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Jeannemarie Lecomte - One of the best experts on this subject based on the ideXlab platform.
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effects of Acetorphan an antidiarrhoeal enkephalinase inhibitor on oro caecal and colonic transit times in healthy volunteers
Alimentary Pharmacology & Therapeutics, 2007Co-Authors: J F Bergmann, P Baumer, S Chaussade, D Couturier, Jeancharles Schwartz, Jeannemarie LecomteAbstract:Acetorphan is a potent enkephalinase inhibitor displaying antidiarrhoeal activity attributable to its intestinal antisecretory action mediated by endogenous enkephalins. The effect of Acetorphan on digestive motility was studied in 12 healthy volunteers. Oro-caecal transit time was evaluated using the sulphasalazine/sulphapyridine method and colonic transit times using radiopaque markers. These measurements were successively performed after one week treatment with an antidiarrhoeal dose of Acetorphan (100 mg t.d.s.) or placebo. There was no significant modification in transit time linked to Acetorphan treatment: total oro-caecal times were 303 +/- 32 min vs. 287 +/- 27 min and colonic transit times 25.8 +/- 5.8 h vs. 31.3 +/- 5.5 h after Acetorphan and placebo, respectively (means +/- S.E.M.). There was no significant modification either in right colonic, left colonic or rectosigmoid segmental transit times, or in the mean number of stools. These results, consistent with those from animal studies, confirm that, unlike classical antidiarrhoeal mu opiate receptor agonists, which act by delaying intestinal transit, Acetorphan does not affect the transit. Antidiarrhoeal activity not accompanied by a delayed intestinal transit could have beneficial therapeutic consequences in the management of infectious diarrhoea. In addition, we show that the sulphasalazine and radiopaque markers methods can be simultaneously applied in the same study.
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racecadotril demonstrates intestinal antisecretory activity in vivo
Alimentary Pharmacology & Therapeutics, 1999Co-Authors: M P Primi, P Baumer, H Berard, L Bueno, Jeannemarie LecomteAbstract:Background Racecadotril (Acetorphan), a potent enkephalinase inhibitor, protects endogenous enkephalins from degradation. Racecadotril exhibits experimental and clinical antidiarrhoeal activity without any effect on intestinal motility, suggesting selective antisecretory activity. The antisecretory effect of racecadotril was directly assessed in the present study. Methods A 1 m, jejunal, Thiry–Vella loop was created in six mongrel dogs, and water and ionic fluxes were evaluated during infusion (2 mL/min) of Tyrode solution labelled with 14C-polyethylene glycol. Fluxes were determined both in the basal state and 5–6 h after commencement of a 2-h infusion of cholera toxin (0.4 μg/mL). Racecadotril (10 mg/kg) or vehicle was given orally with and without prior intravenous administration of naloxone (0.1 mg/kg) or phentolamine (0.2 mg/kg). Results Basal absorption remained unchanged following racecadotril administration; however, racecadotril significantly decreased (P = 0.01) cholera toxin-induced water, sodium, and potassium hypersecretion, from 0.73 ± 0.15 to 0.37 ± 0.13 mL/min; from 125.0 ± 16.1 to 14.7 ± 9.5 μMol/min; and from 3.41 ± 0.66 to 1.66 ± 0.61 μMol/min, respectively. This antisecretory activity of racecadotril was suppressed by naloxone but not by phentolamine. Conclusions This study directly demonstrates the antisecretory activity of racecadotril in relation to the protection of endogenous enkephalins.
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Acetorphan prevents cholera toxin induced water and electrolyte secretion in the human jejunum
European Journal of Gastroenterology & Hepatology, 1997Co-Authors: Thomas A Hinterleitner, Jeannemarie Lecomte, W Petritsch, Gudrun Dimsity, Hugues Berard, Guenter J KrejsAbstract:Objectives Acetorphan is an orally administered inhibitor of enkephalinase in the wall of the digestive tract. It prevents inactivation of endogenous opioid peptides released by submucosal and myenteric neurons. The aim of this study was to examine the effect of Acetorphan on jejunal water and electrolyte transport in healthy volunteers under basal conditions and in a state of intestinal secretion induced by a bacterial enterotoxin. Design Ten volunteers in two groups were studied in an open trial. For the experimental design an intestinal perfusion technique was used. Methods Cholera toxin was used to induce intestinal secretion in a model employing segmental perfusion of the human proximal jejunum. Acetorphan was given orally prior to intrajejunal administration of cholera toxin; its effect on intestinal transport was measured over a period of four hours after exposure to cholera toxin. Serum levels of methylthioether of thiorphan as the main metabolite were measured throughout three experiments to assure sufficient drug absorption. Results Acetorphan had no influence on basal water and electrolyte absorption (133 vs. 140 ml/30 cm x h). In a control group with cholera toxin alone, significant water secretion was induced (131 ml/30 cm x h). Acetorphan completely prevented this secretion by leaving an absorption rate of 27 ml/30 cm x h. Intestinal electrolyte transport was also significantly changed towards absorption by Acetorphan. Conclusion Acetorphan can prevent jejunal water and electrolyte secretion induced by cholera toxin. Enkephalins may thus protect the small intestine from enterotoxin-induced secretion.
