Biomedical subjects

F Bochner

Publications and source records attributed to F Bochner.

At least 37 records · Page 2Linked to original sources

PubMed1991

Lack of effect of paracetamol on the pharmacokinetics and metabolism of codeine in man.

Plasma and urine concentrations of codeine and its measurable metabolites were determined by HPLC in six healthy subjects after a single 30 mg oral dose of codeine either alone or after 7 doses of 1 g paracetamol 8 hourly. After codeine alone, the t1/2 (h), AUC (mumol.l-1.h) and CLR (ml.min-1) for codeine were 2.2, 0.81, and 252 respectively. These were not significantly altered by paracetamol: 2.2, 0.84, and 291 respectively. For codeine-6-glucuronide the values were 2.4, 22.0, and 29.7 respectively. These were not significantly different from those after codeine plus paracetamol: 2.4, 21.9, and 39.6. There were no significant differences between the two treatments in the apparent partial clearances (ml.min-1) of codeine to morphine (88 codeine alone, 70 codeine plus paracetamol), to norcodeine (71 codeine alone, 88 codeine plus paracetamol), and to codeine-6-glucuronide (820 codeine alone, 1022 codeine plus paracetamol). The urinary excretion of codeine-6-glucuronide, morphine, norcodeine, and codeine were not significantly different between the two treatments.

Acetaminophen↗

PubMed1991

Mu receptor binding of some commonly used opioids and their metabolites.

The binding affinity to the mu receptor of some opioids chemically related to morphine and some of their metabolites was examined in rat brain homogenates with 3H-DAMGO. The chemical group at position 6 of the molecule had little effect on binding (e.g. morphine-6-glucuronide Ki = 0.6 nM; morphine = 1.2 nM). Decreasing the length of the alkyl group at position 3 decreased the Ki values (morphine less than codeine less than ethylmorphine less than pholcodine). Analgesics with high clinical potency containing a methoxyl group at position 3 (e.g. hydrocodone, Ki = 19.8 nM) had relatively weak receptor binding, whilst their O-demethylated metabolites (e.g. hydromorphone, Ki = 0.6 nM) had much stronger binding. Many opioids may exert their pharmacological actions predominantly through metabolites.

Animals↗

PubMed1991

Effect of racemic ibuprofen dose on the magnitude and duration of platelet cyclo-oxygenase inhibition: relationship between inhibition of thromboxane production and the plasma unbound concentration of S(+)-ibuprofen.

1. Four healthy male subjects received racemic ibuprofen (200, 400, 800 and 1200 mg), orally, on four occasions, 2 weeks apart, according to a four-way Latin-square design, in order to investigate the influence of increasing dose of ibuprofen on the magnitude and duration of its antiplatelet effect as well as on the relationship between such effect and drug concentration. 2. The antiplatelet effect of ibuprofen was assessed by measuring the inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood. The plasma unbound concentration of S(+)-ibuprofen, the enantiomer shown in an in vitro study to be responsible for the inhibitory effect of platelet TXB2 generation, was measured using an enantioselective method. 3. The maximum percentage inhibition of TXB2 generation increased significantly with dose from a mean +/- s.d. of 93.4 +/- 1.2% after the 200 mg dose to 98.8 +/- 0.3% after the 1200 mg dose, and there was an increase with dose in the duration of inhibition of TXB2 generation. The effect of ibuprofen on platelet TXB2 generation was transient and mirrored the time-course of unbound S(+)-ibuprofen in plasma; on all but one of the 16 occasions, serum TXB2 concentrations returned to at least within 10% of the pretreatment concentrations within 24 h of ibuprofen administration. 4. For each subject, the relationship between the percentage inhibition of TXB2 generation and the unbound concentration of S(+)-ibuprofen in plasma was modelled according to a sigmoidal Emax equation. The mean plasma unbound concentration of S(+)-ibuprofen required to inhibit platelet TXB2 generation by 50% (EC50) was 9.8 +/- 1.0 micrograms l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.

1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine-6-glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h. 3. The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in the seven extensive metabolisers and 8 ml min-1 in the poor metaboliser; to norcodeine the values were 103 +/- 33 ml min-1 and 90 ml min-1; to codeine-6-glucuronide the values were 914 +/- 129 ml min-1 and 971 ml min-1; and intrinsic clearance was 1568 +/- 103 ml min-1 and 1450 ml min-1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗

PubMed1991

Bioinequivalence of four 100 mg oral aspirin formulations in healthy volunteers.

