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Biomedical subjects

G M Frigo

Publications and source records attributed to G M Frigo.

At least 19 recordsLinked to original sources
PubMed2003

Effects of dopaminergic stimulation on peripheral markers of apoptosis: relevance to Parkinson's disease.

We investigated the effects of dopaminergic stimulation on anti-apoptotic protein Bcl-2, pro-apoptotic enzyme caspase- 3, and anti-oxidant/anti-apoptotic enzyme Cu/Zn superoxide dismutase (SOD) in human lymphocytes exposed to dopamine (DA). The same determinations were also carried out in parkinsonian patients treated with L-dopa. Caspase-3 activity and Cu/Zn SOD levels tended to increase when lymphocytes were exposed to low or intermediate doses of DA, while a decrease was observed, particularly in caspase-3 activity, with the higher DA dose. Bcl-2 levels were unaffected. In patients, we observed a negative correlation between Cu/Zn SOD levels and daily intake of L-dopa, which also tended to be negatively correlated with caspase-3 activity, but not with Bcl- 2. Our results show that dopaminergic stimulation is associated with complex changes in regulatory proteins of apoptosis.

Adult↗
PubMed2003

Peripheral markers of apoptosis in Parkinson's disease: the effect of dopaminergic drugs.

In this study, we measured the lymphocyte levels of proteins involved in apoptosis regulation, such as Bcl-2, the peripheral benzodiazepine receptor (PBR), caspase-3, and Cu/Zn superoxide dismutase (Cu/Zn SOD), in patients with Parkinson's disease (PD), either untreated or under therapy with dopaminergic agents (l-Dopa alone or l-dopa + dopamine agonists) and in healthy volunteers. All PD groups showed increased activity of caspase-3, compared to controls, particularly those under treatment only with l-Dopa. In this latter group, the increase in caspase-3 activity was also paralleled by an increase in the concentration of Cu/Zn SOD. In addition, patients taking l-Dopa + dopamine agonists showed marked decrease in Bcl-2 levels and increased PBR expression, which seems in keeping with the hypothesis that PBR may be functionally related to Bcl-2. In conclusion, we found clear modifications in the levels of proteins involved in the control of apoptosis in lymphocytes of PD patients. These changes were disease related but also modulated by the pharmacological treatment, which confirms the potential role of apoptosis in PD pathogenesis and the modulatory influence of dopaminergic agents.

Analysis of Variance↗
PubMed2001

Intestinal motor stimulation by the 5-HT4 receptor agonist ML10302: differential involvement of tachykininergic pathways in the canine small bowel and colon.

5-Hydroxytryptamine (5-HT)4 receptor agonists stimulate gut motility through cholinergic pathways, although there are data suggesting that noncholinergic (tachykininergic) excitatory pathways may also be involved. Differences may exist between the small bowel and colon. Our aims were: (i) to compare the prokinetic effect exerted by the 5-HT4 receptor agonist ML10302 in the canine small bowel and colon in vivo; and (ii) to investigate the role of tachykininergic pathways in mediating this response. In fasting, conscious dogs, chronically fitted with electrodes and strain-gauge force transducers along the small bowel and colon, intravenous injection of ML10302 (35 microg kg-1) immediately stimulated spike activity and significantly increased propagated myoelectrical events at both intestinal levels. In the small bowel, the effects of ML10302 were unchanged by previous administration of the selective NK1 tachykinin receptor antagonist SR140333, the NK2 tachykinin receptor antagonist SR48968, or the NK3 tachykinin receptor antagonist SR142801. In the colon, all tachykinin receptor antagonists significantly inhibited stimulation of spike and mechanical activity by ML10302, without affecting ML10302-induced propagated myoelectrical events. Atropine (100 microg kg-1 i.v.) suppressed the stimulatory effect of ML10302 at both intestinal levels. In conclusion, the 5-HT4 receptor agonist ML10302 induced significant prokinesia both in the small bowel and colon through activation of cholinergic pathways. Tachykininergic pathways are not involved in the ML10302-induced prokinesia in the small bowel, but they play an important role in mediating the colonic motor response to ML10302.

Algorithms↗
PubMed1999

Neutrophil function and opioid receptor expression on leucocytes during chronic naltrexone treatment in humans.

