Bioavailability of a new effervescent tablet of diclofenac.

OBJECTIVE: The bioavailability of a newly developed effervescent tablet containing 50 mg diclofenac Na (DIC-effervesc) was investigated and compared with an enteric-coated dragée (DIC-enteric). SUBJECTS AND METHOD: 24 healthy, male and informed volunteers (mean body weight 78.8 kg, mean age 31.9 years) received in a randomized cross-over design a single dose of 50 mg diclofenac as DIC-effervesc and DIC-enteric. A total of 19 blood samples were obtained before and up to 12 h after administration according to the different properties of the galenic formulation. Diclofenac was analyzed by a sensitive HPLC method with a lower limit of quantification of 20 ng/ml. The bioavailability was compared as ratios of the geometric means of AUC0-infinity and Cmax. RESULTS: DIC-effervesc shows no lag time, a tmax within 30 min and a double peak of Cmax in 15/24 subjects. The mean Cmax (arithm. mean +/- SD) for DIC-effervesc is 950+/-341 ng/ml (first Cmax) and for DIC-enteric 1364+/-335 ng/ml. The mean AUC0-infinity, (arithm. mean +/- SD) amounts to 1097+/-210 ng/ml x h for DIC-effervesc and 1262+/-220 ng/ml x h for DIC-enteric. Based on the point estimator and the 90% interval DIC-effervesc is bioequivalent in respect to amount absorbed (86.4%; 81.8 - 91.3%). DIC-effervesc was well tolerated. CONCLUSION: The new effervescent tablet of diclofenac Na shows a rapid absorption without lag time, the same amount of absorption and a slightly lower Cmax (caused by a double peak phenomenon) in comparison to the enteric-coated dragee. A rapid onset of therapeutic effect is postulated in acute pain disorders.

Valuable research or short stories: what makes the difference?

Accurate communication of scientific research about biological entities is critically dependent on correct identification and naming of the entities involved. This is not a simple task, particularly in a group such as the Triticeae in which there are still many taxa whose limits are only poorly understood. Even if the names used are appropriate at the time a study is completed, subsequent research may lead to a change in the boundaries of some of the entities involved, and consequently in their nomenclature. These factors make it critically important that the identity of the biological entities studied be documented by the preparation of voucher specimens. Voucher specimens enable others to understand the meaning of the names as used by the authors of the paper and maintain the value of the research, even if the systematic framework prevailing at the time of the research is altered. Failure to make voucher specimens can reduce potentially valuable research reports to nothing more than short stories of questionable credibility or, worse, misleading stories. Examples are provided in which voucher specimens extended the longevity of a paper, and others in which the value of a paper was minimized by the lack of voucher specimens.

[The effect of food on theophylline absorption]. / Untersuchung von nahrungsbedingten Veränderungen der Theophyllin-Resorption.

The possible influence of the food and fat content of meals on the bioavailability and pharmacokinetics of a 350 mg sustained release theophylline (CAS 58-55-9) preparation (Bronchoretard) was investigated after single dose oral administration to 18 volunteers in a randomised 3-way crossover design. The treatments investigating administration of the test preparation in a fasting state, after a standard meal and after a high-caloric fat evening meal, according to commonly applied rules, were shown to be equivalent with respect to the extent of bioavailability (AUC) and the observed maximal concentration (Cmax). Pharmacokinetic parameters describing sustained release characteristics were not changed to any relevant degree. As expected, the co-administration of food resulted in a physiologically determined delay in absorption, which is probably not therapeutically relevant during long-term administration.

Study on the influence of food on the absorption of theophylline from a controlled-release preparation.

The possible influence of food and fat content of meals on the bioavailability and pharmacokinetics of a 350 mg sustained-release theophylline (CAS 58-55-9) preparation (Bronchoretard) was investigated after single-dose oral administration to 18 volunteers in a randomized 3-way cross-over design. The treatments investigating an administration of the test preparation in a fasting state, after a standard meal and after a high-caloric fat evening meal, according to the commonly applied rules, could be shown to be equivalent with respect to the amount of bioavailability (AUC) and the observed maximal concentrations (Cmax). Pharmacokinetic parameters describing sustained-release characteristics were not changed either to any relevant degree. As expected, the co-administration of food resulted in a physiologically determined delay in absorption, which probably is not therapeutically relevant during long-term administration.

Pharmacokinetics of physostigmine in man following a single application of a transdermal system.

