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Biomedical subjects

J D Irvin

Publications and source records attributed to J D Irvin.

At least 55 records · Page 3Linked to original sources
PubMed1984

Antihypertensive efficacy of once daily MK-521, a new nonsulfhydryl angiotensin-converting enzyme inhibitor.

The effects of the new nonsulfhydryl-containing oral converting-enzyme inhibitor MK-521 on blood pressure, heart rate, angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration were assessed in 10 hypertensive patients. After a 2-week no-treatment period, patients received placebo and then 14 days each: MK-521 20 mg once daily, hydrochlorothiazide 50 mg once daily and the latter 2 in combination. During the last day of each treatment, the mean (+/- standard deviation) time-averaged (1- to 12-hour) standing diastolic blood pressure decreased from 106 +/- 8 (placebo) to 95 +/- 10 mm Hg with MK-521, 95 +/- 13 mm Hg with hydrochlorothiazide (p less than 0.05 vs placebo) and 88 +/- 11 mm Hg with the combination (p less than 0.05 vs all other treatments). The antihypertensive effect of MK-521 was maintained 24 hours after dosing. Heart rate did not change significantly after MK-521 treatment. MK-521 caused a marked suppression of converting enzyme activity for over 24 hours; plasma renin activity increased significantly after each active treatment and MK-521 significantly decreased the hydrochlorothiazide-induced elevation of plasma aldosterone concentration. In this short-term trial, MK-521 was well tolerated.

Adult↗
PubMed1984

Influence of food on the bioavailability of enalapril.

In a randomized, two-period crossover study in 12 normal volunteers, serum and urine concentrations of the angiotensin-converting enzyme inhibitor enalapril and its active metabolite enalaprilat were determined following administration of a single 40-mg tablet of enalapril maleate administered both in the fasting state and with a standard breakfast. A 7-d interval separated the two treatment periods. Area under the serum concentration-time curves for enalaprilat and urinary recoveries for enalaprilat and total drug did not differ significantly between the fed and fasted conditions. The mean observed maximum serum concentration of enalaprilat was slightly higher for the fasting treatment, but the time to peak concentration was almost identical for the two treatments. Enalapril maleate is unlike the prototype angiotensin-converting enzyme inhibitor captopril in that a standard meal does not appear to influence absorption of this new drug.

Adult↗
PubMed1984

An overview of the clinical pharmacology of enalapril.

Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half-life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function. Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics. Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose-response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once- or twice-daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide. Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate. Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase.

Aldosterone↗
PubMed1984

Initial evaluation of the non-sulfhydryl-containing converting enzyme inhibitor MK-521 in hypertensive humans.

MK-521 is a new orally active, nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Single doses of 2.5, 5.0, 10.0, and 20.0 mg were administered to nine hypertensive patients alternating with placebo. All doses of MK-521 caused profound suppression of ACE activity for more than 24 h and decreased standing diastolic blood pressure for more than 12 h without changes in pulse rate. Although there was no further reduction in blood pressure with doses above 5.0 mg, the duration of action was prolonged for more than 24 h with the higher doses. Serum MK-521 concentrations increased with dosage, and ACE was inhibited maximally at concentrations above 10 ng/ml. In this initial study, MK-521 was well tolerated and proved to be a potent and long-acting antihypertensive agent.

Adult↗
PubMed1983

Inhibition of herpes simplex virus DNA synthesis by pokeweed antiviral protein.

Pokeweed antiviral protein at a concentration of 3 microM inhibited both the synthesis and release of infectious herpes simplex virus type 1 in cell culture by 90 and 99%, respectively. Addition of pokeweed antiviral protein to Vero cell monolayers before virus infection was 10 to 15% more effective in reducing virus yields than was the simultaneous addition of the antiviral protein with virus inoculum. Viral DNA synthesis was inhibited by 90% in cells which had been exposed to the antiviral protein, whereas cellular DNA synthesis was unaffected. No significant inhibition in the synthesis of the majority of viral infected-cell polypeptides was observed early postinfection (7 h), with the exception of infected cell polypeptides 4 and 41, whose syntheses were reduced by 38 and 25%, respectively. At 9 to 21 h postinfection, however, the synthesis of individual infected cell polypeptides was reduced by 48 to greater than 99%.

Animals↗
PubMed1982

Chemical modifications of pokeweed antiviral protein: effects upon ribosome inactivation, antiviral activity and cytotoxicity.

Pokeweed antiviral protein (PAP) is a protein known to inactivate eukaryotic ribosomes by an unknown enzymatic action and inhibit the production of mammalian viruses in tissue culture. This protein was subjected to a variety of chemical modifications to determine their effects upon ribosomal inactivation, antiviral action, and cytotoxicity. It was found that modifications of a number of different amino acid residues had similar effects upon all 3 activities. Also the inactivation of PAP with diethylpyrocarbonate was not due to its reaction with a histidine residue but to a modification of an unidentified amino acid residue.

