Comparison of the analgesic and intestinal effects of fentanyl and morphine in rats.

Clinical studies report a low incidence of intestinal side effects with transdermally administered fentanyl (TTS-fentanyl) in comparison with oral morphine. To support these clinical data, analgesic and intestinal effects of both opioids were compared in rats. After subcutaneous injection, analgesia in the tail withdrawal reaction test was obtained at a peak effect dose of 0.032 mg/kg with fentanyl and 8.0 mg/kg with morphine. This analgesic dose exceeded the ED50 for inhibition of castor oil-induced diarrhea only slightly (1.1 x) in the case of fentanyl (0.028 mg/kg) but markedly (36 x) in the case of morphine (0.22 mg/kg). To reverse completely the antidiarrheal effect of equivalent analgesic doses of the opioids (their ED50S for analgesia lasting 2 hours), much more naloxone was required in the case of morphine (5.4 mg/kg) than in the case of fentanyl (0.19 mg/kg). After oral administration, the difference between both opioids was less pronounced. Analgesia was obtained at 0.85 mg/kg with fentanyl and 32 mg/kg with morphine. This analgesic dose only slightly (1.7 x) exceeded the antidiarrheal dose in the case of fentanyl (0.49 mg/kg) but significantly (6.2 x) in the case of morphine (5.2 mg/ kg). To reverse completely the antidiarrheal effect of equivalent analgesic oral doses of the opioids (their ED50S for analgesia lasting 2 hours), more naloxone was required in the case of morphine (11 mg/kg) than in the case of fentanyl (2.0 mg/kg). Rapid penetration of fentanyl into the brain is thought to be responsible for small dissociation between the analgesic and intestinal effect of this lipophilic opioid. The present data provide preclinical evidence to support the relatively low incidence of intestinal side effects observed clinically with the use of TTS-fentanyl in comparison with orally administered morphine.

Is it possible to predict the clinical effects of neuroleptics from animal data? Part V: From haloperidol and pipamperone to risperidone.

In 1965 the first study of this series reported different effects of neuroleptics in rats, supporting clinical differences. At the one end, haloperidol presented as a potent and specific antagonist of the psychostimulants amphetamine and apomorphine. Haloperidol-like neuroleptics have marked effects on psychomotor agitation, delusions and hallucinations and bind with high affinity to dopamine-D2 receptors. Pipamperone, at the other end, presented with weak "dopamine" antagonism and more striking tryptamine antagonism. Pipamperone is known to improve disturbed sleep, social withdrawal and other symptoms of chronic schizophrenia in the relative absence of extrapyramidal symptoms. These effects have been attributed to central serotonin-S2 antagonism, on the basis of the clinical effects of ritanserin. As shown by the present analysis of relative tryptamine versus apomorphine antagonism of 57 neuroleptics, in comparison to relative S2 vs. D2 binding, there is a continuity in the series. About 30% of the compounds can be considered to act primarily as serotonin antagonists, but few are markedly more potent than pipamperone. In amphetamine-challenged rats pipamperone-like activity is reflected in preferential inhibition of the excessive oxygen consumption rather than of agitation. Risperidone inhibits oxygen consumption (0.016 mg/kg) at the same dose as haloperidol inhibits agitation. Other low-dose effects of risperidone include reversal of amphetamine-induced withdrawal, antagonism of agitation induced by a sequential tryptamine and apomorphine challenge and LSD-antagonism. In dogs, the antiemetic activity of risperidone is characterized by high oral effectiveness which lasts one day and agrees with pharmacokinetic data when allowance is made for the active metabolite 9-hydroxyrisperidone.(ABSTRACT TRUNCATED AT 250 WORDS)

Survey on the pharmacodynamics of the new antipsychotic risperidone.

