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Biomedical subjects

F Bochner

Publications and source records attributed to F Bochner.

At least 55 records · Page 3Linked to original sources
PubMed1990

The antiplatelet effect of daily low dose enteric-coated aspirin in man: a time course of onset and recovery.

We have studied the onset and recovery of inhibition of platelet function by low dose aspirin. Enteric-coated aspirin 50mg daily was administered to five human volunteers for five weeks and then 100mg daily was given for a further five weeks. We studied platelet aggregation and thromboxane formation in response to a range of stimuli: ADP, adrenaline, arachidonate and collagen, and also measured thromboxane formation after coagulation of whole blood (serum thromboxane). The onset of inhibition of platelet aggregation was progressive over several days for each of the four platelet stimuli, and was synchronous with the inhibition of thromboxane formation. Maximum inhibition occurred by day three for the weak stimuli ADP and adrenaline, by day five for the stronger stimuli arachidonate and collagen, but did not occur until day eight for serum thromboxane. Further inhibitory effects on both aggregation and thromboxane generation were observed after 100mg daily. Two weeks after the cessation of aspirin the responses to collagen and arachidonate and serum thromboxane had returned to normal. Platelet aggregation in response to the weaker stimuli, ADP and adrenaline, still showed detectable inhibition two weeks after cessation of aspirin, but had returned to normal by four weeks. These experiments provided no evidence for an effect of aspirin on platelets separate to its effect on cyclooxygenase. The onset and recovery of inhibition of platelet function by low dose aspirin was dependent on the strength of the stimulus studied.

Adolescent↗
PubMed1990

Determination of endogenous concentrations of N1-methylnicotinamide in human plasma and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic assay for the determination of endogenous plasma and urine concentrations of N1-methylnicotinamide was developed. N1-Methylnicotinamide and N1-ethylnicotinamide (internal standard) are reacted with acetophenone in a strong base at 0 degree C, formic acid is added, and the reaction mixture is heated in a boiling water bath, resulting in the formation of fluorescent derivatives. These derivatives were chromatographed on a C18 reverse-phase column using a mobile phase of acetonitrile-triethylamine and 0.01 M heptanesulfonic acid adjusted to pH 3.2. Fluorescent detection was achieved using 366-nm excitation and 418-nm emission filters. Precision and accuracy were generally greater than 90%, interfering peaks did not cochromatograph, and the limit of quantification was 2 ng/ml in plasma using a 0.2-ml sample. The method was used to examine the concentrations of endogenous N1-methylnicotinamide in the plasma of 36 subjects with various pathology. The mean concentration was 18 ng/ml and the range was 6.2 to 116.7 ng/ml. The assay represents a marked improvement on previous methods and is suitable for routine clinical monitoring.

Acetophenones↗
PubMed1990

Drug utilization review in a teaching hospital: experience with vancomycin.

A prospective, two-phase, drug utilization review (DUR) was performed at the Royal Adelaide Hospital (RAH) to determine the extent and pattern of vancomycin use. For all patients commencing oral or parenteral vancomycin, treatment indication, route of administration, duration of therapy, results of culture and sensitivity tests, adverse drug reactions and results of therapeutic drug level monitoring were recorded. Vancomycin courses were classified as being for therapy or prophylaxis and compared with predetermined audit criteria to assess appropriateness of use. During the 8 week initial phase, data on 62 treatment courses in 59 patients were recorded, 50% for therapy and 50% for prophylaxis. Sixty four percent were classified as inappropriate, occurring in 32% of therapeutic courses and 97% of those for prophylaxis. During the 10 week re-evaluation, conducted 10 months later, data for 43 treatment courses in 43 patients were reviewed, 42% for therapy and 58% for prophylaxis. Sixty five percent were inappropriate occurring in 17% of therapeutic courses and 100% of the prophylactic courses. When compared with the initial phase, the re-evaluation demonstrated a decrease in the empirical use of vancomycin in the combination treatment of neutropaenic fever and also in the duration of vancomycin use for surgical prophylaxis. During both study phases, criteria contraventions were mostly due to inappropriate indication or duration of therapy. The cost of inappropriate vancomycin use was reduced by over 50% between survey phases, from $Aus11,500 or 55% of total vancomycin cost during the initial phase to $Aus3,600 or 25.7% during the re-evaluation. The most effective of the remedial strategies implemented after the initial phase was direct consultation with prescriber groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Morphine formation from codeine in rat brain: a possible mechanism of codeine analgesia.

