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Biomedical subjects

O H Drummer

Publications and source records attributed to O H Drummer.

At least 91 records · Page 5Linked to original sources
PubMed1986

Studies on the cytotoxicity of penicillamine in a rat osteogenic sarcoma.

The effect of penicillamine on the growth rate of an osteogenic sarcoma of rats was investigated and compared with cyclophosphamide. Rats were inoculated with a readily transplantable osteogenic sarcoma subcutaneously into the left thigh and treated with penicillamine and cyclophosphamide alone or in combination. Cyclophosphamide inhibited tumour growth. Penicillamine did not delay the appearance or the growth rate of the tumour. Tumour sizes tended to be larger in the penicillamine-treated rats, but there was no evidence that penicillamine interfered with the antitumour effect of cyclophosphamide given in large doses (100 mg/kg).

Animals↗
PubMed1985

Effect of probenecid on the disposition of captopril and captopril dimer in the rat.

The urinary excretion of captopril has been studied in a bladder-cannulated rat model and compared with that obtained after co-administration with probenecid. Probenecid reduced significantly the urinary excretion of captopril from 41% to 21% of the administered dose over a 3-hr period and significantly lowered urine flow rates. In addition, the effect of probenecid on plasma levels of captopril and total captopril (captopril plus disulfides) after oral administration of the disulfide prodrug captopril dimer (10 mg/kg) has been studied in a conscious rat preparation. Co-administration of probenecid (20 mg/kg) given either orally or intravenously increased both the plasma levels of captopril and total captopril (captopril plus captopril disulfides) over a 4-hr period. A prolonged significant inhibition of plasma ACE after co-administration of probenecid and captopril dimer suggests that probenecid may be useful to prolong the action of captopril or the prodrug captopril dimer.

Animals↗
PubMed1984

Captopril disulfide conjugates may act as prodrugs: disposition of the disulfide dimer of captopril in the rat.

The absorption and metabolism of the disulfide dimer conjugate of captopril has been studied in the rat following both oral and intravenous dosing and compared with that of the active monomer, captopril. Metabolism of the dimer to captopril has been shown after both oral and intravenous administration of the dimer (10 mg/kg) with peak plasma levels of captopril (154 ng/ml) occurring at 1 hr post dose. By contrast the peak plasma level of captopril after oral administration of captopril (10 mg/kg) at the same dose was much higher at 678 ng/ml and also occurred at 1 hr post dose. Plasma captopril disulfide species were much higher than the plasma levels of captopril after the administration of either dimer or captopril and tended to persist for much longer than for monomeric captopril particularly after administration of the dimer. Both the dimer and its pharmacologically active product captopril were found in relatively large amounts in lung, kidney and liver following the oral administration of the dimer.

Administration, Oral↗
PubMed1984

High-performance liquid chromatographic determination of platinum (II) in plasma ultrafiltrate and urine: comparison with a flameless atomic absorption spectrometric method.

A technically simple, rapid and sensitive high performance liquid chromatographic assay for cis-dichlorodiammineplatinum (II) in human plasma ultrafiltrate and urine is described. The drug was chelated by exchange with diethyldithiocarbamate and extracted into chloroform. Nickel (II) was used as an internal standard which allows correction for the matrix effects observed with previous chromatographic and spectrometric methods. Chromatography was performed on a mu-Bondapak CN column and the eluent measured spectrophotometrically at 254 nm. Precision and reproducibility were both excellent and the detection limit was less than 50 ng/ml using only 1 ml of biological fluid.

Chromatography, High Pressure Liquid↗
PubMed1984

Combined gas chromatographic-mass spectrometric procedure for the measurement of captopril and sulfur-conjugated metabolites of captopril in plasma and urine.