We report that neutrophil function was impaired in former heroin addicts on chronic naltrexone maintenance. Of the subjects, 62.5% had elevated plasma ACTH, 25% had elevated plasma cortisol and one subject had increased urinary cortisol. All subjects showed enhanced expression of opioid receptors on monocytes, neutrophils and lymphocytes. In vitro, incubation with therapeutically relevant concentrations of naltrexone induced a slow increase of neutrophil cytoplasmatic free Ca(2+)concentrations ([Ca(2+)]()E2>i) and slowed down the [Ca(2+)]()E2>i rise induced by N-formyl-methionyl-leucyl-phenylalanine. Neither naltrexone nor its metabolite beta-naltrexol affected human neutrophil function in vitro. We conclude that impairment of neutrophil function during chronic naltrexone may be related to opioid receptor overexpression. With this regard, the possible role of naltrexone-induced [Ca(2+)]()E2>i changes deserves further investigation. 1999 Academic Press.

Adolescent↗
PubMed1998

Peripheral benzodiazepine receptor expression on leukocytes and neutrophil function during anticonvulsant monotherapy.

Epileptic patients on long-term therapy with a single anticonvulsant showed enhanced expression of peripheral benzodiazepine receptors (pBZrs) on neutrophils, monocytes and lymphocytes. N-Formyl-methionyl-leucyl-phenylalanine-induced chemotaxis was significantly impaired in neutrophils from patients on carbamazepine (p < 0.01 vs. controls). Neutrophils from patients on phenytoin had enhanced phorbol myristate acetate-stimulated O-2 production (p < 0. 01 vs. controls) and neutrophils from patients on valproic acid had impaired phagocytosis frequency and Staphylococcus aureus lethality index (p < 0.01 vs. controls). Overexpression of pBZrs on leukocytes may reflect the clinical response to anticonvulsants and may play a role in the immunological effects of some of these drugs.

Adolescent↗
PubMed1997

Carbamazepine affects neutrophil function through an action on peripheral benzodiazepine receptors.

The aims of this study were to assess the possible role of peripheral benzodiazepine receptors (pBZrs)1 in mediating the in vitro effects of carbamazepine (CBZ) on some neutrophil functions in healthy volunteers and to investigate neutrophil function and pBZr expression in patients with epilepsia on CBZ monotherapy for at least 1 year. In vitro CBZ (42-168 microM) concentration-dependently inhibited chemotaxis induced by N-formyl-methionyl-leucyl-phenylalanine (FMLP) or lipopolysaccharide (LPS)-activated human serum. CBZ did not affect random migration, phagocytosis index, phagocytosis frequency, NBT reduction frequency, C. albicans lethality index and resting superoxide production. The pBZr antagonist PK 11195 (1 microM, per se ineffective) reversed the inhibitory effect of CBZ on chemotaxis induced by endotoxin-activated serum or FMLP. The pBZr agonist Ro 5-4864 (10-100 microM) mimicked the effect of CBZ on chemotaxis induced by endotoxin-activated serum or FMLP and had no effect on the other parameters. Neutrophils from epileptic patients on chronic CBZ monotherapy had impaired FMLP- and serum-induced chemotaxis and enhanced expression of pBZrs on neutrophils. These data strongly suggest an involvement of pBZrs in mediating the in vitro effects of CBZ on chemotaxis; furthermore, impairment of the same neutrophil function parameters and overexpression of pBZrs in patients are consistent with the hypothesis of an in vivo interaction of CBZ with pBZrs.

Adolescent↗
PubMed1994

Effect of desipramine-induced blockade of neuronal uptake mechanisms on adrenoceptor-mediated responses in the guinea-pig colon.