1. The pharmacokinetics of physostigmine were investigated in a three-way cross-over design in six healthy, male volunteers comparing a physostigmine transdermal system (PTS), an oral solution and an i.v. infusion. 2. A single application of the patch over 24 h produced detectable plasma drug concentrations after a mean lag-time of 4 h. Thereafter, the drug was absorbed continuously from the PTS and putative therapeutic plasma concentrations were measured over approximately 18 h. 3. A mean absolute bioavailability of 36% was determined for the transdermal system and 3% for the oral solution. In comparison with the oral solution, interindividual variability of pharmacokinetics was less with the PTS. 4. The mean amount of physostigmine released from the transdermal system after 24 h was 5.7 mg. Because of extensive metabolism, only 2.2 mg of physostigmine were detected systemically. 5. After removing the PTS, the mean apparent half-life of elimination was 4.9 h, compared with 0.5 h for the i.v. infusion. This indicates continued drug absorption from a skin depot. 6. Physostigmine was well tolerated by the volunteers. With the PTS, a mild erythema was observed at the area of application, disappearing within a few hours.

[Comparative studies on biologic availability and pharmacokinetics of bromazepam in tablets]. / Vergleichende Untersuchungen zur Bioverfügbarkeit und Pharmakokinetik von Bromazepam aus Tabletten.

Ten male volunteers participated in a randomized crossover trial to compare the bioavailability of bromazepam (7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one) from two different preparations (Normoc, the test preparation, and a commercially available standard preparation). A single dose of 6 mg bromazepam was given. There was no difference in the USP XX rotating basket dissolution test between both preparations. The pharmacokinetic parameters elimination half-life, maximum plasma concentration and area under the curve were not significantly different. With the test preparation, however, smaller interindividual differences were seen. Only the time to peak plasma concentration showed a statistically significant difference. The test preparation yielded a flatter and smoother plasma bromazepam concentration curve compared with the standard preparation. This seems favourable in the case of subchronic dosing with regard to side effects, e.g. sedation.

[Absorption profile and absolute bioavailability of a theophylline sustained-release preparation]. / Absorptionsprofil und absolute Bioverfügbarkeit eines Theophyllin-Retardpräparats.

In a single-dose crossover study with 16 healthy male nonsmoking volunteers the absorption profile and absolute bioavailability of the sustained release pellets contained in all dosage strengths of Bronchoretard (100, 200, 350, 500 mg anhydrous theophylline) were investigated. One capsule (500 mg theophylline) was given after an evening meal. The reference treatment consisted of an i.v. infusion over 8 h in a total dosage of 350 mg theophylline. Plasma concentration-time profiles were evaluated for 72 h after dosing, respectively start of infusion. Theophylline was measured by high-performance liquid chromatography (HPLC). Absorption profiles (Wagner-Nelson) were derived and the absolute bioavailability was calculated. For the sustained release pellets a liberation/absorption of zero order for 12 h could be noted; the dose-corrected mean absolute bioavailability was 88%. The assumptions of an investigation on absolute bioavailability are discussed and the limitations on generalizability resulting therefrom.

Bioavailability and pharmacokinetic characteristics of two monofluorophosphate preparations with calcium supplement.

Two studies on the rate and extent of bioavailability of fluoride from a single dose of oral preparations of sodium monofluorophosphate (Na2FPO3) combined with calcium supplement were conducted according to a cross-over design on 18 (Study 1) and 20 (Study 2) male healthy volunteers, respectively. Evaluated were: a) tablets containing 76 mg Na2FPO3 (Ref1); b) chewable tablets containing 76 mg Na2FPO3 and 1250 mg calcium carbonate (Test 1); c) effervescent tablets containing 76 mg Na2FPO and 3240 mg calcium lactogluconate/carbonate (Ref 2); d) effervescent tablets containing 76 mg Na2FPO3 and 1250 mg calcium carbonate (Test 2). In all preparations Na2FPO3 was equivalent to 10 mg elemental F. The calcium supplement was equivalent to 500 mg elemental Ca. Fluoride was assayed in serum and in urine by a gas chromatographic method with a limit of quantitation of 10 ng/ml. Test 1 was found equivalent to Ref1 with regard to rate and extent of bioavailability of fluoride in serum. Test 2 (effervescent tablets resulting in an oral solution of Na2FPO3 and calcium salts) was found bioequivalent in rate and extent to Ref2 (effervescent tablets authorized for marketing with the same content in F and Ca equivalents as Test 2). The pharmacokinetics of fluoride from all investigated preparations was characterized by a short lag time, a rapid absorption, a Cmax of fluoride of 291-351 ng/ml (without significant differences between preparations) reached 30-75 min after administration, and a terminal t1/2 of 6-14 h. About 50% of the absorbed fluoride was eliminated with the urine (from 0 to infinity time). The kur.el was 0.06 h-1. The renal clearance 65 ml/min. The preparations were well tolerated by the subjects. In conclusion, Test1 and Test2 represent combinations of Na2FPO3 with calcium supplement which are well tolerated and provide a rapid, reliable and practically complete bioavailability of fluoride. They are therefore suitable for the bone-forming therapy of osteoporosis.

