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Biomedical subjects

F Bochner

Publications and source records attributed to F Bochner.

At least 91 records · Page 5Linked to original sources
PubMed1987

Salicyl phenolic glucuronide pharmacokinetics in patients with rheumatoid arthritis.

The pharmacokinetics of salicyl phenolic glucuronide (SPG) and other salicylic acid (SA) metabolites were studied at three aspirin dosage regimens in eight patients with rheumatoid arthritis. Each patient received 1, 2 and 4 g enteric coated aspirin (ASA) daily in ascending order. At the end of each 2-week dosage period, plasma and urine were collected over a dosage interval for the estimation of various pharmacokinetic parameters. With increasing ASA dosage, mean clearance of SA to SPG was approximately constant (1.8 +/- 0.3, 1.7 +/- 0.2, and 1.5 +/- 0.2 ml/min at 1, 2 and 4 g/day, respectively) when related to plasma concentrations of total SA. The percentage of the ASA dosage recovered in urine as SPG increased from 5.2 +/- 1.1 to 7.1 +/- 1.1 to 10.5 +/- 1.7 at 1, 2 and 4 g/day, respectively. It was concluded, however, that the conversion of SA to SPG is saturable, since the mean clearance of SA to SPG decreased when calculated with respect to the plasma concentration of unbound SA (13.4 +/- 1.6, 11.0 +/- 1.4, and 6.6 +/- 1.9 ml/min at 1, 2 and 4 g/day, respectively). The kinetics of the formation and excretion of salicylurate and the excretion of gentisate were similar to those found in previous studies.

Adult↗
PubMed1987

Reduction of metformin renal tubular secretion by cimetidine in man.

To determine whether cimetidine altered the renal handling of metformin, seven subjects took 0.25 g metformin daily with and without cimetidine 0.4 g twice daily. Blood and urine samples were collected and assayed for metformin, cimetidine and creatinine by h.p.l.c. Cimetidine significantly increased the area under the plasma metformin concentration-time curve by an average of 50% and reduced its renal clearance over 24 h by 27% (P less than 0.008). There was no alteration in the total urinary recovery of metformin when cimetidine was co-administered. The effect of cimetidine on the renal clearance of metformin was time dependent, being significantly reduced up to 6 h following cimetidine. These results appeared to be consistent with competitive inhibition of renal tubular secretion. Cimetidine had no effect on the renal clearance of creatinine, but time-dependent variations in both metformin and creatinine renal clearance were observed. Metformin had no effect on cimetidine disposition. It is concluded that cimetidine inhibits the renal tubular secretion of metformin in man, resulting in higher circulating plasma concentrations. Because of its propensity for causing dose and concentration-dependent adverse effects, the dose of metformin should be reduced when cimetidine is co-prescribed.

Adult↗
PubMed1987

Dipyridamole: pharmacokinetics and effects on aspects of platelet function in man.

1. The effect of dipyridamole on platelet function was measured in twelve normal subjects given 150 or 200 mg tablets as single and multiple doses, and in six subjects given single doses of 25, 50 and 100 mg and multiple doses of 50 mg 8 hourly. 2. Platelet aggregation was measured in response to ADP and collagen. In the subjects given 150/200 mg, the platelets were assayed for content of cyclic AMP and for formation of thromboxane after addition of collagen. The responses to ADP and collagen and the cyclic AMP content were assessed in both the presence and absence of added PGE1. The pharmacokinetics of dipyridamole were studied in all subjects. 3. One hour after 150/200 mg single doses of dipyridamole there was significant inhibition of platelet aggregation in response to both collagen and ADP. There was no detectable effect on aggregation at other time points or with lower doses of dipyridamole. The addition of PGE1 to platelets prior to testing did not enhance the effect of dipyridamole on platelet aggregation. 4. In multiple doses, dipyridamole (150/200 mg twice daily for 11 days) had no detectable effect on platelet aggregation. 5. Dipyridamole did not have any effect on platelet cyclic AMP content, whether or not PGE1 was added prior to assay. 6. Dipyridamole did not affect platelet thromboxane formation. 7. Plasma dipyridamole concentrations were maximal 1-2 h after ingestion, at the same time that inhibition of platelet aggregation was detected. The concentrations declined in a biexponential fashion, with a terminal half life of 24.1 +/- 1.9 h (mean +/- s.e. mean). In six of the 17 subjects, the mean steady state plasma concentration was less than 75% of the value predicted from the single dose data.

