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Clinical Competence↗
Biomedical subjects
W S Mann
Publications and source records attributed to W S Mann.
Angiotensin-converting enzyme inhibitors: new orally active 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones possessing antihypertensive activity.
The preparation of a series of 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) in vitro and in vivo were examined. These compounds are assumed to act as prodrugs since they undergo rapid ring-opening reactions to give the corresponding biologically active free SH compounds when incubated with rat plasma or when treated with aqueous 0.1 N HCl or phosphate buffer (pH 7.4). The thiazepines 23-25 and 30 are potent inhibitors of ACE when administered po to rats and are comparable in potency to captopril (1). The most active thiazines in rats, po, were 42 and 45. Of the benzothiazepines studied, 22a was the most active in inhibiting ACE in the conscious normotensive rat, ID50 = 0.15 mg/kg, po. The acute antihypertensive effects of oral administration of a number of these compounds on mean arterial pressure and heart rate were studied in spontaneously hypertensive rats (SHR) maintained on a sodium-deficient diet.
Administration, Oral↗
Computerizing clinical patient problems: an evolving tool for medical education.
A natural language, free enquiry patient simulation of high fidelity has been developed using low cost microcomputer technology. The simulation is flexible, portable, responsive to individual student needs, and does not require computer literacy. The design is based on the principles of problem-based self-directed learning. The simulation is useful in individual and group learning and evaluation of data management and clinical reasoning skills.
California↗
Celiprolol, a compound possessing weak alpha 2-adrenergic antagonist properties in the dog.
Studies were conducted to evaluate the effects of celiprolol on alpha-adrenergic stimulation of dog saphenous vein rings (postsynaptic effect) and on catecholamine outflow from the dog coronary circulation during sympathetic nerve stimulation in vivo (presynaptic effect). In venous rings, celiprolol, 10(-6) to 10(-4) M, shifted the concentration-response curve to BHT 920 in a concentration-related manner, but had no effect on the response to methoxamine at concentrations less than 10(-4) M. During continuous stimulation of the right stellate ganglion, celiprolol, 1-10 mg/kg i.v., increased the catecholamine concentration in the coronary sinus, while decreasing heart rate. In contrast, propranolol did not affect catecholamine concentration but decreased heart rate, rauwolscine increased both catecholamine concentration and heart rate, and clonidine decreased both catecholamine concentration and heart rate. These results are consistent with the hypothesis that celiprolol possesses weak alpha 2-antagonist properties in addition to its beta 1-blocking activity.
Adrenergic alpha-Agonists↗
Angiotensin-converting enzyme inhibitors. New orally active antihypertensive (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives.
A variety of N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives was synthesized and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) was examined in vitro and in vivo. The acylthio derivatives prepared are assumed to act as prodrugs since they are much less active than the corresponding free SH compounds in vitro and can be expected to act in vivo only after conversion to the free sulfhydryl compounds. A number of these compounds are potent ACE inhibitors that lowered blood pressure in Na-deficient, conscious spontaneously hypertensive rats (SHR), a high renin model. One of the most active members of the series was (S)-N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1 -oxopropyl]glycine (REV 3659-(S), pivopril). Structure-activity relationships are discussed.
Administration, Oral↗
Angiotensin converting enzyme inhibitors. (Mercaptoaroyl)amino acids.
A series of (mercaptoaroyl)amino acids and related compounds was synthesized and tested for ability to inhibit angiotensin converting enzyme (ACE). The most active compound was N-(3-chloro-2-mercaptobenzoyl)-N-cyclopentylglycine, having an in vitro I50 = 0.28 microM. Substitution of the aromatic 3-position by small polar groups enhanced ACE inhibitory activity, whereas bulky groups diminished it. Alteration of the beta relationship between the mercaptan and amide carbonyl or masking of the thiol by acylation reduced activity. Replacement of the thiol by nitro, hydroxy, or carboxy gave compounds lacking ACE inhibitory activity.
Amino Acids↗
Celiprolol--pharmacological profile of an unconventional beta-blocker.
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Adrenergic beta-Antagonists↗
Celiprolol, a potent cardioselective beta 1-adrenoceptor antagonist with mild alpha 2-adrenoceptor antagonist properties.
