EI-2128-1, a novel interleukin-1beta converting enzyme inhibitor produced by Penicillium sp. E-2128

EI-2128-1, a novel interleukin-1beta converting enzyme (ICE) inhibitor, was isolated from the culture broths of Penicillium sp. E-2128. EI-2128-1 selectively inhibited human recombinant ICE activity with IC50 value of 0.59 microM, without inhibiting elastase and cathepsin B. EI-2128-1 also inhibited mature interleukin-1beta secretion from THP-1 cells induced by LPS with IC50 value of 0.28 microM.     

Haemodynamic and humoral effects of oral perindopril, an angiotensin converting enzyme inhibitor, in man.

The tolerance to and dynamic effects of 1 week's oral treatment with the angiotensin converting enzyme inhibitor, perindopril, were assessed in a placebo controlled, parallel group study in 36 normotensive males. The daily dose of perindopril was 1, 2, 4, 8 or 16 mg. The drug was well tolerated and produced no change in routine haematology or serum biochemistry tests. Dose related inhibition of plasma angiotensin converting enzyme was observed. Perindopril 16 mg produced 90% inhibition 4 h after dosing and 60% after 24 h. A dose related rise in plasma renin activity followed doses of 4 mg and over. The renin remained above the normal range for 24 h. Perindopril caused a modest lowering of plasma aldosterone levels but had no effect on plasma adrenaline or noradrenaline levels. Standing diastolic blood pressure was lowered, particularly with 16 mg daily of perindopril but only a slight rise in heart rate occurred. Perindopril appears to be a well tolerated inhibitor of plasma angiotensin converting enzyme, with predictable effects on the renin angiotensin system and blood pressure. An appropriate dose range for further study would appear to be 4 to 16 mg daily.     

EI-1941-1 and -2, novel interleukin-1beta converting enzyme inhibitors produced by Farrowia sp. E-1941. I. Biochemical characterization of EI-1941-1 and -2

EI-1941-1 and -2 isolated from the culture broths of Farrowia sp. selectively inhibited the human recombinant ICE activity with IC50 values of 0.086 and 0.006 microM, respectively, without inhibiting elastase and cathepsin B. EI-1941-1 and -2 also inhibited mature interleukin-1beta secretion from THP-1 cells induced by LPS with IC50 values of 5.0 and 10.3 microM, respectively. Biochemical characterizations of EI-1941-1 and -2 are described in this article.     

Pharmacodynamic, pharmacokinetic and humoral effects of oral zabicipril, an angiotensin converting enzyme inhibitor in normotensive man.

1. Zabicipril, S9650, a new angiotensin converting enzyme inhibitor, was administered to salt-replete, normotensive males in single doses of up to 10 mg. 2. The safety, tolerance and dose-response relationship with regard to inhibition of plasma ACE activity were characterised initially in an open, pilot, dose-finding study in 12 subjects and further explored in a double-blind, parallel group, placebo controlled study in another 30 subjects. 3. The drug was generally well tolerated and produced no change in routine haematology or serum biochemistry tests. 4. Dose related (0.03 to 10 mg) inhibition of plasma converting-enzyme was observed, with 2.5 mg of zabicipril producing over 90% inhibition at 4 h and 60% at 24 h. 5. There were no significant changes in blood pressure or heart rate in normotensive subjects over the dose range studied. 6. A dose related rise in plasma renin activity and angiotensin I was observed. No dose related reduction in plasma aldosterone was observed. 7. These initial studies suggest that zabicipril is a well tolerated inhibitor of converting enzyme with near maximal inhibitory effect occurring at a dose of 2.5 mg. Further exploration of the dose range after single and multiple doses is indicated.     

EI-2346, a novel interleukin-1beta converting enzyme inhibitor produced by Streptomyces sp. E-2346. I. Taxonomy of producing strain, fermentation, isolation, physico-chemical properties, and biological properties

EI-2346, a novel interleukin-1beta converting enzyme (ICE) inhibitor, was isolated from the culture broths of Streptomyces sp. E-2346. EI-2346 selectively inhibited the human recombinant ICE activity with an IC50 value of 3.9 microM, without inhibiting elastase and cathepsin B. EI-2346 also inhibited mature interleukin-1beta secretion from THP-1 cells induced by LPS with an IC50 value of 5.2 microM.     

