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Biomedical subjects

S Garattini

Publications and source records attributed to S Garattini.

At least 73 records · Page 4Linked to original sources
PubMed1993

Effects of synthetic retinoids and retinoic acid isomers on the expression of alkaline phosphatase in F9 teratocarcinoma cells.

Expression of ALP in F9 teratocarcinoma cells is induced by all-trans retinoic acid (ATRA) (Gianni' et al., Biochem. J. 274: 673-678, 1991). The specific ligand for retinoic acid related receptors (RXRs), 9-cis retinoic acid (9-cis RA), and three synthetic analogs binding to the alpha, beta and gamma forms of the retinoic acid receptors (RARs), AM580, CD2019, and CD437, were used to study their effects on alkaline phosphatase (ALP) enzymatic activity and mRNA levels. At concentrations close to the Kd for their respective receptors, 9-cis RA, AM580 (the RAR alpha agonist) and CD437 (the RAR gamma agonist) clearly upregulate the expression of the ALP gene, whereas the effect of CD2019 (the RAR beta agonist) is very modest. A specific inhibitor of the RAR alpha, Ro 41-5253, completely blocks the induction of ALP triggered by AM580, while it has minor effects on the upregulation caused by ATRA, 9-cis RA, CD437 and CD2019. The induction of ALP observed with the various retinoids is inhibited by the contemporaneous treatment with dibutyryl cAMP. The levels of the RAR alpha and gamma transcripts are unaltered, while RAR beta mRNAs are induced by ATRA, AM580, CD437 and to a lower extent by 9-cis RA and CD2019.

Alkaline Phosphatase↗
PubMed1993

Acute noise stress reduces [3H]5-hydroxytryptamine uptake in rat brain synaptosomes: protective effects of buspirone and tianeptine.

Acute noise stress decreased [3H]5-hydroxytryptamine ([3H]5-HT) uptake in synaptosomes from rat hypothalamus, hippocampus and cerebral cortex. The decrease was due to the maximum rate of [3H]5-HT uptake, which peaked 30 min after stress and partly returned to resting values within 4 h, with no changes in affinity (Km values). No changes in [3H]paroxetine binding and basal [3H]5-HT release were found in stressed rats. Tianeptine, given at the dose of 10 mg/kg 1 h before stress, counteracted the noise-induced decrease of 5-HT uptake, since it increased [3H]5-HT uptake in both resting and stressed animals, but did not prevent the rise in plasma corticosterone of stressed rats. Buspirone pretreatment had no effect on [3H]5-HT uptake in resting rats but prevented the noise-induced decrease in [3H]-HT uptake. Diazepam did not modify either the basal or the noise-induced reduction in [3H]5-HT uptake. The evidence that treatments reducing extrasynaptic 5-HT, by increasing its reuptake (tianeptine) or reducing its release (buspirone) in innervated regions are able to modify the stress-induced decrease in 5-HT uptake, further confirms the importance of serotonin in the mechanisms mediating neurochemical responses to stress.

Analysis of Variance↗
PubMed1993

Prognosis of untreated patients with idiopathic membranous nephropathy.

BACKGROUND: Defining the most appropriate treatment for patients with idiopathic membranous nephropathy is a matter of controversy. The course of the disorder is often benign, and the immunosuppressive regimens used in some patients have uncertain benefits and substantial risks. We studied the natural history of idiopathic membranous nephropathy in patients who received only symptomatic therapy. METHODS: We prospectively studied 100 consecutive patients (68 men and 32 women; mean [+/- SD] age, 51 +/- 17 years) with biopsy-proved idiopathic membranous nephropathy. The patients received diuretic or antihypertensive drugs as needed, but no glucocorticoid or immunosuppressive drugs. We examined the patients and measured their urinary protein excretion and serum creatinine concentrations every 6 months for a mean of 52 months. RESULTS: Twenty-four (65 percent) of the 37 patients followed for at least five years had complete or partial remission of proteinuria; in 6 others (16 percent), end-stage renal disease developed, and they required dialysis. As calculated by the Kaplan-Meier method, the estimated probability (+/- the standard error of the estimate) of retaining adequate kidney function was 88 +/- 5 percent after five years and 73 +/- 7 percent after eight years. The prognosis was poorer in men and in patients over 50 years of age, but not in patients with the nephrotic syndrome, hypertension, or hypercholesterolemia. CONCLUSIONS: Most untreated patients with idiopathic membranous nephropathy maintain renal function for prolonged periods and are likely to have spontaneous remission. These results do not support the use of glucocorticoids and immunosuppressive drugs in patients with idiopathic membranous nephropathy.