Celiprolol is a cardioselective beta-adrenoceptor antagonist, with interesting propranolol-insensitive cardiostimulatory, vasodilatory and bronchodilatory effects. Recent reports suggest that mild alpha 2-adrenoceptor antagonism may contribute to these effects. The present investigation further explored the alpha 2 effects of celiprolol. In isolated electrically-stimulated rat atria celiprolol (1.0 and 10 mumol/l) significantly increased the release of [3H]-norepinephrine, consistent with the blockade of pre-junctional alpha 2-adrenoceptors. Evidence for post-synaptic alpha 2-adrenoceptor antagonist activity was obtained in studies of the effects of celiprolol on the pressor response to clonidine and either phenylephrine or methoxamine in perfused hind-limbs of dogs (pretreated with mecamylamine and propranolol) and pithed rats. In the dog, celiprolol (10 mg/kg) significantly inhibited the vasoconstrictor response of clonidine while in the rat higher doses were required (> or = 12.5 mg/kg). Celiprolol did not affect the pressor response induced by alpha 1-agonists. We conclude that celiprolol possesses a mild alpha 2-adrenoceptor blocking action which may contribute to its unconventional profile.
Adrenergic beta-Agonists↗
Angiotensin-converting enzyme inhibitory and antihypertensive activities of pivalopril (RHC 3659-(S)).
Pivalopril (RHC 3659-(S); (S)-N-cyclopentyl-N-(2-methyl-3-pivaloylthiopropionyl) glycine) is a new compound with a hindered sulfur group that has been compared to captopril for oral angiotensin-converting enzyme (ACE) inhibition in rats and dogs and antihypertensive activity in rats. In separate groups of conscious normotensive rats, pivalopril (0.03-1.0 mg/kg, orally [p.o.]) produced a dose-related antagonism of angiotensin I (AngI)-induced pressor effects. The ED50 for pivalopril and captopril was 0.1 mg/kg. In conscious normotensive dogs, pivalopril (incremental doses of 0.01-1.0 mg/kg, p.o.) produced a dose-related antagonism of AngI pressor effects. The ED50 was 0.17 mg/kg for pivalopril and 0.06 mg/kg for captopril. At equieffective doses the two compounds had similar durations of action. In sodium-deficient, conscious spontaneously hypertensive rats (SHR), pivalopril (1-100 mg/kg, p.o.) produced a dose-related reduction in mean arterial pressure. The potency and duration were similar to those of captopril. In the sodium-replete SHR, 5 days of oral dosing with pivalopril, 100 mg/(kg . day), decreased mean arterial pressure more effectively than captopril, 100 mg/(kg . day). No tolerance developed to the antihypertensive effect of either drug. It is concluded that pivalopril is a potent, orally effective ACE inhibitor and antihypertensive agent.
Angiotensin I↗
Enzymic and physiological studies on normal and disused developing fast and slow cat muscles.
1. Contraction time (CT), (1/2) relaxation time ((1/2) RT), maximum twitch-tetanus tensions and the activity of two glycolytic enzymes (aldolase, pyruvic kinase) and two oxidative enzymes (malic and isocitric dehydrogenase) was studied in anterior tibialis (AT) and soleus (SOL) muscles from birth to 18 weeks of age.2. One hind leg of each of six kittens was casted at birth and the above parameters were examined in both casted and contralateral AT and SOL at 18 weeks of age.3. Differentiation of the contraction properties in normal developing fast muscle (AT) was closely paralleled by a marked elevation in glycolytic enzyme activity. Oxidative enzymic activity in AT and SOL was relatively unchanged from birth to 18 weeks of age, as was glycolytic activity in SOL.4. Disuse, due to immobilization, produced atrophy in AT and SOL muscles at 18 weeks of age. The CT of the casted SOL was slightly quicker than normal while the CT of the AT was unchanged. The glycolytic and oxidative enzymic activity in both casted muscles was generally unchanged but the contralateral AT had higher glycolytic activity than normal muscles.
Animals↗
Development of the differential response to succinylcholine in the fast and slow-twitch skeletal muscle of the kitten.
1. The response to SCh has been studied in anterior tibialis and soleus muscles of new-born and neonate cat while, in a separate group of animals of similar ages, the end-plate development in these muscles has been examined.2. At birth, when the contraction times of the anterior tibialis and soleus are not statistically different, the anterior tibialis is 1.4 times more sensitive to SCh blocking action than the soleus, but both muscles were 20-40 times less sensitive than their adult counterparts.3. With maturation, the ratio of the soleus/anterior tibialis contraction time increased to 2.7 while the ratio of the 50% blocking dose of SCh in the soleus/anterior tibialis increased to 2.8, the increases being parallel. The time to 50% recovery at 50% blocking doses of SCh was similar for both muscles at all ages although it was 3 times longer in new-born and 1-week-old animals than in animals 3 weeks of age and older.4. The areas of individual end-plates from these muscles were very similar at birth but by three weeks of age the areas of end-plates from the anterior tibialis were substantially greater than those obtained from soleus.5. We have speculated that the relationship between SCh sensitivity and end-plate area in fast and slow muscle may find its origins in the frequency of the MEPP.
Age Factors↗