Adolescent↗
PubMed1987

A dose-ranging study of the antiplatelet effect of enteric coated aspirin in man.

Enteric coated aspirin was given to eight human volunteers in escalating doses (20, 40, 60, 80, 100 mg daily), each dose being given over two weeks. In addition, to measure the maximum effect of aspirin, each volunteer was given two single doses of 600 mg of soluble aspirin. At the end of each dosing interval we measured platelet aggregation and thromboxane formation in response to four aggregating agents and to whole blood coagulation. The doses of aspirin required to inhibit platelet aggregation in response to various stimuli were: for collagen 60-80 mg, for adenosine diphosphate and adrenaline 60 mg, and for arachidonate 40 mg. For maximum inhibition of thromboxane formation the doses were: for collagen greater than 100 mg, for adenosine diphosphate and adrenaline 60 mg, for arachidonate 80 mg, and for whole blood coagulation 100 mg. Different aspirin doses are required to inhibit the responses to different stimuli. Furthermore, for some stimuli, inhibition of thromboxane generation may require more aspirin than is required for inhibition of aggregation. The clinical implications of these findings are uncertain since we do not know which stimuli are important in arterial thrombosis in man.

Adult↗
PubMed1987

Effect of food on enoxacin absorption.

Fifteen subjects received a single 400-mg oral dose of enoxacin in the fasting state and after carbohydrate and high-fat meals. The carbohydrate meal delayed the time to peak enoxacin concentration in plasma by an average of 0.92 h. The extent of enoxacin absorption was not altered by food.

Administration, Oral↗
PubMed1986

Lack of inhibition of tolbutamide hydroxylation by cimetidine in man.

We have investigated the influence of cimetidine on the disposition of tolbutamide in 7 healthy subjects, who received 250 mg tolbutamide daily for 4 days followed by the concomitant intake of cimetidine 400 mg twice daily for a further 4 days. Cimetidine had no effect on the disposition of tolbutamide, including the unbound hydroxylation clearance rate (324 ml X min-1, tolbutamide alone; 316 ml X min-1, tolbutamide plus cimetidine). The total urinary recovery of carboxy- and hydroxy-tolbutamide metabolites was 85.7 +/- 20.3% of the dose when tolbutamide was given alone and 78.9 +/- 14.3% when given with cimetidine. This lack of a pharmacokinetic interaction suggests selectivity of cimetidine-induced inhibition of Phase I drug oxidation.

Adult↗
PubMed1986

Effect of cimetidine on renal and hepatic drug elimination: studies with triamterene.

A chronic-dosing pharmacokinetic study was carried out in six healthy subjects to examine the potential for cimetidine to reduce the CLR and CLH of triamterene. Blood and urine samples were collected frequently for 24 hours after dosing with triamterene alone (100 mg/day) for 4 days and concomitant cimetidine (400 mg twice daily) for an additional 4 days. Cimetidine significantly reduced the clearance of triamterene by hydroxylation by 32% (P less than 0.016) and the CLR of triamterene by 28% (P less than 0.063), with no change in its protein binding. The CLR of the active sulfate conjugate of triamterene was not altered by cimetidine. There was a reduced recovery of triamterene and its metabolites in urine after cimetidine, suggesting a decreased absorption. These results are consistent with cimetidine inhibiting cytochrome P-450 enzymes in the liver and also competing with triamterene for renal tubular secretion. Despite the pharmacokinetic interaction, cimetidine caused minimal alteration to the natriuretic and antikaliuretic effects of triamterene.

Administration, Oral↗
PubMed1986

Direct measurement of salicylphenolic glucuronide in human urine.

