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Biomedical subjects

A Filippelli

Publications and source records attributed to A Filippelli.

At least 19 recordsLinked to original sources
PubMed2002

Effects of docosahexaenoic acid on [Ca(2+)](i) increase induced by doxorubicin in ventricular rat cardiomyocytes.

The clinical use of doxorubicin (DXR) is limited by cardiotoxicity partially due to interference with intracellular Ca(2+) homeostasis and involving the activation of the sarcoplasmic reticulum (SR) Ca(2+) release channels. It is known that docosahexaenoic acid (DHA) is able to potentiate the sensitivity of cancer cells to DXR. The aim of our study was to further evaluate the effects of DHA on [Ca(2+)](i) overload induced by DXR in adult rat ventricular cardiomyocytes in order to verify if DHA interferes with DXR-induced cardiotoxicity too. [Ca(2+)](i) was measured by microfluorimetry. Our data demonstrated that 100 microM DXR induced a statistically significant [Ca(2+)](i)-increase in cardiomyocytes perfused with CaCl(2) Krebs solution (from 135.7 +/- 15 nM to 560.2 +/- 49 nM, n = 9, p < 0.01) and with Ca(2+)-free Krebs solution (from 89.3 +/- 15 nM to 551.1 +/- 35 nM, n = 9, p < 0.01). Treatment with 10 microM DHA for 20 min significantly suppressed DXR [Ca(2+)](i)- increase in cells perfused with CaCl(2) Krebs solution (142.3 +/- 12 nM, n = 9, p < 0.01) and in Ca(2+)-free procedures (100.4 +/- 12 nM, n = 9, p < 0.01). Caffeine 10 mM significantly increased [Ca(2+)](i) in cardiomyocytes perfused with CaCl(2) Krebs solution (from 135.7 +/- 15 nM to 979.2 +/- 17.8 nM, n = 9, p < 0.01) and with Ca(2+)-free Krebs solution (from 89.3 +/- 15 nM to 891.1 +/- 30 nM, n = 9, p < 0.01). Treatment with 10 microM DHA for 20 min suppressed caffeine [Ca(2+)](i)-increase in cardiomyocytes perfused with CaCl(2) Krebs solution (174.2 +/- 28 nM, n = 9, p < 0.01) and in Ca(2+)-free procedures (161.9 +/- 34 nM, n = 9, p < 0.01). In conclusion, our results suggest that DHA is able to prevent acute modifications of calcium homeostasis induced by DXR probably interfering with SR Ca(2+) release channels.

Animals↗
PubMed2002

Effects of docosahexaenoic acid on calcium pathway in adult rat cardiomyocytes.

In this study we examined the effect of polyunsaturated fatty acids (PUFAs), in particular of docosahexaenoic acid (DHA), on calcium homeostasis in isolated adult rat cardiomyocytes exposed to KCl, ET-1 and anoxia. Free [Ca(2+)](i) in rat cardiomyocytes was 135.7 +/- 0.5 nM. Exposure to 50 mM KCl or 100 nM ET-1 resulted in a rise in free [Ca(2+)](i) in freshly isolated cells (465.4 +/- 15.6 nM and 311.3 +/- 12.6 nM, respectively) and in cultured cells (450.8 +/- 14.8 nM and 323.5 +/- 14.8 nM respectively). An acute treatment (20 minutes) with 10 microM DHA significantly reduced the KCl- and ET-1-induced [Ca(2+)](i) increase (300.9 +/- 18.1 nM and 232.08 +/- 11.8 nM, respectively). This reduction was greater after chronic treatment with DHA (72 h; 257.7 +/- 13.08 nM and 192.18 +/- 9.8 nM, respectively). Rat cardiomyocytes exposed to a 20 minute superfusion with anoxic solution, obtained by replacing O(2) with N(2) in gas mixture, showed a massive increase in cytosolic calcium (1200.2 +/- 50.2 nM). Longer exposure to anoxia induced hypercontraction and later death of rat cardiomyocytes. Preincubation with DHA reduced the anoxic effect on [Ca(2+)](i) (498.4 +/- 7.3 nM in acute and 200.2 +/- 12.2 nM in chronic treatment). In anoxic conditions 50 mM KCl and 100 nM ET-1 produced extreme and unmeasurable increases of [Ca(2+)](i.) Preincubation for 20 minutes with DHA reduced this phenomenon (856.1 +/- 20.3 nM and 782.3 +/- 7.6 nM, respectively). This reduction is more evident after a chronic treatment with DHA (257.7 +/- 10.6 nM and 232.2 +/- 12.5 nM, respectively). We conclude that in rat cardiomyocytes KCl, ET-1 and anoxia interfered with intracellular calcium concentrations by either modifying calcium levels or impairing calcium homeostasis. Acute, and especially chronic, DHA administration markedly reduced the damage induced by calcium overload in those cells.

