Biomedical subjects
A Bianchetti
Publications and source records attributed to A Bianchetti.
Cytosol protein kinase C downregulation in fibroblasts from Alzheimer's disease patients.
We attempted to determine whether changes in protein kinase C (PKC) activity in Alzheimer's disease (AD) brains are also present in cultured skin fibroblasts from living patients. Biopsies collected from shoulder skin were transferred to culture plates with an appropriate growth medium, and histone-directed PKC activity as well as phorbol ester binding were individually determined in soluble and particulate fractions prepared from AD and non-AD fibroblast cell lines. Binding experiments indicated that PKC was unevenly distributed between cytosol (78%) and particulate (22%). The Bmax values for phorbol ester binding in soluble and particulate fractions were similar in AD and non-AD patients. Kd values in the cytosol were 94% higher in AD patients, indicating lower affinity of the enzyme for the ligand. Accordingly, the soluble PKC activity was 30% lower in AD patients. The data suggest that the changes in PKC phosphorylating activity represent a diffuse cellular defect in AD and are not confined to the brain. The alterations of the enzyme may participate in the disregulation in processing of beta-amyloid precursor protein in AD.
Treatment of cognitive impairment secondary to degenerative dementia. Effectiveness of oxiracetam therapy.
The effectiveness of Oxiracetam (1600 mg/day) versus placebo was assessed in a group of 96 out-patients suffering from cognitive disorders secondary to primary degenerative dementia. The study lasted twelve months and was performed in two stage, a) double-blind (26 weeks) and b) open study (26 weeks). The assessment of the results obtained at two, six and twelve months was carried out following both the methodology based on neuropsychological tests and scales, and the study of the simple reaction time by any of a computerized portable tachystoscope. The patients treated with Oxiracetam showed a statistically significant improvement of simple reaction time and cognitive function detected by the Attention matrix. In the placebo group after twelve months a significant worsening of cognitive and global function was observed in comparison with baseline scores. The patients themselves appeared in favor of Oxiracetam. The drug tolerability proved to be very good for the whole duration of the treatment. The authors believe that Oxiracetam favorably acts on the symptoms of senile cerebral deterioration and can improve the capability of information processing, as suggested by the better performances obtained at the reaction time test and at the Attentional Matrix test.
Antidepressant profile in rodents of SR 58611A, a new selective agonist for atypical beta-adrenoceptors.
beta 2-Adrenoceptor agonists possess antidepressant-like activity in animals and man, but their peripheral side-effects prevent their therapeutic use. Atypical beta-adrenoceptors have not been demonstrated in the central nervous system, but are known to exist in peripheral tissues such as the rat colon. We have now studied the antidepressant-like effects in rodents of a new selective atypical beta-adrenoceptor agonist, SR 58611A. SR 58611A was active with minimal effective doses of 0.1-0.3 mg kg-1 i.p. in several models (antagonism of the hypothermia induced by apomorphine and reserpine; potentiation of the toxicity produced by yohimbine; reversal of learned helplessness), but was inactive in the tests of reserpine-induced ptosis and behavioural despair. The antidepressant-like effect of SR 58611A was not antagonised by selective beta 1- or beta 2-adrenoceptor antagonists, but was blocked by high doses of the non-selective beta-adrenoceptor antagonists, propranolol and alprenolol. Unlike beta 2-adrenoceptor agonists, SR 58611A did not reduce locomotor activity or increase water intake at doses up to 10 mg kg-1. Therefore, SR 58611A may represent the prototype of a new class of antidepressant compounds.
Phenylethanolaminotetralines compete with [3H]dihydroalprenolol binding to rat colon membranes without evidencing atypical beta-adrenergic sites.