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the enkephalinase inhibitor Acetorphan in acute diarrhoea a double blind controlled clinical trial versus loperamide
Scandinavian Journal of Gastroenterology, 1993Co-Authors: J Roge, J C Schwartz, P Baumer, H Berard, Jeannemarie LecomteAbstract:The antidiarrhoeal properties of Acetorphan, an inhibitor of enkephalinase (EC 3.4.24.11) that prevents endogenous enkephalin degradation, and loperamide, a mu opiate receptor agonist, were compared. The double-blind study included 69 patients with acute diarrhoea of presumed infectious origin, allocated at random to two parallel groups. Acetorphan and loperamide were both rapidly and similarly effective, diarrhoea resolving in both cases in nearly 2 days. With Acetorphan, however, abdominal distension vanished significantly more rapidly, and reactive constipation was less frequent (8% versus 31% with loperamide). These differences can be accounted for by the distinct mechanisms of antidiarrhoeal activity of the two drugs—that is, primary antitransit effect for loperamide and antisecretory activity for Acetorphan.
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effects of Acetorphan an enkephalinase inhibitor on experimental and acute diarrhoea
Gut, 1992Co-Authors: P Baumer, J C Schwartz, Danquechin E Dorval, J Bertrand, J M Vetel, Jeannemarie LecomteAbstract:Acetorphan is an orally active inhibitor of enkephalinase (EC 3.4.24.11) with antidiarrhoeal activity in rodents apparently through protection of endogenous enkephalins and a purely antisecretory mechanism. Its antidiarrhoeal activity in man was assessed in an experimental model of cathartic induced secretory diarrhoea as well as in acute diarrhoea of presumed infectious origin. In six healthy volunteers receiving castor oil and pretreated with Acetorphan or placebo in a crossover controlled trial, the drug significantly decreased the number and weight of stools passed during 24 hours. About 200 outpatients with severe acute diarrhoea (more than five stools per day) were included in a randomised double blind study of Acetorphan against placebo. The significant antidiarrhoeal activity of Acetorphan was established using a variety of criteria: (i) the duration of both diarrhoea and treatment were diminished; (ii) no Acetorphan treated patient withdrew from the study whereas five dropped out because of worsening in the placebo group; (iii) the frequency of symptoms associated with diarrhoea--for example, abdominal pain or distension, nausea and anorexia--remaining after two weeks was nearly halved; (iv) using visual analogue scales Acetorphan treatment was found more effective than placebo by both investigators and patients. There was statistically no significant difference between Acetorphan and placebo in respect of side effects, particularly constipation, which often accompanies the antidiarrhoeal activity of mu opioid receptor agonists this difference is attributable to the lack of antipropulsive activity of Acetorphan in man. The efficacy and tolerance of Acetorphan suggest that enkephalinase inhibition may represent a novel therapeutic approach for the symptomatic management of acute secretory diarrhoea without impairing intestinal transit.
P Baumer - One of the best experts on this subject based on the ideXlab platform.
