Biomedical subjects

L Dazzi

Publications and source records attributed to L Dazzi.

At least 37 records · Page 2Linked to original sources

PubMed1997

Testing for occult cancer in patients with idiopathic deep vein thrombosis--a decision analysis.

OBJECTIVE: To determine the effectiveness and cost-effectiveness of testing for occult cancer in idiopathic deep vein thrombosis (IDVT). DESIGN: Threshold analysis was performed on the risk-adjusted cancer prevalence in a cost-effectiveness model of ideal testing for selecting cancers with potentially desirable utility (candidate cancers). Decision analysis was employed to compare different testing programs for candidate cancers with that of no testing. Life expectancy (LE) of early- and late-detected cancers and costs of testing were the dimensions of utility. Cost-effectiveness was expressed as marginal cost per year of life saved. The perspective of the third payer was adopted, and a discount rate of 3% was applied to both costs and benefits. DATA SOURCES: Risk of cancer in IDVT, testing policies, test characteristics, and LE were gathered from literature. Costs were provided from our hospital rate book and accounting service. RESULTS: Ideal testing would support a gain of LE of 40 days or more for prostate, colon and bladder cancer in males and for colon, breast and endometrium cancer in females aged from 60 to 69 years. Testing females with colonoscopy and mammography in any sequence provides 70 days of life gained. Testing males with colonoscopy provides 27 days of life gained. Lower and older ages reduce testing effectiveness. The qualitative results are stable over plausible ranges of test characteristics, while variations in the value of benefit for early cancer diagnosis may modify the strategy. Incremental cost-effectiveness ranges from $1,789 to $ 6,979 per year of life gained. CONCLUSIONS: According to the effectiveness criterion adopted, the only worthwhile investigation strategy includes colon and breast cancer in females. Testing for colon cancer in males is desirable at a lower criterion of effectiveness. All the strategies are cost effective.

Aged↗

PubMed1996

Inhibition by the neurosteroid allopregnanolone of basal and stress-induced acetylcholine release in the brain of freely moving rats.

The neurosteroid allopregnanolone is a potent and efficacious modulator of gamma-aminobutyric acid (GABA) type A receptors. The effects of intracerebroventricular injection of allopregnanolone (5 to 15 micrograms/5 microliters) on basal and stress-induced release of acetylcholine were investigated in various regions of the brain areas of freely moving rats and compared with those of the benzodiazepine midazolam (1 to 10 micrograms/5 microliters). Allopregnanolone inhibited (20-55%) basal acetylcholine release from the prefrontal cortex and hippocampus, but not from the striatum, in a dose-dependent manner. At a dose of 10 micrograms, allopregnanolone also completely prevented the increase in hippocampal acetylcholine release induced by foot-shock stress. Midazolam, inhibited basal acetylcholine release in all three brain regions as well as stress-induced acetylcholine release in the hippocampus, and showed a greater potency in these effects than allopregnanolone. These results suggest that endogenous neurosteroids may participate in the GABAergic modulation of central cholinergic function during basal conditions as well as after stress.

Acetylcholine↗

PubMed1995

Enhancement of acetylcholine release by flumazenil in the hippocampus of rats chronically treated with diazepam but not with imidazenil or abecarnil.