[3H]Dihydroalprenolol ([3H]DHA) specific binding (determined by the difference in the presence and absence of 20 microM (-)isoprenaline) to rat colon membranes was saturable (Bmax = 39.6 fmol/mg protein), of high affinity (Kd = 0.87 nM) and stereospecific (IC50 330 and 3510 nM for (-)- and (+)isoprenaline, respectively); the Hill coefficient was close to one, indicating binding homogeneity. [3H]DHA (0.6 nM) specific binding was potently inhibited (Ki range 1.9-3.3 nM) by the non-selective beta-adrenoceptor antagonists pindolol, alprenolol, but not by the non-adrenergic compounds 5-hydroxytryptamine, 8-hydroxydipropylaminotetraline, methysergide, dopamine and verapamil (Ki greater than 10,000 nM). The selective beta 1- and beta 2-adrenoceptor antagonists CGP 20,712A and ICI 118,551 resulted in biphasic competition binding curves, whose low and high affinity components were compatible with two populations of binding sites accounting for about 75 (beta 2) and 25% (beta 1) of total sites. The relative competing potencies of reference adrenergic agonists also suggested a prevalence of beta 2-adrenergic sites. The new agonists phenylethanolaminotetralines (PEATs), highly selective for the atypical beta-adrenoceptors whose abundance in rat colon has been confirmed by comprehensive functional studies, had variable affinity for the [3H]DHA-labelled sites depending on chirality, but with no substantial correlation with their pharmacological potency. Only 40% of [3H]DHA binding, at a concentration about 10 times its Kd for high affinity sites (beta 1 and beta 2), was prevented by saturating concentrations of isoprenaline. Under this condition, the representative PEAT, SR 58611A, highly potent and selective for atypical beta-adrenoceptors in functional tests, and its pharmacologically inactive enantiomer, both inhibited the residual binding equipotently. In conclusion, [3H]DHA binding did not detect atypical beta-adrenoceptor sites in rat colon membranes, most probably because of its weaker affinity for them than for the coexisting beta 1 and beta 2 sites. PEAT stereoisomers proved essential for assessing both the stereospecificity and the functional significance of this atypical binding and to compare their affinity for [3H]DHA-labelled sites and pharmacological potency.
Stimulation of faecal excretion in rats by alpha 2-adrenergic antagonists.
The effects of several alpha-adrenoceptor antagonists on faecal output and water content in rats were investigated. Fed rats were treated either subcutaneously (s.c.) or orally with phentolamine, idazoxan, yohimbine, 1-(2-pyrimidinyl) piperazine (PmP) or prazosin. Drug potencies were compared on the basis of the dose inducing excretion of 1 g dry weight of faeces (AD1) by rats that do not normally excrete any faecal pellet during the observation time. The alpha 2-antagonist, idazoxan (AD1 = 0.25 mg kg-1, s.c.) was approximately 2.5, 4 and 8 times more potent than PmP, phentolamine and yohimbine in promoting faecal excretion. Prazosin, an alpha 1-antagonist with putative affinity for the alpha 2B-receptor subtype, was the least effective (AD1 greater than 5 mg kg-1, s.c.). The same compounds also increased the water content of faeces and had similar potencies by the oral route. Both clonidine (0.15 mg kg-1, s.c.) and atropine (0.2 mg kg-1, s.c.) significantly prevented the effects of all antagonists on faecal excretion. The present results are consistent with the view that rat colon is under tonic inhibitory control of prejunctional alpha 2-adrenergic receptors, whose blockage by specific antagonists induces faecal excretion. The alpha 2A-receptor subtype appears to be the most likely candidate for controlling faecal excretion through inhibition of acetylcholine release.
Effectiveness of oxiracetam therapy in the treatment of cognitive deficiencies secondary to primary degenerative dementia.
The effectiveness of oxiracetam (1600 mg/day) vs placebo was assessed in a group of 96 out-patients suffering from cognitive disorders secondary to primary degenerative dementia. The study, performed in double-blind, lasted 26 weeks and is expected to be continued in open conditions until a whole year of treatment is completed. The assessment of the results obtained at 6 months was carried out following both the methodology based on neuropsychological tests and scales, and the study of the simple reaction time by any of a computerised portable tachystoscope. The patients treated with oxiracetam showed a statistically significant improvement of cognitive function and simple reaction time. No significant variations in the scores of the tests used were observed in the placebo group. The patients themselves appeared in favour of oxiracetam. The drug tolerability proved to be very good for the whole duration of the treatment. The authors believe that oxiracetam favourably acts on the symptoms of senile cerebral deterioration and can improve the capability of information processing, as suggested by the better performances obtained at the reaction time tests.
Further heterogeneity of the beta-adrenoceptor. The phenylethanolaminotetralines: new selective agonists for atypical beta-adrenoceptors.
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In vitro inhibition of intestinal motility by phenylethanolaminotetralines: evidence of atypical beta-adrenoceptors in rat colon.