Animals↗
PubMed2002

Antibiotic use in an Italian university hospital.

The aim of this retrospective observational study was to investigate: a) expenditure for antibiotics with respect to the total pharmacy drug budget and to costs of other medical devices; b) the most frequently used antimicrobial classes and molecules; c) the clinical units that most frequently use antimicrobial therapy; d) the preferred route of administration; e) consumption patterns of antibiotics over two periods (January-September 1999 and January-September 2000). The consumption of a single antimicrobial agent was expressed as daily defined doses (DDD) per 100 bed days. In 1999 drugs accounted for 56% of the total costs but decreased to 46% in 2000. Antibiotics accounted for 15% of the pharmacy's overall acquisition costs in 1999 and dropped to 13% in 2000. In both 1999 and 2000, penicillins were used most, followed by cephalosporins and aminoglycosides. In 1999, the most frequently used antibiotic was amoxicillin (4.02 DDD per 100 bed days) followed by ceftazidime, ampicillin, ceftriaxone, and co-amoxiclav. In 2000 ceftriaxone was the most commonly used antibiotic (4.35 DDD per 100 bed days) followed by co-amoxiclav, amoxicillin, ceftazidime. The general surgery, medical therapy and infectious diseases units accounted for the majority of penicillin consumption, while cephalosporins were most widely used in general surgery, orthopedics and neurosurgery units. Parenteral administration was the most widely used route in both years.

Anti-Bacterial Agents↗
PubMed2001

Nebivolol and airway responsiveness in the rabbit.

Beta-adrenergic receptor antagonists are currently used as first-line therapy in the treatment of hypertension and angina pectoris, but are contraindicated or used with caution in patients with bronchospastic syndromes. In this study we evaluated in vivo the effects of nebivolol on airway responsiveness compared to atenolol, pindolol, and propranolol. In New Zealand white rabbits total lung resistance (R(L)) and dynamic compliance (Cdyn) were calculated. In acute protocol, the animals were intravenously injected with the beta-blockers at different doses while in the chronic protocol, animals were daily injected for 30 days. Furthermore, the changes induced by beta-blockers (higher doses) in R(L) and Cdyn after a treatment with salbutamol were calculated. In acute treatment, airway responsiveness to histamine was not modified by nebivolol at any dosage, but increased significantly following the exposure to the higher doses of the other beta-blockers. In chronic treatment, the thirty-day exposure to nebivolol, did not modify the airway responsiveness to histamine, whereas the other beta-blockers significantly increased airway responsiveness. Moreover, nebivolol affected the salbutamol-induced relaxation less markedly than other beta-blockers do. These data demonstrate that nebivolol respect the other beta-blockers used in this study, does not significantly affect the airway responsiveness, therefore it could be used in patients with both cardiovascular and bronchial diseases more safely than other beta-blockers drugs.

Adrenergic beta-Antagonists↗
PubMed2001

Endothelin-1 increases cholinergic nerve-mediated contraction of human bronchi via tachykinin synthesis induction.

