Biomedical subjects

J H Jonkman

Publications and source records attributed to J H Jonkman.

At least 73 records · Page 4Linked to original sources

PubMed1991

Clinical pharmacokinetics and tolerability of alpidem in healthy subjects given increasing single doses.

In a double-blind, placebo-controlled, cross-over experiment in 21 healthy male volunteers, aged 19 to 27 y, the pharmacokinetics and tolerance of the new anxiolytic drug alpidem (SL80.0342) and its three major metabolites were studied after single doses of 25, 50, 100 and 200 mg. Plasma concentrations of alpidem (in 20 subjects) and metabolites (in 6 subjects) were measured by HPLC over a period of 54 h after dosing. Cmax, tmax and AUC(0-54) and, when possible, t1/2 were determined for alpidem and metabolites and the dose linearity of the parameters was investigated. The time to peak of alpidem was dose independent in most subjects and was short (1-4 h); the mean values at the four dosing levels were 1.9, 1.7, 1.6 and 1.8 h. The peak concentration increased with the dose, the mean values being 17, 34, 88 and 115 ng.ml-1, respectively. In 50% of the subjects Cmax tended to stabilize between the 100 and 200 mg dose. Dose linearity was also present for the AUC, which plateaued between the 100 and 200 mg dose in only 3 out of 20 subjects; the mean AUC was 119, 281, 669 and 1117 ng.ml-1.h, respectively. The apparent half-life of elimination appeared to be dose independent, mean values at the increasing dosing levels being 18.7, 19.9, 18.1, and 17.9 h. A similar relationship between the kinetics parameters and dose of the alpidem was observed for the metabolites SL83.0912, SL80.0522 and SL83.0725. The formation of metabolites was not saturated as their AUCs relative to corresponding alpidem AUCs were not dose related.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

The influence of age on the pharmacokinetics of the antiepileptic agent oxcarbazepine.

The disposition of oxcarbazepine was studied in 12 young and 12 elderly healthy male and 12 young and 12 elderly healthy female volunteers, with emphasis on the influence of age. Oxcarbazepine was administered as a single dose of either 300 mg (men) or 600 mg (women), followed by multiple-dose (300 mg) administration twice a day for 7 days (men) or 6 days (women). Semilogarithmic plasma concentration-time curves showed an increasing decline at decreasing concentrations. Accumulation of the pharmacologically active metabolite monohydroxycarbamazepine was found to be more than one would anticipate on the basis of linear and unchanged pharmacokinetics. Saturation did not seem to occur at the level of renal excretion. No apparent differences between male and female volunteers were observed. A significant higher maximum concentration, higher area under the curve parameters, and a lower elimination rate constant were observed in the elderly. These observations are in line with a smaller renal clearance of monohydroxycarbamazepine in the elderly group. In a clinical situation, these age-related differences are not likely to have important implications. In general, treatment with oxcarbazepine was well tolerated.

Adolescent↗

PubMed1991

The influence of caffeine on the steady-state pharmacokinetics of theophylline.

During this open, two-period crossover study in eight healthy volunteers, 1200 mg anhydrous theophylline was administered as a two-stage infusion during 24 hours on day 6. During one of the 8-day periods, 300 mg caffeine, t.i.d., was administered orally. After the start of the theophylline infusion, plasma concentrations of theophylline and caffeine and urinary excretion of theophylline and four metabolites were determined frequently during 60 hours. With caffeine administration theophylline steady-state concentration and area under the curve increased by 23% and 40%, respectively, whereas the volume of distribution at steady state seemed unchanged. The cumulative urinary excretion of 1-methyluric acid and 1-methylxanthine did not reach a plateau, suggesting a capacity-limiting factor in their formation. Notwithstanding the mutual interference of theophylline and caffeine metabolism, the reduction in apparent total body clearance and elimination rate constant of theophylline by 29% and 31%, respectively, indicated a pronounced influence of concomitant administration of realistic amounts of caffeine.

Administration, Oral↗

PubMed1991

Minor effect of multiple dose omeprazole on the pharmacokinetics of digoxin after a single oral dose.

