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Biomedical subjects

E Ongini

Publications and source records attributed to E Ongini.

At least 91 records · Page 5Linked to original sources
PubMed1991

The neutral endopeptidase-24.11 (enkephalinase) inhibitor, SCH 32615, increases dopamine metabolism in the nucleus accumbens of the rat.

SCH 32615 is a novel inhibitor of the enzyme, neutral endopeptidase (NEP, E.C. 3.4.24.11), the so called 'enkephalinase', which plays a functional role in the degradation of [Met5]- and [Leu5]enkephalin. The present study was designed to assess whether SCH 32615 is able to modify the activity of dopaminergic neurons as reflected by changes in the content of the major dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), in three different areas of the rat brain: the nucleus accumbens, the striatum, and the prefrontal cortex. When administered at analgesically active doses (1-100 mg/kg s.c., 60 min before killing), SCH 32615 induced a dose-dependent increase in dopamine metabolism in the nucleus accumbens but was ineffective in the striatum and in the prefrontal cortex. This effect appears to be mediated via opioid receptors, since it was completely prevented by naloxone (5 mg/kg s.c.). The increase in DOPAC content in the prefrontal cortex elicited by foot-shock was unaffected by pretreatment with SCH 32615. In the nucleus accumbens, dopamine metabolism was increased to the same extent by foot-shock and SCH 32615 administered separately, but these effects were not additive, suggesting that SCH 32615 and foot-shock act via a common mechanism. Taken together, these results support the hypothesis that inhibition of the in vivo degradation of enkephalins induced by the systemic administration of SCH 32615 increases the enkephalinergic tone in the central nervous system and thereby activates the mesolimbic dopaminergic neurons.

Animals↗
PubMed1991

The dopamine D1 receptor is involved in the regulation of REM sleep in the rat.

The dopamine D1 receptor agonist, SKF 38393, and the D1 antagonist, SCH 23390, were studied for their effects on sleep in the rat. Over 6 h, SKF 38393 (0.1-10 mg/kg s.c.) dose dependently reduced the amount of rapid eye movement (REM) sleep and enhanced the duration of wakefulness. The drug affected REM at low doses (ED50 = 0.4 mg/kg) at which wakefulness was unchanged and the characteristic grooming behavior was not apparent. REM changes were characterized by a decrease in the number of episodes with no alteration of latency to the first episode. Over a very low dose range (0.003-0.3 mg/kg s.c.), SCH 23390 enhanced the amount of REM by increasing both number and average duration of episodes. There was also a moderate increase of non-REM sleep but the percent change was less marked than that occurring for REM. Given at 0.003 mg/kg, SCH 23390 prevented the REM changes induced by SKF 38393 (0.3-3 mg/kg). It is suggested that D1 receptors are involved in the regulation of the REM sleep process.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

The neutral endopeptidase-24.11 inhibitor SCH 34826 does not change opioid binding but reduces D1 dopamine receptors in rat brain.

The effect of repeated administration of the neutral endopeptidase-24.11 (NEP) inhibitor SCH 34826 on the kinetic properties of opioid and dopamine binding in the rat cerebral cortex and striatum was investigated. SCH 34826, given at 100 and 300 mg/kg orally twice a day for 14 days, did not alter either Bmax or Kd for the mu, delta, or kappa opioid receptor type in the cortex, as measured by studying binding parameters for the mu-selective ligand [3H][D-Ala2, Me-Phe4,Gly(ol)5]enkephalin (DAGO), the delta-selective ligand [3H][D-Pen2,D-Pen5]enkephalin (DPDPE) and the kappa ligand [3H]ethylketazocine (EKC). SCH 34826 reduced significantly the number of D1 dopamine receptors labeled with [3H]SCH 23390 in the striatum (Bmax was 90 and 84% of controls at 100 and 300 mg/kg, respectively). The number of D2 receptors, measured by [3H]spiperone binding was unaltered. The Kd values for both receptor types were not affected. The data demonstrate that chronic inhibition of enkephalin degradation by SCH 34826 does not alter opioid receptors, whereas it reduces the number of D1 receptors. These findings provide further support for the role of opioids in modulating central dopaminergic systems. As a reduction in the number of D1 receptors is an effect common to antidepressant treatments, the antidepressant potential of NEP inhibitors should be investigated.