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effects of Acetorphan an antidiarrhoeal enkephalinase inhibitor on oro caecal and colonic transit times in healthy volunteers
Alimentary Pharmacology & Therapeutics, 2007Co-Authors: J F Bergmann, P Baumer, S Chaussade, D Couturier, Jeancharles Schwartz, Jeannemarie LecomteAbstract:Acetorphan is a potent enkephalinase inhibitor displaying antidiarrhoeal activity attributable to its intestinal antisecretory action mediated by endogenous enkephalins. The effect of Acetorphan on digestive motility was studied in 12 healthy volunteers. Oro-caecal transit time was evaluated using the sulphasalazine/sulphapyridine method and colonic transit times using radiopaque markers. These measurements were successively performed after one week treatment with an antidiarrhoeal dose of Acetorphan (100 mg t.d.s.) or placebo. There was no significant modification in transit time linked to Acetorphan treatment: total oro-caecal times were 303 +/- 32 min vs. 287 +/- 27 min and colonic transit times 25.8 +/- 5.8 h vs. 31.3 +/- 5.5 h after Acetorphan and placebo, respectively (means +/- S.E.M.). There was no significant modification either in right colonic, left colonic or rectosigmoid segmental transit times, or in the mean number of stools. These results, consistent with those from animal studies, confirm that, unlike classical antidiarrhoeal mu opiate receptor agonists, which act by delaying intestinal transit, Acetorphan does not affect the transit. Antidiarrhoeal activity not accompanied by a delayed intestinal transit could have beneficial therapeutic consequences in the management of infectious diarrhoea. In addition, we show that the sulphasalazine and radiopaque markers methods can be simultaneously applied in the same study.
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racecadotril demonstrates intestinal antisecretory activity in vivo
Alimentary Pharmacology & Therapeutics, 1999Co-Authors: M P Primi, P Baumer, H Berard, L Bueno, Jeannemarie LecomteAbstract:Background Racecadotril (Acetorphan), a potent enkephalinase inhibitor, protects endogenous enkephalins from degradation. Racecadotril exhibits experimental and clinical antidiarrhoeal activity without any effect on intestinal motility, suggesting selective antisecretory activity. The antisecretory effect of racecadotril was directly assessed in the present study. Methods A 1 m, jejunal, Thiry–Vella loop was created in six mongrel dogs, and water and ionic fluxes were evaluated during infusion (2 mL/min) of Tyrode solution labelled with 14C-polyethylene glycol. Fluxes were determined both in the basal state and 5–6 h after commencement of a 2-h infusion of cholera toxin (0.4 μg/mL). Racecadotril (10 mg/kg) or vehicle was given orally with and without prior intravenous administration of naloxone (0.1 mg/kg) or phentolamine (0.2 mg/kg). Results Basal absorption remained unchanged following racecadotril administration; however, racecadotril significantly decreased (P = 0.01) cholera toxin-induced water, sodium, and potassium hypersecretion, from 0.73 ± 0.15 to 0.37 ± 0.13 mL/min; from 125.0 ± 16.1 to 14.7 ± 9.5 μMol/min; and from 3.41 ± 0.66 to 1.66 ± 0.61 μMol/min, respectively. This antisecretory activity of racecadotril was suppressed by naloxone but not by phentolamine. Conclusions This study directly demonstrates the antisecretory activity of racecadotril in relation to the protection of endogenous enkephalins.
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treatment of refractory diarrhoea in aids with Acetorphan and octreotide a randomized crossover study
European Journal of Gastroenterology & Hepatology, 1996Co-Authors: Laurent Beaugerie, P Baumer, H Berard, S Chaussade, Jeancharles Schwartz, W Rozenbaum, G Pialoux, Le Quintrec Y, J M LecomteAbstract:OBJECTIVE To compare the efficacy and tolerance of Acetorphan, an orally active enkephalinase inhibitor whose antidiarrhoeal properties derive from a purely antisecretory activity, to that of octreotide, a subcutaneously administered somatostatin analogue, in the treatment of refractory diarrhoea in AIDS patients. DESIGN An open randomized crossover trial. SETTING The inpatient medical units of three hospitals. PATIENTS Thirteen adult inpatients with AIDS and refractory diarrhoea that lasted for 35 +/- 8 weeks despite use of traditional antidiarrhoeal agents and was characterized by 7.0 +/- 1.2 stools/day, weighing 1033 +/- 174 g/day with a lipid output of 18.8 +/- 3.5 g/day. INTERVENTIONS Acetorphan (100-300 mg thrice daily) and octreotide (50-150 micrograms thrice daily) were given in random order during two 1-week periods. MAIN OUTCOME MEASURES Response was defined as a reduction by at least one-third of both daily stool number and weight. RESULTS The mean daily stool number was reduced to 4.6 +/- 1.1 with Acetorphan (P < or = 0.05) but was 5.6 +/- 1.2 with octreotide (NS). Whereas two patients responded to both treatments, two responded to Acetorphan alone and one to octreotide alone. Daily lipid output in faeces was reduced non-significantly with Acetorphan (11.5 +/- 2.3 g) but was nearly doubled with octreotide (33.7 +/- 12.0 g). Acetorphan was very well tolerated. CONCLUSION Enkephalinase inhibitors may be a useful alternative to somatostatin analogues in the management of refractory diarrhoea in AIDS.