1. The influence of multiple dose administration of omeprazole on the pharmacokinetics of oral digoxin was studied in 10 healthy male volunteers. 2. In a randomized two-way crossover design a single dose of 1 mg digoxin was administered either alone (control) or on day 8 of an 11 day course of omeprazole 20 mg once daily. 3. Plasma digoxin concentrations were measured over 96 h after digoxin administration with a [125I]-r.i.a. method. 4. On average, Cmax and AUC values for digoxin were approximately 10% higher and tmax tended to be shorter during the administration of omeprazole, while the elimination rate constant was unaffected. 5. The increase in AUC(0,96 h) was statistically significant (P less than 0.05), but within the accepted range for bioequivalence. In two subjects the increase was approximately 30%. 6. It is concluded that co-treatment with omeprazole causes a minor increase in the absorption of oral digoxin. The magnitude of this effect is not considered to be clinically relevant for the majority of patients.

Administration, Oral↗

PubMed1990

Percutaneous absorption, metabolic profiling, and excretion of the penetration enhancer azone after multiple dosing of an azone-containing triamcinolone acetonide cream in humans.

Radioactive Azone (1.6%; 1-dodecylazacycloheptan-2-one) was incorporated in a therapeutic formulation containing triamcinolone acetonide at a concentration of 0.05%. This cream (TAZ) was applied for four consecutive days to human volunteers on the same 24-cm2 application area on the forearm for 12 h under occlusion. The percutaneous absorption of Azone as measured in the excreta appeared to be only 3.47 +/- 0.33% during the whole study period. Azone-derived radioactivity was predominantly excreted by the kidneys (97.8 +/- 0.4%). From the urinary excretion plot, it could be deduced that the flux of Azone through human skin increased during the study period, reaching a plateau within 2-3 d. Accumulation of Azone in the stratum corneum did not occur. Only unchanged Azone could be detected in the stratum corneum. Excretion was mainly in the form of very polar metabolites. Compared with pure Azone, the therapeutic formulation did not influence the metabolism, excretion route, or urinary elimination rate of the penetration enhancer.

Azepines↗

PubMed1990

Development of a laboratory robotic system for automated bioanalytical methods--I. The determination of theophylline in human plasma: a comparison between the robotized and manual method.

The quality of bioanalytical methods is often determined by the quality of sample preparation. Using a robot for sample treatment may give better results than manual sample preparation, since the robot lacks human behaviour and incidental errors that are part of it. The use of a laboratory robot has the additional advantage of giving each sample the same analytical history, resulting in better reproducibility. An automated method has been developed for the analysis of drugs in plasma using a laboratory robot. Theophylline was used as a probe drug. Sample preparation was automated with a Zymate II robot, followed by separation and quantitation on an HPLC-system. The robotic method showed a good correlation with the manual method, while sample throughput was doubled.

Chemistry, Clinical↗

PubMed1990

Development of a laboratory robotic system for automated bioanalytical methods--II. A robot computer program for guarding totally automated bioanalytical methods.

The application of fully automated, unattended sample preparation performed by a laboratory robot for the analysis of drugs in biological samples requires the prevention of system failures which may arise in the on-line coupled chromatographic system or in other components of the robotic system. A computer program has been developed which can help to detect such problems. The control program for the robotic sample preparation contains a number of safety measures to intercept robotic or human errors. A routine is implemented, guarding for chromatographic malfunctions and errors in dispensing liquids by the robot. After detection of trouble, sample preparation is interrupted.

Algorithms↗

PubMed1990

Effect of theophylline on cortisol plasma concentrations in patients with chronic obstructive pulmonary disease.

To further understand the therapeutic action of theophylline, we investigated, in a randomized double-blind crossover study, the effects of a 4-day treatment with two different dosage regimens of theophylline on the circadian rhythm of cortisol plasma concentrations in seven COPD patients. Both theophylline regimens resulted in plasma concentrations in the therapeutic range (more than 7.5 mg/l). No significant differences between placebo and the active trial periods in the circadian rhythm of cortisol secretion were found. These results suggest that cortisol secretion is not influenced by therapeutic plasma concentrations of theophylline.

Aged↗

PubMed1989

Phenotypic differences in dextromethorphan metabolism.