1. In some asthmatics, muscarinic receptor antagonists are effective in limiting bronchoconstrictor response, suggesting an abnormal cholinergic drive in these subjects. There is a growing body of evidences indicating that cholinergic neurotransmission is also enhanced by endothelin-1 (ET-1) in rabbit bronchi, mouse trachea and in human isolated airway preparations. 2. We investigated the role of secondary mediators in ET-1 induced potentiation of cholinergic nerve-mediated contraction in human bronchi, in particular the possible role of neuropeptides in this phenomenon. 3. Bronchial tissues after endothelin treatment were exposed to a standard electrical field stimulation (EFS) (30% of EFS 30 Hz)-induced contraction. In addition, in some experiments, preparations were treated with a tachykinin NK(2) receptor antagonist and subsequently exposed to the same protocol. HPLC and RIA were performed on organ bath fluid samples. Moreover, the human bronchi were used for the beta-PPT (preprotachykinin) mRNA extraction and semiquantitative reverse transcription polymerase chain reaction (RT - PCR), prior to and 30-40 min following ET-1 challenge. 4. The selective tachykinin NK(2) receptor antagonist, SR48968, was effective to reduce ET-1 potentiation of EFS mediated contraction. HPLC or RIA showed significant increased quantities of NKA in organ bath effluents after EFS stimulation in bronchi pretreated with ET-1. Finally, beta-PPT mRNA level after stimulation of bronchi with ET-1 was increased about 2 fold respect to control untreated bronchi. 5. In conclusion, this study demonstrated that, at least in part, the ET-1 potentiation of cholinergic nerve-mediated contraction is mediated by tachykinin release, suggesting that in addition to nerves, several type of cells, such as airway smooth muscle cell, may participate to neuropeptide production.

Acetylcholine↗
PubMed2001

Effects of nebivolol on human platelet aggregation.

It has been documented that beta-adrenergic antagonists can influence platelet aggregation by a mechanism independent of their ability to antagonize beta-adrenoceptors. Nebivolol, a selective beta1-adrenergic receptor antagonist with additional hemodynamic effects, is able to vasodilate human forearm vasculature by acting on the L-arginine/nitric oxide pathway. Constitutive nitric oxide synthase is present also in human platelets, resulting in the formation of nitric oxide, an endogenous inhibitor of platelet aggregation. The aim of this study was to investigate the effects of nebivolol on platelet aggregation and in particular to determine the involvement of the platelet L-arginine/nitric oxide pathway. Propranolol, a nonselective beta-adrenergic antagonist, and carvedilol, a beta-blocker with vasodilating properties, were compared with nebivolol on platelet activity. Plasma from healthy male subjects was used. Platelet aggregation was achieved with adenosine diphosphate (ADP) (3 microM) and collagen (1 microg/ml), using the Born turbidimetric method to measure platelet aggregation. Our results showed that nebivolol, propranolol, and carvedilol all had an inhibitory effect on both ADP- and collagen-induced platelet aggregation. Nebivolol exhibited the greatest inhibition effect on platelet aggregation. The mechanism responsible for the inhibitory effect of nebivolol appeared to involve a nitric oxide-dependent pathway. Indeed, L-arginine augmented the inhibitory effects of nebivolol on platelet aggregation induced by collagen and ADP. Furthermore, the inhibitory effect of nebivolol on platelet aggregation was reduced in the presence of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). In conclusion, we have demonstrated in this study that nebivolol's mechanism of platelet aggregation inhibition differs from that of other beta-adrenergic antagonists by being partially dependent on nitric oxide production.

Adenosine Diphosphate↗
PubMed2000

Periaqueductal gray matter metabotropic glutamate receptors modulate formalin-induced nociception.

The role played by periaqueductal gray (PAG) matter metabotropic glutamate receptors (mGluRs) in the modulation of persistent noxious stimulation was investigated in mice. The formalin test was used as a model of persistent pain. Intra-PAG microinjections of (S)-3, 5-DHPG (25 and 50 nmol/mouse) and L-CCG-I (30 and 60 nmol/mouse), agonists of group I and group II mGluRs, respectively, decreased the nociceptive response (-92+/-6% and -89+/-8%, respectively) during the late phase. No change of the early nociceptive phase was observed after (S)-3,5-DHPG or L-CCG-I treatments. These effects were antagonized by a pretreatment with CPCCOEt (40 nmol/mouse) and (2S)-alpha-EGlu (30 nmol/mouse). CPCCOEt is a selective antagonist of group I mGlu receptors, while (2S)-alpha-EGlu is an antagonist of group II. Intra-PAG microinjections of L-SOP (60 and 120 nmol/mouse), a selective agonist of group III mGluRs, induced an increase of the nociceptive response (+95+/-7%) during the late hyperalgesic phase. (R,S)-alpha-M-SOP (70 nmol/mouse), a selective antagonist of group III mGluRs, completely antagonized the L-SOP-induced effect. These results show that PAG mGluRs participate in modulating the late hyperalgesic behaviours induced by formalin. It seems, therefore, possible that group I and group II mGluRs positively modulate PAG antinociceptive descending pathway following a persistent noxious stimulation, while group III mGluRs modulate it negatively.