The O-demethylation of codeine to morphine was demonstrated in rat brain homogenate. Maximal formation occurred at 10 minutes, with a Vmax of 5.93 +/- 0.16 nmol/g brain/h and Km of 37.82 +/- 4.99 microM. The formation was significantly (P less than 0.05) greater in the microvessel-rich brain fraction. Intraperitoneal injection of codeine in the rat resulted in brain concentrations of morphine which could not be solely attributed to transfer of morphine from the blood stream across the blood-brain barrier. Morphine formed in the brain after codeine administration may be an important mechanism for codeine-induced analgesia.

Analgesia↗
PubMed1990

Effect of aspirin infusions on platelet function in humans.

1. The inhibitory effects of aspirin on platelet function in vitro have been shown to be both time (over 3 h) and concentration (1-10 mumol/l) dependent. 2. To determine if these effects occurred in vivo, four volunteers received intravenous infusions on four occasions, to give constant plasma aspirin concentrations of 0, 1, 2 and 4 mumol/l over 3 h. Infusions were performed at intervals of at least 2 weeks. 3. Before and during the infusions, blood was taken for assay of aspirin concentrations, and measurements of platelet aggregation in response to collagen, adenosine 5'-pyrophosphate and arachidonate. Thromboxane generation after stimulated platelet aggregation and whole-blood coagulation was also measured. 4. At each aspirin concentration, both platelet aggregation and thromboxane generation in response to collagen and arachidonate were inhibited progressively over the 3 h infusion period. Greatest inhibition was seen during the 4 mumol/l infusion, which produced maximal or near-maximal inhibition by the third hour. 5. Thromboxane generated during whole-blood coagulation was similarly inhibited in both a time- and concentration-dependent manner throughout all aspirin infusions. 6. The progressive nature of the inhibition of platelet function with these low aspirin concentrations may be due to either slow aspirin transport across the platelet membrane or delayed interaction with cyclo-oxygenase.

Adenosine Diphosphate↗
PubMed1990

Simultaneous determination of dextromethorphan and three metabolites in plasma and urine using high-performance liquid chromatography with application to their disposition in man.

A simple, sensitive, and reproducible high-performance liquid chromatrography assay is described for the simultaneous determination of dextromethophan, dextrorphan, 3-hydroxymorphinan, and 3-methoxymorphinan in plasma and urine. A conventional solvent-solvent extraction procedure was used for the isolation of the analytes from plasma and urine samples. The compounds were separated on a cyano column (150 x 4.6 mm, 5-micron particle size) using a mobile phase of acetonitrile/triethylamine/distilled water (17:0.06:82.94, vol/vol), pH 3.0, and then were measured by fluorescence detection. Calibration curves in the range 2-200 ng/ml for plasma and 0.05-10 micrograms/ml for urine were linear and passed through the origin. The precision and accuracy were greater than 90% and the lowest detectable concentrations were 0.5 ng/ml for 3-hydroxymorphinan and 3-methoxymorphinan and 1 ng/ml for dextromethorphan and dextrophan in plasma. The utility of this method is demonstrated in a preliminary study of dextromethorphan metabolism and pharmacokinetics in man.

Chromatography, High Pressure Liquid↗
PubMed1990

Amiloride disposition in geriatric patients: importance of renal function.