Polymorphic differences in dextromethorphan metabolism were observed in three studies conducted in a total of 44 subjects (of Dutch origin) administered 60 mg dextromethorphan hydrobromide as an OROS tablet. Mean plasma dextromethorphan (DM) concentrations after a single dose and at steady state were 4-75 times higher in the poor metabolizers (PM) relative to the extensive metabolizers (EM). Following a single dose, the mean areas under the plasma concentration-time curve (AUC, 0-24 hr) of DM, total dextrorphan (DR), and total 3-hydroxymorphinan (HM) were 6.9-fold higher, 17.4-fold lower, and 11-fold lower, respectively, for the PM than for the EM. Correspondingly, steady-state AUC values were 52.8 times higher, 6.7 times lower, and 3.3 times lower for DM, total DR, and total HM, respectively, for the PM relative to the EM. Drug/metabolite ratios (DMR) for amounts excreted in the urine of DR and HM indicated polymorphism in O-demethylation of DM since DMR for PM was 352 and 338 times higher than that for EM for DR and HM, respectively. However, polymorphism in N-demethylation was not observed. Ratios of conjugated/free dextrorphan and 3-hydroxymorphinan excreted in the urine suggest also a lack of conjugative capacity in the PM, relative to the EM. The overall incidence of PM was 9.1% in this population.

Administration, Oral↗

PubMed1989

Effects of alpha-interferon on theophylline pharmacokinetics and metabolism.

1. The influence of alpha-interferon (Roferon-A) on the pharmacokinetics and metabolism of theophylline was studied in healthy adults. Roferon-A was administered as an intra-muscular injection (3 x 10(6) iu) once-a-day over 3 days. One week prior to and immediately after this course a single 20 min aminophylline infusion (4 mg kg-1) was given. 2. Blood samples for theophylline analysis were taken over 48 h. Urine was collected up to 72 h and assayed for theophylline and its major metabolites 3-methylxanthine, 1,3-dimethyluric acid and 1-methyluric acid. 3. Pharmacokinetic parameters for theophylline in plasma were calculated. From urinary excretion data the overall metabolic clearance of theophylline and clearances for formation of the metabolites were calculated. 4. After interferon administration, there was a significant increase of approximately 15% in the mean values of the terminal elimination half-life, area under the curve and mean residence time of theophylline in association with a similar decrease in plasma clearance (P less than 0.05). Formation clearances of the metabolites tended to be smaller after treatment, but only the change in the overall clearance of theophylline was significantly different (P less than 0.05). There was no systematic shift in the metabolic pattern of theophylline. 5. Additional investigations of the influence of the duration of alpha-interferon treatment are necessary before definite conclusions can be drawn about the mechanism and the clinical relevance of the described interaction.

Adult↗

PubMed1989

Effect of theophylline and enprofylline on bronchial hyperresponsiveness.

The effect of increasing intravenous doses of theophylline and enprofylline, a new xanthine derivative, on bronchial responsiveness to methacholine was studied in eight asthmatic patients. Methacholine provocations were carried out on three days before and after increasing doses of theophylline, enprofylline, and placebo, a double blind study design being used. Methacholine responsiveness was determined as the provocative concentration of methacholine causing a fall of 20% in FEV1 (PC20). The patients were characterised pharmacokinetically before the main study to provide an individual dosage scheme for each patient that would provide rapid steady state plasma concentration plateaus of 5, 10, and 15 mg/l for theophylline and 1.25, 2.5, and 3.75 mg/l for enprofylline. Dose increments in the main study were given at 90 minute intervals. FEV1 showed a small progressive decrease after placebo; it remained high in relation to placebo after both drugs and this effect was dose related. Methacholine PC20 values decreased after placebo; mean values were higher after theophylline and enprofylline than after placebo (maximum difference 2.0 and 1.7 doubling doses of methacholine); the effect of both drugs were dose related. Thus enprofylline and theophylline when given intravenously cause a small dose related increase in FEV1 and methacholine PC20 when compared with placebo.

Adult↗

PubMed1989

Omeprazole: pharmacology, pharmacokinetics and interactions.