Animals↗
PubMed2000

Role of hyperbaric oxygen exposure in reduction of lipid peroxidation and in multiple organ failure induced by zymosan administration in the rat.

The aim of the present study was to evaluate the effects of hyperbaric oxygen (HBO) therapy on multiple organ failure induced by zymosan. Administration of zymosan (500 mg/kg) in the rat induced neutrophil infiltration in the lung, liver, and intestine as evaluated by increase in myeloperoxidase (MPO) activity. Therefore, lipid peroxidation was significantly increased in zymosan-treated rats. This inflammatory process coincided with the damage of lung, liver, and small intestine. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine in the lung, liver, and small intestine of zymosan-shocked rats. HBO (2 absolute Atmosphere) exposure attenuates the increase in the tissue levels of MPO and malondialdehyde (MDA) caused by zymosan in the lung, liver, and intestine. In addition, HBO (2 absolute Atmosphere) was effective in preventing the development of lung, liver, and intestine injury. Taken together, the present results demonstrate that HBO may also be an efficacious treatment in multiple organ failure induced by zymosan.

Animals↗
PubMed1999

Periaqueductal gray matter glutamate and GABA decrease following subcutaneous formalin injection in rat.

Glutamate and GABA are important nociception modulating transmitters in specific brain regions, i.e. the spinal cord, the thalamic nuclei and the periaqueductal gray (PAG). However, quantitative and topographical changes in glutamate and GABA release in these brain regions during peripheral inflammation episodes have not been characterized in awake animals. To address this issue, an in vivo microdialysis study was carried out in freely moving rats in order to analyze PAG extracellular glutamate and GABA concentrations following unilateral formalin injection into the dorsal skin of the right hind-paw. Both glutamate and GABA release decreased after the injection of formalin during phase I and phase II of hyperalgesia. Because naloxone prevented the decrease of GABA and glutamate release induced by formalin, this study shows that, in vivo, a nociceptive stimulation may activate opioidergic fibres into the PAG. The increased release of endogenous opioids may, in turn, inhibit the activity of the GABAergic neurons (i.e. opioid disinhibition). Formalin injection also decreased extracellular glutamate concentration. However, we found that intra-PAG perfusion with tetrodotoxin only decreased GABA, but not glutamate dialysate values. Although it should be reasonable to speculate that opioids also inhibit glutamate fibres, further investigation is needed to clarify whether or not the dialysate glutamate we measured reflects change in the metabolism or neurotransmitter pool of this amino acid.

Analysis of Variance↗
PubMed1999

Endothelin-1 affects capsaicin-evoked release of neuropeptides from rat vas deferens.

Capsaicin-sensitive neurones release a number of neuropeptides, such as substance P, neurokinin A, somatostatin and calcitonin gene-related peptide (CGRP), which exert a number of effects on smooth muscle tissues. Endothelin-1 was thought to potentiate the capsaicin-evoked release of neuropeptides from sensory neurones of the rat. We have investigated the neuromodulatory effects of endothelin-1 on capsaicin-induced release of neurotransmitters from rat vas deferens. Capsaicin and human alpha calcitonin gene-related peptide (human alphaCGRP) reduced the rat vas deferens twitch responses induced by electrical field stimulation. Human beta calcitonin gene-related peptide-(8-37) [human betaCGRP-(8-37)] (1 microM), a selective alphaCGRP receptor antagonist, antagonized the inhibitory effects of both drugs. Endothelin-1 concentration dependently evoked an increase in basal tone of the musculature and potentiated the amplitude of the electrically stimulated responses, blocking inhibitory effects of capsaicin but not of human alphaCGRP. Moreover, endothelin-1 did not markedly change the inhibitory effects of papaverine (0.1-100 microM) or isoprenaline (1 nM-100 microM) on responses to electrical field stimulation. FR 139317 [(N,N-hexamethylene) carbamoyl-Leu-D-Trp(N-Me)-D-2-Pya], a selective endothelin ET(A) receptor antagonist, administered 30 min before endothelin-1 restored the capsaicin effects whereas BQ 788 [Dmpc-gamma-MeLeu-D-Trp-(1-methoxycarbonyl)-D-Nle], a selective endothelin ET(B) receptor antagonist, was completely ineffective. The endothelin-1-induced block of the capsaicin effect was resistant to tetrodotoxin (1 microM) and 30-min pre-treatment with MEN 10.627 (cyclo[(Met-Asp-Trp-Phe-Dap-Leu) cyclo (2beta-5beta)]), a selective tachykinin NK2 receptor antagonist, did not abolish the endothelin-1 effect on the inhibitory response to capsaicin. These results suggest that endothelin-1 selectively inhibits the capsaicin-induced release of neurotransmitters from rat vas deferens and these effects are mediated via endothelin ET(A) receptors but not by tachykinin release.