Analgesics↗
PubMed1991

Simple measurement of isepamicin, a new aminoglycoside antibiotic, in guinea pig and human plasma, using high-performance liquid chromatography with ultraviolet detection.

Isepamicin, the 1-N-(S-alpha-hydroxy-beta-aminopropionyl) derivative of gentamicin B, is a new aminoglycoside antibiotic, which not only has most of the properties of amikacin but also is effective against several amikacin-resistant strains of bacteria. The drug was assayed in guinea-pig and human plasma with a high-performance liquid chromatographic procedure using precolumn derivatization with 1-fluoro-2,4-dinitrobenzene and ultraviolet detection. Linearity was established over the range 0.5-40 micrograms/ml using 50 microliters of plasma. Accuracy has a mean relative error of less than 3% and precision a mean coefficient of variation of 5%. Isepamicin was determined without interference from plasma constituents or other drugs commonly prescribed during aminoglycoside therapy. This procedure correlates well with radioimmunoassay and can be used either in experimental studies or therapeutic monitoring of plasma levels.

Animals↗
PubMed1991

Effects of selected beta-adrenergic blocking agents on sleep stages in spontaneously hypertensive rats.

The effects on sleep of six beta-adrenergic blockers (propranolol, dilevalol, pindolol, metoprolol, celiprolol and atenolol) which differ in their pharmacological characteristics were studied in spontaneously hypertensive rats. Electroencephalographic activity was recorded for 6 hr after p.o. administration of drugs or vehicle, and the stages of wakefulness, rapid eye movements (REM) sleep and non-REM sleep (non-REM) were classified thereafter. In separate experiments antihypertensive activity of each drug was assessed by the tail-cuff technique. The most common effect of the beta-blockers examined was a decrease of the duration of REM. The effect was marked for propranolol (10-100 mg/kg), celiprolol (10-100 mg/kg) and pindolol (1-10 mg/kg), whereas it occurred at low doses, but not at high doses for metoprolol (10 mg/kg) and atenolol (3 and 10 mg/kg). Dilevalol induced a moderate REM decrease at 30 mg/kg only. For the beta-1 antagonists, the dose reducing REM substantially (ED30) was slightly above (1.4- to 3.7-fold) that effective on blood pressure (ED10), whereas the separation was high for pindolol (17.4-fold) and dilevalol (22.4-fold). Conversely, propranolol displayed a weak antihypertensive activity in this model and was more potent on REM than in reducing blood pressure. Propranolol, celiprolol and atenolol also increased duration of wakefulness. Considering the pharmacological characteristics of the beta-blockers examined, it is suggested that selective beta-1 antagonism and interaction with other neurotransmitters, such as serotonin, are relevant to the potential effects of this class of antihypertensive drugs on sleep function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1990

Role of 5-HT2 receptors in serotonin-induced contraction in the human mammary artery.

We studied the effects of serotonin (5-HT) on isolated human mammary arteries obtained from patients undergoing coronary by-pass grafting. 5-HT induced a concentration-dependent contractile response in the mammary artery, with an EC50 value of 0.34 microM. The 5-HT2 antagonist, ketanserin, reversed the contractions evoked by 5-HT in a competitive manner at a low concentration (10(-8) M), whereas non-competitive antagonism was apparent at higher concentrations (5 X 10(-8)-5 X 10(-7) M). To investigate whether the alpha 1-blocking component of ketanserin plays a role in the response observed in this vessel, we evaluated the effect of ketanserin on contractions induced by (-)-norepinephrine. Ketanserin, in concentrations up to 10(-7) M, did not influence the norepinephrine-induced contractions. Moreover, a threshold concentration of 5-HT (10(-7) M) amplified the contractile effect induced by norepinephrine (5 X 10(-8) M), and this response was inhibited by ketanserin (10(-7) M). The selective 5-HT3 antagonist, GR 38032F, did not affect the 5-HT-induced contractions. These findings indicate that the human mammary artery is a vascular tissue sensitive to 5-HT. The 5-HT2 receptor subtype appears to mediate the response.