Omeprazole is a prodrug which is converted to its active form only at the site of action, namely the parietal cell. There it binds irreversibly with H+-K+-ATPase (the gastric proton pump), which causes an effective and long-lasting inhibition of gastric acid secretion. The pharmacokinetic profile of omeprazole is rather complicated, showing concentration-dependent elimination kinetics and an oral bioavailability which increases with the dose and during repeated administration. For the choice of dosage regimens this has minor consequences, in view of the wide therapeutic range of omeprazole and because an almost continuous maximum effect is obtained with once daily oral administration of 20-40 mg. Omeprazole may influence the pharmacokinetics of concurrently administered drugs by an inhibition of their oxidative metabolism. For most drugs studied thus far, the influence is less or even negligible in comparison with the influence of cimetidine, with the exception of diazepam. For every new combination of omeprazole with a drug that has a critical therapeutic range the consequences of a possible interaction should be studied.

Biological Availability↗

PubMed1989

Food interactions with sustained-release theophylline preparations. A review.

Currently, theophylline is being used predominantly as sustained-release capsules or tablets. In the mid-seventies the first preparations for use with a dosage interval of 12 hours (twice-daily preparations) were introduced. Since 1983, theophylline preparations that can be given with an interval of 24 hours (once-daily preparations) have become available. The release of theophylline from some of these products can be influenced (either increased or decreased) by concomitant intake of food. With some preparations the composition of the meal (especially the fat content) has an influence on the degree of effect. The consequence may be an effect on the rate of absorption or on the amount absorbed, or both simultaneously. This could result in an unexpected shift of the plasma theophylline concentration. Such a shift is therapeutically undesirable, because theophylline has a fairly narrow therapeutic range. A review is given of those food interactions with the sustained-release theophylline preparations, both twice-daily and once-daily products, that are currently on the world market. Special attention is paid to the specific (bio)pharmaceutical characteristics of the different products, and to the influence of the composition and timing of the meals. For each preparation the effect of food on the following pharmacokinetic parameters is discussed: area under the plasma concentration-time curve, peak plasma drug concentration and time to reach this peak. Where possible, the results for both adults and children are discussed. There are indications that children are more susceptible to food-effects than adults. The regulatory aspects are mentioned briefly. Clinically important effects of food have been observed with the following twice-daily products: 'Theo-Dur Sprinkle', 'Theolair SR' (= 'Nuelin SR') and 'Theograd'. Pronounced effects could have an even greater impact with once-daily preparations, as the total daily dose will be given at a single time. A particularly sudden release of a major part of the dose ('dose-dumping') may result in toxic plasma concentrations. Among these products, clinically important effects in children have been reported with 'Theo-24' and 'Uniphyl'.

Biological Availability↗

PubMed1989

Bioequivalence studies: single vs multiple dose.

Bioequivalence of different preparations of the same drug substance has gained considerable importance over the last few years due to increasing generic substitution. The procedure that the manufacturer of the generic test preparation has to show bioequivalence with an appropriate reference preparation is scientifically accepted and laid down in international regulations. However, the necessity of single- vs multiple-dose bioequivalence studies has not been discussed in detail with the exception of the Dutch and US guidelines on sustained-release theophylline formulations, where multiple-dose studies are specifically required. This paper compares the conclusions drawn from single- and multiple-dose studies in the same subjects and recommends appropriate pharmacokinetic characteristics.

Adult↗

PubMed1989

Chronopharmacodynamics and kinetics after symmetric and asymmetric multiple theophylline doses in patients with chronic obstructive pulmonary disease.

In a randomized double-blind crossover study, the effects of 4 days of symmetric or asymmetric dosing with sustained-release theophylline (Sabidal-SR) were compared with placebo in ten patients with chronic obstructive pulmonary disease in a stable state. The doses were 450 mg b.i.d. and 270 mg plus 630 mg, respectively. Special attention was paid to circadian rhythms in pharmacokinetics and pharmacodynamic effects, during 24 h of measuring. The peak plasma theophylline concentrations at night with a symmetric dosage were lower than with an asymmetric dosage: 11.5 mg/l (+/- 3.8) and 13.6 mg/l (+/- 4.4), respectively. Both theophylline regimens caused a significant increase in vital capacity (8%) and in forced expiratory volume in one second (15%), and also a decrease of specific viscous work of breathing (49%). There were no significant differences in pharmacodynamic effects between the symmetric and asymmetric dosing regimen. An exception was the heart rate, that increased significantly only with an asymmetric dose. We found no correlation between the theophylline plasma concentration and the changes in lung function and heart rate. Theophylline had no influence on subjective findings of the patients, nor on the oxygen saturation of the blood during sleep.