Indirect measurement of salicylphenolic glucuronide (SPG) has suggested that the formation of this metabolite from therapeutic doses of salicyclic acid (SA) is capacity-limited in humans. A direct high performance liquid chromatographic (HPLC) assay for SPG in human urine is described. SPG was prepared by a published method and purified by HPLC. On treatment with beta-glucuronidase, SPG yielded the expected amount of SA. Spectroscopic data, melting point, and optical rotation of the glucuronide and/or its triacetyl dimethyl ester derivative were consistent with the proposed structure. SPG was assayed using a 5-micron C18 column (temperature 55 degrees C) and fluorescence detection. A nonlinear gradient mobile phase at a flow rate of 2 ml/min was used, beginning with 100% 0.1 M pH 2.1 phosphate buffer and finishing with 84% buffer, 16% acetonitrile. Total run time was 25 min. Urine (10 microliter) was injected directly on the column, and quantitation was performed using urine standards. Within-run precision for SPG ranged from 1.2% at 150 mg/L to 2.4% at 5 mg/L. The limit of detection was less than 1 mg/L. A pilot study in two volunteers, each receiving a single 500-mg dose of sodium salicylate, was carried out to validate the usefulness of the assay.

Adult↗
PubMed1986

Dose-dependent inhibition of phosphoinositide metabolism in human platelets by aspirin in vitro and in vivo.

The effects of aspirin on the metabolism of phosphoinositides in human platelets were studied in vitro and in vivo. Eight volunteers received, at two-weekly intervals, a single dose of 10, 30, 100 or 600 mg aspirin. Before the first dose platelets were taken and incubated in vitro with a range of concentrations (10 nM-100 microM) of aspirin. Formation of inositol phosphates (IP) was measured in [3H]-inositol labelled platelets after incubation with collagen and thrombin for 30 min, a time at which a maximal increase in [3H]-IP was observed. The in vitro IC50 for inhibition of the response to collagen by aspirin was approximately 1 microM; the in vivo ID50 was 40-50 mg. Aspirin did not fully inhibit the collagen stimulated IP formation either in vitro or in vivo, and the response to thrombin was unaffected. The ID50 and IC50 of aspirin is thus in accord with the doses of aspirin associated with inhibition of platelet aggregation and thromboxane production in other studies. The possible relevance of these data to the clinical uses of aspirin is discussed.

Adult↗
PubMed1986

Selectivity of the cimetidine-induced alterations in the renal handling of organic substrates in humans. Studies with anionic, cationic and zwitterionic drugs.

Cimetidine reduces the renal clearances of the organic cations procainamide and n-acetylprocainamide in humans and in vitro preparations by inhibition of renal cationic proximal tubular secretion. The aim of this study was to investigate in humans the selectivity of cimetidine in altering the renal handling of three different organic ions as drug substances: anion (cephalothin), cation (ranitidine) and zwitterion (cephalexin). The study was conducted in six healthy subjects who received the above drugs as single doses with and without chronic cimetidine administration. Cimetidine had no statistically significant (P greater than .05) effect on cephalothin disposition including renal clearance, but significantly reduced the renal clearance of ranitidine by over 40% between 4 and 12 hr after administration, with a concomitant increase in ranitidine plasma concentrations and elimination half-life prolongation. In addition, the renal clearance of cephalexin was reduced by cimetidine by 27% between 1 and 2 hr, but there was no change in cephalexin plasma concentrations and elimination half-life. These findings confirmed the hypothesis that cimetidine-mediated inhibition of renal drug clearance in humans is selective for a common cationic secretory transport mechanism in the proximal tubule of the kidney, rather than a nonspecific action on renal function.

Adult↗
PubMed1985

Plasma and synovial fluid gentisate in patients receiving salicylate therapy.

Our study was undertaken to assay gentisate, an oxidation metabolite of salicylate, in plasma and synovial fluid (SF) samples from patients taking antiinflammatory doses of aspirin. A close correlation between plasma and SF concentrations was found for (1) salicylate, (2) salicylurate, and (3) gentisate, in 20 patients studied. Our data suggest ready equilibration of these compounds between the plasma and synovial spaces. In vitro experiments confirmed that in the presence of an oxy radical flux, salicylate is oxidized to gentisate. However, no evidence was obtained to implicate peripheral conversion of salicylate to gentisate in inflamed joints where oxy radicals may be produced.

Arthritis, Rheumatoid↗
PubMed1984

Disposition of and clinical response to salicylates in patients with rheumatoid disease.

