Time-dependent resonant scattering: an analytical approach.

A time-dependent description is given of a scattering process involving a single resonance embedded in a set of flat continua. An analytical approach is presented which starts from an incident free particle wave packet and yields the Breit-Wigner cross-section formula at infinite times. We show that at intermediate times the so-called Wigner-Weisskopf approximation is equivalent to a scattering process involving a contact potential. Applications in cold-atom scattering and resonance enhanced desorption of molecules are discussed.

Preclinical evaluation of the abuse potential of Pitolisant, a histamine H3 receptor inverse agonist/antagonist compared with Modafinil.

BACKGROUND AND PURPOSE: Pitolisant, a histamine H3 receptor inverse agonist/antagonist is currently under Phase III clinical trials for treatment of excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse potential was investigated using in vivo models in rodents and monkeys and compared with those of Modafinil, a psychostimulant currently used in the same indications. EXPERIMENTAL APPROACH: Effects of Pitolisant on dopamine release in the nucleus accumbens, on spontaneous and cocaine-induced locomotion, locomotor sensitization were monitored. It was also tested in three standard drug abuse tests i.e. conditioned place preference in rats, self-administration in monkeys and cocaine discrimination in mice as well as in a physical dependence model. KEY RESULTS: Pitolisant did not elicit any significant changes in dopaminergic indices in rat nucleus accumbens whereas Modafinil increased dopamine release. In rodents, Pitolisant was without any effect on locomotion and reduced the cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no conditioned hyperlocomotion were evidenced with this compound in rats whereas significant effects were elicited by Modafinil. Finally, Pitolisant was devoid of any significant effects in the three standard drug abuse tests (including self-administration in monkeys) and in the physical dependence model. CONCLUSIONS AND IMPLICATIONS: No potential drug abuse liability for Pitolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of Modafinil.

Synthesis and evaluation of amides surrogates of dopamine D3 receptor ligands.

Isosteric replacement of the amide function and modulation of the arylpiperazine moiety of known dopamine D3 receptor ligands led to potent and selective compounds. Enhanced bioavailability and preferential brain distribution make compound 6c a good candidate for pharmacological and clinical evaluation.

BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology.

Histamine H3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H3 receptor. On the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity approximately 50% higher than that of ciproxifan. Its in vitro potency was approximately 6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.

Effect of hyperbaric oxygen on oxygen uptake and measurements in the blood and tissues in a normobaric environment.

OBJECTIVE: To examine venous partial pressure of oxygen (PvO(2)), transcutaneous oxygen tension (tcPO(2)), and VO(2)MAX in a normobaric environment after a single hyperbaric oxygen (HBO(2)) treatment. METHODS: This was a prospective study of conditions after the intervention compared with baseline. The participants were 10 moderately trained (VO(2)MAX = 57.6 ml/kg/min) men. Two HBO(2) treatments consisting of breathing 95% oxygen at 2.5 atmospheres absolute (ATA) for 90 minutes were administered on non-consecutive days. Baseline testing included measures of VO(2)MAX, tcPO(2), and anthropometry. At 6.0 (1.0) minutes after the first HBO(2) treatment, a VO(2)MAX test was performed. After the second HBO(2) treatment, leg and chest tcPO(2) and PvO(2) were monitored for 60 minutes. RESULTS: VO(2)MAX, running time, and peak blood lactate were not altered after the HBO(2) treatment. Leg tcPO(2) was lower (p = 0.003) and chest tcPO(2) was unchanged after the HBO(2) treatment compared with baseline values. PvO(2) was significantly (p<0.001) lower in the first three minutes after treatment than subsequent values, but no other differences were found. CONCLUSIONS: A single HBO(2) treatment at 2.5 ATA for 90 minutes does not raise PvO(2), tcPO(2), or VO(2)MAX in a normobaric, normoxic environment.

Efficacy and tolerability of racecadotril in acute diarrhea in children.

