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Biomedical subjects

L C Iorio

Publications and source records attributed to L C Iorio.

At least 37 records · Page 2Linked to original sources
PubMed1984

Selective affinity of 1-N-trifluoroethyl benzodiazepines for cerebellar type 1 receptor sites.

In binding studies with rat brain membranes, 1,4-benzodiazepines containing a trifluoroethyl moeity at the 1-N position, including halazepam and quazepam, had significantly higher affinities for binding sites in cerebellum than in cortex. This selectivity for cerebellar sites is not a property of benzodiazepines without the trifluoroethyl moiety, but is similar to that seen with the triazolopyridazines. Since halazepam and quazepam, like the triazolopyridazines, have behavioral effects in animals at doses much lower than those that cause ataxia, it is tempting to attribute this separation of pharmacologic activities to differential activity at subpopulations of benzodiazepine receptors. Further work is necessary to clarify this possibility.

Animals↗
PubMed1984

Evaluation of the CNS properties of SCH 29851, a potential non-sedating antihistamine.

SCH 29851 [8-chloro[6,11-dihydro-11-(1-carboethoxy-4-piperidylidene)- 5-H-benzo [5,6]cyclohepta[1,2-b]-pyridine] was discovered as part of a search for a new antihistamine without effects on the central nervous system (CHS). Antihistaminic potency and duration of action of SCH 29851 and other antihistamines were assessed by inhibition of histamine-induced lethality in guinea pigs and histamine-induced paw edema in mice. Evaluation of possible CNS effects included gross observation of mice, rats, dogs and monkeys, prevention of electroshock-induced convulsions, acetic acid-induced writhing and physostigmine-induced lethality in mice and biochemical measures related to sedative liability such as displacement of in vivo 3H-mepyramine binding in mouse brain and in vitro 3H-WB 4101 binding in guinea pig cortex. Comparisons were made to several antihistamines considered to be sedative to varying degrees, including diphenhydramine, promethazine, chlorpheniramine and azatadine and to the newer antihistamines terfenadine and astemizole which are reported to be non-sedating in man at doses that antagonize the effects of histamine peripherally. SCH 29851 had antihistamine activity in the tests used with a potency at least comparable to most standards and was devoid of activity in all the functional and biochemical models used as indices of CNS activity. It is expected that SCH 29851 should be an effective, long acting, antihistamine in man without sedative effects at therapeutic doses.

Animals↗
PubMed1983

Effects of selected drugs on spontaneously occurring abnormal behavior in beagles.

A sub-population of beagles with abnormal behavioral patterns has been identified, isolated and tested for responsively to selected classes of psychoactive drugs. The abnormal behavior was ameliorated by anxiolytics and antidepressants but not by antipsychotics, an antihistaminic, an alpha-adrenergic blocker, a beta-adrenergic blocker, or an anticholinergic drug. Improvement occurred after a single dose of the anxiolytic drugs but did not occur until 10-18 days after daily dosing with standard tricylic antidepressants and the MAO inhibitor isocarboxazid. This delayed onset in beagles resembles that seen on use of these drugs in humans. The results with these drugs suggest that the abnormal behaviors of the beagles are related to anxiety and are in part depressive in nature. This colony provides an animal model of abnormal behavior which allows evaluation of the anxiolytic and antidepressant effects of drugs and estimates of the onset of action of antidepressant drugs.

Amobarbital↗
PubMed1983

Determination of analgesic drug efficacies by modification of the Randall and Selitto rat yeast paw test.

This report describes a modified Randall and Selitto (1957) rat yeast paw test that can evaluate differences in efficacy of different analgesics. The modifications consist of a decrease in the rate of acceleration of the noxious stimulus (mechanical pressure) on the inflamed paw from 20 to 12.5 mmHg/sec and an extension of the cut-off time from 15 to 60 sec. All the narcoticlike drugs tested (morphine, codeine, and pentazocine) increased the response latencies of the inflamed paws to the cut-off time. The nonsteroidal antiinflammatory-like drugs tested (acetylsalicylic acid, acetaminophen, indomethacin, phenylbutazone, and proquazone) showed plateaus in their analgesic effects (i.e., increasing the dose failed to produce significantly greater increases in the response latencies compared to the next lower dose). Zomepirac (80-240 mg/kg p.o.) did not show this plateau effect, but was unable to increase response latencies to greater than 30 sec because of the toxicity of higher doses (320 mg/kg p.o.). Flunixin NMG (the meglumine salt of flunixin), a nonnarcotic analgesic, did not display a plateau effect and increased response latencies to maximum values. The methodology was therefore able to discriminate analgesics active against mild to severe clinical pain (narcoticlike) from those only useful against mild to moderate pain (nonnarcotic-like).

Analgesics↗
PubMed1983

SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems.

SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) possesses pharmacologic effects similar to standard antipsychotics, including selective supression of conditioned avoidance responding in rats and squirrel monkeys, blockade of apomorphine-induced stereotypy in rats and blockade of methamphetamine-induced lethality in aggregated mice. At effective doses in these tests, no changes in gross behavior, neurological or autonomic function were observed. In contrast to the standards tested, SCH 23390 blocked dopamine-stimulated adenylate cyclase at concentrations (IC50 = 0.01 microM) about 2000 times lower than those needed to block spiperone binding (IC50 = 24 microM). This suggests specific D1-receptor antagonism. Inability of SCH 23390 to cause hyperprolactinemia, considered to be a D2-receptor effect, is consistent with this hypothesis. SCH 23390 showed lower increases in dopamine turnover suggesting that the blockade of SCH 23390 may be more specific for post- than presynaptic sites. Additional evidence for the selectivity of SCH 23390 among putative postsynaptic dopamine sites includes its lack of effect on apomorphine-induced hypothermia or emesis. Based on these results, it is postulated that SCH 23390 is a selective D1-receptor antagonist.

Animals↗
PubMed1982

Potentiation of [D-ala2]enkephalinamide analgesia in rats by thiorphan.

The effect of thiorphan, an inhibitor of enkephalin dipeptidyl carboxypeptidase, was tested in the rat tail-flick test. When given alone up to 100 mg/kg s.c., thiorphan had no effect. However, thiorphan (30 mg/kg, s.c.) potentiated intraventricularly administered [D-Ala2,Met5]enkephalinamide (DEAEM) and its [Leu5]-derivative, whereas it had no effect on [D-Ala2,Met5]enkephalin, [D-Met2,Pro5]enkephalinamide, or morphine. Potentiation of DAEAM by thiorphan was dose-responsive and naloxone reversible. The most efficient enhancement of the analgesic effects of DAEAM was seen when the two drugs were co-administrated in rapid succession. Thus, thiorphan potentiation of opioid-peptide induced analgesia in the rat is similar to that seen in the mouse.

Amino Acids, Sulfur↗
PubMed1982

Role of serotonin in the blockade of muricidal behavior by tricyclic antidepressants.

Dose-response curves for the ability of three tricyclic antidepressants, imipramine, desmethylimipramine and amitriptyline to inhibit muricidal behavior were measured after treatment with a tryptophan-free diet and after administration of p-chloroamphetamine. Both treatments, which have been reported to specifically reduce central levels of serotonin, decreased the ability of the drugs to inhibit muricide. The results suggest that all three antidepressants block muricide in part through their effects on serotonin.

Aggression↗
PubMed1982

The sedative-hypnotic properties of quazepam, a new hypnotic agent.

7-Chloro-1-(2,2,2-trifluoroethyl)-5-(o-fluorophenyl)-1,3-dihydro-2H-1, 4-benzodiazepine-2-thione (Sch 16134, quazepam) is a new hypnotic drug with demonstrated clinical efficacy. Quazepam has been shown in our laboratories to have potent hypnotic activity and fewer side effects at effective doses than flurazepam, which was studied concurrently. Hypnotic potency was estimated in mice via antagonism of electroshock-induced convulsions (ECS), potentiation of hexobarbital-induced sleeping time, and chlorprothixene potentiation. The respective oral ED50's (95% fiducial limits) in the 3 tests were 0.9 (0.4-2.0), 0.5 (0.3-0.8) and 0.05 (0.02-0.08) mg/kg for quazepam and 1.6 (1.1-2.3), 0.6 (0.4-1.0) and 0.11 (0.07-0.42) mg/kg for flurazepam. The duration of action of quazepam as measured by antagonism of ECS in mice was similar to that of flurazepam at equi-effective doses but quazepam had a faster onset. When potential tolerance to hypnotic efficacy was studied, quazepam did not show tolerance after dosing 20 mg/kg p.o. twice daily (b.i.d.) for 5 days, whereas tolerance was seen with flurazepam at equi-effective doses b.i.d. for 5 days. In conscious, unrestrained squirrel monkeys and cats, quazepam produced sedation with less ataxia and less evidence of CNS stimulant action than flurazepam. On the basis of the aforementioned studies, quazepam should be an effective hypnotic with less potential for ataxia, paradoxical excitation, and tolerance than flurazepam.

Animals↗
PubMed1982

Pharmacological studies with quazepam, a new benzodiazepine hypnotic.