This review reports on the pharmacodynamics of the new antipsychotic risperidone. The primary action of risperidone is serotonin 5-HT2 receptor blockade as shown by displacement of radioligand binding (Ki: 0.16 nM), activity on isolated tissues (EC50: 0.5 nM), and antagonism of peripherally (ED50: 0.0011 mg/kg) and centrally (ED50: 0.014 mg/kg) acting 5-HT2 receptor agonists in rats. Risperidone is at least as potent as the specific 5-HT2 receptor antagonist ritanserin in these tests. Risperidone is also a potent dopamine D2 receptor antagonist as indicated by displacement of radioligand binding (Ki: 1.4 nM), activity in isolated striatal slices (IC50: 0.89 nM), and antagonism of peripherally (ED50: 0.0057 mg/kg in dogs) and centrally acting D2 receptor agonists (ED50: 0.056-0.15 mg/kg in rats). Risperidone shows all effects common to D2 antagonists, including enhancement of prolactin release. However, some central effects such as catalepsy and blockade of motor activity occur at high doses only. Risperidone is 4-10 times less potent than haloperidol as a central D2 antagonist in rats and it differs from haloperidol by the following characteristics: predominant 5-HT2 antagonism; LSD antagonism; effects on sleep; smooth dose-response curves for D2 antagonism; synergism of combined 5-HT2/D2 antagonism; pronounced effects on amphetamine-induced oxygen consumption; increased social interaction; and pronounced effects on dopamine (DA) turnover. Risperidone displays similar activity at pre- and postsynaptic D2 receptors and at D2 receptors from various rat brain regions. The binding affinity for D4 and D3 receptors is 5 and 9 times weaker, respectively, than for D2 receptors; interaction with D1 receptors occurs only at very high concentrations. The pharmacological profile of risperidone includes interaction with histamine H1 and alpha-adrenergic receptors but the compound is devoid of significant interaction with cholinergic and a variety of other types of receptors. Risperidone has excellent oral activity, a rapid onset, and a 24-h duration of action. Its major metabolite, 9-hydroxyrisperidone, closely mimics risperidone in pharmacodynamics. Risperidone can be characterized as a potent D2 antagonist with predominant 5HT2 antagonistic activity and optimal pharmacokinetic properties.

Pharmacological profile of the new potent neuroleptic ocaperidone (R 79,598).

Ocaperidone, a new benzisoxazolyl piperidine neuroleptic, was compared with haloperidol, risperidone and ritanserin in a large series of pharmacological tests. Ocaperidone inhibited dopamine agonist (apomorphine, amphetamine or cocaine)-induced behavioral effects at low doses (0.014-0.042 mg/kg) and was, thereby, equipotent with haloperidol (0.016-0.024 mg/kg) and 2.0 to 8.3 times more potent than risperidone. Ocaperidone completely blocked the dopamine agonist behavior at slightly higher doses (0.064 mg/kg) and was, thereby, more potent and efficacious than haloperidol (0.097-0.13 mg/kg) and risperidone (0.59-1.17 mg/kg). The dissociation between inhibition of apomorphine behavior and induction of catalepsy was as high for ocaperidone (22) as for risperidone (20) and higher than for haloperidol (8), suggesting risperidone-like low extrapyramidal side effect liability. Ocaperidone also antagonized serotonin agonist (tryptamine, mescaline or 5-hydroxytryptophan)-induced behavioral effects (0.011-0.064 mg/kg) and was, thereby, equipotent with risperidone (0.014-0.056 mg/kg) and at least as potent as ritanserin (0.037-0.13 mg/kg). Ocaperidone displayed its serotonin and dopamine antagonism at the same dose levels, in contrast to risperidone, which was a predominant serotonin antagonist. Apart from protection from compound 48/80 lethality (0.042 mg/kg) and norepinephrine lethality (0.097 mg/kg), which were not considered to hinder its clinical application, no additional secondary effects were observed at low doses of ocaperidone. In the apomorphine test in dogs, ocaperidone was very potent (i.v., s.c. and p.o. ED50 values: less than 1.0 micrograms/kg) and showed a rapid onset (less than 0.5 h) and long duration of action (24 h) after p.o. administration. Ocaperidone is concluded to be a highly potent and efficacious dopamine-D2 antagonist with concomitant, equivalent serotonin 5-HT2 antagonism. Ocaperidone is expected to exert pronounced haloperidol-like effects on the positive symptoms of schizophrenic patients but with risperidone-like low extrapyramidal side effect liability and improved patient compliance.

Behavioral disinhibition and depression in amphetaminized rats: a comparison of risperidone, ocaperidone and haloperidol.

The mixed serotonin-2/dopamine-D2 antagonists risperidone and ocaperidone were compared with the specific D2 antagonist haloperidol for their ability to antagonize amphetamine (10 mg/kg, s.c.)-induced stereotypy in rats. Four successive stages of amphetamine antagonism were differentiated: 1) disinhibition: reversal of stationary stereotypy into the hyperactivity normally observed with lower doses of amphetamine; 2) inhibition: the first significant reduction of activity; 3) normalization: reduction of activity to the level of nonamphetaminized rats; and 4) suppression: reduction of activity to 50% of the level of nonamphetaminized rats. Ocaperidone and risperidone were equipotent with haloperidol for disinhibition (0.0062-0.011 mg/kg). However, the disinhibition was maintained over a wider dose range with risperidone (factor 84) than with haloperidol (9.0) and ocaperidone (4.1) and was also more pronounced in magnitude with risperidone. Ocaperidone was equipotent with haloperidol for inhibition (0.013-0.025 mg/kg) and normalization (0.074-0.080 mg/kg) but 4.4 times less potent for suppression of activity (0.71 vs. 0.16 mg/kg). Risperidone became progressively less potent than haloperidol: 4.4 times for inhibition, 9.6 times for normalization and 22 times for suppression of activity. The present data are consistent with the hypothesis that serotonin-2 antagonism compensates for the functional consequences of D2 receptor blockade. The implications for the clinical application of the compounds are discussed.