A gas chromatographic-mass spectrometric method is described for the simultaneous measurement of the novel anti-hypertensive drug captopril, and the following metabolites: captopril disulfide dimer, S-methyl captopril, and S-methyl captopril sulfone. With this method all derivatives can be chromatographed using conventional gas chromatography of hexafluoroisopropyl esters in one temperature-programmed run and these can then be quantitated using selected-ion monitoring techniques. Using urine or plasma, captopril, S-methyl captopril and the disulfide dimer of captopril in concentrations as low as 1 ng/ml, 10 ng/ml and 25 ng/ml, respectively can be detected. The reproducibility of the method is satisfactory both within-assay and inter-assay. This technique has demonstrated that the pattern of urinary excretion of these compounds in both man and rat was similar. Excretion of unchanged captopril, S-methyl captopril and the disulfide dimer over 6 h in man given captopril (50 or 100 mg) chronically was 18.3%, 0.97% and 3.06%, respectively. Corresponding excretion of these three compounds in the rat following a single 10 mg/kg dose was 18.3%, 2.69% and 1.8%, respectively. A possible sulfone oxidation product of S-methyl captopril was not detected in the urine of either man or rat.

Animals↗
PubMed1984

Gastric and intestinal absorption of captopril in acutely and chronically treated rats: comparison with salicylic acid.

The gastric and intestinal absorption of captopril, an orally active angiotensin-converting enzyme inhibitor was determined using rat in situ gastric pouch and intestinal loop techniques and compared with the absorption of another acidic drug, salicylic acid, whose absorption has been well established from both gastric and intestinal sites. Captopril absorption was determined at two initial intraluminal concentrations in acute (untreated) rats and in rats that had been chronically treated with captopril. Salicylic acid absorption was determined at one concentration in acute rats. During the 40-min experimental period, captopril absorption at the 4.6 mM dose from the gastric pouch was 17.0 +/- 1.8% and 17.9 +/- 5.4% in acute and chronically treated rats, respectively, and 33.6 +/- 9.2% and 23.7 +/- 7.6%, respectively, from the intestinal loop. At the 11.5 mM dose the captopril absorption in 40 min was 13.7 +/- 2.7% and 17.3 +/- 4.2% from the gastric pouch of acutely and chronically treated rats, respectively, and 17.8 +/- 4.2% and 22.9 +/- 3.3%, respectively, from the intestinal loop. As similar fractions of the different administered doses were absorbed from the respective gastric and intestinal sites in both acutely and chronically treated rats, the absorption process of captopril appears to be principally by passive diffusion and unaffected by chronic administration of captopril. In comparison, salicylic acid was absorbed more rapidly and to a greater extent from both the gastric and intestinal preparations. The percent of salicylic acid absorbed into the plasma at the 11.5 mM dose was 44.8 +/- 4.4% and 65.3 +/- 5.3% from the gastric and intestinal preparations, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Pharmacology of combined alpha-beta-blockade. I.

Several compounds of the chemical class arylethanolamines have been shown to possess combined alpha- or vasodilator and beta-adrenoceptor blocking properties. The first drug was labetalol (AH5158)[5-(1-hydroxy-2)1-methyl-3-phenylpropyl(amino)-ethyl (salicylamide)]. Others include medroxalol, bucindolol and YM-09538, which differ from labetalol either by the nature of the substitution on the primary benzene ring and/or on the terminal nitrogen. All of these drugs are non-selective beta-blockers, except for bucindolol whose selectivity has not been carefully defined. The rationale for the development of this group of drugs was the knowledge that blockade of one adrenoceptor subtype causes reflex stimulation of the other, i.e. vasoconstriction after nonspecific beta-blockade and tachycardia after alpha-blockade. Since both of these compensatory responses act to prevent a fall in blood pressure, a relatively weak blockade of both receptor types should act synergistically to produce a lowering of blood pressure with minimal physiological disturbance. Haemodynamic studies have confirmed that the additional alpha-blocking properties of labetalol produce a pattern of haemodynamic changes unlike that of propranolol and other simple beta-adrenoceptor blocking agents. Peripheral vascular resistance, which falls acutely during the initial administration of the drug, tends to fall further during prolonged administration and the pulse rate tends to remain only slightly lower than pretreatment levels. In addition, at normal dose levels cardiac output is maintained by a compensatory increase in stroke volume. Thus, blood pressure is lowered largely by a reduction in vascular resistance, and although the heart rate falls significantly during exercise, the cardiac output is maintained by an increase in stroke volume. This pattern of events is different to that seen with beta-blocking agents which consistently reduce cardiac output during exercise. Currently labetalol is the only member of this group of drugs which is in established clinical use. Its antihypertensive efficacy has been confirmed in many studies and it has been shown to be effective in the management of both hypertensive emergencies and in the long term management of severe hypertension. It is particularly valuable in allowing a reduction in the number of drugs required for adequate blood pressure control. The early theoretical prediction that postural hypotension would occur with high doses is now acknowledged to be labetalol's major dose-limiting side effect. Most of the available pharmacokinetic data on labetalol were derived from studies which utilised a fluorimetric assay.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1983