The effects of long-term treatment (three times a day for 3 weeks) with pharmacologically active doses of the novel anxiolytics and anticovulsants abecarnil (0.5 mg/kg, IP) and imidazenil (0.5 mg/kg, IP) on basal hippocampal acetylcholine release in freely moving rats were compared with those of diazepam (3 mg/kg, IP). Challenge doses of diazepam, abecarnil, and imidazenil decreased the extracellular acetyl-choline concentration in the hippocampus by the same extent in animals chronically treated with the respective drug or vehicle. Moreover, the abrupt discontinuation of long-term treatment with diazepam, abecarnil, or imidazenil failed to affect hippocampal acetylcholine release during the first 5 days of withdrawal. In contrast, the acute administration of the benzodiazepine receptor antagonist flumazenil (1 mg/kg, IP) 2 days after diazepam withdrawal elicited a marked increase (65%) in acetylcholine release in the hippocampus. Flumazenil failed to induce the same effect 5 days after diazepam withdrawal or 2 or 5 days after discontinuation of long-term treatment with abecarnil or imidazenil. These results indicate that (i) the inhibitory effects of full (diazepam), partial (imidazenil), and selective (abecarnil) benzodiazepine receptor agonists on acetylcholine output in rat hippocampus are not affected by repeated drug administration; (ii) discontinuation of long-term treatment with each type of agonist does not affect hippocampal cholinergic mechanisms; and (iii) flumazenil increases acetylcholine release only in the hippocampus of rats chronically treated with diazepam. Together, these data further differentiate the pharmacology of benzodiazepine receptor full agonists from that of partial and selective agonists.

Acetylcholine↗

PubMed1995

Modulation of basal and stress-induced release of acetylcholine and dopamine in rat brain by abecarnil and imidazenil, two anxioselective gamma-aminobutyric acidA receptor modulators.

The effects of imidazenil (6-(2-bromophenyl)-8-fluoro-4-H-imidazo[1-5-a][1-4]benzodiazepine-3- carboxamide) and abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), new partial and selective benzodiazepine recognition site agonists, respectively, on basal and stress-induced hippocampal acetylcholine and cortical dopamine release were determined with the microdialysis technique in freely moving rats. The actions of these new anxioselective and anticonvulsant drugs were compared with those of diazepam and midazolam, two classical benzodiazepine full agonists. Abecarnil (0.05-1 mg/kg i.p.), imidazenil (0.05-1 mg/kg i.p.), diazepam (2.5-10 mg/kg i.p.) and midazolam (2.5-10 mg/kg i.p.) inhibited basal hippocampal acetylcholine release in a dose-dependent manner. In contrast, whereas diazepam and midazolam significantly decreased dopamine release in the prefrontal cortex, abecarnil and imidazenil had no effect on basal dopamine output. The effects of these drugs on both acetylcholine and dopamine release were antagonized by the benzodiazepine receptor antagonist flumazenil (1 mg/kg i.p.). Foot-shock stress (0.2 mA for 500 msec/sec) delivered for 8 min induced a rapid and marked (+75%) increase in hippocampal acetylcholine output that persisted for approximately 40 min. Foot-shock stress also increased dopamine release in the cerebral cortex; the effect was maximal (+90%) after 20 min and persisted for approximately 30 min. Prior administration of abecarnil or imidazenil at a dose (0.05 mg/kg) that did not significantly affect the basal release of either acetylcholine or dopamine completely prevented the effect of stress on the output of these neurotransmitters, an effect mimicked by higher doses of diazepam (2.5 mg/kg) and midazolam (2.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1994

Neuroleptics cause stimulation of dopamine D1 receptors and their desensitization after chronic treatment.

Recent evidence indicates that the neuroleptic-induced increase of in vivo acetylcholine output in the striatum does not depend on the relief of cholinergic neurons from the inhibitory control by dopamine, but on increased dopamine output onto dopamine D1 receptors. The present microdialysis study was aimed at finding if the neuroleptic-induced increase in striatal acetylcholine release persists after chronic treatment, and how it is correlated with dopamine output. Rats were chronically treated with the dopamine D2 receptor antagonists, haloperidol and (-)-sulpiride (0.5 mg/kg and 50 mg/kg i.p., respectively, daily, for 30 days). The stimulant effect of both neuroleptics on striatal dopamine release persisted unaltered throughout the chronic treatment (by about 100% over basal values). In contrast, the enhancing effects of haloperidol and (-)-sulpiride on striatal acetylcholine release remained unchanged up to day 12 of treatment. Thereafter, tolerance developed, so that both neuroleptics became totally ineffective on day 30 of treatment. Both on day 1 and 30, the neuroleptic-induced dopamine release was reversed by gamma-butyrolactone (gamma-hydroxybutyric acid lactone), suggesting that this effect is mediated by enhanced neuronal activity. On day 1 and day 10, the neuroleptic-induced acetylcholine release was antagonized by the blockade of dopamine D1 receptors with SCH 39166 (trans-(-)-(6aS,13bR)-11-chloro-6,6a,7,8,9,13b- hexahydro-7-methyl-5H-benzo[d]napht[2,1-b]azepine-12-ol, hydrochloride) (0.5 mg/kg i.p.). SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine-7,8-diol hydrochloride) (5 mg/kg i.p.) increased acetylcholine release by about 50% in control rats and in rats treated with (-)-sulpiride or haloperidol for up to 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1994