Animals↗
PubMed1982

Purification and partial characterization of another form of the antiviral protein from the seeds of Phytolacca americana L. (pokeweed).

1. The pokeweed antiviral protein, previously identified in two forms (PAP and PAP II) in the leaves of Phytolacca americana (pokeweed) [Obrig. Irvin & Hardesty (1973) Arch. Biochem. Biophys. 155, 278-289; Irvin, Kelly & Robertus (1980) Arch. Biochem. Biophys. 200, 418-425] is a protein that prevents replication of several viruses and inactivates ribosomes, thus inhibiting protein synthesis. 2. PAP is present in several forms in the seeds of pokeweed. One of them, which we propose to call 'pokeweed antiviral protein from seeds' (PAP-S) was purified in high yield (180 mg per 100 g of seeds) by chromatography on CM-cellulose, has mol.wt. 30 000, and is similar to, but not identical with. PAP and PAP II. 3. PAP-S inhibits protein synthesis in a rabbit reticulocyte lysate with an ID50 (concentration giving 50% inhibition) of 1.1 ng/ml (3.6 x 10(-11) M), but has much less effect on protein synthesis by whole cells, with an ID50 of 1 mg/ml (3.3 x 10(-5) M), and inhibits replication of herpes simplex virus type 1.

Amino Acids↗
PubMed1982

A comparative pilot study of enalapril, a new converting enzyme inhibitor, and hydrochlorothiazide in essential hypertension.

Eight patients with essential hypertension completed a double-blind, randomly allocated crossover comparison of either 5 or 10 mg enalapril maleate, 50 mg hydrochlorothiazide, or their combination administered once daily during sequential two-week periods. Blood pressure, pulse rate, plasma renin activity, angiotensin-converting enzyme activity, plasma aldosterone concentration, and urinary electrolytes were monitored for 24 hours after placebo and on days 1 and 14 of each treatment period. After two weeks of each treatment, only the combination of enalapril and hydrochlorothiazide significantly lowered the mean seated diastolic blood pressure (SDBP). Likewise, SDBP control (less than or equal to 90 mm Hg) was achieved only after combination therapy; six of the eight patients were controlled by the combination for up to 24 hours. The initial SDBP response to combination therapy differed with the sequence of drug addition; however, by day 14 the responses were comparable, regardless of whether hydrochlorothiazide or enalapril was first given. Mean converting enzyme activity was suppressed by enalapril in all patients, though it did not always correlate with changes in SDBP or plasma aldosterone. Mean plasma renin activity increased, but the increase was significant only on the combination. There were no serious adverse effects.

Adult↗
PubMed1982

Effects of enalapril, a new converting enzyme inhibitor, in hypertension.

The new angiotensin converting enzyme inhibitor enalapril maleate was given in single oral doses of 2.5, 5, and 10 mg to 11 hospitalized patients with uncomplicated essential hypertension who were on a 150-mEq sodium diet. All doses of enalapril induced reduction of mean seated diastolic blood pressure (SDBP). The magnitude of the initial SDBP reduction was not dose related, but the duration of effect was longer (greater than 12 hr) after the 5 and 10 mg. After dosing, mean plasma angiotensin converting enzyme activity (ACE) and aldosterone concentration (PAC) fell, while plasma renin activity (PRA) rose. Serum concentrations of the active diacid from of enalapril increased linearly with dosage; ACE was inhibited maximally at concentrations above 10 ng/ml. During repeated dosing in the outpatient trial there was attenuation of the antihypertensive effect (12 to 24 hr after dosing) in eight of 10 patients. Despite dose increases only two patients achieved SDBP control (less than or equal to 90 mm Hg). In the five patients in whom 50 mg/day hydrochlorothiazide was added near the end of the trail mean SDBP was further reduced. Enalapril was well tolerated. Further studies of the drug, especially in combination with diuretic, are needed.

Adult↗
PubMed1982

Enantiomers of indacrinone: a new approach to producing an isouricemic diuretic.

Racemic indacrinone is a potent loop diuretic with transient uricosuric properties in certain nonhuman primates and in man. After chronic treatment, hyperuricemia develops presumably because of enhanced proximal tubular urate reabsorption secondary to extracellular fluid volume contraction. The natriuretic and uricosuric activities are associated with both enantiomers, but the (-)-enantiomer is significantly more potent as a natriuretic agent than the (+). Acutely, in Cebus monkeys, both enantiomers appear to have similar uricosuric activity. The difference in the natriuretic potency between the two enantiomers provides the possibility of altering the enantiomer ratio from its naturally occurring 1:1 ratio to another combination which would enhance the uricosuric action [more (+) relative to (-)] while preserving the potent natriuretic action of the (-). In healthy volunteers, a 1:4 ratio [(-):(+)] was isouricemic after 7 days of treatment and a 1:8 mixture lowered mean serum urate by 13%. Presumably, the desired ratio of (-):(+) will be in the range 1:4-1:9. Further enhancement of the diuretic profile of this compound may be obtained by adding sufficient amiloride to produce isokalemia.