An early phase I study to determine the tolerance, safety and pharmacokinetics of idebenone following multiple oral doses.

Ten healthy male volunteers participated in this Phase I multiple dose study with CV-2619 (6-[10-hydroxydecyl]-2,3- dimethoxy-5-methyl-1,4-benzoquinone, idebenone). Each volunteer received single oral doses of 100 mg CV-2619 on study days 1 and 35, and during days 2 to 34, 300 mg daily in three divided doses. Blood and urine samples were collected for pharmacokinetic analysis of CV-2619 and its two major metabolites. CV-2619 was well tolerated with regard to the subjective and objective assessments made during the study. There were no changes in clinical laboratory values which could be directly attributed to the administration of CV-2619. The elimination of CV-2619 appeared to be biphasic with a mean terminal elimination half-life of 18 h. Levels of metabolites in serum were too low to provide adequate description of their elimination kinetics. CV-2619 and its metabolites showed no tendency to accumulate over the 35-day period.

[Absorption profile and absolute bioavailability of a theophylline--retard preparation]. / Absorptionsprofil und absolute Bioverfügbarkeit eines Theophyllin-Retardpräparats.

Absorption Profile and Absolute Bioavailability of a Theophylline Retard Preparation. In a single-dose cross-over study with 16 healthy male nonsmoking volunteers the absorption profile and absolute bioavailability of the retard pellets contained in all dosage strengths of Bronchoretard (100, 200, 350, 500 mg anhydrous theophylline) were investigated. One capsule (500 mg theophylline) was given after an evening meal. The reference treatment consisted of an i.v. infusion over 8 h in a total dosage of 350 mg theophylline. Plasma concentration-time profiles were evaluated for 72 h after dosing, respectively start of infusion. Theophylline was measured by high-performance liquid chromatography (HPLC). Absorption profiles (Wagner-Nelson) were derived and the absolute bioavailability was calculated. For the retard pellets a liberation/absorption of zero order for 12 h could be noted; the dose-corrected mean absolute bioavailability was 88%. The assumptions of an investigation on absolute bioavailability are discussed and the limitations on generalizability resulting therefrom.

[The biological availability of cefadroxil given simultaneously with N-acetylcysteine]. / Ermittlung der Bioverfügbarkeit von Cefadroxil bei gleichzeitiger Gabe von N-Acetylcystein.

A preliminary study revealed that similarly to the antibiotics amoxillin, thiamphenicol, erythromycin and doxycycline, the oral cephalosporin cefadroxil (CAS 66592-87-8) can be administered simultaneously with the mucolytic n-acetylcysteine (CAS 616-91-1). In the present study 12 healthy male volunteers received in a randomised cross-over design a single oral dose of 1000 mg cefadroxil or a single oral dose of 1000 mg cefadroxil (Bidocef) plus 200 mg n-acetylcysteine. The two study days were separated by a wash-out period of one week. To determine the pharmacokinetic profile of cefadroxil, plasma and sputum were analysed by HPLC at defined intervals. Regarding the bioavailability of cefadroxil, the free combination is bioequivalent to the individual component. After administration of cefadroxil plus n-acetylcysteine, a higher cefadroxil concentration was found in the sputum compared to an administration of cefadroxil alone. However, the difference was not statistically significant. According to the results, simultaneous administration of the oral cephalosporin cefadroxil and the mucolytic n-acetylcysteine is possible without changes in the bioavailability of cefadroxil being observed.

[Relative bioavailability of paracetamol from tablets and suppositories as well as of paracetamol and codeine in a combination tablet]. / Relative Bioverfügbarkeit von Paracetamol aus Tabletten und Zäpfchen sowie von Paracetamol und Codein aus einer Kombinationstablette.