Differential effects of abecarnil on basal release of acetylcholine and dopamine in the rat brain.

Abecarnil (0.1-1 mg/kg i.p.), a new anxioselective and anticonvulsant ligand of benzodiazepine receptors, like diazepam (2.5-10 mg/kg i.p.) inhibited in a dose-dependent manner the basal release of acetylcholine in the hippocampus of freely moving rats. In contrast, whereas diazepam inhibited the basal output of dopamine in the prefrontal cortex, abecarnil had no such effect. The effects of both abecarnil and diazepam were antagonized by prior treatment with flumazenil at a dose (1 mg/kg i.p.) that per se had no effect on acetylcholine or dopamine release. The results suggest that abecarnil has different intrinsic efficacies at gamma-aminobutyric acid type A (GABAA) receptors involved in the regulation of acetylcholine release in the hippocampus and dopamine release in the prefrontal cortex, two brain areas important in cognitive function and emotional state, respectively.

Acetylcholine↗

PubMed1994

The benzodiazepine receptor antagonist flumazenil increases acetylcholine release in rat hippocampus.

The benzodiazepine receptor antagonist flumazenil (2.5-20 mg/kg i.p.) increased acetylcholine (ACh) release by up to 85% in the hippocampus of freely moving rats. In contrast, the benzodiazepine receptor full agonist diazepam (2.5-10 mg/kg i.p.) decreased ACh release up to a maximum of 45% in the same brain area. Injection of flumazenil (10 pmol) or diazepam (10 pmol) into the medial septum increased (95%) or reduced (50%), respectively, ACh release in the hippocampus. The maximum effect produced by those drugs was of the same magnitude as that observed after systemic injection. The changes in hippocampal cholinergic function elicited by activation and blockade of benzodiazepine receptors in the medial septum may thus play a crucial role in the alterations of the cognitive processes elicited by benzodiazepine receptor ligands.

Acetylcholine↗

PubMed1994

Effects of propofol, pentobarbital and alphaxalone on t-[35S]butylbicyclophosphorothionate binding in rat cerebral cortex.

The effects of propofol, pentobarbital, alphaxalone, etomidate and diazepam on t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to membrane preparations from rat cerebral cortex were studied in the absence of gamma-aminobutyric acid (GABA). Addition of low concentrations (3-10 microM) of propofol to washed membrane preparations (devoid of GABA) markedly enhanced [35S]TBPS binding (maximal enhancement, 85%), whereas higher concentrations (50-100 microM) inhibited this parameter. Diazepam also enhanced [35S]TBPS binding in this preparation (maximal enhancement, 38%). In contrast, pentobarbital, alphaxalone and etomidate decreased [35S]TBPS binding in a concentration-dependent manner. The propofol-induced increase in [35S]TBPS binding in washed membranes was completely reversed by the addition of GABA at a concentration (0.3 microM) that alone did not modify [35S]TBPS binding (78% increase with 10 microM propofol alone, 33% decrease in the additional presence of GABA). The ability of GABA to reverse the effect of propofol on [35S]TBPS binding in washed membranes was shared by pentobarbital (200 microM) and alphaxalone (3 microM); etomidate (20 microM) only partially antagonized the effect of propofol. Diazepam at a concentration (30 microM) that alone had no effect on [35S]TBPS binding failed to modify the propofol-induced increase in [35S]TBPS binding, whereas at a concentration (3 microM) that alone increased [35S]TBPS binding the effect of diazepam was additive with that of propofol. The addition of bicuculline to washed membranes failed to abolish the increase in [35S]TBPS binding induced by propofol or diazepam, but completely antagonized the effects of pentobarbital, alphaxalone and etomidate.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗

PubMed1994

Co-dergocrine (Hydergine) regulates striatal and hippocampal acetylcholine release through D2 receptors.