1. The absorption and disposition of the potassium sparing diuretic amiloride were determined in nine elderly patients aged 71 to 87 years and in eight young (25 to 38 years) subjects following oral administration of 5 mg amiloride HCl daily to steady-state. 2. The maximum and steady-state plasma amiloride concentrations were significantly (P less than 0.05 and P less than 0.001) higher in the elderly patients. The renal clearance of amiloride was lower in the elderly than in young subjects (102 +/- 36 ml min -1 vs 300 +/- 64 ml min-1, P less than 0.001) as was the urinary excretion of amiloride (36 +/- 13 vs 62 +/- 18% of the dose, P less than 0.01). 3. The steady-state plasma amiloride concentration correlated significantly (r2 = 0.61, P less than 0.001) with amiloride renal clearance and with creatinine clearance (r2 = 0.59, P less than 0.001). There was a very strong positive correlation between renal amiloride clearance and creatinine clearance (r2 = 0.76, P less than 0.001). The slope of the regression line was 2.5 indicating substantial proximal tubular secretion of amiloride. 4. Sodium and potassium excretion, along with urine volume were significantly (P less than 0.05) lower in the elderly (by 39, 45 and 34% respectively). 5. The disposition of amiloride was highly dependent on renal function, with higher plasma amiloride concentrations in the elderly reflecting diminished renal function. The dose of amiloride should be titrated to individual response, and the lower potassium excretion in the elderly patients suggests that the dose of amiloride could be reduced in this group of patients.

Adult↗
PubMed1989

Direct determination of codeine-6-glucuronide in plasma and urine using solid-phase extraction and high-performance liquid chromatography with fluorescence detection.

A sensitive and selective method was developed for the direct determination of codeine-6-glucuronide in plasma and urine using high-performance liquid chromatography (HPLC) with fluorescence detection. Codeine-6-glucuronide was synthesised and its purity estimated using acid and enzyme hydrolysis. The hydrolysis of codeine-6-glucuronide by beta-glucuronidase was incomplete and urine reduced the extent of hydrolysis. Codeine-6-glucuronide was recovered from plasma using a solid-phase extraction column and separated on a reversed-phase C18 HPLC column. The assay showed good reproducibility and accuracy (within 10%), and standard curves were linear between 32 and 1600 ng/ml in plasma and between 0.32 and 160 micrograms/ml in urine. The assay has been applied to the study of the pharmacokinetics and metabolism of codeine in patients.

Chromatography, High Pressure Liquid↗
PubMed1989

Simultaneous determination of codeine, norcodeine and morphine in biological fluids by high-performance liquid chromatography with fluorescence detection.

A novel high-performance liquid chromatographic method for the determination of codeine, norcodeine and morphine in plasma and urine has been developed. The compounds were separated on a cyano column (15 cm x 4.6 mm, 5 microns particle size) using a mobile phase of acetonitrile-triethylamine-distilled water (4:0.1:95.9, v/v) pH 3.1 and then determined by fluorescence detection. Calibration curves in the range 5-200 ng/ml for plasma and 0.1-10 micrograms/ml for urine were linear and passed through the origin. The imprecision and inaccuracy of the assay were less than 10% and the limits of detection were 2 ng/ml for all three compounds in human plasma.

Adult↗
PubMed1989

Measurement of aspirin concentrations in portal and systemic blood in pigs: effect on platelet aggregation, thromboxane and prostacyclin production.

Low doses of enteric-coated aspirin were administered orally to pigs. Plasma aspirin concentrations measured in blood obtained simultaneously from permanent catheters in a systemic artery and portal vein for 6 hours after dosage showed a large variation in the plasma aspirin concentration: time profile between pigs. After 50 mg single dose the ratio of the arterial: portal area under the plasma concentration versus time curve (AUC) was 0.63 +/- 0.08 (mean +/- SE, n = 6). In three pigs which received all three dosage regimens, the arterial: portal AUC ratios were 0.48 +/- 0.05 after 50 mg single dose, 0.52 +/- 0.02 after 100 mg single dose and 0.47 +/- 0.02 after 100 mg daily for 1 week. Platelet aggregation in response to sodium arachidonate (1.65 mM) was completely abolished after chronic aspirin administration of 100 mg daily. Thromboxane production (pg/10(6) platelets) induced by this stimulus decreased from 536 +/- 117 before aspirin to 57 +/- 14 after aspirin (mean +/- SE, n = 4; p = 0.03). Aortic prostacyclin synthesis, measured as 6-keto PGF1 alpha (ng/disc after 10 min incubation), was 1.66 +/- 0.28 (mean +/- SE, n = 4) in untreated pigs and 0.95 +/- 0.25 (n = 5) in treated pigs (p = 0.07). Results from this study support the idea that a difference between aspirin concentrations in the portal and systemic circulations can be achieved. Whether this can be translated into a clinically useful differential effect on the vessel wall compared to the platelet remains to be determined.