The disposition of salicylic acid (SA) and its metabolites and the clinical response to long-term aspirin treatment at varying doses were assessed in patients with rheumatoid disease. Steady-state kinetics of SA (total and unbound), salicyluric acid (SUA), gentisic acid (GA), and clinical status were estimated weekly in 10 patients with rheumatoid arthritis. Eight received a soluble aspirin form and two received an enteric-coated form. The starting dose of aspirin in each patient was 1.8 gm (soluble) or 1.95 gm (enteric-coated) daily. Weekly increments in dose were made until a satisfactory clinical outcome was achieved. The final aspirin dose range was 3.6 to 8.1 gm daily, which resulted in mean steady-state plasma SA concentrations (CpSA) from 56 to 375 mg/l. Since the mean total CpSA increased approximately proportionately over the dose range, there was little change in total SA clearance. By contrast, increasing aspirin dosage resulted in decreased clearance and disproportionate increases in unbound SA (CpuSA). The maximum velocity of conversion of SA to SUA (Vm) increased significantly, from 57.3 +/- 11.7 mg/hr at an aspirin dose of 1.8 gm/day to 71.4 +/- 19.4 mg/hr at the next highest dose (2.7 to 3.6 gm/day), with no further change with increasing dosage. Km ranged from 0.4 to 1.2 mg/l for CpuSA and from 5.5 to 17.2 for total CpSA. Renal clearance of SUA (ClSUA) ranged from 124 to 893 ml/min and correlated with creatinine clearance. ClGA ranged from 23 to 164 ml/min, and ClSA ranged from 0.1 to 17.1 ml/min; neither correlated with creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Dose and concentration dependent effect of ranitidine on procainamide disposition and renal clearance in man.

The pharmacokinetics of oral procainamide (1 g) were investigated in six healthy subjects during chronic dosing with ranitidine 150 mg twice daily, and in three of the subjects when ranitidine 750 mg was administered over 12 h. The procainamide area under the plasma concentration-time curve was significantly (PQ0.02) increased by ranitidine (27.761.5 vs 31.561.8 mg l-1 h) with a significant reduction in renal clearance (379632 vs 309630 ml/min, PQ0.02). There was no change in half-life. The N-acetylprocainamide (NAPA) area under the plasma concentration-time curve was also significantly (PQ0.02) elevated by ranitidine (8.661.2 vs 9.761.3 mg 1-1 h) due to a reduction in renal clearance from 187630 to 168628 ml/min. The larger dose of ranitidine produced greater alterations in the procainamide and NAPA pharmacokinetics. Ranitidine reduced the absorption of procainamide by 10% and by 24% at the higher dose level. Two-hourly renal clearance values of procainamide were significantly (PQ0.05) reduced in the 2 to 10 h period and for NAPA between 0 to 6 and 8 to 10 h. The larger ranitidine dose reduced the renal clearances of procainamide and NAPA over the control period at each 2-hourly time period. The reductions in renal clearance are most likely mediated by competition for the renal tubular cationic secretory pathway. Clinical implications arising from this study suggest a reduction in procainamide dosage may be necessary in a small, select number of patients with high plasma ranitidine concentrations, e.g., the elderly; furthermore, failure of therapeutic response for some drugs may be due to ranitidine-induced impaired gastrointestinal absorption.

Adolescent↗
PubMed1984

Plasma cortisol delivery from oral cortisol and cortisone acetate: relative bioavailability.

Plasma cortisol levels were measured before and for 6 h after the intravenous injection of 50 mg cortisol as sodium succinate and oral administration of 50 mg cortisol and 50 mg cortisone acetate in 10 subjects with primary or secondary adrenal failure and in two normal volunteers. Peak cortisol levels of 1518 +/- 190 nmol 1(-1) (mean +/- s.e. mean) and 739 +/- 74 nmol 1(-1) were found 1.46 +/- 0.25 and 1.79 +/- 0.16 h after oral cortisol and cortisone acetate respectively. The relative bioavailability of oral cortisol and cortisone acetate varied widely (cortisol 26-91%, mean 54 +/- 6.9%, cortisone acetate 21-95%, mean 44 +/- 6.5%) but despite this wide variation there was, in individual subjects, a highly significant correlation between the bioavailability of the two steroids (r = 0.870, P less than 0.001). This suggests that the wide interindividual variations in plasma cortisol levels seen after oral cortisone acetate are not related to variations in bioconversion of cortisone.

Administration, Oral↗