The effect of Co-dergocrine (Hydergine) on acetylcholine (ACh) release in the striatum and hippocampus has been studied by means of brain microdialysis and compared to the effect of SKF 38393 and of LY 171555 selective D1 and D2 dopamine (DA) receptor agonists, respectively. Co-dergocrine (1 and 5 mg kg-1 i.p.) as well as LY 171555 (0.2 and 0.5 mg kg-1 i.p.) decreased the extracellular concentration of ACh in the striatum, whereas SKF 38393 (5 and 10 mg kg-1 i.p.) increased it. On the other hand, Co-dergocrine (1 and 5 mg kg-1), LY 171555 (0.2 and 0.5 mg kg-1) and SKF 38393 (5 and 10 mg kg-1) increased ACh release in the hippocampus in a dose-dependent way. These results show that Co-dergocrine, which is widely used in the treatment of senile mental decline, enhances the release of ACh in the hippocampus in a similar manner to both D1 and D2 DA agonists. This effect might be relevant for the amelioration of cognitive processes. Moreover, our results which demonstrate that Co-dergocrine is able to decrease the release of ACh in the striatum, as are selective D2 agonists, suggest that Co-dergocrine may have a potential therapeutic benefit in Parkinsonian dementia.

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

PubMed1994

Does dopamine exert a tonic inhibitory control on the release of striatal acetylcholine in vivo?

The role of dopamine transmission on striatal acetylcholine release was investigated by using brain microdialysis. Blockade of dopamine D2 receptors with (-)-sulpiride or haloperidol increased acetylcholine release to a maximum of 80% (after 50 and 0.5 mg/kg, respectively). This effect was prevented by blockade of dopamine D1 receptors with 0.5 mg/kg SCH 39166 or 0.1 mg/kg SCH 23390, or by depletion of dopamine stores after 5 mg/kg reserpine + 150 mg/kg alpha-methyltyrosine. Treatment with SCH 39166, SCH 23390 or reserpine + alpha-methyltyrosine reduced acetylcholine release by about a maximum of 30%. Stimulation of dopamine D2 receptors with LY 171555 (quinpirole) at a low, sedative dose (0.05 mg/kg) reduced acetylcholine release by about 30% with no further reduction at higher doses up to 1 mg/kg. Moreover, LY 171555 (0.1 mg/kg) given to SCH 39166 (0.5 mg/kg)- or SKF 38393 (20 mg/kg)-pretreated rats did not decrease acetylcholine release, suggesting that its effect is through a dopamine D1 receptor-mediated mechanism. In contrast, in dopamine-depleted rats, LY 171555 0.1 mg/kg became more effective in decreasing acetylcholine release (about 70%) also after SCH 39166 (0.5 mg/kg) pretreatment (about 80%), thus acting independently of dopamine D1 receptor mechanisms. These results indicate that, in normal circumstances, endogenous dopamine facilitates striatal acetylcholine release through dopamine D1 receptors. The results argue against the commonly accepted view that dopamine D2 receptors exert a tonic inhibitory control on acetylcholine release. Moreover, they suggest that dopamine D2 receptors, in circumstances of dopamine depletion, may exert an inhibitory control on acetylcholine release independent of dopamine D1 receptor mechanisms.

Acetylcholine↗

PubMed1993

Inhibition of hippocampal acetylcholine release by benzodiazepines: antagonism by flumazenil.

Diazepam (2.5-10 mg/kg i.p.) and midazolam (2.5-10 mg/kg i.p.) decreased acetylcholine release in the hippocampus of freely moving rats. This effect was antagonized by pretreatment with flumazenil (1 mg/kg i.p.). These results show that activation of benzodiazepine receptors reduces the in vivo release of acetylcholine in the hippocampus, suggesting that the septo-hippocampal cholinergic system, which has a major role in the regulation of cognitive functions, is under inhibitory control exerted by gamma-aminobutyrate (GABA) neurons.