Absorption↗

PubMed1988

Comparison of the in vitro dissolution properties and in vivo steady-state pharmacokinetics of two sustained-release theophylline preparations.

The sustained-release properties and relative bioavailability of Theolin Retard and Pharphylline Retard were studied in eight healthy adults after treatment for five days with twice daily 450 mg, respectively 425 mg. During the day-time dosing interval on the fourth and fifth day theophylline plasma concentrations were assayed by HPLC. After intake of Theolin Retard, minimum theophylline plasma concentrations were significantly higher, fluctuations in theophylline plasma concentrations were significantly smaller and t75 (the period within a dosing interval during which the plasma concentration exceeds 75% of the maximal concentration) was significantly longer than after Pharphylline Retard. Maximal concentrations and AUC values were not significantly different. For both products the plasma concentration time-curves on day 5 were significantly lower than on day 4. In vitro dissolution tests confirmed the more sustained release of theophylline from Theolin Retard. These results indicate an equal extent of absorption from the two products but better sustained-release properties for Theolin Retard.

Adult↗

PubMed1988

The pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis and in patients with chronic renal disease.

We have studied the pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis, patients with chronic renal failure, and healthy subjects, and have assessed the predictive value of routine tests of liver function and renal function (creatinine clearance) for theophylline and enprofylline total body clearances. Theophylline clearance was significantly decreased in the patients with liver cirrhosis compared with both the patients with renal failure and the healthy subjects (the mean values in the three groups were 24, 47, and 46 ml.h-1.kg-1 respectively. Enprofylline clearance was significantly decreased in the patients with chronic renal failure, compared with both the patients with liver cirrhosis and the healthy subjects (the values in the three groups were 64, 250, and 289 ml.h-1.kg-1 respectively. There was a strong correlation between creatinine clearance and enprofylline clearance, while there was only a poor correlation between the liver function tests and theophylline clearance. It appears that in various clinical situations enprofylline elimination can be predicted more precisely than theophylline elimination, which may make the drug safer in clinical practice.

Adult↗

PubMed1988

Pharmacokinetic and pharmacodynamic comparison of a new controlled-release formulation of metoprolol with a traditional slow-release formulation.

The plasma concentration-time profile and haemodynamic effects of metoprolol after the administration of metoprolol CR (a new multiple-unit controlled-release formulation) and metoprolol SR (a traditional slow-release formulation) once daily, were investigated in 12 healthy men. Data were collected over one 24-h dose interval at steady state after five days of treatment. The study was a randomized, three-way, cross-over comparison of metoprolol CR, 100 mg, metoprolol SR, 100 mg, and placebo. The reduction in exercise heart rate in relation to placebo treatment was used as a measure of beta 1-blockade. The metoprolol plasma concentration-time profile during treatment with metoprolol CR was smooth and uniform, showing a more controlled release profile than that obtained with metoprolol SR. This was demonstrated by the significantly longer time period during which the plasma concentration exceeded 75% of the maximum concentration (T75), for metoprolol CR compared with metoprolol SR (p less than 0.05). The percentage peak-trough fluctuation in plasma metoprolol concentration was significantly smaller for metoprolol CR than for metoprolol SR (p less than 0.001). These pharmacokinetic differences between metoprolol CR and metoprolol SR produced a different duration of clinically relevant beta 1-blockade, defined as a reduction in exercise heart rate of greater than 10%. By this definition metoprolol CR was still effective in seven subjects and metoprolol SR in two subjects 24 h after dosing. The percentage peak-trough fluctuation in exercise heart rate over the dose interval was significantly smaller for metoprolol CR than for metoprolol SR (p less than 0.001), thus demonstrating a more even beta 1-blockade with metoprolol CR.

Adult↗