkyl intermediates, yielded declenperone and milenperone and also the “symmetrical” compound domperidone, which was pharmacologically unusual by its specific peripheral dopamine antagonism. Declenperone was the most potent serotonin antagonist of that series, and replacement of the benzimidazolinonepropyl by the quinazolinedioneethyl moiety led to ketanserin, which was devoid of residual dopamine antagonism. Very potent serotonin S2-antagonists were also obtained by using intermediates prepared from 2-aminoaza-heterocycles. Pirenperone and setoperone had a complex pharmacological profile, including significant dopamine and norepinephrine antagonism. These activity components were absent from the profile of R 56413 and ritanserin, which were obtained by using the fourth intermediate, benzhydrylenepiperidine. R 56413 and ritanserin are the most specific of the presently known serotonin S2-antagonists.

Rimcazole (BW 234U), a novel antipsychotic agent whose mechanism of action cannot be explained by a direct blockade of postsynaptic dopaminergic receptors in brain

Abstract: Rimcazole is a novel antipsychotic agent free of extrapyramidal side effects as judged by its profile in animal behavioral models and by results of early clinical trials in acute schizophrenic patients. The present study shows that rimcazole is different biochemically from the typical and atypical neuroleptics. Concentrations of 10−5 to 10−4 M are necessary to achieve even weak effects on dopamine-stimulated adenylate cyclase activity (D1 receptors), [3H]dopamine binding in mesolimbic and striatal areas of rat brain. Rimcazole's extremely weak potency as a D2 receptor blocker in brain was readily apparent when compared to several other neuroleptics: It was 160 times weaker than sulpiride, the least potent striatal D2 receptor blocker studied, and 10,000 times weaker than haloperidol, the most potent. Rimcazole had no effect on many of the enzymes involved in catecholamine synthesis and metabolism in vitro, did not effect the synthesis of [3H]dopamine from [3H]tyrosine in vivo, and did not alter the effects of a dopaminergic agonist and a dopaminergic antagonist on [3H]dopamine synthesis in vivo. It was moderately potent as an inhibitor of serotonin (5-HT2) receptors but had only weak effects on muscarinic cholinergic, α1–, α2 –, β –adrenergic, benzodiazepine, GABA, adenosine (A1 and A2), glycine, serotonin (5-HT1), imipramine, neurotensin, and phencyclidine receptors and calcium channels in binding assays. It was a moderately potent, competitive inhibitor of dopamine uptake in vitro and had no pharmacologically relevant effects on the spontaneous release of biogenic amines from isolated nerve endings. These data suggest that if rimcazole is shown to be a clinically effective antipsychotic agent, it will be the first antipsychotic whose mechanism of action cannot be explained by a direct blockade of postsynaptic dopaminergic (D2) receptors in brain.

Anticonvulsant profile of flunarizine

Abstract: The purpose of the study was to examine in a multi-experimental profile the purported similarity between the anticonvulsant effects of flunarizine, diphenylhydantoin, and carbamazepine. The compounds were injected at different time intervals and by different routes, and their effects were examined in a genetic model of epilepsy (audiogenic seizures in mice), against maximal seizures induced by bicuculline in mice and rats and in a seizurethreshold test (bicuculline infusion) in rats. All three compounds primarily affected tonic seizures. In the bicuculline seizure test, this was an all-or-none effect. In this test, flunarizine differed from diphenylhydantoin and carbamazepine in that it increased the threshold for clonic-hindpaw seizures. Thus, flunarizine, apart from antagonizing tonic seizures, also increased the threshold for generalization. Further, in agreement with previous experiments (maximal metrazol test and kindling), the duration of action of flunarizine is longer than that of diphenylhydantoin and carbamazepine. Finally, the degree of ataxia and neurological deficits caused by a high p.o. dosis of flunarizine was assessed. A slight neurological deficit and ataxia occurred 1 hr after p.o. administration of 160 mg/kg of flunarizine. By way of analogy with diphenylhydantoin, as a working hypothesis, it is suggested that the anticonvulsant actions of flunarizine result from reducing Na+ currents in neurons, although a direct effect on Ca2+ movements cannot be excluded.

