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Biomedical subjects

G Menke

Publications and source records attributed to G Menke.

At least 19 recordsLinked to original sources
PubMed1994

[Absolute bioavailability of folic acid after oral administration of a folic acid tablet formulation in healthy volunteers].

5 mg folic acid were administered in two sessions to 9 female and 8 male healthy subjects within a balanced 2-way crossover trial either as one Folsan tablet (CAS 59-30-3, test preparation A) or as 2.5 ml of an injection solution (Folsan 2, reference preparation B). Folic acid was determined in serum and urine collected in fractions over 12 h after administration by means of a radioassay. Before each session a saturation period of 9 days duration was performed by administering 1 tablet per day containing 5 mg folic acid followed by a 4-day wash-out period. The mean predose serum level of folic acid amounted to 17.9 +/- 5.62 ng/ml before the oral and 18.2 +/- 5.73 ng/ml before the intravenous administration. The post dose serum levels were corrected with the individual predose levels. After oral administration of test preparation. A a mean peak serum concentration of 243 +/- 33.0 ng/ml (Cmax) was obtained after 2.24 +/- 0.85 h (tmax). The mean area under the corrected serum level time curve was determined with 1160 +/- 177 ng x h/ml (AUC(0-12)). 6 min after intravenous administration serum levels ranged from 559 to 1490 ng/ml. Following correction with the individual predose levels the mean area under the curve amounted to 1550 +/- 249 ng x h/ml. The individual bioavailability ratios of AUC(0-12) (A versus B) varied between 49.3% and 96.7%. The mean absolute bioavailability of folic acid was 76.2% +/- 13.8% (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

[Pharmacokinetics and relative bioavailability of iron and folic acid in healthy volunteers].

The pharmacokinetics and the relative bioavailability of iron and of folic acid was investigated in a randomized, balanced 2-way cross-over study with 14 healthy male participants. The drugs were given in a combined preparation dragée (Ferro-Folsan) containing 100 mg of ferrous-II-sulfate x 1.5 H2O (CAS 13463-43-9) and 0.85 mg of folic acid (CAS 59-30-3). Other established preparations were used as reference drugs. All subjects had a normal iron body level and were brought to a saturated folic acid level prior to the investigation. After administration of 2 dragées of the test medication and determination of serum iron level until 9 h p.a., a relative bioavailability of 64%, compared to an equal dose of a ferrous-II-sulfate-ascorbic acid reference solution, was calculated. From the serum folate AUC (0-9 h) the relative bioavailability was evaluated with 97% for the oral formulation compared to the i.m. administration. The ratio of the cumulative renal folate excretion in the 0-9 h interval amounted to 76% for the oral compared to the i.m. administration. However, in order to understand this differing result it should be kept in mind that during the first hours following parenteral administration a greater amount of the unchanged compound is renally excreted than after oral dosing. This is presumably based upon the different rate of absorption following both administrations with a steeper absorption phase following the parenteral dose.

Administration, Oral↗
PubMed1993

[Bioavailability of folic acid following intramuscular and intravenous administration to healthy volunteers].

Bioavailability of Folic Acid Following Intramuscular and Intravenous Administration to Healthy Volunteers 2 mg folic acid (Folsan 2, CAS 59-30-3) were either i.m. or i.v. administered as injection solution to 15 male healthy subjects within an open balanced two-way crossover study. The concentration-time profile of folic acid was determined up to 12 h p.a. in serum and urine using a radioassay. Each change-over phase included a 9 days lasting saturation phase with once-per-day oral administration of a tablet containing 5 mg folic acid. Saturation was performed in order to guarantee filled-up endogenous folate storage compartments in the body of the subjects. After a four-day wash-out phase the subjects were confined and the basic serum level and basic renal 0-12 h folate excretion determined. On the following morning the respective dose of 2 mg folic acid was either i.m. or i.v. applied to the subjects (treatment day 14). 11 (i.m.) and 15 (i.v.) venous blood specimens were drawn up to 12 h p.a. and urine collected following the same schedule as the day before in 4 different fractions. The mean predose level of folic acid in serum was 13.2 +/- 4.85 ng/ml before the i.m. administration and 13.3 +/- 5.59 ng/ml before i.v. administration. The serum concentration data following the respective single administrations were corrected by subtraction of the individual predose values. After 0.50 +/- 0.19 h (mean tmax) the folate serum level increased by 101 +/- 27.2 ng/ml after the i.m. dose. Serum concentration decreased in the following 6-8 h approximately to the predose values.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Pharmacokinetics of the analgesic o-carbamoylphenoxyacetic acid.