Female↗
PubMed1990

5-Hydroxytryptamine induces contraction in isolated human mammary artery: effect of ketanserin.

5-hydroxytryptamine (5HT) treatment produced dose-related contractions in the human internal mammary artery with an EC50 value of 3.4 X 10(-7) M. The 5HT2 receptor antagonist ketanserin reversed the contractions evoked by 5HT in a competitive manner at a low concentration (10(-8) M), whereas a noncompetitive antagonism was apparent at higher concentrations (5 X 10(-8) M to 5 X 10(-7) M). The alpha 1-blocking component of ketanserin was evaluated by studying the effect of ketanserin upon the contractile response evoked by norepinephrine. Up to 10(-7) M, ketanserin did not influence norepinephrine-induced contractions. These findings indicate that the mammary artery is a vascular tissue sensitive to contractions induced by 5HT and that the drug ketanserin antagonizes this contractile response through the 5HT2 receptor subtype.

Female↗
PubMed1990

Effects of the enkephalinase inhibitor SCH 34826 on the sleep-waking cycle and EEG activity in the rat.

The sedative effect of SCH 34826, an enkephalinase inhibitor, was evaluated by studying electroencephalographic (EEG) activity, behaviour and the sleep-waking cycle in the rat. The reference opioid, morphine, was used for comparison. After administration of morphine (10 mg/kg s.c.) the rats were motionless and stuporous at first and then hyperactive. An increase of slow wave sleep, at the expense of both wakefulness and REM sleep was recorded, with high-amplitude slow wave bursts appearing in the EEG tracings during the waking, albeit stuporous, phase. Relative spectral power in the 1-4 and 12-16 Hz bands was increased and there was a shift of the dominant frequency to a lower frequency. The specific opioid antagonist, naltrexone, readily reversed most of these effects. The drug SCH 34826 (10-100 mg/kg p.o.) had no effect on the parameters examined; large doses (300 and 1000 mg/kg p.o.) induced restlessness in some animals, resulting in increased waking. This effect was antagonized by naltrexone. The data indicate that SCH 34826, at doses far greater than those proposed for clinical use, is devoid of sedative liability and does not induce any of the behavioural or EEG effects typical of morphine.

Animals↗
PubMed1990

The D1 dopamine receptor antagonist SCH 23390 enhances REM sleep in the rat.

The effect of the D1 dopamine receptor antagonist SCH 23390 on sleep patterns was studied in rats by means of the electroencephalographic (EEG) technique. Haloperidol, an established D2 antagonist neuroleptic, was used for comparison. Over a very small dose range (0.003-0.03 mg/kg, subcutaneously), SCH 23390 significantly increased the time spent in total sleep, including rapid eye movement (REM) and non-REM sleep. The magnitude of the overall change of REM sleep was considerably greater than that of non-REM sleep. Enhancement of the amount of REM was characterized by increase in number of episodes but no change of latency to the first period of REM. Haloperidol increased non-REM sleep at 0.3-3 mg/kg, orally, but did not affect other measures of REM. Considering the small dose range at which SCH 23390 was effective, and the fact that REM and non-REM sleep may be unrelated events, it is suggested that promotion of REM sleep is a specific effect induced by selective blockade of D1 receptors.

Animals↗
PubMed1990

Aminoglycoside dosing regimen and pharmacokinetic parameters in the guinea pig.

To complement a study on aminoglycoside dosing regimen and ototoxicity in the guinea pig, we designed an experiment to examine: (1) the effect of dosing regimen on guinea pig pharmacokinetic parameters, and (2) possible differential accumulation after repeated intramuscular administrations of netilmicin and amikacin (150 mg/kg/day) for 7 days by 1 or 3 daily injections. The area under the curve (AUC infinity) and the maximum plasma concentration (Cmax) were dose-dependent. Within each regimen, no significant difference was observed between days 1 and 7. Little or no accumulation was observed after 21 days of treatment. The results show a good dose-dependence of AUC infinity and Cmax and are in accordance with data from human studies. Moreover, the fact that no accumulation occurred in the guinea pig suggests that it is a suitable animal model to evaluate the relation between aminoglycoside ototoxicity and dosing regimen.