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the enkephalinase inhibitor Acetorphan in acute diarrhoea a double blind controlled clinical trial versus loperamide
Scandinavian Journal of Gastroenterology, 1993Co-Authors: J Roge, J C Schwartz, P Baumer, H Berard, Jeannemarie LecomteAbstract:The antidiarrhoeal properties of Acetorphan, an inhibitor of enkephalinase (EC 3.4.24.11) that prevents endogenous enkephalin degradation, and loperamide, a mu opiate receptor agonist, were compared. The double-blind study included 69 patients with acute diarrhoea of presumed infectious origin, allocated at random to two parallel groups. Acetorphan and loperamide were both rapidly and similarly effective, diarrhoea resolving in both cases in nearly 2 days. With Acetorphan, however, abdominal distension vanished significantly more rapidly, and reactive constipation was less frequent (8% versus 31% with loperamide). These differences can be accounted for by the distinct mechanisms of antidiarrhoeal activity of the two drugs—that is, primary antitransit effect for loperamide and antisecretory activity for Acetorphan.
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l Acetorphan inhibiteur de l enkephalinase dans la diarrhee aigue etude croisee en double insu versus loperamide
Médecine et chirurgie digestives, 1993Co-Authors: J Roge, P Baumer, H Berard, Jeancharles Schwartz, J M LecomteAbstract:Les proprietes antidiarrheiques de l'Acetorphan, un inhibiteur de l'enkephalinase (EC 3.4.24.11) empechant la degradation des enkephalines endogenes, et du loperamide, un agoniste des recepteurs mu des opiaces, ont ete comparees. L'etude en double insu a inclus 69 patients ayant une diarrhee aigue presumee d'origine infectieuse, randomises en deux groupes paralleles. L'Acetorphan et le loperamide ont une action rapide et identique sur la diarrhee qui disparait dans les 2 jours. Toutefois avec l'Acetorphan, le ballonnement abdominal s'amende significativement plus rapidement et la constipation reactionnelle est moins frequente, 8% vs 31 %, avec le loperamide
H Berard - One of the best experts on this subject based on the ideXlab platform.
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racecadotril demonstrates intestinal antisecretory activity in vivo
Alimentary Pharmacology & Therapeutics, 1999Co-Authors: M P Primi, P Baumer, H Berard, L Bueno, Jeannemarie LecomteAbstract:Background Racecadotril (Acetorphan), a potent enkephalinase inhibitor, protects endogenous enkephalins from degradation. Racecadotril exhibits experimental and clinical antidiarrhoeal activity without any effect on intestinal motility, suggesting selective antisecretory activity. The antisecretory effect of racecadotril was directly assessed in the present study. Methods A 1 m, jejunal, Thiry–Vella loop was created in six mongrel dogs, and water and ionic fluxes were evaluated during infusion (2 mL/min) of Tyrode solution labelled with 14C-polyethylene glycol. Fluxes were determined both in the basal state and 5–6 h after commencement of a 2-h infusion of cholera toxin (0.4 μg/mL). Racecadotril (10 mg/kg) or vehicle was given orally with and without prior intravenous administration of naloxone (0.1 mg/kg) or phentolamine (0.2 mg/kg). Results Basal absorption remained unchanged following racecadotril administration; however, racecadotril significantly decreased (P = 0.01) cholera toxin-induced water, sodium, and potassium hypersecretion, from 0.73 ± 0.15 to 0.37 ± 0.13 mL/min; from 125.0 ± 16.1 to 14.7 ± 9.5 μMol/min; and from 3.41 ± 0.66 to 1.66 ± 0.61 μMol/min, respectively. This antisecretory activity of racecadotril was suppressed by naloxone but not by phentolamine. Conclusions This study directly demonstrates the antisecretory activity of racecadotril in relation to the protection of endogenous enkephalins.