Adult↗
PubMed1993

The role of d-norfenfluramine in the indole-depleting effect of d-fenfluramine in the rat.

The importance of d-norfenfluramine in regard to the indole-depleting action of d-fenfluramine has not been well studied in sensitive animal species. The present study therefore examined the intensity and time course of the neurochemical effects of i.p. injected d-fenfluramine (2.5 and 5 mg/kg) and d-norfenfluramine (2.5 mg/kg) in vehicle- and SKF-525A-pretreated rats, relating the effects to the brain concentration-time profiles of the drug and its active metabolite. At the lower dose d-fenfluramine caused only a small, short-lasting decrease in brain serotonin (5-HT) without affecting the 5-hydroxyindoleacetic acid (5-HIAA). Higher doses affected both 5-HT and 5-HIAA (50-60 and 30-40% reductions, respectively), the effect being maximal for at least 8 h. d-Norfenfluramine reduced the brain content of 5-HT and 5-HIAA less (by about 30%) than 5 mg/kg d-fenfluramine did. Brain concentrations of d-norfenfluramine at the time of the maximal depletion of indoles were close to those of the metabolite after 5 mg/kg d-fenfluramine, indicating that the acute indole-depleting effects did not depend solely on the brain concentrations of its nor-metabolite. SKF-525A changed the metabolite-to-parent drug ratios in brain without appreciably influencing the action of d-fenfluramine. However, the maximum decrease in indole content caused by 2.5 mg/kg d-fenfluramine in SKF-525A-pretreated rats was only 12% of the control level, although the brain concentration of unchanged drug was comparable to that after 5 mg/kg d-fenfluramine in vehicle-pretreated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Anorectic effect and brain concentrations of D-fenfluramine in the marmoset: relationship to the in vivo and in vitro effects on serotonergic mechanisms.

The present study investigated the anorectic activity of d-fenfluramine (d-F) and the relationship with brain levels of unchanged drug and its metabolite d-norfenfluramine (d-NF) in marmosets, relating them to neurochemical effects on the serotoninergic system. d-F and d-NF were equally active in reducing food intake (ED50 about 3 mg/kg, p.o.). However, the brain concentrations of the metabolite required to reduce food intake after synthetic d-NF were more than twice those after d-F, indicating that d-NF contributes to but does not completely explain the anorectic effect of d-F. At this dose d-F did not appreciably modify the serotonin (5-HT) and 5-hydroxyindoleacetic (5-HIAA) contents of the brain regions examined, except for a slight enhancement of 5-HIAA in hippocampus. In vitro in brain cortical synaptosomes d-F inhibited [3H]5-HT uptake more potently than d-NF, as in other species. d-F and d-NF showed similar potency in stimulating [3H]5-HT release, in a Ca++ dependent manner. The tritium released by d-F and d-NF appeared to be mainly unmetabolized [3H]5-HT. Like in other species the marmoset too has saturable and specific [3H]d-F binding sites, for which d-NF has lower affinity. d-F and d-NF have low affinities for 5-HT receptor subtypes, except that d-NF has appreciable affinity for 5-HT1C and 5-HT1D receptors. Unlike in rodents but similarly to primates in the striatum the pharmacology of 5-HT receptors seems to correspond to the 5-HT1D subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The effects of single and repeated anorectic doses of 5-hydroxytryptamine uptake inhibitors on indole levels in rat brain.

