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P Angeli

Publications and source records attributed to P Angeli.

At least 73 records · Page 4Linked to original sources
PubMed1996

Bicyclic dioxolanes as potential antimuscarinic agents.

A series of rigid compounds--derivatives of 2,2-diphenyl-[1,3]-dioxolan-4-ylmethyl-dimethylamine methiodide (1b)--has been synthesized and tested to evaluate affinity and selectivity for M1, M2, and M3 muscarinic receptors. The stereochemistry of the annulation does not influence the activity; the optimal distance between nitrogen and the benzhydryl group seems to be that with the nitrogen in the rigid ring (2b) or the nitrogen directly bound at the cyclopentane nucleus (9b, 11b). The different structure-activity relationships between tertiary amines (a series) and the corresponding quartnerary salts (b series) suggest a different binding to the receptor sites.

Animals↗
PubMed1995

Treatment of patients with cirrhosis and refractory ascites using LeVeen shunt with titanium tip: comparison with therapeutic paracentesis.

It has recently been suggested that insertion of a titanium tip at the venous end of the LeVeen shunt drastically reduces the rate of shunt obstruction. To assess whether the LeVeen shunt with titanium tip improves the results obtained with therapeutic paracentesis, 81 patients with cirrhosis and refractory ascites were randomly assigned to therapy with paracentesis plus intravenous albumin (42 patients) or LeVeen shunt with titanium tip (39 patients). If patients were readmitted for ascites during follow-up, those in the first group were treated with paracentesis, and those in the LeVeen shunt group by the insertion of a new valve or a new shunt if obstruction was demonstrated. During first hospitalization, both treatments were equally effective in removing ascites. Complications were similar in both groups except for a higher rate of severe bacterial infection in the LeVeen shunt group. The mean duration of hospitalization was shorter in the paracentesis group than in the shunt group. During follow-up, the total number of readmissions and the number of readmissions for ascites were higher in the paracentesis group than in the shunt group (252 vs. 99, P < .001; and 193 vs. 43, P < .001, respectively). The total time in hospital, however, was similar (38 +/- 38 vs. 39 +/- 43 days, P = NS). Three patients had obstruction of the shunt during first hospitalization and 14 patients had a total of 22 obstructions during follow-up. Long-term survival was similar in both groups. The insertion of a titanium tip at the venous end of the LeVeen shunt does not prevent obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Long-term effect of nadolol or nadolol plus isosorbide-5-mononitrate on renal function and ascites formation in patients with cirrhosis. GTIP Gruppo Triveneto per l'Ipertensione Portale.

The association beta-blockers plus nitrates has been reported to impair renal function and renal sodium handling, leading to increased risk of development of ascites, or worsening of a preexisting ascites, or increase in the requirements of diuretic agents. In 81 patients with cirrhosis and esophageal varices, participating in a multicenter controlled clinical trial of prophylaxis of variceal bleeding comparing nadolol (NAD) plus isosorbide-5-mononitrate (I5M) with NAD alone, renal function, presence of ascites, and diuretic requirements were assessed at inclusion and after 6 months of follow-up. No significant variation in s-urea or s-creatinine was observed in either group, Three patients in the nadolol group and two in the NAD plus I5M developed ascites at 6 months (P = .70), and a need to increase diuretic regimen was observed in four and three patients, respectively (P = .76). Decrease in heart rate and in mean arterial pressure was similar in the two groups. There was a significant correlation between increases in s-creatinine and decrease in mean arterial pressure in the whole series (P = .015). Only in patients treated with the association was there a significant larger proportion of patients ascitic who became anascitic, than of patients anascitic who became ascitic (P = .03). In patients treated with the association, there was a significantly larger decrease in hepatic venous pressure gradient (P = .05). It is concluded that patients treated with the association NAD plus I5M are not at increased risk of developing renal dysfunction or worsening of ascites compared with patients treated with NAD alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Selective blockade of muscarinic M2 receptors in vivo by the new antagonist tripitramine.