Animals↗
PubMed1989

Stereoselective plasma protein binding of ibuprofen enantiomers.

We have developed a novel and reproducible method for determining the plasma protein binding of the two ibuprofen enantiomers in the presence of each other. The method involves the use of radiolabelled racemic ibuprofen, equilibrium dialysis, derivatization of the enantiomers to diastereomeric amides, high-performance liquid chromatography, and radiochemical analysis. We have determined the plasma protein binding of R(-)- and S(+)-ibuprofen in 6 healthy male volunteers after the oral administration of 800 mg racemic ibuprofen. The mean time-averaged percentage unbound of the R(-)-enantiomer, 0.419 was significantly less than that of the S(+)-enantiomer, 0.643, consistent with stereoselective plasma protein binding. The percentage unbound of each ibuprofen enantiomer was concentration-dependent over the therapeutic concentration range and was influenced by the presence of its optical antipode.

Adult↗
PubMed1989

Deconjugation of p-hydroxytriamterene sulphate in the rat.

1. The extent of deconjugation of p-hydroxytriamterene sulphate was studied in rats, by h.p.l.c., after i.v., i.p., and oral administration. 2. After i.v. administration, deconjugation accounted for 29-54% of the recovered dose as free p-hydroxytriamterene in urine and faeces. Following i.p. administration, 70-88% was deconjugated and 72-96% was deconjugated after oral administration. Most of the p-hydroxytriamterene was recovered in faeces.

Administration, Oral↗
PubMed1988

The absorption and disposition of enoxacin in healthy subjects.

Enoxacin is a new orally active, synthetic broad-spectrum antibacterial drug of the fluorinated quinolone class. The pharmacokinetics and renal handling of this drug have not been thoroughly investigated, in particular, with specific analytical methodology. Sixteen healthy, young subjects received a single 400-mg oral dose of enoxacin after an overnight fast and multiple blood samples and all urine were collected for 33 hours. Enoxacin in plasma and urine and oxo-enoxacin in urine were determined by a high-performance liquid chromatographic method. Enoxacin was absorbed rapidly, with tmax values ranging from 0.5 to 2.5 hours. The variability in the AUC values of 35% was reduced to 23% when variations in body weight were taken into consideration. The terminal half-life ranged from 4.2 to 6.8 hours and the unbound fraction in plasma was 0.33 +/- 0.07. In urine, 44 +/- 9% of the dose was recovered as unchanged enoxacin and 5.4 +/- 3.9% as oxo-enoxacin; there was no evidence of conjugates of enoxacin in urine. Renal clearance of enoxacin was 230 +/- 92 mL/min, with 17 +/- 8% of this being due to glomerular filtration and 83 +/- 8% being due to tubular secretion. These data indicate that the major potential drug interactions affecting enoxacin disposition are likely with drugs competing for renal proximal tubular secretion and hepatic elimination. These conclusions regarding enoxacin are likely to be applicable to the fluorinated quinolones in general.

Administration, Oral↗
PubMed1988

Pharmacokinetics of low-dose oral modified release, soluble and intravenous aspirin in man, and effects on platelet function.