Eight healthy male volunteers took part in this study to determine the relative bioavailability of Treuphadol oblong tablets (500 mg paracetamol), Treuphadol Plus oblong tablets (500 mg paracetamol, 30 mg codeine phosphate) and Treuphadol suppositories (750 mg paracetamol) against commercial tablets (500 mg paracetamol). Plasma levels of paracetamol and codeine, plus saliva levels of paracetamol for the two paracetamol only formulations, were determined by HPLC and the pharmacokinetic parameters established. The AUC data for paracetamol showed that all four preparations were bioequivalent. The saliva levels of paracetamol demonstrated a good correlation to the corresponding plasma levels. The pharmacokinetic data of codeine from the Treuphadol Plus tablet were compared with corresponding data from the literature. The bioequivalence of codeine when based on this comparison can also be assured.

Suprofen sustained release kinetics in healthy male volunteers. 1st communication: a single dose open crossover bioavailability study of suprofen sustained release tablets versus capsules.

An open crossover study was performed in 12 healthy male volunteers to compare the bioavailability of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) 600 mg sustained release tablets versus the suprofen capsule (2 X 200 mg). The pharmacokinetic profiles in plasma and urine were determined by a HPLC assay. In the dose range studied, the two suprofen formulations were not associated with any clinically significant effects on the blood pressure, heart rate or ECG. The results of the physical and neurological examinations showed no abnormal results. The results of haematology, clinical chemistry and urinalysis also showed no significant modifications. However, increased serum creatinine values were observed in some volunteers following suprofen administration. A drug relationship to this finding cannot be excluded with certainty. Two volunteers complained of nausea and vomiting following administration of two suprofen capsules. For this reason, volunteer no. 9 was withdrawn by the investigator from the study and replaced by an eligible substitute. In general, single doses of the two suprofen formulations investigated, were subjectively and objectively well tolerated. From the suprofen plasma-concentration time profiles, it was apparent that, whilst the elimination of suprofen was similar for both formulations, there was a marked delay in absorption of the tablet formulation. This formulation resulted in statistically significantly later maximum plasma levels and longer mean residence time (p less than 0.001). In comparison to the reference capsule formulation, the tablet had statistically significantly lower (75%) bioavailability. Measurement of suprofen concentrations in the urine indicated that less than 1% of the administered dose was excreted by this route.

Effect of gallbladder contraction induced cholagogia on the pharmacokinetic profile of a sustained-release theophylline formulation.

Bile excretion might change the physiological milieu of the duodenum resulting in enhanced absorption of a drug due to increased solubilisation. This possible influence of bile salts following stimulation of gallbladder emptying via the release of cholecystokinin on the pharmacokinetics of a sustained-release theophylline (CAS 58-55-9) preparation (Bronchoretard) was evaluated in this study. An open, randomised 3-way cross-over study in 12 healthy, non-smoking volunteers was selected to prove or reject this hypothesis. All subjects received 500 mg of the sustained-release theophylline formulation under two different cholagogia stimulating test conditions and under a fasting reference condition. A standard breakfast and i.m. application of cholecystokinin enabled modulation of bile flow; a moderate and extreme contraction of the gallbladder could be induced after a standard breakfast and after i.m. application of cholecystokinin, respectively. Following a standard breakfast, gallbladder volumes were approximately halved (50.6%) compared to the baseline volume after 79 min. Injection of 0.3 micrograms/kg body weight cholecystokinin resulted in quick and complete gallbladder evacuation (94.6%) 36 min after the application of this cholagogue stimulus. Gallbladder volumes remained approximately constant under fasting conditions. This manipulation of bile flow did not influence concentration/time profiles of the sustained-release theophylline preparation compared to the fasting condition. Even almost complete evacuation of the gallbladder after application of cholecystokinin did not modify concentration/time profiles of theophylline in a relevant way. An unintentional rapid release of theophylline could be excluded for this sustained-release formulation for all three treatments, as not a single case of dose-dumping was observed. Furthermore, in vitro dissolution investigations using surfactants are neither predictive of food effects nor bile influence on in vivo absorption at least for the sustained-release formulation tested.

[The effect of pretreatment with ranitidine on the pharmacokinetics and gastrointestinal transit of a sustained-release theophylline preparation]. / Wirkung der Vorbehandlung mit Ranitidin auf Pharmakokinetik und gastrointestinale Passage eines Theophyllin Retard-Präparates.