Prevention of experimental amnesia by peripherally administered cholecystokinin octapeptide in the rat

Abstract: The effect of subcutaneously injected cholecystokinin octapeptide (CCK-8) on amnesia induced by electroconvulsive shock (ECS), CO2 inhalation, or cycloheximide injection was investigated in rats. In normal rats, single administration of CCK-8 had no significant effect on the passive avoidance response. Treatment with ECS, CO2, or cycloheximide markedly decreased the latency of the passive avoidance response, but CCK-8 in doses from 0.1 to 10 μg/kg could prevent the induced amnesia when injected 30 min before the training trials, immediately after foot shock or amnesic treatments, and 30 min before the first retention test. The results indicate that peripheral administration of CCK-8 is effective in preventing amnesia in the rat.

Novel approaches to the pharmacotherapy of schizophrenia

Abstract: Numerous attempts to extend the pharmacotherapy of schizophrenia beyond conventional neuroleptics are reviewed. Clozapine and melperone are atypical neuroleptics that produce few extrapyramidal side effects during acute usage and possible less tradive dyskinesia with prolonged use. Decreasing dopamingeric activity with a tyrosine hydroxylase inhibitor or dopamine autoreceptor agonists may also be of value. Neuroleptics that block voltage-sensitive calcium channels or calcium channel blockers per se have been advocated for treatment of negative symptoms or the deficit state. Among other possible clinical approaches reviewed are: beta adrenergic blockers, clonidine, tryptophan, 5-hydroxytryptophan, fenfluramine, GABA drugs, including high dose benzodiazepines, lithium, carbamazepine, opioid agonists and antagonists, gamma-endorphins, TRH analogs and vasopressin. Most studies indicate these agents produce inconsistent or slight-to-modest benefits, either in comparison with standard neuroleptic drugs or inaddition to neuroleptics, in groups of schizophrenic patients, including some double blind placebo-controlled trials. Those individuals who do respond sometimes, but not always, fail to relapse when the experimental drug is discontinued or fail to respond to it in subsequent trials. Consistent with the presumed heterogeneity of schizophrenia, there is some evidence supporing non-neuroleptic drug treatment for specific schizophrenic subtypes. The various stages of this usually life-long disorder, together with the possible mutability of the underlying etiological factors over time, requires the utmost care in clinical trials.

Comparison of the effects of pinacidil and its metabolite, pinacidil-N-oxide, in isolated smooth and cardiac muscle

Abstract: The effects of pinacidil and its major metabolite, pinacidil-N-oxide, were compared in isolated smooth and cardiac muscle preparations. Wide variation occurred in the sensitivity of different smooth muscle preparations to the relaxant effect of pinacidil. Relaxant sensitivity of pinacidil was greatest in the one vascular preparation examined, the rat aorta, where the ED50 for pinacidil was approximately 0.5 μM. Pinacidil was equally potent in relaxing serotonin- or norepinephrine-contracted aortic preparations. Although pinacidil was also a smooth muscle relaxant in the guinea pig trachea, guinea pig ileum, rat vas deferens, and rat stomach funds, the ED50 ranged from 1--25 μM in these smooth muscle preparations. In the trachea, pinacidil was most effective in relaxing histamine-induced contractions as compared to contractions induced by carbamylcholine. Thus, bronchodilatory effects of pinacidil might be most apparent when bronchoconstriction is produced by allergic responses that result from histamine release. Pinacidil was least effective in quiescent rat uterine smooth muscle, where approximately 80% of the maximum contractile response to oxytocin was maintained in the presence of 10−4 M pinacidil. Although a direct cardiostimulatory effect of hydralazine has been postulated, no direct stimulatory effect on guinea pig cardiac rate or force occurred with pinacidil. Furthermore, an inhibitory effect on rate and force of atrial responses occurred only in higher doses of pinacidil. The major metabolite of pinacidil, pinacidil-N-oxide, also relaxed the rat aorta, although it was approximately eight- to tenfold less potent than pinacidil. These data are consistent with the contention that pinacidil-N-oxide would contribute to the antihypertensive activity seen after pinacidil only when plasma levels were approximately tenfold greater than the parent compound. Furthermore, because of the relative insensitivity of other smooth and cardiac.