BACKGROUND & AIMS: Oral rehydration therapy is the only treatment recommended by the World Health Organization in acute diarrhea in children. Antisecretory drugs available could not be used because of their side effects, except for racecadotril, which is efficient in acute diarrhea in adults. METHODS: The efficacy and tolerability of racecadotril (1.5 mg/kg administered orally 3 times daily) as adjuvant therapy to oral rehydration were compared with those of placebo in 172 infants aged 3 months to 4 years (mean age, 12.8 months) who had acute diarrhea. The treatment groups were comparable in terms of age, duration of diarrhea, number of stools, and causative microorganism at inclusion. RESULTS: During the first 48 hours of treatment, patients receiving racecadotril had a significantly lower stool output (grams per hour) than those receiving placebo. The 95% confidence interval was 43%-88% for the full data set (n = 166; P = 0.009) and 33%-75% for the per-protocol population (n = 116; P = 0.001). There was no difference between treatments depending on rotavirus status. Significant differences between treatment groups were also found after 24 hours of treatment: full data set (n = 167; P = 0.026) and per-protocol population (n = 121; P = 0.015). Tolerability was good in both groups of patients. CONCLUSIONS: This study demonstrates the efficacy (up to 50% reduction in stool output) and tolerability of racecadotril as adjuvant therapy to oral rehydration solution in the treatment of severe diarrhea in infants and children.

Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin and angiotensin-converting enzyme, in rats and humans.

The aim of this study was to assess the antihypertensive activity of fasidotril, a dual inhibitor of neprilysin (NEP) and angiotensin I-converting enzyme (ACE), in various models of hypertension in rats (spontaneously hypertensive rats [SHR]; renovascular Goldblatt 2-kidney, 1-clip rats; and deoxycorticosterone acetate [DOCA]-salt hypertensive rats) and in patients with mild-to-moderate essential hypertension. Fasidotril treatment (100 mg/kg PO twice daily for 3 weeks) resulted in a progressive and sustained decrease in systolic blood pressure (-20 to -30 mm Hg) in SHR and Goldblatt rats compared with vehicle-treated rats and prevented the progressive rise in blood pressure in DOCA-salt hypertensive rats. After a 4-week placebo run-in period, 57 patients with essential hypertension were included in a randomized double-blind, placebo-controlled, parallel-group study and received orally either fasidotril (100 mg twice daily) or placebo for 6 weeks. Blood pressure was measured during the 6 hours after the first intake and then at trough (12 hours after the last intake) on days 7, 28, and 42. The first dose of fasidotril had no significant effect on blood pressure. After 42 days, compared with placebo, fasidotril lowered supine systolic and diastolic blood pressures by 7.4/5.4 mm Hg and standing blood pressure by 7.6/6.8 mm Hg. Fasidotril, a dual NEP/ACE inhibitor, was an effective oral antihypertensive agent during chronic treatment in high-renin renovascular rats, normal-renin SHR, and low-renin DOCA-salt hypertensive rats and in patients with essential hypertension.

An overview of clinical studies with racecadotril in adults.

Since preclinical studies had indicated the potential efficacy and tolerability of racecadotril for the treatment of diarrhoea in man, a series of studies was carried out to assess the clinical effects of racecadotril. These studies were also designed to evaluate whether racecadotril possessed the clinical properties that had been previously identified for an ideal agent to treat infectious diarrhoea. The pure antisecretory action of racecadotril was confirmed in these clinical studies, as was the drug's rapid onset of action. The high therapeutic index of racecadotril was combined with a lack of effect on the central nervous system. Finally, racecadotril was found to be effective in treating acute diarrhoea in double-blind studies against both placebo and the mu opiate receptor agonist, loperamide. The efficacy of racecadotril in acute diarrhoea was not associated with adverse gastrointestinal effects, and its adverse events profile was similar to that of placebo. It was concluded that racecadotril offers a new approach to the treatment of diarrhoea via its mechanism of action as a true antisecretory agent.

Effect of long-term therapy with fasidotril, a mixed inhibitor of neprilysin and angiotensin-converting enzyme (ACE), on survival of rats after myocardial infarction.