Amikacin↗
PubMed1990

Relation of dosing regimen to aminoglycoside ototoxicity: evaluation of auditory damage in the guinea pig.

Groups of guinea pigs were injected intramuscularly for 21 days with netilmicin or amikacin 150 mg/kg/day by one or three daily injections. Amikacin was also tested at 225 mg/kg/day with each dosing regimen. Auditory function was evaluated during the experiment by reflexological and electrophysiological tests. Morphological damage to the inner ear was also evaluated. Netilmicin had no effect on the auditory function nor did it damage the organ of Corti. Conversely, amikacin impaired the auditory function and produced loss of hair cells in a dose-related manner. The effect was equally marked with both dosing regimens of 225 mg/kg/day, whereas a slight decrease of auditory impairment was observed with 150 mg/kg administered once a day. The data suggest that administration of a single daily dose of aminoglycosides does not increase the risk of ototoxicity specifically associated with each compound.

Amikacin↗
PubMed1989

Functional coupling of GABAA receptors and benzodiazepine recognition site subtypes in the spinal cord of the rat.

The interaction between GABAA receptors and benzodiazepine (BZD) recognition site subtypes in the spinal cord of the rat was investigated. Computer analysis of displacement curves for [3H]flunitrazepam [( 3H]FNT) binding by 2-oxo-quazepam (2OXOQ) indicated the presence of two subtypes of BZD recognition sites in this region. Type I sites accounted for approximately 25% of the total number of BZD recognition sites, the remainder being Type II sites. A similar proportion of Type I and Type II sites was obtained by Scatchard analysis of the saturation curves for [3H]FNT, [3H]2OXOQ and [3H]ethyl-beta-carboline-3-carboxylate [( 3H]beta CCE) binding. The in vitro addition of GABA (10(-8)-10(-4) M) to spinal cord membrane preparations produced an increase in the binding of [3H]FNT and [3H]2OXOQ. The maximal enhancement produced by GABA was 50 and 82% above control values for [3H]FNT and [3H]2OXOQ, respectively. In contrast, GABA stimulated both [3H]FNT and [3H]2OXOQ binding in the cerebellum to a similar extent. We also evaluated the effects of different ligands for BZD recognition sites on the binding of [3H]GABA to spinal cord membranes, as compared with brain areas containing a higher proportion ( greater than 30%) of Type I sites. Diazepam, quazepam and the beta-carboline, ZK 93423, enhanced the specific binding of [3H]GABA in a concentration-dependent manner (10(-7)-10(-5) M) in the cerebral cortex and hippocampus but not in the spinal cord and cerebellum. These results indicate that there is a regional variation in the interaction between GABA and BZD recognition sites in the central nervous system.

Animals↗
PubMed1989

Binding sites for [3H]2-oxo-quazepam in the brain of the cat: evidence for heterogeneity of benzodiazepine recognition sites.

In the present study, the distribution of benzodiazepine recognition site subtypes in the brain of the cat was investigated. To this aim, the binding properties of [3H]2-oxo-quazepam ([3H]2OXOQ) and [3H]beta-CCE, two ligands with preferential affinity for Type I benzodiazepine recognition sites, were compared to binding parameters for [3H]flunitrazepam ([3H]FNT) in different areas of the cat brain. The ratio of [3H]2OXOQ to [3H]FNT binding sites indicated that, in the cerebellum, Type I sites accounted for 90% of the total number of benzodiazepine recognition sites. The cerebral cortex, thalamus and mesencephalic reticular formation had also a high proportion of Type I sites (73-78%), whilst the two subtypes were almost equally distributed in the hippocampus, amygdala and bulbar reticular formation. A similar distribution of subtypes of benzodiazepine recognition sites was indicated by the ratio of [3H]beta CCE to [3H]FNT binding sites for different areas of the brain. These results demonstrate the existence of heterogeneity of recognition sites for benzodiazepines in the brain of the cat and support the view that [3H]2OXOQ preferentially labels Type I sites.

Animals↗
PubMed1989

Effects of nonsedating histamine H1-antagonists on EEG activity and behavior in the cat.