The antimuscarinic effects of tripitramine (1, 1, 24--tris[[5, 11-dihydro-6-oxo-6H-pyrido [2,3-b][1,4]- benzodiazepin-11-yl)carbonyl]methyl]-8, 17-dimethyl-1, 8, 17, 24-tetraazatetracosane tetraoxalate), a member of a series of polymethylene tetraamines with in vitro cardioselectivity, were assessed in two in vivo preparations: anaesthetized and pithed rats. The well-known M2 selective antagonist methoctramine was used in a comparative study. Tripitramine (0.0202 mumol/kg i.v.) proved to be a potent antagonist at cardiac M2 receptors that mediate the decrease in heart rate in the pithed rat; the same dose of this antagonist in the anaesthetized rat did not significantly affect the depressor action of methacholine mediated by vascular M3 receptors. In the pithed rat, this dose did not affect the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarine or McN-A-343. These in vivo data are consistent with the in vitro findings and confirm that tripitramine is a more potent and selective muscarinic M2 receptor antagonist than methoctramine.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1995

Hepatic arterial resistance in cirrhosis with and without portal vein thrombosis: relationships with portal hemodynamics.

BACKGROUND/AIMS: Little information is available on hepatic arterial hemodynamics in cirrhosis because of the invasiveness of methods. Hepatic arterial resistance indexes were evaluated noninvasively by Doppler ultrasonography and were correlated with portal hemodynamics evaluated both noninvasively and invasively. METHODS: Hepatic arterial resistance indexes, portal blood flow velocity and volume, and portal vein congestion index were evaluated in 31 controls and 171 cirrhotic patients with (n = 13) or without (n = 158) portal vein thrombosis. Resistance to portal blood flow was also calculated in 15 patients from hepatic venous pressure gradient, measured by hepatic vein catheterization, and portal blood flow. RESULTS: Resistance indexes were significantly higher in cirrhotics without portal thrombosis than in controls (pulsatility index, 1.30 +/- 0.29 vs. 0.89 +/- 0.09; P < 0.001; resistive index, 0.71 +/- 0.07 vs. 0.59 +/- 0.04; P < 0.001). In patients with portal thrombosis, the pulsatility index (1.86 +/- 0.39) and resistive index (0.81 +/- 0.06) were significantly higher than in controls (P < 0.001) and in patients without thrombosis (P < 0.001). Resistance indexes directly correlated with portal resistance (P < 0.01), the congestion index (P < 0.01), and the degree of esophageal varices (P < 0.01). CONCLUSIONS: Hepatic arterial resistance indexes increase in cirrhosis, particularly with portal vein thrombosis. The pathophysiology of the increase in hepatic arterial resistance seems to be parallel to that of portal resistance.

Adult↗
PubMed1995

Aquaretic effect of the kappa-opioid agonist RU 51599 in cirrhotic rats with ascites and water retention.

BACKGROUND & AIMS: It has recently been described that kappa-opioid receptor agonists inhibit antidiuretic hormone secretion and promote water excretion in humans and experimental animals. The aim of this study was to evaluate the aquaretic efficacy of the kappa-opioid receptor agonist RU 51599 in conscious cirrhotic rats with ascites and water retention. METHODS: In protocol 1, arterial pressure, heart rate, and renal water metabolism were measured in basal conditions and then were measured for 120 minutes after the administration of Ringer's solution (n = 8; 0.4 mL) or RU 51599 (n = 7; 1 mg/kg). In protocol 2, plasma antidiuretic hormone concentration was measured (n = 6) before and 60 minutes after administration of RU 51599 (1 mg/kg). In protocol 3, the effect of RU 51599 (n = 9; 1 mg/kg) was compared with that of the V2-receptor antagonist SKF 100398 (n = 9; 30 micrograms/kg). RESULTS: RU 51599 administration induced a profound diuretic and aquaretic effect without altering arterial pressure and heart rate. In protocol 2, the kappa-opioid agonist reduced by about 50% plasma antidiuretic hormone levels (from 6.6 +/- 0.9 to 3.4 +/- 0.6 pg/mL; P < 0.05). Finally, the improvement in renal water metabolism induced by RU 51599 was similar to that produced by the V2-receptor antagonist. CONCLUSIONS: RU 51599 has a potent aquaretic effect in cirrhotic rats with water retention, suggesting that kappa-opioid receptor agonists may be useful for the treatment of water retention and dilutional hyponatremia in cirrhosis.

Analysis of Variance↗
PubMed1995

Stimulation of cholinergic receptors in the medial preoptic area affects sleep and cortical temperature.