In order to clarify whether adrenoceptors in the guinea-pig distal colon are under sympathetic control, we assessed possible variations in the sensitivity to adrenoceptor agonists after blockade of neuronal catecholamine uptake mechanisms by desipramine (DMI). First, experiments were carried out to investigate the effects of DMI added in the organ bath on propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow, electrically evoked noradrenaline overflow and longitudinal smooth muscle tone. Secondly, we studied the effects of adrenoceptor agonists on the above parameters in untreated animals and in animals chronically treated with DMI. DMI added in the organ bath at concentrations equal to or higher than 30 nM inhibited all the parameters under study. Thus, when evaluating the effect of DMI on concentration-response curves to adrenoceptor agonists, concentrations which were per se inactive were used. DMI added in the organ bath at concentrations up to 30 nM potentiated the inhibitory effects of exogenous noradrenaline on propulsion velocity and acetylcholine overflow, but it did not affect the concentration-response curve to exogenous noradrenaline on longitudinal smooth muscle tone. Furthermore, 30 nM DMI inhibited propulsion velocity during sympathetic nerve stimulation. In preparations obtained from animals chronically treated with DMI, no significant change of propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow was found with respect to untreated animals. Nevertheless, in such preparations subsensitivity to isoprenaline (acting mainly on muscular beta-adrenoceptors) and clonidine (acting on neuronal alpha 2-adrenoceptors) and super-sensitivity to phenylephrine were observed. Electrically evoked noradrenaline overflow was enhanced, in a frequency-dependent way, by yohimbine and inhibited by clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

Inhibition of endogenous acetylcholine release by blockade of voltage-dependent calcium channels in enteric neurons of the guinea-pig colon.

The effects on acetylcholine release from the guinea-pig colon of the N-type calcium channel blocker omega-conotoxin GVIA (omega-conotoxin), the L-type calcium channel blocker nifedipine and the putative blocker of T-type channels, flunarizine, have been investigated. Endogenous basal acetylcholine release and electrically (1 Hz, 1 ms, 450 mA)-evoked overflow in the presence of cholinesterase inhibitor were studied. omega-Conotoxin (1-10 nM) and nifedipine (0.03-3 microM) dose-dependently inhibited basal and electrically-evoked acetylcholine release. Maximal inhibition of basal or electrically-evoked acetylcholine release was about 40% for nifedipine and about 75% for omega-conotoxin. The potency of nifedipine was inversely related to the external calcium concentration: its EC50 value in low-calcium medium (0.5 mM) was as low as 12 nM. Flunarizine inhibited acetylcholine release only at concentrations higher than 0.2 microM. Our results are consistent with an involvement of N- and L-type calcium channels in the control of the endogenous acetylcholine release from the guinea-pig colon.

Acetylcholine↗
PubMed1993

Opioid pathways exert a tonic restraint in the guinea-pig isolated colon: changes after chronic sympathetic denervation.

We have studied the effects of naloxone on acetylcholine and noradrenaline release in the guinea-pig isolated distal colon, and have assessed the effect of naloxone on electrically-induced contractions of the longitudinal muscle and non-adrenergic, non-cholinergic (NANC) relaxations of the circular muscle coat. Naloxone dose-dependently increased resting and electrically-evoked acetylcholine release and electrically-evoked noradrenaline release. Naloxone was more potent in increasing resting acetylcholine release in colonic specimens obtained after chronic sympathetic denervation. Naloxone (1 microM) did not affect electrically-induced contractions of the longitudinal muscle, while it enhanced NANC relaxations of the circular muscle. The effects observed with naloxone in the present experiments suggest that opioid pathways exert a tonic restraint on neurotransmission in the guinea-pig colon. After suppression of the adrenergic inhibitory tone, the functional relevance of opioid pathways seems to be increased.

Acetylcholine↗
PubMed1993

Immunological adverse effects of anticonvulsants. What is their clinical relevance?

Long term administration of anticonvulsants is sometimes associated with impairment of the humoral and/or cellular immune response. Furthermore, certain well known adverse reactions to antiepileptics may have an immunotoxicological origin e.g. lymphadenopathy, pseudolymphoma and systemic lupus erythematosus. However, two important questions remain unresolved. First, the possibility that epilepsy per se might be primarily associated with immune alterations makes it difficult to assess the pathogenetic role of a specific drug, especially in a patient population usually on multiple drug therapy. Secondly, the clinical relevance of some of the observed immunological abnormalities is still highly controversial. This review is intended to give an outline of the present state of knowledge on the effects of anticonvulsants on humoral, cellular and nonspecific immunity, with particular regard to some of the major clinical conditions that have been ascribed to drug-induced immune dysregulation, such as pseudolymphoma and systemic autoimmune diseases. The immunotoxic potential of anticonvulsants appears to be low, and immunological monitoring is not usually required except in patients with known immune defects.