Acetylcholine↗

PubMed1993

Evidence that neuroleptics increase striatal acetylcholine release through stimulation of dopamine D1 receptors.

The relative role of D1 and D2 dopamine receptors in the neuroleptic-induced increase of striatal acetylcholine (ACh) release was investigated using brain microdialysis in freely moving rats. Administration of (-)-sulpiride, haloperidol and clozapine, produced a dose-related increase in ACh release in the striatum. Maximal increase by 52, 45 and 73% over basal values was produced by the dose of 20, 0.25 and 10 mg/kg i.p. of (-)-sulpiride, haloperidol and clozapine, respectively. Administration of the D1 receptor antagonist SCH 23390 (0.1 mg/kg s.c.) decreased ACh output by 30%, completely suppressed the stimulant effect of (-)-sulpiride and haloperidol and only modestly reduced that of clozapine. The inhibitory effect of SCH 23390 vs. (-)-sulpiride or haloperidol-induced ACh output was shared by SCH 39166 (1 mg/kg i.p.), another specific D1 receptor antagonist. On the other hand, SCH 23390 (0.1 mg/kg s.c.) was ineffective in reducing atropine-induced increase in ACh release. A combined treatment with reserpine (5 mg/kg i.p.) and alpha-methyltyrosine (150 mg/kg i.p.), 6 h beforehand, prevented the enhancement of ACh release induced by both (-)-sulpiride and haloperidol, whereas only reduced that by clozapine. The results indicate that neuroleptics increase striatal ACh release by enhancing endogenous extracellular dopamine acting on D1 receptors, and suggest that these receptors play a major physiological role in controlling ACh release in the striatum.

Acetylcholine↗

PubMed1993

Anticonvulsant doses of 2-chloro-N6-cyclopentyladenosine, an adenosine A1 receptor agonist, reduce GABAergic transmission in different areas of the mouse brain.

The possible relationship between A1 adenosine receptors and the gamma-aminobutyric acid (GABAA) receptor complex was evaluated in the mouse brain. We studied the effect of in vitro addition and in vivo administration of 2-chloro-N6-cyclopentyladenosine (CCPA), the most selective ligand for A1 receptors, on the biochemical parameters used currently to evaluate GABAergic function. In vitro, CCPA (0.01-100 microM) failed to modify [3H] GABA binding, [3H]flunitrazepam binding, t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding and muscimol-stimulated 36Cl- uptake. On the contrary, in vivo, CCPA (1.4-27.6 mumol/kg i.p.) increased [35S]TBPS binding in membranes from the cerebral cortex, hippocampus, striatum and substantia nigra, but not from the cerebellum, thalamus, hypothalamus and olfactory tubercle. The specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxantine (9.8 mumol/kg i.p.) abolished the effect of CCPA on [35S]TBPS binding, indicating that the action of this compound is mediated by its interaction with A1 receptors. Diazepam (1.7 mumol/kg i.p.), a positive modulator of GABAergic transmission, antagonized the increase of [35S]TBPS binding induced by CCPA. CCPA (2.8-8.3 mumol/kg i.p.) antagonized convulsions induced by isoniazid, an inhibitor of GABA synthesis, but neither antagonized nor potentiated isoniazid-induced increase of [35S]TBPS binding. CCPA (2.8-8.3 mumol/kg i.p.) antagonized the convulsions induced by pentylenetetrazol (398 mumol/kg i.p.), methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (50 mumol/kg i.p.) and bicuculline methiodide (9.8 mumol/kg i.p.). The results show that, in spite of its anticonvulsant activity, CCPA reduces the function of the GABA-coupled chloride channel function. This finding suggests that the anticonvulsant target sites are different from those involved in the action of CCPA on GABAA receptors.

Adenosine↗

PubMed1970