1. The new compounds phenylethanolaminotetralines (PEAT), unlike the reference beta-adrenoceptor agonists isoprenaline (Iso), ritodrine (Ri) and salbutamol (Sal), produced half-maximal inhibition of spontaneous motility of rat isolated proximal colon at substantially lower concentrations (EC50 2.7-30 nM) than those inducing beta 2-adrenoceptor-mediated responses (relaxation of guinea-pig isolated trachea and rat uterus) and had virtually no chronotropic action (EC50 greater than 3 x 10(5) M) on the guinea-pig isolated atrium (a beta 1-adrenoceptor-mediated response). 2. The nonselective beta-adrenoceptor antagonists alprenolol and propranolol prevented the inhibition of rat colon motility by the PEAT with low and different potencies (pA2 values around 7.5 and 6.5 respectively). Conversely alprenolol and propranolol had a higher and similar potency (pA2 values around 9.0) in preventing typical beta 1 or beta 2-responses (increase in atrial frequency by Iso or tracheal relaxation by Ri or Sal). 3. The selective beta-adrenoceptor antagonists CGP 20712A (beta 1) and ICI 118,551 (beta 2) either alone or in combination, did not prevent rat colon motility inhibition by the representative PEAT SR 58611A, which was also fully resistant to alpha-adrenoceptor, acetylcholine, dopamine, histamine, opioid and 5-hydroxytryptamine antagonists. 4. These results indicate that the PEAT are a new class of beta-adrenoceptor agonists and suggest that their preferential intestinal action may be accounted for by selectivity for atypical beta-adrenoceptors, abundant in the rat colon and distinct from the currently recognized beta 1 and beta 2 subtypes.
Nutritional intake, socioeconomic conditions, and health status in a large elderly population.
The nutritional intake of a large population of noninstitutionalized older people living in an urban area was studied in relation to socioeconomic conditions (living environment, income, and education) and health status (affective, functional, and physical health) to identify the subgroups at risk for malnutrition. Twenty-four-hour dietary recall was used to determine the percentage of older subjects with dietary intake of specific nutrients below two thirds of the 1980 Recommended Dietary Allowances. Ninety percent of the older people examined showed inadequate intake of thiamine and vitamin B6, and 30% to 40% demonstrated deficiencies of vitamin A, vitamin C, niacin, vitamin B12, calcium, and iron; only 10% of subjects had inadequate intake of protein. Poor nutritional intake was correlated more strongly with socioeconomic conditions, functional level, and affective status than with physical health status.
Inhibition of rat colonic motility and cardiovascular effects of new gut-specific beta-adrenergic phenylethanolaminotetralines.
We have investigated the ability of the new putative beta-adrenergic agonists phenylethanolaminotetralines (PEAT) to inhibit intestinal motility in relation to their cardiovascular effects, in ethylurethane-anesthetized rats. The representative PEAT SR 58375A, SR 58572A and SR 58539B and the reference beta-adrenergic agonists isoproterenol, salbutamol and ritodrine caused dose-related inhibition of proximal colon spontaneous motility: ED50 (microgram/kg, i.v.) 210, 92 and 19; 5.6, 176 and 201, as listed. This inhibition was prevented by the beta-adrenergic antagonist alprenolol, but not by desipramine (which prevented the inhibition of colonic motility by tyramine and enhanced that by norepinephrine). The minimal effective doses (MED) of isoproterenol, salbutamol and ritodrine raising heart rate and/or lowering blood pressure (by 10 to 20%), was substantially lower (about 1/10 to 1/150) than their ED50 for inhibition of colonic motility. The MED raising heart rate of the three PEAT, on the other hand, was about twice (SR 58375A and SR 58572A) to five (SR 58539B) times their ED50 for inhibition of colonic motility. None of the PEAT lowered blood pressure up to the top tested dose. Therefore the PEAT may prove preferable to the currently best tolerated beta-adrenoceptor agonists, because they appear less liable to induce cardiovascular side effects. This supports the prospective therapeutic interest of PEAT for intestinal hypermotility disorders.
Are too many drugs prescribed for the elderly after all?
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Reduction of normal food intake in rats and dogs and inhibition of experimentally induced hyperphagia in rats by CM 57373 and fenfluramine.
The anorectic effect of CM 57373 in dogs and in rats food-deprived or with experimentally induced hyperphagia (cafeteria-diet hyperphagia and insulin hyperphagia) was compared to the effect of serotoninergic anorectic drug dl-fenfluramine. CM 57373 and dl-fenfluramine administered orally caused a dose-related reduction of food consumption by food-deprived rats (ID50 = 7.4 mg/kg and 2.5 mg/kg respectively). The oral ID50 in dogs was 2.4 mg/kg for CM 57373 and 1.1 mg/kg for dl-fenfluramine. This animal species tolerated CM 57373 better than dl-fenfluramine. The latter induced mydriasis, dyskinesia and reduced spontaneous activity. The anorectic effects of CM 57373 and dl-fenfluramine in cafeteria-diet hyperphagic rats were comparable. Tolerance to the anorectic effect developed in rats treated with both CM 57373 and dl-fenfluramine although tolerance was initially less pronounced with CM 57373 than dl-fenfluramine. The brain serotonin levels of cafeteria-fed rats were unchanged by CM 57373 throughout treatment whereas dl-fenfluramine decreased the monoamine levels starting from the 8th day. Both drugs reduced 5-hydroxyindolacetic acid levels. CM 57373 (7.4 mg/kg p.o.) and dl-fenfluramine (2.5 mg/kg p.o.) markedly reduced the overeating caused by insulin injection. These results indicate that CM 57373 shows several characteristics of drugs that act via serotonin to depress food intake in various animal species.