EI-1941-1 and -2, novel interleukin-1 beta converting enzyme inhibitors Produced by Farrowia sp. E-1941. II. Taxonomy of producing strain, fermentation, isolation, physico-chemical properties, and biological properties

EI-1941-1 and -2, novel interleukin-1 beta converting enzyme (ICE) inhibitors, were isolated from the culture broths of Farrowia sp. E-1941. EI-1941-1 and -2 selectively inhibited the human recombinant ICE activity with IC50 values of 0.086 and 0.006 microM, respectively. Taxonomy and fermentation of the producing strain and isolation, physico-chemical properties, structure elucidation, and biological properties of EI-1941-1 and -2 are described.     

Control of essential hypertension with captopril, an angiotensin converting enzyme inhibitor.

1 Captopril, an orally active angiotensin converting enzyme inhibitor, was compared with hydrochlorothiazide (HCT) in the treatment of mild and moderate essential hypertension. 2 Twenty outpatients received no antihypertensive therapy for 2 weeks, after which they were given placebo for 8 weeks. Since their diastolic blood pressure remained above 100 mm Hg, they were then randomized to receive either captopril (twelve patients) or HCT (eight patients) for a 4-week titration period. If the supine diastolic blood pressure (SDBP) was normalized, (less than or equal to 90 mm Hg) by the end of titration period, the established regimen was continued for an 8-week maintenance period; if not, the alternate drug was added in increasing doses for up to 4 weeks and the combined therapy was maintained for the remaining 4 weeks. 3 After the first 4 weeks of therapy, both groups showed a statistically significant decrease in both systolic and diastolic blood pressure. Normalization of SDBP occurred in 75% of patients treated with captopril alone, and the addition of HCT produced normalization in the remainder. HCT alone resulted in normalization of SDBP in 50% of patients and the blood pressure of the remaining patients was normalized after the addition of captopril. 4 Captopril given orally, either alone or in conjunction with HCT, is an effective agent for the control of mild and moderate essential hypertension. 5 In our series the main side effects encountered were vertigo and dizziness, transient eosinophilia, a rise of BUN and or/a rise of SGPT or SGOT.     

Effect of TNF-alpha on the induction of apoptosis in murine macrophages: role of interleukin-1 beta converting enzyme

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces apoptosis in various cell types via its binding to TNF-receptors (TNF-R). Involvement of ICE-like protease in the induction of TNF-alpha mediated apoptosis in murine macrophage was investigated using ICE inhibitor YVAD-cmk (Tetrapeptide-Acetyl-Try-Val Ala-Asp-Chloromethyl ketone). Macrophages treated with TNF showed a time dependent decrease in cell viability with a simultaneous increase in the percent of cells showing apoptotic morphology and an increase in percent DNA fragmentation, a quantitative measure of apoptosis. However, incubation of macrophage in medium containing TNF and YVAD-cmk had inhibitory effect on the TNF-induced apoptosis of macrophage. This finding suggests that ICE-like protease may be involved in the induction of apoptosis in macrophage by TNF-alpha.     

Influence of the new angiotensin converting enzyme inhibitor ramipril on several models of acute inflammation and the adjuvant arthritis in the rat

Paw oedema in the rat by carrageenin and kaolin partially caused by Hageman factor activation was potentiated by the new angiotensin converting enzyme (ACE) inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl-L-alanyl]-(lS,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid] (ramipril, Hoe 498) due to its inhibition of kininase II which results in increased bradykinin levels. A dose of 1 microgram ramipril injected into the hind paw of Sprague-Dawley rats concomitantly with, or 1 mg/kg given orally 30 min before administration of the irritants, led to significantly increased inflammatory reactions. The same effects were observed when ramipril was administered 3 h after carrageenin. In the kallikrein-kinin-deficient Brown-Norway rat strain Mai Pfd/f, ramipril did not significantly alter the paw oedema induced as described above. In addition, pretreatment of Sprague-Dawley rats with 10 mg/kg i.v. bromelains completely prevented the potentiation of inflammation by ramipril. Paw oedema provoked by the Hageman factor non-activators serotonin, dextran, ovalbumin and anti-rat IgG was not potentiated by ramipril. The chronic adjuvant arthritis in Lewis rats was not influenced by daily oral treatment with 0.1-3 mg/kg ramipril. Thus, in the rat only those inflammatory reactions involving kinins, presumably generated by Hageman factor activators, are potentiated by ramipril and presumably by other ACE-inhibitors.     

Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor.

1. We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2. In conscious rabbits, cFP (5 mg kg-1, i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-1), and inhibited the pressor response to right atrial angiotensin I (10-100 ng kg-1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg-1h-1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3. In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg-1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 micrograms kg-1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4. CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 microM respectively), and inhibited rat plasma ACE activity (KI = 2.4 microM). Addition of phosphoramidon (10 microM), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of prolonged administration of the angiotensin converting enzyme inhibitor CGS 16617 in normotensive volunteers

Summary A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 16617, has been evaluated in normotensive subjects during acute and prolonged administration.Single ascending doses of CGS 16617 20 to 100 mg were given to 9 normotensive volunteers at one week intervals and the changes in blood pressure, plasma ACE and renin activity were examined up to 72 h after drug intake. Also, CGS 16617 50 mg/day or placebo were given for 30 days to 8 and 6 normotensive subjects, respectively, maintained on an unrestricted salt diet. Blood pressure was measured daily in the office and ambulatory blood pressure profiles were also obtained before, during and after therapy, using the Remler M 2000 blood pressure recording system.CGS 16617 was an effective and long lasting ACE inhibitor. It did not induce a consistant change in blood pressure, but, the individual responses were very variable and several subjects experienced a clear decrease in the average of the blood pressures recorded during the daytime.     

Enalapril, an inhibitor of angiotensin converting enzyme, increases the junctional conductance in isolated heart cell pairs.

The effect of enalapril and angiotensin II on junctional conductance (gj) of isolated rat heart cell pairs was investigated. It was found that enalapril (1 micrograms/ml) increases gj by 106 +/- 3.1% (SEM) (n = 20) within 4 min. The effect of enalapril on gj was not suppressed by propranolol (10(-6) M) or by a cAMP-dependent protein kinase inhibitor. Angiotensin II (1 micrograms/ml) reduced gj by 55%. These observations might indicate that an intrinsic renin-angiotensin system in heart is involved in the control of gj in cardiac muscle.     

Reduction of the severity of experimental gastric and duodenal ulceration by interleukin-1 beta

Interleukin-1 beta (IL-1 beta) has been reported to stimulate prostaglandin synthesis by the rat stomach in vitro and to inhibit gastric acid secretion in vivo. We have therefore tested the hypothesis that IL-1 beta might have protective actions in experimental models of gastroduodenal ulceration. IL-1 beta, given i.p., dose and time dependently reduced the severity of ethanol-induced gastric damage. A pretreatment time of 90 min was found to produce the greatest reduction of damage, while doses of 0.1 micrograms/kg or greater were found to produce significant effects. The protective actions of IL-1 beta were abolished by prior boiling or by pretreatment of the animals with indomethacin, and were not shared by the nonapeptide fragment 163-171. IL-1 beta also reduced the severity of gastric damage induced by indomethacin and the duodenal ulceration induced by cysteamine. The results indicate that IL-1 beta has protective actions in three separate experimental models of gastroduodenal ulceration. The mechanism of action of IL-1 beta is not entirely clear, but contributions of endogenous prostaglandin synthesis and inhibition of gastric acid secretion cannot be excluded.     

Effects of an angiotensin converting enzyme inhibitor, ramipril, on intracranial circulation in healthy volunteers. off.

1. The effects of a single oral dose (10 mg) of ramipril on (a) systemic haemodynamics (arterial pressure, cardiac output), (b) carotid artery haemodynamics (blood flow and diameter, pulsed Doppler technique), (c) intracranial haemodynamics (middle cerebral artery mean blood velocity, transcranial Doppler technique), and (d) renin-angiotensin system (plasma converting enzyme and renin activities) have been investigated and compared with those of a placebo during the 24 h period following administration in a randomized, double-blind and cross-over study performed in six healthy volunteers. 2. Ramipril induced a strong and sustained inhibition of plasma converting enzyme activity (-96% at 4 h, -63% at 24 h) and an increase in plasma renin activity (+993% at 8 h). 3. As compared with placebo, ramipril did not significantly affect arterial blood pressure, heart rate, cardiac output and total peripheral resistance. 4. Ramipril significantly increased carotid blood flow (by 27% at 8 h) without significantly changing carotid artery diameter, indicating, given the unchanged arterial pressure, an arteriolar vasodilation in the carotid territory. 5. The middle cerebral artery mean blood flow velocity underwent spontaneous modifications during the placebo period but these changes were not affected by ramipril. This lack of influence of ramipril on intracranial haemodynamics suggests that the drug-induced arteriolar vasodilation and increase in carotid blood flow only concern the extracranial, musculo-cutaneous part of the carotid territory.     