The medial preoptic area (MPA), a cholinoceptive brain area devoid of cholinergic cells, plays an important role in the regulation of different physiological functions, particularly sleep control and thermoregulation. To investigate the effects of the stimulation of cholinergic receptors in this area on sleep and cortical temperature (Tcort), carbachol (a mixed cholinergic agonist) was directly microinjected into the MPA of freely moving rats. Carbachol (0.25 and 0.5 microgram, corresponding to 1.37 and 2.74 nmol) microinjection induced an increase in wakefulness and an inhibition of both slow wave and desynchronized sleep phases. The temperature of the cerebral cortex was reduced in comparison with control conditions (saline microinjection). Sterile needle insertion and saline microinjections induced a significant increase in Tcort, but no changes in the sleep-wake cycle compared with the handling of the animal. The results suggest that 1) carbachol microinjection into the MPA can activate an arousal-generating system and affect thermoregulatory mechanisms, and 2) sleep and temperature responses may be dissociated.

Animals↗
PubMed1995

Pentatomic cyclic agonists and muscarinic receptors: a 20 years review.

The results of 20 years of structure-activity relationship (SAR) studies of pentatomic cyclic agonists on muscarinic receptors are reported and commented. Our results are compared with the findings obtained from quantitative structure-activity relationship (QSAR) studies and from those of molecular biology. The results from all three approaches point in the same direction and should help in the future design of new muscarinic agonists.

Animals↗
PubMed1995

Role of nitric oxide and prostacyclin in the control of renal perfusion in experimental cirrhosis.

Nitric oxide (NO) and prostacyclin (PGI2) are two important modulators of renal function under normal conditions; however, little is known on their contributory role in cirrhosis with ascites. In this study, mean arterial pressure, renal hemodynamics, and sodium excretion were measured in 15 rats with cirrhosis and ascites and 16 control rats. Animals were studied in normal conditions, after inhibiting the synthesis of NO (N omega-nitro-L-arginine, 50 micrograms.kg-1.min-1) or prostaglandins (lysin acetylsalicylate, 15 mg.kg-1).min-1 and following the concomitant inhibition of both systems. Cirrhotic rats showed increased systemic pressure sensitivity and blunted renal vasoconstrictor response to nitric oxide inhibition as compared with control rats. As a consequence, the glomerular filtration rate increased in cirrhotic rats but not in control rats. In both groups of animals, NO inhibition was associated with significant increased urinary sodium and fractional sodium excretion. The only significant effect observed after prostaglandin biosynthesis inhibition was a decrease in renal plasma flow in cirrhotic rats. The concomitant inhibition of both systems reduced renal plasma flow and did not change glomerular filtration rate, with no differences between control and cirrhotic rats. Prostaglandin inhibition did not prevent the natriuretic effect of the NO inhibitor in both groups of animals. These results indicate that in experimental cirrhosis both NO and PGI2 play an important role in the maintenance of renal perfusion within normal limits.

Animals↗
PubMed1994

Selective blockade of different brain stem muscarinic receptor subtypes: effects on the sleep-wake cycle.

Changes induced in the sleep-wake cycle by pontine microinjections of muscarinic antagonists were studied in freely moving rats, instrumented for chronic polygraphic recordings. Pirenzepine (PIR), methoctramine (MET) and p-fluoro-hexahydro-siladifenidol (p-F-HHSiD), which are highly selective M1, M2 and M3 antagonists, respectively, were dissolved in 0.1 microliter of sterile isotonic saline (0.2 microliter of distilled water for p-F-HHSiD) and injected into the pontine reticular nucleus, where the administration of 0.5 microgram carbachol (a mixed muscarinic agonist) induced a 52% increase in the amount of desynchronized sleep (DS) over a 6 h recording period. The blockade of M2 receptors was shown to (i) antagonize DS, by increasing its latency and decreasing its percentage, (ii) decrease slow wave sleep, and (iii) enhance wakefulness. These effects were dose-dependent. No changes in the sleep-wake cycle were observed following microinjection of M1 or M3 antagonists. The results support the hypothesis that at the brain stem level only M2 receptors are involved in sleep mechanisms and, particularly, in the generation and maintenance of DS.

Animals↗
PubMed1994

Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis.