The pharmacokinetics of low-dose aspirin and the resulting salicylic acid were studied in 6 healthy volunteers. Each received a single 50-mg dose of (1) oral modified release capsules, (2) oral solution and (3) intravenous solution. The volunteers also received 50 mg modified release capsules daily for 6 days to determine the effect on collagen, ADP and arachidonate induced platelet aggregation and thromboxane production, and to compare the pharmacokinetics after repeated dosing with the parameters obtained after the single dose. The formulation and route of administration profoundly influenced several pharmacokinetic parameters for aspirin: the maximum concentration (Cmax, ng.ml-1) was 221 and 191 after modified release for single and chronic dosing respectively, 1323 after the oral solution and 6000 after intravenous injection; the time to achieve this maximum concentration (tmax, h) was 3.42 and 3.02 after modified release for single and chronic dosing respectively, and 0.29 after the oral solution; the area under the plasma drug concentration versus time curve (AUC, microgram.h.ml-1) was 0.38 and 0.27 after modified release single and chronic dosing respectively, 0.68 after the oral solution and 1.57 after intravenous injection. The elimination of aspirin after the two solutions was at least biphasic. The terminal phase rate constant ranged from 1.52 h-1 after intravenous injection to 1.88 h-1 after the oral modified release form. The absorption of the oral forms of aspirin was complete as reflected by the total recovery of the doses as salicylic acid in urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Inhibition of platelet aggregation and thromboxane production by low concentrations of aspirin in vitro.

1. The aspirin concentrations previously reported to inhibit platelet aggregation in vitro (40-500 mumol/l) are much greater than those required in vivo in man (5 mumol/l). 2. Human platelet-rich plasma was incubated with buffer or various aspirin concentrations at 37 degrees C for up to 4.5 h. Platelet aggregation and thromboxane generation were measured in response to collagen (0.4-6.3 micrograms/ml) and adenosine 5'-pyrophosphate (0.5-4 mumol/l). 3. The concentration of aspirin needed to inhibit platelet aggregation in response to a critical concentration of aggregating agent (lowest concentration to cause greater than 50% aggregation) was lower than that required for higher concentrations of aggregating agent. 4. With more prolonged incubation times with aspirin, lower concentrations of aspirin inhibited platelet aggregation. 5. Inhibition of platelet aggregation and thromboxane formation by 10 mumol/l aspirin was maximal by 90 min. There was progressive inhibition by 3 mumol/l aspirin during incubation for 270 min. By the end of this time there was also significant inhibition by 1 mumol/l aspirin. 6. The apparent discrepancy between inhibitory aspirin concentrations in vivo and those observed in vitro in previous studies appears to have been resolved by extending the incubation time of platelets with low aspirin concentrations, thus mimicking the conditions in vivo.

Aspirin↗
PubMed1988

Sensitive high-performance liquid chromatographic assay for determination of amiloride in biologic fluids using an ion-pair extraction method.

The paucity of data on disposition of the potassium-retaining diuretic amiloride is mainly owing to the lack of sensitive and specific analytic methods for measuring the drug in biologic fluids. Poor lipophilicity and extremely low plasma concentrations impose severe constraints. A method is described for analysing plasma and urine concentrations of amiloride using an ion-pair extraction method and high-performance liquid chromatography (HPLC) with fluorescence detection. Amiloride and internal standard triamterene form an ion-pair with bromothymol blue at pH 7.6. The ion-pairs are extracted into diethyl ether: dichloromethane (2:1), and back-extraction into 0.1% tetrabutylammonium hydroxide liberates the drugs from their ion pairs. Analyses are performed using HPLC with a reverse-phase C18 column and a mobile phase of 11% acetonitrile and 0.5% triethylamine adjusted to pH 3. Amiloride is quantified using fluorescence detection (366-nm excitation, 418-nm emission cutoff). Retention times are 2.2 and 6.0 min for amiloride and triamterene, respectively. The sensitivity limit is 0.2 ng/ml, and recovery is 82% for amiloride and 71% for triamterene. Calibration curves are linear (range 0.25-25 ng/ml for plasma and 0.05-2.0 micrograms/ml for urine). Inter- and intraday assay variability is less than 8% and precision is within 5%. The assay is of sufficient sensitivity and specificity for the study of the pharmacokinetics of amiloride in humans.

Amiloride↗