7-Chloro-1-(2,2,2-trifluoroethyl)-5-(o-fluorophenyl)-1, 3-dihydro-2H-1,4-benzodiazepine-2-thione (Sch 16134, quazepam) demonstrated high safety and effective hypnotic properties. Toxicity of quazepam in mice was extremely low at the largest doses administered of 5000 mg/kg p.o. and 1370 mg/kg i.p. as compared to LD50 values for flurazepam of 756 (635-889) mg/kg p.o. and 254 (234-280) mg/kg i.p. In cats, quazepam did not produce overt toxicity even at the highest dose administered, 1000 mg/kg p.o., whereas death occurred after the administration of flurazepam at a median dose of 250 mg/kg p.o. In addition, flurazepam produced central excitation and convulsions. Quazepam did not affect hemodynamic parameters in conscious dogs and anesthetized cats. Autonomic functions were virtually unaffected by the drug in anesthetized cats. In interaction studies in mice, quazepam did not interact with cimetidine while it potentiated the sedative activity of alpha-methyldopa, ethanol and propranolol. The CNS depressant properties of quazepam were further investigated by studying its effects on spontaneous motor activity in mice and EEG pattern in immobilized cats. In mice, quazepam reduced locomotor activity at doses which did not impair motor coordination thus differing from flurazepam which did. In the EEG study, quazepam produced a slow wave EEG pattern comparable to that of physiological sleep, while flurazepam induced a similar EEG activity which alternated with a fast frequency pattern of moderate amplitude. Quazepam also showed potent anticonvulsant activity. These results suggest that quazepam is likely to be a safe and effective sleep-promoting agent.

Animals↗
PubMed1981

Sleep-inducing effects of three hypnotics in a new model of insomnia in rats.

Sleep-inducing effects of hypnotic drugs are difficult to demonstrate in rats because of high baseline sleep times. Most increases in slow wave sleep (SWS) following the administration of hypnotics have been found to be at the expense of REM sleep rather than waking. In the first experiment we found that rats chronically implanted with electrodes for recording ECoG and EMG slept significantly less during the first two hours of the dark period when housed under 16-hr light 8-hr dark (16L/8D) than when housed under 12L/12D conditions. The second experiment examined the effects of flurazepam, phenobarbital and thalidomide administered orally at the onset of the two-hour period of increased waking resulting from the 16L/8D lighting. All three drugs caused dose-dependent reductions in waking and increases in SWS with no alterations in REM% of total sleep time. Sleep onset latency was also significantly was also significantly reduced by all three drugs. As in man, flurazepam was the most potent, and thalidomide was the least potent of the hypnotics in rats.

Animals↗
PubMed1980

Protection from shock-induced seizures as a measure of hypnotic potency of drugs.

Mice injected with drug or vehicle were administered a 13 mA shock via corneal electrodes. The number of mice in which the shock produced a tonic seizure was recorded. The dose that blocked seizures in 50% of mice (ED50) was determined for each drug. The drugs evaluated consisted of 15 hypnotics, two antidepressants and two antihistamines. All hypnotics and antidepressants, and one antihistamine, caused a dose-dependent suppression of seizures. The ED50's were highly correlated with hypnotic potency in man. The advantages of this procedure, as compared to others currently used for the evaluation of hypnotic potential of novel compounds, are discussed.

Animals↗
PubMed1980

Blockade by l-lysine of non-narcotic analgesics.

The antinociceptive effects of the non-narcotic analgesics clonixin, flunixin, acetylsalicylic acid, aminopyrine and phenylbutazone in the yeast paw test were blocked by l-lysine. Blockade occurred at doses of l-lysine which did not affect pain threshold. The site(s) or mechanism of action of blockade could not be determined with certainty. It appears unlikely that l-lysine prevented the analgesics from getting to active sites since plasma or brain levels of flunixin were not altered for up to 2 hr after drug administration and binding of flunixin to plasma protein was not affected. Blockade by l-lysine appears to occur at least in part at a peripheral site since it was not blockade by l-arginine or l-ornithine which compete for a common transport system with l-lysine and, hence, would have reduced the effect of l-lysine if its actions were central. However, blockade within the central nervous system cannot be ruled out. Antagonism by l-lysine does not seem to involve endogenous serotonin since it was not reversed by the serotonin precursor, 5-hydroxytryptophan, or by fluoxetine, a specific blocker of serotonin uptake. In contrast to the block of non-narcotic analgesics, l-lysine potentiated the antinociceptive effects of morphine.

Aminopyrine↗
PubMed1979

Benzodiazepine blockade of passive-avoidance task in mice: a state-dependent phenomenon.

Four benzodiazepines (diazepam, chlordiazepoxide, halazepam, lorazepam) were tested for their effects on the acquisition of a passive-avoidance task in mice. This was done to determine whether amnesic effects, as reported in humans after diazepam and lorazepam, could be demonstrated by blockade of passive-avoidance responding in mice and, if so, to investigate the possible causes of the blockade by studying the relationships between the blockade and times of drug administration. Each of these benzodiazepines, at doses that did not alter overt behavior, blocked acquisition of the passive-avoidance response when they were administered to mice prior to the training session, but not when they were administered after the training session or prior to testing 24 h later. The block of avoidance responding was reversed, however, when the drugs were administered prior to both training and test sessions. These results suggest that state-dependent learning occurred; i.e., apparent amnesia occurred in the test session with untreated mice that had undergone passive-avoidance learning 24 h earlier under the influence of drug.

Animals↗