BACKGROUND: Several studies carried out in a limited number of patients demonstrated a wide range of overestimation of glomerular filtration rate (GFR) by serum creatinine level and creatinine clearance (Ccr) in liver disease. METHODS: We simultaneously evaluated Ccr, inulin clearance, and predicted GFR calculated from serum creatinine level in 56 cirrhotic patients. Inulin clearance was considered the gold standard for GFR evaluation. RESULTS: The sensitivity of serum creatinine level, predicted GFR, and Ccr in detecting renal failure was 18.5%, 51%, and 74%, respectively. On the basis of inulin clearance, patients were divided into two groups: those with normal GFR (mean, 106 +/- 34 mL/min per 1.73 m2) (group 1, 29 patients) and those with reduced GFR (mean, 56 +/- 19 mL/min per 1.73 m2) (group 2, 27 patients). Predicted GFR and Ccr were accurate markers of GFR in group 1 patients, while both overestimated GFR by about 50% in group 2 patients. An increased tubular secretion of creatinine accounted for the disparity between Ccr and inulin clearance in these patients. CONCLUSIONS: Our results indicate that renal failure is greatly underestimated on the basis of serum creatinine level and Ccr in cirrhotic patients. Clinical implications of this observation include excessive dosage of potentially nephrotoxic drugs and failure to recognize renal impairment induced by such medical treatments as diuretic therapy or paracentesis.

Adult↗
PubMed1994

Clinical significance of the evaluation of hepatic reticuloendothelial removal capacity in patients with cirrhosis.

The reticuloendothelial system plays an important role in the prevention of bacterial infection in patients with cirrhosis. Few data are available, however, on its activity in such patients. The aim of this study was to evaluate the maximum removal capacity of hepatic reticuloendothelial system in patients with cirrhosis on the basis of study of the removal kinetics of increasing amounts of 99mTc millimicrospheres and to verify its value as a prognostic factor for death and development of spontaneous bacterial peritonitis. Common clinical and biochemical parameters, Pugh score, maximum removal capacity, aminopyrine metabolic capacity and galactose elimination capacity were measured in 43 patients with cirrhosis (33 with alcoholic cirrhosis, 8 with posthepatitic cirrhosis and 2 with cryptogenic cirrhosis). Hepatic plasma flow and indocyanine green plasma clearance were also measured in 16 of these patients. Reference range of maximum removal capacity was determined in seven normal subjects. Maximal removal capacity below the normal range was found in 24 patients (56%). In the whole series maximum removal capacity averaged 16 +/- 12 micrograms/kg body wt/min (mean +/- S.D.). Maximal removal capacity was significantly correlated with serum albumin, prothrombin index, Pugh score, aminopyrine breath test, galactose elimination capacity and indocyanine green plasma clearance but not with hepatic plasma flow. During follow-up of up to 48 mo, spontaneous bacterial peritonitis developed in six patients, all with impaired maximum uptake capacity, and 11 patients died. Survival was significantly shorter in patients with impaired maximum removal capacity than in those with normal maximum removal capacity (log-rank test: p = 0.024).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Renal effects of natriuretic peptide receptor blockade in cirrhotic rats with ascites.

The aim of this study was to assess the effect of HS-142-1, a recently discovered specific antagonist of endogenous natriuretic peptides, on systemic hemodynamics, renal function, and the renin-aldosterone system in rats with cirrhosis and ascites. The study consisted of three protocols, each including 10 conscious control rats and 10 conscious rats with carbon-tetrachloride-induced cirrhosis with ascites. In protocol 1, HS-142-1 administration (by intravenous bolus of 20 mg.kg-1.body weight in all protocols) was not associated with significant changes in mean arterial pressure, heart rate, cardiac output or total peripheral resistance in the two groups of animals. In protocol 2, HS-142-1 induced a significant reduction in glomerular filtration rate (from 4.2 +/- 0.5 to 2.6 +/- 0.3 ml/min, p < 0.025) in control animals. A decrease in renal plasma flow and an increase in renal vascular resistance also occurred, but these changes were not statistically significant. In cirrhotic rats, HS-142-1 resulted in a significant decrease in renal plasma flow (from 10.9 +/- 0.7 to 4.3 +/- 0.6 ml/min, p < 0.001) and a significant increase in renal vascular resistance (from 6.0 +/- 0.6 to 16.3 +/- 2.7 mm Hg.min.ml-1, p < 0.025). Glomerular filtration rate decreased more in cirrhotic rats with ascites than in control rats (from 3.8 +/- 0.3 to 1.3 +/- 0.2 ml/min, p < 0.001). Changes in urine flow rate and urinary sodium excretion rate paralleled those of glomerular filtration rate in both groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Increased nitric oxide-dependent vasorelaxation in aortic rings of cirrhotic rats with ascites.