Beta-adrenoceptor-blocking drugs: current status and the significance of partial agonist activity.

There is some evidence that partial agonism is an important property of beta-blocking drugs, and this property may be exploited to produce a new range of positive inotropic drugs. With the established beta-adrenoceptor-blocking drugs, the level of partial agonist activity is weak and the dose-response curve for this property is shallow. However, its absence appears to increase the likelihood of inducing bronchospasm and bradycardia, and drugs that lack intrinsic sympathomimetic activity appear more likely to be associated with rebound cardiac arrhythmias on cessation of treatment. The idea of a small level of hormone activity--in this case, catecholamine activity--being necessary to maintain normal cardiac and perhaps bronchial function is not new. Minimal doses of steroids are essential to maintaining the inotropic action of cardiac muscle. There is now enough accumulated evidence to suggest that a minimal degree of beta-adrenoceptor stimulation is also important for normal bronchial and cardiac function, and its absence increases the incidence of bradycardia and the risks of bronchospasm and rebound arrhythmias.

Adrenergic beta-Agonists↗
PubMed1983

S-methylation of captopril. Demonstration of captopril thiol methyltransferase activity in human erythrocytes and enzyme distribution in rat tissues.

The presence of a methyltransferase enzyme in human red blood cells (RBCs) capable of S-methylation of captopril is described. The apparent Michaelis-Menten (Km) constant for captopril was 0.5 mM and the maximum velocity (Vmax) was 0.391 pmoles S-methylcaptopril (mg protein)-1 min-1. There is some evidence presented to show that S-methylcaptopril inhibited its own formation with a ki value of 5.81 mM. Captopril thiol methyltransferase activity was also examined in rat tissues and was found to be present in all tissue studied. Subcellular localisation studies in rat liver suggest that the enzyme was microsomal in origin. The order of activity was liver greater than heart greater than spleen greater than lung greater than kidney much greater than RBC (rat). This tissue distribution was quite different from previous studies using other thiol substrates and is consistent with more than one form of thiol methyltransferase enzyme in tissues.

Animals↗
PubMed1983

Tissue distribution of captopril, reducible captopril conjugates and S-methylcaptopril in the rat.

The tissue distribution of captopril, an antihypertensive drug possessing a free sulfhydryl group, and its sulfur-conjugated metabolites was studied in rats by gas chromatography-mass spectrometry at 15, 30 and 60 min following a single 10 mg/kg oral dose of captopril. It was found that tissue accumulation of captopril was rapid with both free and oxidized-forms already present at 15 min post-dose. A maximum concentration of captopril was achieved at 30 min in tissues studied, being substantially higher in kidney (14.2 micrograms/g), with lesser amounts occurring in liver, lung, heart, blood cells, spleen and plasma in that order. Oxidized disulfide forms of captopril were usually present in the same or slightly higher proportion than free captopril except for liver which only contained detectable disulfides at 15 min after oral dosing. S-methylcaptopril was also present at 30 min in all tissues examined with highest levels occurring in liver and kidney (1.05 micrograms/g) followed by plasma, lung, heart, spleen and blood cells.