Animals↗
PubMed1999

Injection of endothelin-1 into the raphe obscurus of rats induces depressor responses predominantly through endothelin ET(A) receptors.

We used in vitro autoradiography to identify the endothelin-1 receptor subtype(s) in the nucleus raphe obscurus of rats. These studies showed dense binding of [125I]PD 151242 (for endothelin ET(A) receptors), while tissues incubated with [125I]BQ3020 (for endothelin ET(B) receptors) had low binding. In addition, we examined the effects of the endothelin receptor antagonists FR 139317 (endothelin ET(A) receptor-selective antagonist), SB 209670 (endothelin ET(A)/ET(B) receptor-non-selective antagonist) and BQ-788 (endothelin ETB receptor-selective antagonist) on the blood pressure responses following administration of endothelin-1 into the nucleus raphe obscurus. The basal mean arterial blood pressure (MABP) of the rats was 110+/-7 mmHg (n = 5). This was decreased in a dose-dependent manner by endothelin-1 (0.1, 1 and 10 pmol) microinjected into the nucleus raphe obscurus. This effect occurred within 1-6 s and recovered within 4+/-1.2 min at a dose of 10 pmol. The doses of 0.1 pmol and 1 pmol ET-1 had responses which lasted 1+/-0.4 min and 2+/-0.2 min, respectively. Small decreases in heart rate accompanied the MAP responses to endothelin-1. For instance, the heart rate decreased by 16+/-4 beats min(-1) after 10 pmol endothelin-1 (control, 366+/-6 beats min(-1), n = 5). Decreases in blood pressure induced by endothelin-1 were greatly reduced by pre-administration to the nucleus raphe obscurus of FR139317 (5 nmol/rat) or SB209670 (3 nmol/rat; 97+/-7% and 95+/-6%, P < 0.01, n = 5, respectively), but were not affected by BQ-788 (50 nmol/rat; 8+/-3%, P > 0.05, n7 = 5). The antagonists did not influence heart rate when injected to the nucleus raphe obscurus prior to endothelin-1. FR 139317 (0.5 nmol) and SB209670 (0.3 nmol) had no effects on endothelin-induced changes in arterial blood pressure. Therefore, the autoradiographic study showed that there are binding sites for ET-1 within the nucleus raphe obscurus of rats, which are predominantly of ET(A) type. The in vivo study showed that ET(A) receptors are the predominant mediators of depressor responses induced by endothelin-1 injected into this nucleus.

Animals↗
PubMed1999

Endothelin-1 induced bronchial hyperresponsiveness in the rabbit: an ET(A) receptor-mediated phenomenon.