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treatment of refractory diarrhoea in aids with Acetorphan and octreotide a randomized crossover study
European Journal of Gastroenterology & Hepatology, 1996Co-Authors: Laurent Beaugerie, P Baumer, H Berard, S Chaussade, Jeancharles Schwartz, W Rozenbaum, G Pialoux, Le Quintrec Y, J M LecomteAbstract:OBJECTIVE To compare the efficacy and tolerance of Acetorphan, an orally active enkephalinase inhibitor whose antidiarrhoeal properties derive from a purely antisecretory activity, to that of octreotide, a subcutaneously administered somatostatin analogue, in the treatment of refractory diarrhoea in AIDS patients. DESIGN An open randomized crossover trial. SETTING The inpatient medical units of three hospitals. PATIENTS Thirteen adult inpatients with AIDS and refractory diarrhoea that lasted for 35 +/- 8 weeks despite use of traditional antidiarrhoeal agents and was characterized by 7.0 +/- 1.2 stools/day, weighing 1033 +/- 174 g/day with a lipid output of 18.8 +/- 3.5 g/day. INTERVENTIONS Acetorphan (100-300 mg thrice daily) and octreotide (50-150 micrograms thrice daily) were given in random order during two 1-week periods. MAIN OUTCOME MEASURES Response was defined as a reduction by at least one-third of both daily stool number and weight. RESULTS The mean daily stool number was reduced to 4.6 +/- 1.1 with Acetorphan (P < or = 0.05) but was 5.6 +/- 1.2 with octreotide (NS). Whereas two patients responded to both treatments, two responded to Acetorphan alone and one to octreotide alone. Daily lipid output in faeces was reduced non-significantly with Acetorphan (11.5 +/- 2.3 g) but was nearly doubled with octreotide (33.7 +/- 12.0 g). Acetorphan was very well tolerated. CONCLUSION Enkephalinase inhibitors may be a useful alternative to somatostatin analogues in the management of refractory diarrhoea in AIDS.
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the enkephalinase inhibitor Acetorphan in acute diarrhoea a double blind controlled clinical trial versus loperamide
Scandinavian Journal of Gastroenterology, 1993Co-Authors: J Roge, J C Schwartz, P Baumer, H Berard, Jeannemarie LecomteAbstract:The antidiarrhoeal properties of Acetorphan, an inhibitor of enkephalinase (EC 3.4.24.11) that prevents endogenous enkephalin degradation, and loperamide, a mu opiate receptor agonist, were compared. The double-blind study included 69 patients with acute diarrhoea of presumed infectious origin, allocated at random to two parallel groups. Acetorphan and loperamide were both rapidly and similarly effective, diarrhoea resolving in both cases in nearly 2 days. With Acetorphan, however, abdominal distension vanished significantly more rapidly, and reactive constipation was less frequent (8% versus 31% with loperamide). These differences can be accounted for by the distinct mechanisms of antidiarrhoeal activity of the two drugs—that is, primary antitransit effect for loperamide and antisecretory activity for Acetorphan.
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l Acetorphan inhibiteur de l enkephalinase dans la diarrhee aigue etude croisee en double insu versus loperamide
Médecine et chirurgie digestives, 1993Co-Authors: J Roge, P Baumer, H Berard, Jeancharles Schwartz, J M LecomteAbstract:Les proprietes antidiarrheiques de l'Acetorphan, un inhibiteur de l'enkephalinase (EC 3.4.24.11) empechant la degradation des enkephalines endogenes, et du loperamide, un agoniste des recepteurs mu des opiaces, ont ete comparees. L'etude en double insu a inclus 69 patients ayant une diarrhee aigue presumee d'origine infectieuse, randomises en deux groupes paralleles. L'Acetorphan et le loperamide ont une action rapide et identique sur la diarrhee qui disparait dans les 2 jours. Toutefois avec l'Acetorphan, le ballonnement abdominal s'amende significativement plus rapidement et la constipation reactionnelle est moins frequente, 8% vs 31 %, avec le loperamide
Daniel Dusser - One of the best experts on this subject based on the ideXlab platform.