Animals↗
PubMed1983

An in situ gastric pouch technique for direct measurement of the gastric absorption of drugs in the rat.

The preparation of an in situ gastric pouch technique that will allow a direct measurement of drug absorption is described. This technique has been developed in rats, but could be easily utilized in different laboratory animals. This technique has the major advantages of providing a direct measurement of the quantity of drug crossing the gastric mucosa into the bloodstream and enabling a direct comparison with results obtained using in situ intestinal loop preparations.

Absorption↗
PubMed1982

Positive chronotropic responses produced by alpha-adrenoreceptors in the pithed rat.

1 Phenylephrine (1-100 microgram/kg, intravenously) produced dose-dependent increases in heart rate and blood pressure in the pithed rat. 2 The positive chronotropic response to phenylephrine (10 microgram/kg) was reduced in a dose-dependent manner by propranolol (0.01-0.3 mg/kg), but higher doses of propranolol (up to 3 mg/kg) did not reduce the response by more than about 50%. The residual response was virtually abolished by phentolamine (0.3 mg/kg) or prazosin (3 microgram/kg). Labetalol (3 mg/kg) which has both alpha- and beta-blocking activity, also abolished the positive chronotropic response. 3 The pressor response to phenylephrine (1-30 microgram/kg) was enhanced by propranolol (1 mg/kg) and abolished by phentolamine (1 mg/kg) and prazosin (30 microgram/kg). Labetalol (3 mg/kg) reduced the response to phenylephrine by 73%. 4 Propranolol (0.3 mg/kg) completely blocked the chronotropic and vasodepressor effects of isoprenaline (0.1 microgram/kg). 5 It is concluded that phenylephrine acts on both alpha 1- and beta 1-adrenoreceptors to produce an increase in heart rate, on alpha 1-adrenoreceptors to produce vasoconstriction and on beta 2-adrenoreceptors to produce vasodilation. This latter effect is usually masked by the predominant vasoconstrictor action.

Adrenergic alpha-Antagonists↗
PubMed1982

Demonstration of a S-methyl metabolite of captopril in patients undergoing chronic captopril therapy.

1. The formation of the S-methyl metabolite of captopril has been demonstrated for the first time in the urine of five patients receiving chronic captopril therapy. 2. Patients were studied following a 100 mg oral dose of captopril. 3. Excretion values for S-methylcaptopril were 0.66 mg and 0.31 mg at 0-3 h and 3-6 h postdose. Captopril excretion was at these two collections 15.5 mg and 2.3 mg, respectively.

Captopril↗
PubMed1981

High-performance liquid chromatographic assay of perhexiline maleate in plasma.

A sensitive assay is described for the calcium antagonist perhexiline maleate. Alkalinized plasma was extracted with nb-hexane, the organic phase was evaporated, and the residue was dansylated prior to analysis by reversed-phase high-performance liquid chromatography using a fluorescence detector. Perhexiline was resolved from its mono- and dihydroxylated metabolites, and the limit of sensitivity was 5 ng of perhexiline/ml. This limit represents approximately 100 times the sensitivity of the previously described GLC assay. Single-dose pharmacokinetic studies were performed with 150- and 300-mg oral doses of perhexiline maleate in five patients with severe angina pectoris and impaired left ventricular function. Peak plasma perhexiline levels occurred 3-6 hr after drug ingestion in four patients and after 12-18 hr in the fifth patient. The mean elimination half-life, measured 24 hr after drug ingestion, varied with plasma perhexiline concentration. It was 11.2 +/- 2.1 hr after the 150-mg dose and 19.1 +/- 2.8 hr after the 300-mg dose. The mean ratio of areas under the concentration-time curve for the 300-versus 150-mg doses ws 5.3:1, suggesting that hepatic metabolism of perhexiline may be saturable and that the bioavailability of perhexiline is dose dependent.