Amiloride↗
PubMed1981

Reversal of the inhibitory effects of the pokeweed antiviral protein upon protein synthesis.

Protein synthesis directed by natural mRNA is more sensitive to the inhibitory action of the pokeweed antiviral protein than synthesis directed by poly-(uridylic acid). Investigations into the nature of this difference revealed that pokeweed antiviral protein does not inhibit the initiation stage of protein synthesis and that the expression of pokeweed antiviral protein inhibition is dependent upon the K+ and Mg2+ concentrations used in the protein synthesis assay. Ribosomes treated with pokeweed antiviral protein function as efficiently as untreated ribosomes if assayed at either high Mg2+ or low K+ concentrations. The influence of ionic conditions upon the individual elongation factor reactions shows that pokeweed antiviral protein inhibition of the elongation factor two translocation reaction is sensitive to ionic conditions but that the inhibition of the elongation factor one-mediated enzymatic binding is not sensitive to changes in these conditions. The results suggest that the unknown enzymatic effect of pokeweed antiviral protein produces a conformational change in ribosome, which is reversed under conditions which favor a more compact ribosomal structure.

Magnesium↗
PubMed1981

Pharmacology of enantiomers and (-) p-OH metabolite of indacrinone.

Indacrinone, a racemic mixture, is a loop-blocking diuretic with effects on uric acid elimination that differ from those of furosemide. A series of studies in healthy men was undertaken to characterize the pharmacologic activity of the positive (+) and negative (-) enantiomers (E) of indacrinone and its (-) p-OH metabolite, (-) MET. All subjects were on sodium- and potassium-controlled diet; each experiment was similar in design and included placebo and positive controls. Oral (-)E and (-)MET exerted dose-related natriuretic and diuretic effects; intravenous doses of (-)E were more effective than (-)MET. The effects of (-)E and (-)MET on serum uric acid were the same as those reported with indacrinone. After (-)E, both (-)E and generated (-)MET appeared to contribute to the natriuresis. (+)E induced dose-related decreases in serum uric acid up to 24 hr after dosage; at the higher doses of (+)E, the hypouricemic effects were of the order of those after 500 mg of probenecid. Thus, indacrinone is a novel loop diuretic with enantiomers and a (-)MET, each of which has a different pharmacologic profile.

Adult↗
PubMed1980

Inhibition of elongation factor 2-dependent translocation by the pokeweed antiviral protein and ricin.

The pokeweed antiviral protein and the toxin ricin are two plant proteins which enzymatically inactivate eukaryotic ribosomes and cause the inhibition of the elongation cycle of protein synthesis. Their mode of inhibition of protein synthesis has been attributed to either the inhibition of enzymatic binding of aminoacyl-tRNA to the acceptor site of the ribosome or its subsequent translocation to the donor site. In this communication, we show that the treatment of ribosomes with either the pokeweed antiviral protein or ricin results in the inhibition of the elongation factor 2-catalyzed translocation of acceptor site aminoacyl-tRNA to the donor site. The inhibitory effects of both proteins are identical and are partially reversed by excess concentrations of elongation factor 2.

Animals↗
PubMed1980

Comparison of oral indacrinone with furosemide.

The oral dose response and time course of action of indacrinone was compared with that of furosemide in six healthy men on a sodium and potassium-controlled diet. The single doses were 5, 10, 20, 40, and 80 mg indacrinone and 20, 40, and 80 mg furosemide. Diuretic, natriuretic, and kaliuretic effects revealed that indacrinone was more potent, had a longer duration of action, and induced a greater sodium for equivalent potassium loss during its period of peak activity than furosemide. During the 8 hr after drug, all doses of indacrinone decreased serum uric acid levels and increased uric acid clearance while furosemide generally increased serum uric acid and decreased uric acid clearance. After 24 hr, serum uric acid and uric acid clearance were the same for the two drugs. A rise in plasma renin activity was observed 2 hr after an 80-mg dose of furosemide but not after indacrinone.

Adult↗
PubMed1980

Inhibition of herpes simplex virus multiplication by the pokeweed antiviral protein.

The pokeweed antiviral protein inhibited the multiplication of herpes simplex virus type 1 in cell culture. The extent of antiviral activity was proportional to the length of time that the antiviral protein was present postinfection. The results demonstrate that the continued presence of the pokeweed antiviral protein is necessary for the maximum inhibition of virus yields.

Antiviral Agents↗