Disposition of SDZ ENA 713, an acetylcholinesterase inhibitor,in the rabbit

The disposition of SDZ ENA 713, indicated for the treatment of Alzheimer's disease, was studied in non-pregnant, pregnant, and lactating New Zealand white rabbits. ³H-SDZ ENA 713 was administered as single oral or intravenous dose (1.09 mg kg⁻¹) and as multiple oral doses (1.09 mg kg⁻¹) daily for 7 days. Serial blood and milk samples, selected tissues and excreta samples were collected. Radioactivity was determined in all biological samples by liquid scintillation counting. Concentrations of unchanged SDZ ENA 713 and its phenolic metabolite, ZNS 114-666, were measured by GC-MS. Pharmacokinetic parameters were determined by model independent methods. The rate and onset of absorption were rapid (t_max 1.3±0.58 h) and the extent of absorption was essentially complete. Concentrations of SDZ ENA 713 were below the limit of quantification (0.98 ng mL⁻¹) after oral administration. Following intravenous administration, SDZ ENA 713 was extensively distributed (V_ss=3.1 L kg⁻¹) and rapidly cleared (Cl=2.7 L h⁻¹ kg⁻¹). The radioactivity was primarily excreted via the kidneys (86% of dose). In pregnant rabbits receiving multiple oral doses, the fetus to placentae tissue ratio of radioactivity averaged 0.5. Passage of radioactivity from blood into milk was rapid (t_max=2 h) and the milk:blood AUC ratio of radioactivity averaged 1.5. No unchanged SDZ ENA 713 was detected in the milk samples; however, there were measurable concentrations of the phenolic metabolite (C_max=82.9 ng mL⁻¹). The milk to blood ratio of the phenolic metabolite averaged 2.3. In conclusion, SDZ ENA 713 underwent extensive presystemic metabolism following oral administration. There was moderate transfer of drug-related materials across the placenta. Projecting the rabbit data to humans, it is suggested that nursing neonates would not be exposed to unchanged SDZ ENA 713 following oral doses to nursing mothers. © 1998 John Wiley & Sons, Ltd.     

Synergism between interleukin-1 beta and interferon-gamma, an inducer of nitric oxide synthase, in rat lung fibroblasts.

An L-arginine-dependent pathway, by which L-arginine is metabolised to citrulline and nitrogen oxides, has been recently identified in some cell types. In cultured rat lung fibroblasts the presence of L-arginine was necessary for the production of nitrite to be induced by rat recombinant interferon-gamma and synergistically enhanced by lipopolysaccharide and interleukin-1 beta. Lipopolysaccharide and interleukin-1 beta did not induce nitrite biosynthesis by themselves. Biosynthesis was apparently dependent on tetrahydrobiopterin, since it could be blocked by diaminohydroxypyrimidine, an inhibitor of tetrahydrobiopterin synthesis. Dexamethasone blocked nitrite production by a receptor-mediated mechanism. These data indicate that rat lung fibroblasts express an L-arginine-dependent nitric oxide synthase which can be induced by some mediators of inflammation.     

Regulation of uterine smooth muscle bradykinin receptors by bradykinin levels and angiotensin converting enzyme inhibitor in the rat

1. Bradykinin infusion (0.1 microgram/min i.v.) decreased the number of uterine bradykinin receptors by 20% at Day 2. Bradykinin receptors returned to control levels at Day 7. 2. Captopril infusion (1.7 micrograms/min i.v.) induced prolonged decreases in the number of uterine bradykinin receptors of 15% at Day 2 and of 13% at Day 7, respectively. 3. The number of uterine bradykinin receptors was increased in two-kidney, one clip hypertensive rats by 19%. 4. These results suggest that endogenous bradykinin participates in the regulation of uterine bradykinin receptors. 5. Decreased uterine bradykinin receptors induced by captopril might reflect increased endogenous bradykinin.