Aged↗
PubMed1981

Combined high-performance liquid chromatographic procedure for measuring 4-hydroxypropranolol and propranolol in plasma: pharmacokinetic measurements following conventional and slow-release propranolol administration.

An assay is described for the simultaneous determination of propranolol and its active metabolite, 4-hydroxypropranolol, in human plasma. Both compounds were separated from an ethereal extract by high-performance liquid chromatography employing a C18 bonded-phase column. Detection of the effluent was by fluorescence. Suitable fluorescent spectrometers and wavelength settings that allow optimum detection of both compounds have been described. The limit of sensitivity was 2 ng/ml for both propranolol and 4-hydroxypropranolol. Mean peak plasma levels of propranolol and 4-hydroxypropranolol in six patients receiving a single dose of a slow-release 160-mg formulation of propranolol were 28 and 6 ng/ml, respectively. These levels were about one-tenth the level obtained following a single conventionally prepared dose of propranolol (160 mg). Peak levels were delayed and plasma levels of propranolol persisted for a longer period with the slow-release formulation. Area under the curve estimates suggested that the bioavailability of the slow-release formulation following single-dose administration was about one-third that of the conventional preparation.

Adult↗
PubMed1980

High-pressure liquid chromatographic determination of ranitidine, a new H2-receptor antagonist, in plasma and urine.

An assay is described for the determination of a new H2-receptor antagonist, ranitidine, and its desmethyl metabolite in human plasma and urine. Alkalinized plasma or urine was extracted with methylene chloride, the organic phase was evaporated, and the reconstituted residue was analyzed by high-pressure liquid chromatography using a reversed-phase column. Two other identified metabolites of ranitidine, the S-oxide and N-oxide, were separated chromtographically from both ranitidine and the desmethyl metabolite. However, these metabolites could not be quantitative due to poor analytical recovery and interference from endogenous components. The sensitivity limits were 5 ng/ml for ranitidine and 15 ng/ml for desmethylranitidine. Plasma samples from two volunteers who were given oral ranitidine (0.1, 0.2, and 0.4 mg/kg) at 1-week intervals were assayed. Peak levels of 30--130 ng/ml were achieved between 40 and 120 min after dosage, followed by an elimination half-life of 2.9-3.9 hr. Plasma levels of ranitidine were still detectable at 8 hr but were below the sensitivity of the assay by 24 hr. Plasma levels of the desmethyl metabolite were seldom above the threshold sensitivity of the assay. Urinary excretion of unmetabolized ranitidine accounted for 77% of the administered dose, whereas only 4% appeared as desmethylranitidine.

Adult↗
PubMedDate not supplied

Pharmacokinetic comparison of a combination tablet of enalapril and hydrochlorothiazide with enalapril and hydrochlorothiazide tablets administered together and separately.

Enalapril and hydrochlorothiazide (HCT) are established single agent treatments for mild hypertension and cardiac failure and are a potent combination in more severe or resistant cases. We have compared the pharmacokinetics of enalaprilat (the active metabolite of enalapril) and HCT in a four-way comparison of a combination tablet of enalapril (10 mg)/HCT (25 mg) with a single dose of an enalapril tablet (10 mg), a single dose of a HCT tablet (25 mg) and simultaneous administration of separate tablets of enalapril (10 mg) and HCT (25 mg) in normotensive volunteers (n = 12, 21-26 years). Each subject received all four treatments and the study was conducted as a randomized, latin square, open design with at least 1 week washout between studies. Overall, HCT was bioequivalent under all conditions and enalaprilat was bioequivalent when given in combination with HCT either as one tablet or as two separate tablets. However, when given with HCT, the mean AUC and Cmax of enalaprilat were reduced up to 20 per cent compared with enalapril administered alone. This is unlikely to be of clinical significance as the differences did not reach statistical significance and the total enalaprilat excreted in the urine over 96 h was similar after all treatments.

Adult↗