1. The effects of acute and repeated equiactive anorectic doses (ED50) of recently marketed 5-hydroxytryptamine (5-HT) uptake inhibitors on the content of brain indoles were compared in rats in relation to the brain regional concentrations of unchanged drug and its known active metabolite. 2. Single intraperitoneal (i.p.) doses of the anorectic ED50 of fluoxetine (35 mumol kg-1), fluvoxamine (60 mumol kg-1), paroxetine (20 mumol kg-1) and sertraline (49 mumol kg-1) slightly reduced brain 5-hydroxyindoleacetic acid (5-HIAA), with regional differences, this being compatible with 5-HT uptake blockade. Only fluvoxamine and sertraline significantly enhanced the content of 5-HT in the cortex. 3. The regional sensitivity to the acute effect of a given drug was not related to any preferential drug distribution, as these compounds distributed almost uniformly in the brain areas considered (cortex, striatum and hippocampus). 4. Repeating the same doses twice daily, i.p. for 14 days, however gave a different picture, fluvoxamine having little or no effect on the content of indoles and fluoxetine, paroxetine and sertraline lowering both 5-HT and 5-HIAA in all the brain regions compared to pair-fed control animals, 1 h after the last dose. 5. One week later only fluoxetine-treated animals still had reduced brain 5-HT, this probably being related to the accumulation of its main metabolite norfluoxetine in rat brain after chronic dosing. 6. Further studies on the relationship between the long-term neurochemical changes and anorectic activity are required but it appears from these results that anorectic drugs with similar acute effects on 5-HT uptake may differ in their long-term effects on 5-HT mechanisms.

1-Naphthylamine↗
PubMed1993

Neurochemical mechanism of action of anorectic drugs.

Studies with dexfenfluramine, an anorectic agent which releases 5-hydroxytryptamine (5-HT) from nerve terminals and inhibits its reuptake, have considerably increased our knowledge of the role of 5-HT in feeding control. 5-HT1B receptors mediate the satiating effect of dexfenfluramine, whereas the mechanism by which 5-HT uptake inhibitors such as fluoxetine and sertraline cause anorexia is not clear. Anorexia induced by (+)-amphetamine, phentermine, diethylpropion and phenylpropanolamine seems to be the result of their ability to increase the release of noradrenaline and/or dopamine from nerve terminals and inhibit their reuptake or, in the case of phenylpropanolamine, to stimulate directly alpha 1-adrenoceptors. It has been suggested that beta- and alpha 1-adrenoceptors and D1 dopamine receptors are involved in their effect on food intake. The difficulties of extrapolation across species limit our knowledge of the mechanism of the anorectic action in humans. Significant advances in the treatment of feeding pathology will be linked to identifying new receptor types and subtypes for neurotransmitters and quantifying and modelling eating disorders such as binge-eating and food craving.

Animals↗
PubMed1993

Pharmacological activities of chlorpromazine involved in the inhibition of tumour necrosis factor production in vivo in mice.

Chlorpromazine (CPZ) was shown to inhibit tumour necrosis factor (TNF) production in vivo. Several drugs sharing one of the various pharmacological activities of CPZ were tested in endotoxin-treated mice. It was found that alpha-blockers (prazosin, idazoxan, phenoxybenzamine), antiserotoninergics (methysergide, methergoline) and antihistamine (chlorpheniramine, promethazine) also inhibited TNF production indicating that the effectiveness of CPZ in protecting from endotoxin shock is due to its multiple pharmacological activities.

Adrenergic alpha-Antagonists↗
PubMed1992

Feeding pattern studies suggest that d-fenfluramine and sertraline specifically enhance the state of satiety in rats.

The effects of d-fenfluramine (1.5 mg/kg) and sertraline (10 mg/kg), administered intraperitoneally once daily for seven days were studied on feeding parameters of rats over various periods. On the first day of treatment both drugs markedly reduced meal size and meal duration during the first hour and, to a lesser extent, the first 4 h. No effects were seen later. The size and duration of eating bouts were also markedly reduced by both drugs in the first hour. There was no significant effect of either drug on meal frequency in any period. Only d-fenfluramine significantly reduced the rate of eating within 4 h from the start of testing. Sertraline, but not d-fenfluramine, markedly increased locomotor activity in the first 4 h after the start of testing. The d-fenfluramine effect on eating rate disappeared by the second day whereas total intake and meal size were still reduced on day five. By days six and seven however the d-fenfluramine-treated rats did not differ from the controls. During the seven-day treatment sertraline always reduced total food eaten and meal size but caused only transient changes of locomotor activity and eating rate. Since the effects of d-fenfluramine and sertraline on meal size and food intake could be separated from the effects on eating rate and arousal, it appears that at appropriate doses these drugs specifically increase the satiating effect of food. Tolerance to this effect appears to develop more rapidly for d-fenfluramine than for sertraline.

1-Naphthylamine↗