OBJECTIVE: Two hormonal systems with opposite effects are activated in congestive heart failure: the renin-angiotensin system that promotes vasoconstriction, cardiac hypertrophy and salt retention, and the atrial natriuretic factor (ANF), which has vasorelaxant and natriuretic effects. It could be of therapeutic interest to associate prevention of angiotensin II formation, by inhibition of angiotensin I-converting enzyme (ACE), with potentiation of the ANF effects, by inhibition of neprilysin (NEP). METHODS: The effects of long-term therapy with fasidotril, a mixed NEP/ACE inhibitor, were assessed in rats submitted to coronary artery ligation. Twenty-four hours after ligation, 172 rats were assigned to either placebo or fasidotril therapy (180 mg/kg/day, orally) for 40 weeks. The date of spontaneous death was recorded, myocardial infarct size was determined and rats were classified as having small, moderate or large infarcts. RESULTS: In rats with moderate infarcts, fasidotril prolonged survival, 50% of the control rats dying during the 40-week observation period compared with 30% of treated rats (P = 0.04, log-rank test)). In rats with large infarcts, mortality was significantly reduced during the initial 25 weeks of therapy, during which 23.5% of animals died compared to 53.8% in untreated rats (P = 0.015). Cardiac hypertrophy was significantly attenuated by fasidotril for the three infarct sizes. Plasma renin activity was not increased by therapy, which presumably reflected the inhibition of renal renin secretion by endogenous ANF. Fasidotril therapy had no significant effects on arterial blood pressure and heart rate. CONCLUSION: In addition to its beneficial effects on survival and cardiac hypertrophy, the lack of hypotensive effect of fasidotril is of interest by reducing the risk of renal hypoperfusion and differentiates the mixed inhibitor from selective ACE inhibitors.

Racecadotril demonstrates intestinal antisecretory activity in vivo.

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 microgram/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 microMol/min; and from 3.41 +/- 0.66 to 1.66 +/- 0.61 microMol/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.

Effects of racecadotril and loperamide on bacterial proliferation and on the central nervous system of the newborn gnotobiotic piglet.

METHODS: The effects of 4 days of oral administration of different doses of two drugs, an enkephalinase inhibitor (the antisecretory agent, racecadotril) and a mu-receptor agonist (loperamide), on intestinal growth of a bacterial nonpathogenic strain (Escherichia coli E 404) and on the central nervous system (CNS) were compared in newborn gnotobiotic piglets. RESULTS: The E. coli content of the proximal jejunum (segment S1) and the E. coli ratio of stomach:segment S1 were similar in the racecadotril (20 mg/kg b.d., n = 5) and control groups. In contrast, in the loperamide group (1 mg/kg b.d., n = 4), the E. coli content of segment S1 and the E. coli ratio stomach:S1 were both significantly higher than with racecadotril or control (P = 0.04 and 0.005, respectively, for E. coli content; P = 0.05 and 0.03, respectively, for stomach:S1). There were no clinical signs of neurotoxicity and no deaths with racecadotril given orally at a high dose of 130 mg/kg b.d. (n = 5)--nearly 60 times the paediatric dosage. In contrast, an equivalent high dose of loperamide (5 mg/kg b.d.) resulted in death in three out of four piglets. CONCLUSIONS: In contrast to loperamide, racecadotril did not induce bacterial overgrowth and did not produce central neurotoxicity.

Comparison of racecadotril and loperamide in adults with acute diarrhoea.

METHODS: A multicentre, randomized, double-blind, double-placebo, parallel-group study was carried out to compare the efficacy, tolerability, and safety of racecadotril (100 mg three times daily) and loperamide (2 mg after each diarrhoeic stool) in 157 adults with acute diarrhoea. Patients were treated for 7 days or until recovery, if this took place earlier. RESULTS: Both groups of patients passed similar numbers (mean +/- S.E.M.) of stools before recovery (3.5 +/- 0.5 for racecadotril vs. 2.9 +/- 0.4 for loperamide), and the duration of diarrhoea (mean +/- S.E.M.) was similar in both groups (14.9 +/- 2.0 h for racecadotril and 13.7 +/- 2.2 h for loperamide). Both treatments reduced the incidence of associated symptoms and signs during the study, and both were similarly well tolerated. However, more patients on loperamide reported rebound constipation during treatment (18.7% vs. 9.8% with racecadotril). CONCLUSIONS: The enkephalinase inhibitor, racecadotril, and the intestinal transit inhibitor, loperamide, were similarly and rapidly effective in resolving the symptoms and associated signs of diarrhoea.

Racecadotril versus placebo in the treatment of acute diarrhoea in adults.