Endothelin-1 (ET-1) is a potent and efficacious spasmogen of airway smooth muscle. Recent observations suggest that an increased intrapulmonary production of ET-1 may occur in asthma. Our previous study showed that endothelin-1 induced bronchial hyperresponsiveness to inhaled histamine in the rabbit. The aim of this study was to investigate whether the ET(A) and ET(B) receptors mediate the bronchial hyperresponsiveness induced by endothelin-1 in the rabbit. Our data showed that bronchial hyperresponsiveness induced by ET-1 was significantly inhibited (P<0.01) by the ET(A) receptor-selective antagonist, FR 139317 (from 2.5 to 10 mg kg(-1)). Moreover, bosentan (from 2.5 mg kg(-1) to 10 mg kg(-1)), an ET(A)/ET(B) receptor antagonist, also inhibited the bronchial hyperresponsiveness achieved 24 h following endothelin-1 challenge (P<0.01), but with no difference from FR 139317. The ET(B) receptor agonist, sarafotoxin S6c (from 25 microg to 2.5 mg kg(-1)) did not modify airway responsiveness to inhaled histamine in the rabbit. These results indicate that bronchial hyperresponsiveness induced by ET-1 may be mediated by ET(A) receptor activation.

Administration, Inhalation↗
PubMed1999

Endothelin receptor antagonists reduce the pressor effects of angiotensin II into the periaqueductal gray area of rats.

Injection of ANGII (0.01, 0.1 and 1 nmol/rat) into the periaqueductal gray (PAG) area significantly (P<0.01) increased, in a dose-dependent manner, the mean arterial blood pressure (MAP). The increases in blood pressure induced by ANGII (1 nmol; 37 +/- 4 mmHg, n=5) were greatly reduced (>85%) by pre-administration of the ET(A) receptor antagonist FR139317 (5 nmol/rat) to the PAG area, but were unaffected by the ET(B) receptor antagonist BQ-788 (5 nmol/rat). SB209670, non-selective ET(A)/ET(B) receptor antagonist, also reduced the effect induced by ANGII. These results suggest that endogenous endothelin-1, via an action on ET(A) receptors, may contribute to the pressor effects of ANGII within the PAG area of rats.

Angiotensin II↗
PubMed1999

Effect of hyperbaric oxygen therapy in experimental subcutaneous and pulmonary infections due to Pseudomonas aeruginosa.

About 80% of nosocomial infections are caused by aerobic bacteria. Pseudomonas aeruginosa is a Gram-negative bacterium belonging to the Pseudomonadaceae family; P. aeruginosa is responsible for 6-22% of all hospital infections. The aim of this study was to evaluate the efficacy of hyperbaric oxygen (HBO2) therapy (2 atm abs x 55 min.day-1) alone for 8 days and combined with antibiotic chemotherapy (amikacin 15 mg.kg-1.day-1 for 8 days by intraperitoneal route) in rats infected subcutaneously and via the pulmonary route. In the rats infected by P. aeruginosa, HBO2 induced a reduction in mortality and morbidity with bacteria eradication in blood culture, bronchial aspirate, and skin biopsies when compared to control. These effects were increased by the use of amikacin, an antibiotic used for the treatment of sensitive Gram-negative bacteria.

Amikacin↗
PubMed1998

Neuronorm is a potent and water soluble neurokinin A receptor antagonist.

We report here the synthesis and preliminary pharmacological characterization of a novel water soluble Neurokinin A receptor antagonist named Neuronorm. The synthesis was achieved in high yield by a combination of classical peptide synthesis methodologies, in both solution and solid phase. The pharmacological properties as neurokinin A receptor antagonist were assessed in in vitro experiments on rat vas deferens and guinea pig trachea, and were compared to those of MEN10627.

Animals↗
PubMed1998

A novel super-potent neurokinin A receptor antagonist containing dehydroalanine.

We report here the synthesis and preliminary pharmacological characterization of a novel Neurokinin A receptor antagonist. This molecule contains a dehydroalanine residue. It displays a high conformational rigidity and possesses very high activity. Its pharmacological properties as a neurokinin A receptor antagonist were assessed in in vitro experiments on rat vas deferens and were compared to those of Neuronorm and MEN10627.

Alanine↗
PubMed1998

Research on heterocyclic compounds, Part 40. 2-Phenylimidazo[1,2-a]pyridine-3-carboxylic acid derivatives: synthesis and antiinflammatory activity.

A series of 2-phenylimidazo[1,2-a]pyridine-3-carboxylic esters, acids, and amides were synthesized and pharmacologically tested in order to evaluate their antiinflammatory and analgesic activity and their ulcerogenic action on the gastro-intestinal tract. The most active member of this series of compounds was found to be 6-methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylic acid (5c).

Animals↗