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role of neutral endopeptidase and kininase ii on substance p induced increase in nasal obstruction in patients with allergic rhinitis
The American review of respiratory disease, 1994Co-Authors: A Lurie, J A Nadel, G Roisman, H Siney, Daniel DusserAbstract:We studied the role of neutral endopeptidase (NEP) and kininase II (angiotensin-converting enzyme; ACE) in the modulation of exogenous substance P (SP)-induced nasal response in normal subjects and in patients with allergic rhinitis. We measured the nasal conductance in response to increasing doses of SP 2 h after oral administration of either placebo or the ACE inhibitor, cilazapril (5 mg), or the NEP inhibitor, Acetorphan (300 mg), given in a randomized, double-blind, cross-over manner. We performed three separate studies: Acetorphan versus placebo and cilazapril versus placebo, in normal subjects (n=6 and n=8, respectively), and Acetorphan versus cilazapril versus placebo in patients with allergic rhinitis (n=6)
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role of neutral endopeptidase and kininase ii on substance p induced increase in nasal obstruction in patients with allergic rhinitis
American Journal of Respiratory and Critical Care Medicine, 1994Co-Authors: A Lurie, J A Nadel, G Roisman, H Siney, Daniel DusserAbstract:We studied the role of neutral endopeptidase (NEP) and kininase II (angiotensin-converting enzyme; ACE) in the modulation of exogenous substance P (SP)-induced nasal response in normal subjects and in patients with allergic rhinitis. We measured the nasal conductance in response to increasing doses of SP 2 h after oral administration of either placebo or the ACE inhibitor, cilazapril (5 mg), or the NEP inhibitor, Acetorphan (300 mg), given in a randomized, double-blind, cross-over manner. We performed three separate studies: Acetorphan versus placebo and cilazapril versus placebo, in normal subjects (n = 6 and n = 8, respectively), and Acetorphan versus cilazapril versus placebo in patients with allergic rhinitis (n = 6). In normal as well as in rhinitic subjects, SP decreased nasal conductance in a dose-dependent fashion (p 0.5). In normal subjects, Acetorphan potentiated the decrease in nasal conductance (p 0.9). Conversely, with cilazapril, the nasal response to SP was greater in patients with allergic rhinitis than in normal subjects (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Pierre Dumont - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Pharmacological Properties of 2-[S-Acetylthiorphan]-l,3-diacylaminopropan-2-ol Derivatives as Chimeric Lipid Drug Carriers Containing an Enkephalinase Inhibitor
Pharmaceutical Research, 1995Co-Authors: Didier M. Lambert, Jacques H. Poupaert, Frank Mergen, Catherine F. Berens, Pierre DumontAbstract:The design of 1,3-diacylaminopropan-2-ols as CNS-directed carrier groups is based on their resemblance to endogenous lipids and the properties of pseudotriglyceride esters to facilitate the brain penetration of therapeutic agents. 2-[S-acetylthiorphan]-l,3-diacylaminopropan-2-ols, differing from the nature of 1,3-acyl chains, were synthesized and evaluated in vivo using the hot-plate jump test. The compounds exhibited naloxone reversible analgesic properties. The effects were superior to those of parent compounds thiorphan and S-acetylthiorphan. The palmitoyl derivative showed also activity at 0.8 mmol/kg after oral administration. Like Acetorphan, a thiorphan prodrug, these compounds were poor substrates for brain enkephalinase, suggesting the release of the pharmacological active inhibitor at the site of action in the brain.
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Analgesic potency of S-acetylthiorphan after intravenous administration to mice.
European Journal of Pharmacology, 1993Co-Authors: Didier M. Lambert, F. Mergen, Jacques H. Poupaert, Pierre DumontAbstract:As hydrolysis in serum of Acetorphan to acetylthiorphan (N-[(R,S)-3-acetylmercapto-2-benzylpropanoyl]glycine) has been evidenced, both the neutral endopeptidase inhibition in vitro by acetylthiorphan and analgesic potency of acetylthiorphan after intravenous administration to mice in two analgesic models, the hot-plate and the tail-flick tests, were compared with those of thiorphan and Acetorphan. Acetylthiorphan showed a decreased degree of neutral endopeptidase inhibition (IC50 = 316 +/- 38 nM) compared to thiorphan (IC50 = 1.8 +/- 0.2 nM). After intravenous administration followed by the hot-plate jump latency test, acetylthiorphan elicited a degree of analgesia equivalent to that with Acetorphan but longer lasting. Like Acetorphan and thiorphan, acetylthiorphan was devoid of analgesic activity in the tail-flick test. The results indicated that S-acetylation of the thiol function in acetylthiorphan ensures sufficient lipophilicity to permit crossing of the blood-brain barrier and that acetylthiorphan acts via a prodrug mechanism.