General pharmacology of the four gastrointestinal motility stimulants bethanechol, metoclopramide, trimebutine, and cisapride.

The pharmacological profile of bethanechol (CAS 674-38-4), metoclopramide (CAS 364-62-5), trimebutine (CAS 39133-31-8) and cisapride (CAS 81098-60-4) was studied in a series of simple pharmacological tests in rats and dogs. Bethanechol stimulated both gastric emptying and intestinal propulsion but displayed also the well-known behavioral effects of a direct muscarinic acetylcholine receptor agonist. Metoclopramide showed the profile of a centrally active dopamine D2 antagonist. In addition, metoclopramide displayed a stimulant effect on spontaneous gastric emptying in rats, an effect that could not be related to dopamine D2 antagonism. The only effect observed with trimebutine was protection from castor oil diarrhea, probably due to its reported interaction with peripheral opiate receptors. Cisapride was a potent stimulant of gastric emptying in rats, 7 times more potent than metoclopramide. Cisapride was also a very specific gastrokinetic, over a large dose range (specificity ratio: greater than or equal to 20) devoid of effects indicative for direct interaction with dopamine or acetylcholine receptors. The relationship between the differential activity profiles of the compounds in the present study and differences in their mechanism of action and side-effect liability is discussed.

Normalization of small intestinal propulsion with loperamide-like antidiarrheals in rats.

Gastrointestinal propulsion and the presence of diarrhea were assessed in rats pretreated with various opioids and challenged orally with either castor or paraffin oil, which both contained phenol red as a marker of gastrointestinal propulsion. In solvent-pretreated rats, diarrhea was always observed within 90 min after castor oil, reflecting a state of hyperpropulsive activity of the gut, but never (up to 8 h) after paraffin oil, reflecting normal intestinal propulsion (which amounted to an average distance of 91% of the total length of the small intestine in 90 min). Paraffin oil propulsion was blocked (to values less than 60%) by all opioids tested with the exception of the gut-selective compounds loperamide, loperamide oxide and fluperamide oxide (ED50s: greater than or equal to 160 mg/kg). Castor oil diarrhea was antagonized by all opioids tested and, at comparable but slightly (1.3-2.6 times) higher doses, propulsion was normalized to values (less than 100%) comparable to those measured in paraffin oil-challenged control rats. Castor oil propulsion was further reduced to subnormal values (less than 60%) by still higher doses of the opioids, comparable to those that blocked propulsion after paraffin oil. However, the required dose increment varied consistently among the opioids tested and ranged, depending on gut selectivity, from a factor 2.3 times the antidiarrheal dose for narcotic analgesics such as pethidine and dextromoramide to greater than 300 for antidiarrheals such as loperamide, loperamide oxide and fluperamide oxide. Protection from diarrhea and normalization of propulsion showed a close correlation; both failed to correlate with central analgesic activity and are thought to be mediated via peripheral opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Is in vivo dissociation between the antipropulsive and antidiarrheal properties of opioids in rats related to gut selectivity?