METHODS: A two-centre, double-blind, parallel-group, randomized study was carried out to compare the efficacy and tolerability of racecadotril (100 mg three times daily) and placebo in 70 adult patients with acute diarrhoea. An objective criterion of antisecretory activity, stool weight, was used. RESULTS: Racecadotril produced a significant (P = 0.025) decrease in stool weight during the first day of treatment compared with placebo, and was also associated with significantly fewer diarrhoeic stools than placebo after 1 day of treatment (p = 0.027). Racecadotril and placebo were equally well tolerated, and the frequency of symptoms and signs was similar in both groups after 4 days of treatment. Fewer patients on racecadotril suffered from abdominal distension following treatment (5.6% vs. 18.2% on placebo). CONCLUSIONS: Racecadotril acts rapidly to resolve acute diarrhoea and has an incidence of adverse events similar to that of placebo.

Comparison of racecadotril and loperamide in children with acute diarrhoea.

METHODS: A multicentre, parallel-group, double-blind, double-placebo study was carried out to compare the efficacy, tolerability, and safety of racecadotril and loperamide in children aged 2 to 10 years who were suffering from acute diarrhoea. Patients received racecadotril (1.5 mg/kg) or loperamide (0.03 mg/kg) three times daily plus matching placebo until recovery. Fifty-two children received racecadotril and 50 loperamide. RESULTS: Patients on racecadotril passed a mean (+/- S.E.M.) of 2.7 +/- 0.4 stools before recovery compared with 2.1 +/- 0.4 stools for loperamide. The duration of diarrhoea was similar with both treatments. The incidence of adverse events was lower with racecadotril than with loperamide (11.5% vs. 22%), and significantly more patients on loperamide suffered from constipation (58% vs. 36.5%; P = 0.03). Moreover, significantly more children receiving loperamide required concomitant medication during the study (38% v 19.2%; P = 0.047). Measurement of abdominal circumference at the final consultation, 6 days after entry to the study, revealed no significant differences between treatments. CONCLUSIONS: Racecadotril and loperamide were equally effective in treating acute diarrhoea in these children, and racecadotril had a superior tolerability and safety profile.

Acute natriuretic effect of fasidotrilat, a mixed inhibitor of neutral endopeptidase and angiotensin I-converting enzyme, in rats with heart failure.

The acute diuretic and natriuretic effects of fasidotrilat, a mixed inhibitor of neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) were evaluated in control and myocardial-infarcted rats. Fasidotrilat injection (10 mg/kg i.v.) had no significant effect on arterial blood pressure and led to significant elevations in urine volume (+57% in control rats and +114% in infarcted rats) and of urinary sodium excretion (+81% in control rats and +225% in infarcted rats). Comparison between control and infarcted rats showed that fasidotrilat-induced changes in diuresis and natriuresis were higher in infarcted rats (2.4-fold for diuresis and 4.7-fold for natriuresis, p < 0.05), despite a lower perfusion pressure (-10 mm Hg) in infarcted rats. These data show the potential therapeutic interest of mixed NEP/ACE inhibitors in congestive heart failure.

A randomized controlled trial of the effect of naproxen on delayed onset muscle soreness and muscle strength.

OBJECTIVE: To determine the effect of naproxen in attenuating the symptoms (muscle soreness level) and signs (plasma creatine kinase [CK] activity and muscular strength decrement) of delayed onset muscle soreness (DOMS) induced by repeated bouts of eccentric exercise. DESIGN: The design was a randomized, double-blind, placebo-controlled, crossover trial with two testing phases of 8 days' duration that were separated by a "washout" period of 7 days. SETTING: University-based sports science center. PARTICIPANTS: Twenty healthy male volunteers who responded to a notice in the university's athletic complex. INTERVENTIONS: Eccentric single-leg exercises were performed on days 1, 3, and 4 to induce DOMS in the quadriceps muscles. Naproxen or placebo tablets (500 mg) were taken orally twice per day beginning on day 2 and continuing until the end of the testing phase. MAIN OUTCOME MEASURES: Perception of muscle soreness and knee extensor torque were evaluated daily throughout each phase. Plasma CK levels were evaluated on days 1, 3, 6, and 8 of each phase. RESULTS: After the eccentric exercise, plasma CK levels were similarly elevated in both naproxen and placebo conditions (F=1.42; p=0.25). After DOMS developed, naproxen reduced the perception of soreness on day 3, when muscle soreness was highest (F=2.20; p=0.04). After treatments with naproxen, peak quadriceps torque during leg extension at 60 degrees/s was higher than that after treatment with the placebo (F=4.77; p=0.04). There were no significant differences between the naproxen and placebo conditions for leg extension at 180 degrees/s (F= 1.66; p=0.21) and 300 degrees/s (F=0.71; p=0.41). CONCLUSION: The data indicate that therapeutic doses of naproxen do not prevent CK release into the plasma but decrease the perception of muscle soreness and positively influence quadriceps peak torque.