Antibody Formation↗
PubMed1993

Differential effects of antimuscarinic agents on intestinal motility in the conscious dog.

In this study we investigated the effects of antimuscarinics with different selectivity on the intestinal migrating myoelectric complex (MMC) in five fasting, conscious dogs, chronically fitted with electrodes along the small bowel. Furthermore, we evaluated the chronotropic and mydriatic effects to assess the in vivo selectivity of the agents tested. Dose-response studies were performed with the following drugs administered i.v.: atropine, telenzepine (M1 antagonist), AF-DX 116 [11,2-(diethylamino)methyl-1-piperidinyl-acetyl-5,11-dihydro-6H-pyrido-2 ,3b- 1,4-benzodiazepine-6-one (M2 antagonist)] and 4-diphenylacetoxy-N- methylpiperidine methiodide (4-DAMP) (M3 antagonist). All the antimuscarinics tested dose-dependently increased the duration of the MMC period and inhibited spike activity, except low-dose telenzepine (3-10 nmol/kg), which shortened the MMC period and stimulated spike activity. High-dose telenzepine (> 100 nmol/kg) mimicked the inhibitory effect of atropine on the intestine. ED50 values for delay of MMC onset were 87,232, > 10,000 and 129 nmol/kg for atropine, telenzepine, AF-DX 116 and 4-DAMP, respectively. At doses lengthening the MMC period, atropine and 4-DAMP also induced tachycardia and mydriasis. At doses shortening the MMC period, telenzepine had no effect on pupil diameter or heart rate, except at the dose of 10 nmol/kg, which reduced heart rate. Finally, AF-DX 116, at doses inducing marked tachycardia, had a minor intestinal effect and no mydriatic effect. The present data are consistent with the hypothesis that both M1 and M3 receptors are involved in the regulation of the MMC: M1 receptors are probably located on an inhibitory pathway, whereas M3 receptors mediate excitatory stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effect of calcium channel blockers on postprandial gastrointestinal motility in the dog.

We have compared the ability of nifedipine and lacidipine, a new 1,4-dihydropyridine, to interfere with postprandial gastrointestinal motility. Five conscious dogs, fitted with 8 bipolar electrodes along the gastrointestinal tract, were studied. Gastrointestinal spike activity was evaluated by means of a computer system. Lacidipine (8 micrograms kg-1) was administered as an i.v. bolus immediately followed by a 10 micrograms kg-1 h-1 i.v. infusion for 3 h, starting 30 min before a standard meal. This dose of lacidipine decreased systolic blood pressure by approximately 20%. Nifedipine was used at equihypotensive doses (30 micrograms kg-1 i.v. bolus followed by 300 micrograms kg-1 h-1 i.v. infusion). Lacidipine had no effect on either gastric or intestinal postprandial spike activity. Nifedipine significantly delayed the appearance of the fed pattern and reduced the number of spikes in the small bowel, while it had no effect on gastric spike activity. We conclude that equihypotensive doses of lacidipine and nifedipine differ in their effects on the gastrointestinal tract, lacidipine having a better cardiovascular selectivity profile than nifedipine, and that the sensitivity to nifedipine varies in different parts of the gut.

Animals↗
PubMed1992

Supersensitivity to morphine after chronic sympathetic denervation in guinea-pig colon.

The possible role of opioid systems in the adaptive changes which follow chronic sympathetic denervation in the guinea-pig colon has been studied by comparing the effects of the opioid agonist morphine in control animals and after chronic sympathetic denervation. Supersensitivity to the inhibitory effects of morphine on the peristaltic reflex was observed after chronic sympathetic denervation, while the potency against acetylcholine release was unmodified. Our results suggest that a modification of the opioid system occurs after sympathetic denervation in the guinea-pig colon. Supersensitivity to endogenous opioids at a site different from that regulating acetylcholine release could account for the counter-regulation of intestinal motility after chronic sympathetic denervation.