The single dose pharmacokinetics of 4 commercially available 100 mg oral aspirin formulations were studied in 6 healthy men and 6 healthy women. Two of the formulations were rapid release ('Cardiprin' 100, 'Platelin') and the other 2 were enteric coated formulations ('Astrix' 100, 'Cartia'). There were marked differences in the plasma concentration-time profiles between the rapid release and the enteric coated formulations. There were no significant differences (p greater than 0.05) in the mean time to achieve maximum aspirin concentrations between 'Cardiprin' 100 (0.48 h) and 'Platelin' (0.35 h), but this was significantly prolonged (p less than 0.001) for 'Astrix' 100 (3.73 h) and even more prolonged for 'Cartia' (6.84 h). Similar between-formulation differences were seen in the areas under the plasma concentration-time curves, for which the rank order was 'Cardiprin' 100 (1.60 mg/L.h) = 'Platelin' (1.54 mg/L.h) greater than 'Astrix' 100 (0.73 mg/L.h) greater than 'Cartia' (0.56 mg/L.h). For 'Cardiprin' 100, 'Platelin' and 'Astrix' 100 plasma aspirin concentrations were below 5 micrograms/L by 7 h after ingestion, whereas for 'Cartia' aspirin was detectable for up to 16 h, giving the appearance of sustained release. The enteric coated formulations produced the greatest variability in the plasma aspirin concentration vs time profiles. The urinary recovery of salicylate was greater than 80% of the administered dose for all 4 formulations. The clinical significance of the marked pharmacokinetic differences observed with these 4 low-dose aspirin formulations is not known.

Administration, Oral↗

PubMed1991

Thebaine O-demethylation to oripavine: genetic differences between two rat strains.

1. Codeine O-demethylation to morphine is mediated by cytochrome P450 IID1 (rat), or P450 IID6 (man), and exhibits genetic polymorphism. Thebaine is a precursor in the formation of endogenous morphine and codeine in man, being O-demethylated to oripavine. 2. The objective of the present study was to ascertain whether the O-demethylation of thebaine to oripavine was mediated by cytochrome P450 IID1 in rat liver microsomes. 3. Thebaine O-demethylation showed strain differences in female Sprague-Dawley (SD) and female Dark-Agouti (DA) rats, which serve as a model for the human debrisoquine/sparteine metabolism phenotypes. 4. The total intrinsic clearance of thebaine to oripavine was high (19.7 ml/h per mg protein) in SD rats, indicating that oripavine is a major metabolite of thebaine. A 3-fold lower intrinsic clearance was observed in DA rats (6.7 ml/h per mg protein). 5. Thebaine O-demethylation was inhibited by quinine and known substrates of cytochrome P450 IID1/P450 IID6, supporting the major involvement of cytochrome P450 IID1 in oripavine formation in rats.

Animals↗

PubMed1991

Polymorphic metabolism of opioid narcotic drugs: possible clinical implications.

The oxidative metabolism of many drugs is under genetic control. The enzyme responsible for this reaction for this group of drugs is cytochrome P-450IID6. Humans can be classified either as extensive metabolisers or, if lacking this enzyme, poor metabolisers. The incidence of poor metabolisers in caucasian subjects is 7-10%. The hepatic O-demethylation of codeine to morphine, quantitatively a minor metabolic process, represents this type of genetic polymorphism and has been studied in human pharmacokinetic studies, human urinary recovery studies, and in human and rat liver microsome experiments. Based on the current understanding that the analgesic effect of codeine is mediated primarily through morphine, one might anticipate that poor metabolisers would not obtain pain relief from codeine. The clinical significance of this polymorphism to the antidiarrhoeal and antitussive properties of codeine is not known. Others opioids (dihydrocodeine, hydrocodone, oxycodone, and thebaine) are structurally similar to codeine and their metabolism (O-demethylation at the 3 position) might also be under genetic control. Pharmacogenetics may play an important role in explaining the wide variability of the clinical response to many opioid drugs.

Alfentanil↗

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↗