Hypnotic drug use among the elderly living at home.
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Inhibition of rat colon motility by stimulation of atypical beta-adrenoceptors with new gut-specific agents.
The new putative beta-adrenergic agonists SR 58306A, 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol hydrochloride and SR 58339A, 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1- (3-chlorphenyl) ethanol hydrochloride, were studied in vitro in comparison with reference compounds. SR 58306A and SR 58339A, unlike isoprenaline and the beta2 selective adrenergic agonists salbutamol and ritodrine, potently inhibited rat colon spontaneous contractions (EC50 5.9 and 1.1 x 10(-7) M) without increasing guinea-pig atrium frequency or relaxing guinea-pig trachea. The nonselective beta-adrenergic antagonists alprenolol, pindolol and propranolol competitively antagonized the action of SR 58306A on the colon, which was not prevented by either of the selective antagonists atenolol (beta 1) and ICI 118551 (beta 2). In the same preparation only alprenolol competitively antagonized isoprenaline; antagonism by either pindolol or propranolol was not competitive. These results suggest that in the rat colon isoprenaline interacts with different beta-receptor subclasses, whereas our new gut-specific compounds such as SR 58306A inhibit colonic motility by selectively stimulating atypical beta-adrenoceptors.
Comparison of the gastric antisecretory effects of ramixotidine dihydrochloride (CM 57755), a new H2 receptor antagonist, and cimetidine in dogs.
This paper compares the effects of ramixotidine dihydrochloride (CM 57755) with those of cimetidine on gastric acid secretion and gastrin release in conscious dogs chronically fitted with Heidenhain pouches and/or gastric fistulae. At equimolar doses, intravenous (i.v.) or intragastric (i.g.) CM 57755 caused similar inhibition of dimaprit- or pentagastrin-induced secretion than cimetidine. Acid secretion stimulated by a meat meal was significantly reduced by both CM 57755 and cimetidine. Neither CM 57755 (4.5 and 9 mumol/kg) nor cimetidine (4 mumol/kg) modified gastrin release, while cimetidine (8 mumol/kg) significantly increased it. Judging from these results, while CM 57755 appears to be an inhibitor of gastric acid secretion induced by different stimulants in dogs with potency comparable to cimetidine. The increase in plasma gastrin levels seen after cimetidine but not after CM 57755 suggests that cimetidine releases gastrin by a mechanism independent of H2 receptor antagonism.
Acute effects of intravenous infusions of alcohol on baroreceptor sensitivity in essential hypertension.
To assess the acute effects of alcohol on baroreceptor reflex in moderate and heavy drinkers with essential hypertension and in healthy subjects who drank moderately, four groups of age and sex matched subjects were studied. Group 1 consisted of 10 healthy subjects (age range 21-50 (mean 37.4(10.5) years), who usually drank less than 200 g of alcohol per week; group 2 patients (age range 21-50 (mean 37.4(10.3) years) with mild or moderate essential hypertension and whose weekly alcohol consumption was less than 200 g; and groups 3 and 4 patients with mild or moderate hypertension (age range 21-50 (mean 37.2(10.2) years and 21-52 (mean 38.1(10.4) years respectively), who usually drank greater than 700 g of alcohol per week. In groups 1-3 an infusion of alcohol (7 mg.kg-1.min-1) in 500 ml of 5% glucose was administered for 1 h to keep blood concentrations constant (6-7 g.litre-1), whereas in group 4 the dose was doubled (blood concentration 10-11 g.litre-1). Baroreceptor sensitivity was measured by the phenylephrine method before and after alcohol infusion and one or two days later before and after infusion of 500 ml of 5% glucose. In healthy subjects and in moderate drinkers with hypertension the alcohol reduced baroreflex sensitivity significantly (from 17.5(9.5) to 13.8(8.4); p less than 0.01 and from 15(10) to 10.5(6.7) ms.mmHg-1, p less than 0.01 respectively), whereas in the heavy drinkers with hypertension it was significantly reduced only at the highest dose of alcohol (from 12.5(6) to 7.9(3.5) ms.mmHg-1; p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)