The central effects of the newly-developed antihistamines (H1-receptor antagonists) loratadine, astemizole, mequitazine and terfenadine were evaluated by studying brain electrical activity (EEG), sleep-waking patterns and behavior in the cat. The different stages of the sleep-waking cycle, i.e., wakefulness (W), spindle sleep (SS), slow wave sleep (SWS) and REM sleep (REM) were evaluated. The power spectrum analysis of the EEG was obtained by a computerized technique. For comparison, the sedating agent diphenhydramine was examined. Given at 3 mg/kg orally, a dose slightly above that effective therapeutically, diphenhydramine markedly affected behavior and all sleep stages. In particular, it depressed REM and increased SS (drowsiness). The EEG showed occasional spikes typical of subconvulsive states. Loratadine did not modify either sleep patterns or behavior over the 3-30 mg/kg dose range orally, which is far above that used clinically. The EEG, evaluated either visually or by spectral power analysis, was unaffected. Astemizole at 10 and 30 mg/kg PO reduced REM, markedly altered behavior at 30 mg/kg, but did not modify EEG activity. Mequitazine, at low doses (1-10 mg/kg PO), enhanced SS and decreased SWS and REM. Like diphenhydramine, mequitazine induced EEG changes typical of subconvulsive states and affected EEG power over the frequency range of 0.1-15.0 Hz. Terfenadine did not change sleep patterns and slightly affected behavior only at the high dose of 30 mg/kg orally; EEG activity was not influenced. These data show that: a) diphenhydramine and mequitazine appear to produce CNS effects by altering basic processes within the brain; b) astemizole and terfenadine seem to cross the blood-brain barrier at high doses only; c) loratadine has the lowest liability to produce central side effects. Of the sleep features examined, REM appeared to be the most sensitive stage to blockade of central H1-receptor pathways.

Animals↗
PubMed1989

Interaction of selected vasodilating beta-blockers with adrenergic receptors in human cardiovascular tissues.

beta- And alpha 1-adrenoceptor antagonist properties of bufuralol, carvedilol, celiprolol, dilevalol, labetalol, and pindolol were investigated in human myocardium and mammary artery using binding techniques and functional studies. In myocardial membranes, beta-adrenoceptor antagonists showed monophasic competition isotherms for [125I]pindolol binding with high affinity (Ki from 1-100 nM), except for celiprolol which displayed a biphasic competition isotherm (pKi = 6.4 +/- 0.06 for beta 1- and 4.8 +/- 0.07 for beta 2-adrenoceptors). Drug interactions with alpha 1-adrenoceptors were evaluated in human mammary artery by [3H]prazosin binding and by measuring contractile responses to norepinephrine (NE). Labetalol and carvedilol showed a moderate affinity for alpha 1-adrenoceptors (pKi = 6.2 +/- 0.01 and 6.1 +/- 0.06, respectively), and inhibited NE-induced contractions (pA2 = 6.93 +/- 0.23 and 8.64 +/- 0.24, respectively). Dilevalol, bufuralol, and pindolol displayed weak effect both in binding (Ki in micromolar range) and functional experiments (pA2 = 5.98, 5.54, and 6.23, respectively). Celiprolol did not show antagonist properties up to 100 microM in functional studies, but displayed a slight affinity for alpha 1-adrenoceptors in binding studies. The data indicate that the vasodilating activity of these beta-adrenoceptor antagonists is caused in some instances by an alpha 1-adrenoceptor antagonism (labetalol, carvedilol), whereas for the others alternative mechanisms should be considered.

Adrenergic beta-Antagonists↗
PubMed1988

High-performance liquid chromatographic determination of netilmicin in guinea-pig and human serum by fluorodinitrobenzene derivatization with spectrophotometric detection.

A high-performance liquid chromatographic procedure for netilmicin determination in guinea-pig and human serum using pre-column derivatization with 1-fluoro-2,4-dinitrobenzene and UV detection is described. Linearity was established over the range 0.5-40 micrograms/ml using only 50 microliters of serum. Accuracy and precision were good, with a mean coefficient of variation less than 5% and a mean relative error less than 4%. This procedure correlates well with an enzyme multiplied immunoassay technique and has a sensitivity similar to those of published fluorescence derivatization methods.

Animals↗