Acetylcholine↗
PubMed1992

Interaction between (-)naloxone and morphine in modifying superoxide generation from human granulocytes.

The effect of the opioid agonist morphine and of the (-) and (+) stereoisomers of the antagonist naloxone were studied on superoxide generation from human granulocytes. Morphine or naloxone had no effect on basal or phorbol 12-myristate 13-acetate (PMA)-stimulated superoxide generation. Combined equimolar (-)naloxone and morphine concentrations (0.1 pM-0.1 microM) inhibited PMA-stimulated superoxide generation, while combined (+)naloxone and morphine had no effect. The stereospecific effect of naloxone suggests the involvement of opioid receptors. Thus, inhibition of superoxide generation by combined (-)naloxone and morphine could result from the unmasking of non opioid effects of morphine. It is suggested that the opioid control of oxidative metabolism in human granulocytes could involve multiple receptors mediating opposite effects.

Adult↗
PubMed1991

Pharmacological activity and safety of trandolapril (RU 44570) in healthy volunteers.

The pharmacological activity and safety of the new angiotensin converting enzyme (ACE) inhibitor trandolapril (RU 44570) has been evaluated in ten healthy male volunteers given 2 mg once daily for seven days. Assessment criteria included evaluation of plasma ACE and renin activity and aldosterone levels in the supine and standing positions, monitoring of blood pressure, heart rate and electrocardiogram, routine blood and urine laboratory tests, and evaluation of adverse effects. Plasma ACE activity (both in the supine and standing positions) was significantly lower after the first dose and was almost completely suppressed after 7 days of treatment. Plasma renin activity with the subjects in both positions was significantly increased at the end of treatment. Plasma aldosterone did not vary significantly, except for an increase in the standing position after 7 days of wash-out. No significant changes occurred in blood pressure, heart rate, electrocardiogram, blood or urine laboratory tests. No adverse effects were reported, in particular, no orthostatic hypotension, cough or episodes of bronchospasm occurred. It is concluded that oral trandolapril 2 mg o.d. is an effective and long-lasting ACE inhibitor with a good safety profile on repeated dosing. Further studies are warranted to investigate its therapeutic application as well as its safety profile after long-term administration.

Adult↗
PubMed1991

Selectivity of Ca2+ channel blockers in inhibiting muscular and nerve activities in isolated colon.

1. Potency and efficacy of nifedipine, verapamil and diltiazem and of Bay K 8644 in modifying propulsion and nerve or smooth muscle activities have been compared in the guinea-pig isolated distal colon. Both the neuronal and muscular effects of Ca2+ channel blockers seem to develop at concentrations that are devoid of any significant effect apart from that on Ca2+ channels. 2. Nifedipine, verapamil and diltiazem were all able to impair propulsion, resting and stimulated acetylcholine (ACh) release and smooth muscle contractility in a concentration-dependent way. However, some degree of selectivity for neuronal and muscular effects could be observed. Nifedipine was more than 500 fold more potent than verapamil in relaxing musculature but less than twice as potent in reducing ACh release. On the other hand, verapamil was the most efficacious Ca2+ channel blocker tested in inhibiting ACh release, its effects being inversely correlated to the external Ca2+ concentration, and completely abolished by Bay K 8644. 3. By comparing the potencies exhibited by each drug against peristaltic reflex, smooth muscle contractility and ACh release, verapamil proved to be almost as potent in slowing the peristaltic reflex as in reducing ACh release, while nifedipine was about 100 fold more potent against the peristaltic reflex than against ACh release, but nearly equal against the peristaltic reflex and smooth muscle tone. Therefore, interference with cholinergic neurotransmission is likely to play a major role in the antipropulsive effect of verapamil, while peristaltic reflex impairment by nifedipine is likely to be dependent on inhibition of smooth muscle. 4. A facilitatory effect of Bay K 8644 on both the efficiency of the peristaltic reflex and the nonadrenergic, non-cholinergic (NANC) nerve-mediated relaxation could be observed at concentrations at least 10 fold lower than those required to affect ACh release or smooth muscle. 5. It is concluded that the effects of Ca2+ channel blockers on neurotransmitter release may be relevant to their effects on the gastrointestinal motor function.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