Stimulation of gastroduodenal motor activity: Dopaminergic and cholinergic modulation

Abstract: The effects of domperidone, cisapride, metoclopramide and bethanechol were determined on antroduodenal coordination, in vitro in the gastroduodenal preparation of the guinea pig and in vivo in conscious Beagle dogs implanted with strain gauge force transducers. In vitro dopamine inhibited and the dopamine antagonist domperidone stimulated antroduodenal coordination. The effect of domperidone was blocked by atropine or tetrodotoxin, but not by hexamethonium. Propranolol, prazosin, and yohimbine did not enhance antroduodenal coordination. Only at one of the concentrations tested did bethanechol moderately enhance antroduodenal coordination. Cisapride stimulated antroduodenal coordination in a dose-dependent manner. This effect could also be blocked by atropine or tetrodotoxin. Metoclopramide (at higher concentrations) also enhanced antroduodenal coordination. The order of potency (expressed in terms of EC50-values) was domperidone (1.4 × 10−7 M) = cisapride (1.9 × 10−7 M) ≥ ≥ metoclopramide (2.2 × 10−5 M). In vivo in conscious Beagle dogs, similar results were obtained. Bethanechol did not enhance antroduodenal coordination. In this case, the order of potency (expressed in terms of the percentage increase in antroduodenal coordination at 0.31 mg/kg, i.v.) was cisapride (208%) ≥ domperidone (152%) = metoclopramide (138%). Thus, domperidone, cisapride and, to a lesser extent, metoclopramide, but not bethanechol, can effectively improve antroduodenal coordination. The stimulatory effects of domperidone are mediated via specific dopamine receptors (i.e., different from α1-, α2- or s-adrenergic receptors), located on postganglionic nerves in the myenteric plexus. The stimulatory effects of cisapride are mediated via cholinergic nerves in the myenteric plexus and the moderate effects of metoclopramide may be mediated via both mechanisms.

Pharmacokinetics and tissue distribution of astemizole in the dog

Abstract: The pharmacokinetics of a single oral dose of 3H-astemizole (AST) of 1 mg/kg was studied in Beagle dogs and compared with that of a tracer dose superposed at the end of a subchronic experiment. Single and superposed doses were equally well absorbed, and elimination half-lives of AST and of its metabolites were similar at both occasions (t1/2s = 3–5 d). Steady-state was reached after 2–3 weeks of daily dosing. AST and its metabolite desmethylastemizole (DES-AST) were extensively distributed, mainly to well perfused tissues but only poorly to brain, muscle, and fat. All tissue levels were many times higher than the corresponding plasma concentrations. The superposed tracer dose was well stirred in the tissue compartments and showed instantaneous equilibrium with pretreatment levels. Tissue/plasma level ratios of AST and DES-AST remained constant with time, indicating that the elimination from tissues proceeded at a similar rate to that from plasma. The extensive distribution of AST and DES-AST is explained by a strong, but reversible tissue binding that appears to be rate-limiting for the elimination from the body.

Excretion and biotransformation of astemizole in rats, guinea-pigs, dogs, and man

Abstract: The excretion and biotransformation of astemizole (AST) were studied after single administration in rats (0.16 or 10 mg/kg), guinea-pigs (0.16 mg/kg), dogs (1 or 10 mg/kg) and humans (30 mg), using three different radiolabels. Orally administered AST was well absorbed and almost completely metabolized in rats, dogs, and humans, whereas in guinea-pigs about 17% of dose was excreted as parent AST. In the four species urinary excretion of the radioactivity (5–15%) was much less than their fecal excretion (60–90%). Excretion rate of the radioactivity decreased in the order rat ≥ guinea-pig ≥ dog ≥ man. In male rats, biliary excretion amounted to 70% at 24 hr after dosing, whereas about 45% of the biliary radioactivity was subjected to enterohepatic circulation. The major metabolites were characterized by high performance liquid chromatography (HPLC) and mass spectrometry. A mass balance of the metabolites was made up by HPLC with on-line radioactivity detection. The major metabolic pathways of AST in the four species were oxidative O-demethylation, aromatic hydroxylation at the benzimidazole moiety, and oxidative N-dealkylation at the piperidine nitrogen. Phenolic metabolites resulting from the two former pathways were excreted as their glucuronides in the bile. Desmethylastemizole (DES-AST) was the main metabolite in rats, 6-hydroxy-desmethylastemizole (6-OH-DES-AST) the main metabolite in dogs. In humans, about equal relative amounts of DES-AST, 6-OH-DES-AST, and norastemizole were found. Sex differences in rats were only minor. The mass balance of the metabolites after a 6-week dosing at 1 mg/kg/day in dogs was very similar to that after a single dose.

Selectivity of agonists and antagonists at D2dopamine receptors compared to D1 and S2receptors

Abstract: The common dopamine agonists (dopamine, apomorphine, ADTN, and N-propylnorapomorphine) are not selective D1 or D2 dopamine receptors, affecting both simultaneously. SK&F 38393 is selective for D1, while bromocriptine and (D2)D2LYD2171555 are selective for D2. The neuroleptic with the highest D2/S2 selectivity is eticlopride with an affinity 3,200-fold higher for the D2 dopamine receptor compared to the S2 serotonin receptor. Such selective neuroleptics may be clinically useful and may also help in measuring the elevated D2 density in vivo by positron emission tomography in the brains of schizophrensis.