A scintigraphic and pharmacokinetic study of the behavior of Bronchoretard forte (theophylline, CAS 58-55-9) was carried out in 8 healthy male volunteers to evaluate the sensitivity of the preparation to changes in gastric pH. The volunteers were pretreated with ranitidine (CAS 66357-35-5) (150 mg b.i.d.) or placebo for three days prior to and on the study day to reduce gastric acidity. The effect of the pretreatment with ranitidine on gastric pH was measured on the day before study begin and the mean pH was significantly increased compared to the placebo (ranitidine pH 2.2 +/- 2.4; placebo pH 1.6 +/- 2.0, p < 0.01 Wilcoxon Signed Rank test). All subjects were pretreated with theophylline for 3 days (500 mg b.i.d.) to achieve steady state. On the study day, the volunteers swallowed two theophylline sustained release capsules, radiolabelled by inclusion of indium-111 micronised Amberlite resin, and the gastrointestinal transit was followed continuously for 14 h using gamma scintigraphy with a further image at 24 h. Blood samples were taken from each subject throughout the study to determine the pharmacokinetic profile of theophylline in the sustained release formulation. No significant differences were found in the gastrointestinal transit of the labelled microparticulates between the data obtained from the group treated with ranitidine and that from the placebo group. Plasma theophylline concentration profiles were identical for the two treatments. These data indicate that the theophylline sustained release formulation is not sensitive to the effects of major changes in gastric H+ concentration.

[The effect of bile secretion on the pharmacokinetics of a theophylline sustained-release preparation]. / Einfluss einer Gallenausschüttung auf die Pharmakokinetik eines Theophyllin-Retardpräparates.

Bile excretion changes the physiological milieu of the duodenum, possibly resulting in enhanced absorption of a drug due to increased solubilisation. This possible influence of bile salts following stimulation of gallbladder emptying by the release of cholecystokinin on the pharmacokinetics of a sustained release theophylline (CAS 58-55-9) preparation (Bronchoretard) was evaluated in this study. An open, randomised, 3-way crossover study in 12 healthy, non-smoking volunteers was selected to prove or reject this hypothesis. All subjects received 500 mg of the sustained release theophylline formulation under two different cholagogia stimulating test conditions compared with a fasting reference condition. A standard breakfast and i.m. administration of cholecystokinin enabled a reproducible modulation of bile flow: a moderate and extreme contraction of the gallbladder could be induced after a standard breakfast and after i.m. administration of cholecystokinin, respectively. Following a standard breakfast, gallbladder volumes were approximately halved (50.6%) compared to the baseline volume after 79 min. Injection of 0.3 microgram/kg body weight cholecystokinin resulted in fast and complete gallbladder evacuation (94.6%) 36 min after the application of this cholagogue stimulus. Gallbladder volumes remained more or less constant under fasting conditions. This manipulation of bile flow did not influence concentration/time profiles of the sustained release theophylline preparation compared to the fasting condition. Even almost complete evacuation of the gallbladder after administration of cholecystokinin did not modify the concentration/time profile of theophylline in a relevant way. An unintentional rapid release of theophylline could be excluded for this sustained release formulation for all three treatments, as not a single case of dose dumping was observed. Furthermore, in vitro dissolution investigations using synthetic surfactants can predict neither food effects nor bile influence on the in vivo absorption at least for the sustained release formulation tested.

Effect of pretreatment with ranitidine on the pharmacokinetics and gastrointestinal transit of a sustained release theophylline preparation.

A scintigraphic and pharmacokinetic study of the behaviour of (Bronchoretard forte, CAS 58-55-9) was carried out in 8 healthy male volunteers to evaluate the sensitivity of the preparation to changes in gastric pH. Volunteers were pretreated with ranitidine (CAS 66357-35-5) (150 mg b.d.) or placebo for three days prior to and on the study day to reduce gastric acidity. The effect of the pretreatment with ranitidine on gastric pH was measured on the prestudy day and the mean pH was significantly reduced compared to the placebo (ranitidine pH 2.2 +/- 2.4; placebo pH 1.6 +/- 2.0, p less than 0.01 Wilcoxon Signed Rank test). All subjects were pretreated with theophylline for 3 days (500 mg b.d.) to achieve steady-state. On the study day the volunteers swallowed two theophylline sustained release capsules radiolabelled by inclusion of indium-111 micronised Amberlite resin and the gastrointestinal transit followed continuously for 14 h using gamma scintigraphy with a further image at 24 h. Blood samples were taken from each subject throughout the study to determine the pharmacokinetic profile of theophylline when presented in the sustained release formulation. No significant differences were found in the gastrointestinal transit of the labelled microparticulates between the data obtained from the group when treated with ranitidine or placebo. Plasma theophylline concentration profiles were identical for the two treatments. These data indicate that the theophylline sustained release formulation is not sensitive to the effects of major changes in gastric H+ concentration.