Acetorphan prevents cholera-toxin-induced water and electrolyte secretion in the human jejunum.

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.

Bioavailability, antinociceptive and antiinflammatory properties of BP 2-94, a histamine H3 receptor agonist prodrug.

(R)alpha-Methylhistamine [(R)alpha-MeHA], a potent and selective histamine H3 receptor agonist in vitro and in vivo in rodents, was found to display comparatively low plasma level in healthy human volunteers, attributable to an extensive methylation of the drug's imidazole ring by histamine-N-methyltransferase. To limit this inactivation process, BP 2-94, ie., (R)-(-)-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino]phenylmethyl] phenol, was selected as a prodrug. A sensitive radioimmunoassay was developed to study the generation of (R)alpha-MeHA slowly released from BP 2-94 in vitro and in vivo by chemical hydrolysis. In mice after oral administration of BP 2-94 high levels of both prodrug and (R)alpha-MeHA were detected in plasma and various tissues except in the brain. In humans receiving 0.1 mmol BP 2-94 orally, plasma levels of (R)alpha-MeHA-like immunoreactivity decayed with a t(1/2) more than 24 hr, the area under the curve being two orders of magnitude higher than after oral administration of (R)alpha-MeHA. BP 2-94 displayed antiinflammatory and antinociceptive properties in rodents, related to the H3 receptor stimulation. It dose-dependently inhibited capsaicin-induced plasma protein extravasation in many rat tissues with ED50s of 0.6 to 14 micromol/kg p.o., and maximal reductions by 35 to 87%. BP 2-94 also reduced zymosan-induced paw swelling in mice with an ED50 of 1 micromol/kg p.o. and showed marked activity in the phenylbenzoquinone-induced writhing (ED50 = 0.03 micromol/kg, p.o.) or formalin tests in mice, but not in the hot plate jump test. From its pharmacokinetics and pharmacological profile BP 2-94 appears to be a promising novel therapeutic agent in disorders such as asthma, migraine or a variety of inflammatory diseases and pain associated with these disorders.

Treatment of refractory diarrhoea in AIDS with acetorphan and octreotide: a randomized crossover study.

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.

Hemodynamic effects of acute and chronic treatment with aladotril, a mixed inhibitor of neutral endopeptidase and angiotensin I-converting enzyme, in conscious rats with myocardial infarction.

The aim of the present study was to determine, in rats with myocardial infarction, the systemic and cardiac hemodynamic effects of aladotrilat and of its prodrug, aladotril, both of which display inhibitory activity toward both neutral endopeptidase (NEP, EC. 3.4.24.11) and angiotensin I-converting enzyme (ACE). The effects of acute intravenous injection of aladotrilat (30 mg/kg bolus injection plus 30 mg/kg/hr infusion) were measured for 1 hr in conscious infarcted rats and compared with the effects of SQ 28,603, a selective NEP inhibitor (30 mg/kg bolus injection plus 30 mg/kg/hr infusion), and captopril, a selective ACE inhibitor (10 mg/kg bolus injection plus 10 mg/kg/hr infusion). Unlike SQ 28,603, aladotrilat and captopril produced a slight fall in mean arterial blood pressure. The three treatments had no significant effect on heart rate and rate of increase of left ventricular pressure (LV + dP/dt) but caused significant decreases in left ventricular end-diastolic pressure (LVEDP). The effect of aladotrilat on decreasing LVEDP was faster than those of captopril or SQ 28,603. In chronic experiments, groups of rats received orally, twice daily, captopril (10 mg/kg), aladotril (100 mg/kg) or vehicle. Treatments were started 18 to 20 hr after coronary artery ligation and continued for 4 weeks. Hemodynamic parameters and cardiac hypertrophy were measured at the end of therapy. Unlike aladotril, captopril treatment resulted in significant decreases in mean arterial blood pressure and left ventricular systolic pressure (approximately 15 mm Hg) and produced renal vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)