Cognitive disorders related to immune dysfunction: Novel animal models for drug development

Abstract: With the recent emphasis on drug development for mental disorders of late life, a need has arisen for animal models useful in preclinical evaluation of potential treatment strategies. Although the animal models now available exhibit behavioral and neurological commonalities with their target clinical syndromes, few models incorporate etiologic similarities. A review of the literature is presented relating immune factors to aging-associated cognitive disorders, and parallels are drawn to immune factors and related behavioral impairments in autoimmune New Zealand black and nonautoimmune C57BL/6 mice. These mouse strains are proposed as potentially useful immunologic models for both theoretical investigation and drug development.

Development and clinical use of the new gastrointestinal prokinetic drug cisapride (R 51 619)

Abstract: Cisapride is a new gastrointestinal prokinetic substance that is devoid of antidopaminergic and direct muscarinic activity. This was evidenced by a lack of effect on prolactin release and gastric secretion. In man, cisapride stimulates lower esophageal, gastric, small intestinal, and colonic motility. Accordingly, cisapride significantly improves esophageal reflux disorders, gastroparesis, and constipation and has been successfully used in the treatment of clinical conditions that result from a deficient motor coordination.

Itraconazole (R 51 211): A clinical review of its antimycotic activity in dermatology, gynecology, and internal medicine

Abstract: Itraconazole was highly effective in skin infections caused by dermatophytes and yeasts. In addition, vaginal candidosis responded well to oral itraconazole therapy. Treatment periods for superficial mycoses ranged from 2 to 3 days in vaginal infections to up to 2 months in tinea pedis. The daily dose in superficial mycoses ranged from 50 mg to 200 mg (median 100 mg). In systemic mycoses, itraconazole is the first compound active in sporotrichosis since the advent of potassium iodide in 1901. It has also been shown to be active in aspergillosis and chromomycosis in man. The median daily dose of itraconazole administered in systemic mycoses was 100 mg (50–800 mg). The median treatment length in systemic mycoses was 6 months (15 days-2.5 years).

Prostaglandins, prostacyclin, and thromboxane in cardiovascular diseases

Abstract: Prostaglandins appear to play an important role in or to be found therapeutically useful in various cardiovascular diseases, such as hypertension, arrhythmias, ventricular fibrillation, arterial thrombosis, myocardial ischemia, myocardial infarction, certain types of angina pectoris, atherosclerosis, circulatory shock, and peripheral arterial diseases, etc. Prostacyclin and prostaglandins E1, E2, and D2 are considered beneficial, while thromboxane A2 and prostaglandin F2α are considered harmful and their formations should be inhibited. Inhibition of the formation of the vasodepressor prostaglandins, such as prostacyclin and prostaglandin E2, in humans and animals leads to increase in arterial blood pressure and total peripheral resistance as well as to decrease the efficacy of most antihypertensive drugs, which suggests that these vasodepressor prostaglandins play an important role in hypertension. Most prostaglandins exert antiarrhythmic activity. Prostacyclin and thromboxane synthetase inhibitors are particularly effective in myocardial infarction/reperfusioninduced arrhythmias and ventricular fibrillation (sudden cardiac death) where the classical antiarrhythmic agents are not very effective. Prostacyclin and thromboxane synthetase inhibitors are effective in reducing myocardial infarct size, increasing coronary blood flow, and inhibiting arterial thrombosis. Atheroclerosis may result from decrease in prostacyclin formation in the blood vessel wall due to inhibition by the concentration of lipid peroxides in the blood. Prostacyclin stimulates cholesterol ester hydrolase, the enzyme that converts cholesterol ester to free cholesterol for mobilization out of the cells. PGE2 inhibits acyl CoA cholesterol-O-acyltransferase (ACAT), the enzyme that catalyzes the reesterification of free cholesterol. Therefore, prostacyclin, PGE2, and their stable analogs may be useful for the prevention and induction of regression of atherosclerosis. Prostacyclin, PGE1, and other stable prostaglandin analogs, such as iloprost and viprostol, have been reported to be beneficial for the treatment of peripheral arterial diseases. It is very likely that new drugs that affect the prostaglandin systems will be introduced for the prevention and treatment of various cardiovascular diseases in the very near future.