To assess whether aortic vessels of rats with cirrhosis and ascites possess an enhanced vascular response to endothelium-derived, nitric oxide-dependent vasodilators, we performed relaxation studies in isolated aortic rings of 21 control rats and 24 rats with carbon tetrachloride-induced cirrhosis and ascites. We carried out studies after contracting the vessels with norepinephrine. We measured endothelium-dependent vasodilator response by administering increasing concentrations of acetylcholine (10(-6) to 10(-2) mol/L) and ADP (10(-7) to 10(-4) mol/L). We evaluated endothelium-independent response by giving increased concentration of sodium nitrite (10(-5) to 10(-2) mol/L). The maximal absolute tension developed in response to norepinephrine was significantly decreased in cirrhotic rings (816 +/- 72 mg, p < 0.025) compared with control (1,425 +/- 75 mg) rings. Dose-response curves for endothelium-dependent vasodilators were shifted to the left in aortic rings of cirrhotic rats, and EC50 for acetylcholine and ADP were significantly decreased in cirrhotic (0.8 +/- 0.15 mmol/L and 0.42 +/- 0.16 mumol/L, p < 0.025 and p < 0.01, respectively) than in control rings (1.91 +/- 0.33 mmol/L and 3.09 +/- 0.82 mumol/L). In both acetylcholine- and ADP-stimulated vessels, differences between cirrhotic and control rings disappeared after nitric oxide synthesis inhibition with N omega-nitro-L-arginine (10(-4) mol/L). No difference in the relaxing effect of sodium nitrite was observed between cirrhotic and control rings. These results therefore demonstrate for the first time enhanced in vitro vascular responsiveness to nitric oxide-dependent vasodilators in rats with cirrhosis and ascites, giving further support to the concept that nitric oxide activity is increased in cirrhosis.

Acetylcholine↗
PubMed1994

Dialkylaminoalkyl esters of 2,2-diphenyl-2-alkylthioacetic acids: a new class of potent and functionally selective muscarinic antagonists.

The synthesis and pharmacological activity as muscarinic antagonists of a number of 2-alkylthio-2,2-diphenylacetic acid esters are reported. The compounds studied are potent muscarinic antagonists and many of them show from moderate to high selectivity toward M2 or toward M1 and M2 receptors when tested on tissues but lack selectivity on five muscarinic human receptors (m1-m5) cloned and expressed in CHO-K1 cells. As a consequence, the compounds behave as functionally selective antagonists. Those showing M2 selectivity appear to be good drug candidates for the treatment of cognitive disorders connected with central cholinergic deficit.

Animals↗
PubMed1994

HS-142-1, a potent antagonist of natriuretic peptides in vitro and in vivo.

To determine whether HS-142-1 (HS), a potent atrial natriuretic peptide (ANP) receptor antagonist, also inhibits the effects of brain natriuretic peptide (BNP), urodilatin (URO), and C-type natriuretic peptide, in vitro studies were carried out, demonstrating that HS inhibited production of cGMP by rat fetal lung fibroblast cells induced by ANP, BNP, URO, and C-type natriuretic peptide. Acute clearance studies were conducted in euvolemic Munich-Wistar rats under inactin anesthesia to characterize the effects of HS in vivo. In response to ANP, BNP, or URO (4 micrograms/kg priming dose plus 0.5 micrograms/kg per minute for 20 min), urine flow, absolute sodium excretion rates, and fractional sodium excretion exhibited similar increases (four- to fivefold) in vehicle-treated rats; these responses were, however, completely abolished by prior HS treatment. The tendency for GFR to rise during the infusion of natriuretic peptides (NP) was also blocked after HS. By contrast, HS did not block the renal effects of L-arginine, a precursor of nitric oxide, or of furosemide. Furthermore, the inhibition of endogenous NP by HS was associated with small but significant reductions in GFR and absolute and fractional sodium excretion in normal rats under euvolemic but not hydropenic conditions. These studies provide evidence that the observed effects of HS in vivo and in vitro are mediated exclusively by receptors of NP. Together, these data support the view that HS is a highly specific ligand for NP receptors, capable of antagonizing the renal effects not only of exogenous ANP, but also those of BNP and URO.

Animals↗
PubMed1994

1,3-oxathiolane muscarinic ligands modified at the cationic head.

In order to develop compounds which may be useful in the treatment of memory and cognitive disorders we have synthesized and tested some 1,3-oxathiolane derivatives bearing an amidine function instead of the classical ammonium head, with the aim of improving brain penetration. The compounds were tested on peripheral and central models of muscarinic receptors. The results show that, unlike for other series of muscarinic ligands, this modification results in the reduced potency of antagonists, shifts the activity of agonists toward weak antagonism and does not introduce any noteworthy subtype selectivity.

Amidines↗