The antipropulsive activity of a series of opioids in the charcoal test was compared with their antidiarrheal activity in the castor oil test and their analgesic activity in the tail withdrawal test. The obtained antipropulsive/antidiarrheal potency ratios varied from 0.71 to greater than 552 [pethidine (oral ED50's in mg/kg: 21.5/30.2), fentanyl (0.77/0.49), dextromoramide (5.39/2.90), methadone (14.2/6.38), codeine (98.4/10.8), morphine (56.6/5.21), diphenoxylate (8.15/0.54), nufenoxole (74.7/1.72), difenoxin (7.10/0.16), loperamide oxide (greater than 160/0.34) and loperamide (greater than 160/0.29)]. The above ratios correlated with the gut selectivity of the compounds as defined by their analgesic/antidiarrheal potency ratios (r = 0.92, P less than 0.001). Furthermore, inhibition of propulsion was found to correlate with central analgesic activity (r = 0.93, P less than 0.001) but not with protection from diarrhea (r = 0.023, P greater than 0.05). Indeed, gut-selective opioids such as loperamide and loperamide oxide failed to affect propulsion up to doses more than 450 times their antidiarrheal doses. In contrast, alpha 2-adrenoceptor agonists delayed propulsion at doses comparable to their antidiarrheal doses [clonidine (0.085 vs 0.021), lidamidine (2.35 vs 1.66)] and anticholinergics inhibited propulsion even at doses many times below their antidiarrheal doses [atropine (0.26 vs 9.30), dexetimide (0.13 vs 5.03) and isopropamide (0.78 vs 74.6)]. The present results indicate that the in vivo inhibition of gastrointestinal propulsion by opioids in rats is mediated by a central action. Effects on intestinal fluid transport or, alternatively, on motility events distal to the ileocecal junction rather than effects on propulsion through the small intestine, seem to be the primary mechanism of antidiarrheal action of gut-selective opioids such as loperamide and loperamide oxide.

Differential effects of the new antipsychotic risperidone on large and small motor movements in rats: a comparison with haloperidol.

Risperidone, a new antipsychotic agent, was studied for its effects on spontaneous motor activity in rats in comparison with haloperidol. Motor activity was recorded via the optical scanning technique (horizontal and vertical activity) and via a recently developed technique based on the piezo-electric principle which, in contrast to optical scanning, is very sensitive to small, stationary movements (piezo activity). Risperidone and haloperidol at low doses depressed both vertical activity (ED50s: 0.062 and 0.038 mg/kg, respectively) and horizontal activity (0.18 and 0.060 mg/kg, respectively). With increase of dose, motor activity decline was significantly faster with haloperidol than with risperidone. Moreover, haloperidol also rapidly depressed piezo activity (ED50: 0.085 mg/kg) whereas risperidone depressed this component of motor behaviour at much higher doses only (ED50: 2.80 mg/kg). Visual inspection did not reveal abnormal behavioural movements following the test compounds. Risperidone, therefore, preserves normal small movements over a much larger dose interval than haloperidol; this effect may be related to its relatively low cataleptogenic activity and potentially also to a reduced EPS liability. The present results further confirm that the piezo technique may complement the optical scanning method, and thereby enhance the information on the extent that test compounds modify behaviour.

Further validation of in vivo and in vitro pharmacological procedures for assessing the alpha 2/alpha 1-selectivity of test compounds: (1). Alpha-adrenoceptor antagonists.

Twenty one chemically dissimilar alpha-adrenoceptor antagonists were assessed in 7 different tests. The potencies of the compounds to protect rats from norepinephrine lethality were closely correlated with their potencies for inhibition of [3H]WB4101, but not of [3H]clonidine, [3H]idazoxan, [3H]rauwolscine or [3H]yohimbine binding to rat brain homogenates. The reverse was found for the potencies of the compounds to prevent the antidiarrheal effect of clonidine. The in vivo anti-norepinephrine/anti-clonidine potency ratios were highly correlated with the ratios between the in vitro potency to inhibit [3H]WB4101 binding on one hand and [3H]clonidine, [3H]idazoxan, [3H]rauwolscine or [3H]yohimbine binding on the other. The reliability of the above models for measuring alpha 1- and alpha 2-adrenoceptor antagonistic activity and selectivity is discussed.

Further validation of in vivo and in vitro pharmacological procedures for assessing the alpha 2/alpha 1-selectivity of test compounds: (2). Alpha-adrenoceptor agonists.

Eighteen chemically dissimilar alpha-adrenoceptor agonists were assessed in 6 different tests. The antidiarrheal activity of the compounds was highly correlated with the diuretic activity. Both activities were highly correlated with the inhibition of [3H]clonidine or [3H]idazoxan binding; the degree of correlation with inhibition of [3H]WB4101 binding or with antiptotic activity was much less. Antiptotic activity was better correlated, although still poorly, with inhibition of [3H]WB4101 binding than with inhibition of [3H]clonidine or [3H]idazoxan binding. The in vivo antiptotic/diuretic or antiptotic/antidiarrheal potency ratios both reflected the known alpha 2/alpha 1-selectivity of the compounds tested and were significantly correlated with the in vitro potency ratios between inhibition of [3H]WB4101 binding on one hand and of [3H]clonidine or [3H]idazoxan binding on the other. The reliability of the above models for measuring alpha 1- and alpha 2-adrenoceptor agonistic activity and selectivity is discussed.