Platelet activating factor and inflammation in atherogenesis: Targets for drug development

Abstract: There is substantial evidence that the pathogenesis of atherosclerosis has one or more inflammatory components. As arterial injury is a primary event in the disease initiation and progression, inflammatory agents which injure and thus increase permeability of the arterial endothelium may lead to the development of atherosclerosis. The actions of circulatory mediators of inflammation to increase endothelial permeability may consequently accelerate entry or infiltration of lipid and other plasma macromolecules into the vessel wall. Reviewed are the biological properties of platelet activating factor (PAF), a potent lipid mediator believed to play a role in such disease states as allergic asthma, inflammation, systemic shock, myocardial ischemia, and allograph rejection. Emphasized are the actions of PAF related to increased endothelial permeability, cardiovascular actions and pathological profiles which indicate a role in the development of atherosclerosis and heart disease.

The neuropharmacological profile of tefludazine, a potential antipsychotic drug with dopamine and serotonin receptor antagonistic effects

Abstract: The neuropharmacology of tefludazine, a new neuroleptic with phenylindan structure, has been investigated in comparison with cis(Z)-flupentixol, fluphenazine, haloperidol, methiothepin, thioridazine, and clozapine. Tefludazine showed potent dopamine (DA) antagonistic activity in a broad range of test models in vitro and in vivo in mice, rats, and dogs (receptor binding, antagonism of DA agonist-induced behavior, inhibition of conditioned avoidance, catalepsy, etc.). High oral activity and long duration of action was found. Interestingly, the cataleptogenic potency at the time of peak effect was seven times weaker than the antistereotypic activity, in contrast with that observed with cis(Z)-flupentixol, fluphenazine, and haloperidol. In addition to DA antagonism, tefludazine was equipotent at 5-HT receptors (in vitro receptor binding, 5-HT antagonism in isolated peripheral tissue, cardiovascular 5-HT antagonism, antagonism of I-5-HTP- and 5-MeODMT-induced behaviors). No antimuscarinic and low α-adrenoceptor blocking effect was found in pithed rats and in denervated cat nictitating membrane preparation. The DA/5-HT activity profile of tefludazine resembled that of methiothepin, which, however, had potent α-adrenoceptor blocking effect. It is concluded that tefludazine has a neuropharmacological profile that should combine antipsychotic potential with lower risk of extrapyramidal symptoms.

Ketoconazole: From an antimycotic to a drug for prostate cancer

Abstract: The observation in a few patients that gynecomastia developed during an antifungal therapy with 200 mg ketoconazole daily set the stage for a totally new application for this drug. By administering 400 mg ketoconazole orally, every 8 hr, serum testosterone levels in or close to the castrate range were obtained within 1 day in prostate cancer patients. In addition, the adrenal androgens androstenedione and dihydroepiandrosterone were dramatically reduced. The effect was due to an interaction with cytochrome P450-dependent enzymes active in the sex steroid-synthesizing organs. Clinical improvement and a lowering of acid phosphatase were achieved within the first few days in previously untreated patients, and long-term objective responses were obtained. A remarkable subjective and objective response to ketoconazole high dose was noticed in several patients who no longer responded to previous hormonal manipulations. Tolerance to the therapy was acceptable. Long-term side effects were mainly related to the mechanism of action. Hepatotoxicity was rare. In some cases, gastric intolerance interfered with the therapy. The observation during antifungal therapy of a very rare side effect, namely, gynecomastia, has thus opened up new perspectives for patients afflicted with one of the main male cancers.

Effect of hot plate temperature on the antinociceptive activity of mixed opioid agonist-antagonist compounds

Abstract: The effects of four different hot plate temperatures (49.5, 53, 55, and 60°C) on the antinociceptive activity of butorphanol, nalbuphine, pentazocine, and morphine were determined. Antinociception, as measured by an increase in percent maximum possible effect (%MPE) derived from time to paw lick in mice increased with dose for all compounds except nalbuphine at all temperatures. Nalbuphine elicited activity (50% MPE) at one dose (3 mg/kg) at 49.5°C. Butorphanol, 10 mg/kg, and pentazocine, 10 mg/kg, produced 100% MPE and 80% MPE at 49.5°C and 53°C, respectively. Only morphine (20 mg/kg) produced 100% MPE at all temperatures. Since every compound exhibited antinociceptive activity at 49.5°C at some dose below toxicity, it is suggested that this is the preferred temperature to screen for mixed opioid compounds.