The pharmacokinetics of o-carbamoylphenoxyacetic acid was studied in 9 male healthy subjects following a single i.m. administration of 1000 mg of this compound in form of its sodium salt. Venous blood specimens were drawn up to the 10th h p.a. and the plasma concentration of o-carbamoylphenoxyacetic acid and its metabolite salicylamide were determined using a specific HPLC-assay. Following injection, o-carbamoylphenoxyacetic acid was rapidly distributed in the body since the maximal plasma concentration occurred within 0.37 +/- 0.08 h and was determined with 23.5 +/- 7.51 micrograms/ml in mean. In the following, the plasma concentration declined rapidly as well according to the mean terminal elimination half-life of 0.93 +/- 0.23 h. By contrast, plasma concentration of the metabolite salicylamide was comparatively low. Mean maximal plasma concentration amounted to only 0.18 +/- 0.03 microgram/ml and the peak concentration occurred 1.08 +/- 0.43 h after injection. The mean of the individual areas under the plasma concentration time profiles AUC(O-t) was 30.2 +/- 3.96 micrograms x h/ml for the parent compound and 0.69 +/- 0.14 microgram x h/ml for the metabolite. The relative mass portion of salicylamide vs o-carbamoylphenoxyacetic acid in systemic circulation was estimated with 0.008 comparing mean Cmax and with 0.023 comparing the mean areas AUC(O-t). A possible interpretation of these findings might be that a relatively stable ether bond exists in o-carbamoylphenoxyacetic acid which has to be cleaved during the formation of salicylamide. Due to the moderate rate of metabolic conversion, only minor quantities of salicylamide appeared in the systemic circulation. Furthermore, its peak concentration occurred at a time 2-3 times later than that of the parent compound.

Adult↗
PubMed1990

Concentrations of isosorbide dinitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate in human vascular and muscle tissue under steady-state conditions.

The concentrations of isosorbide dinitrate (ISDN), isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN) were determined in plasma (PL), saphenous vein wall (SV) and pectoral muscle (PM) from 8 patients undergoing coronary bypass surgery. The patients were pretreated for 2 days with ISDN 240 mg per day (standard release formulation) in 4 doses of 40 mg and one dose of 80 mg. The plasma and tissue samples were obtained during the operation, 10-12 h after the last dose. Isosorbide-2-mononitrate and isosorbide-5-mononitrate were present in plasma and tissues in the same concentration ranges with molar concentration ratios of 0.88 (IS-2-MN: PM/PL), 0.85 (IS-5-MN: PM/PL), 0.99 (IS-2-MN: SV/PL) and 1.06 (IS-5-MN: SV/PL). Mean ISDN concentrations in tissue were considerably higher than in plasma; the molar concentration ratios were 4.9 (SM/PL) and 7.21 (SV/PL). The accumulation of ISDN in vessel walls may contribute to its greater vascular action compared to the mononitrates, but it may also facilitate the development of tolerance during long-term treatment.

Aged↗
PubMed1988

Drug input rate from the GI-tract. Michaelis-Menten kinetics and the bioavailability of slow release verapamil and nifedipine.

We present evidence, from studies with slow release verapamil and nifedipine, for Michaelis-Menten metabolism during first pass through the liver. Drug input rate from the GI-tract after an oral dose appears to be a determinant of bioavailability. Highest oral bioavailabilities are observed with standard release formulations at high dosage. The bioavailability of slow release formulations with a zero order release kinetic is lower than standard release formulations and related to the dissolution rate in vitro. In addition, (a) the presence of non-linear absorption kinetics offers a further explanation for the considerable inter-patient variability in AUC since the ability of drug to cross the liver is a function of the concentrations attained in portal blood which will be dependent on dissolution conditions prevailing in the GI-tract, (b) depending on the choice of the dose and dosage interval of the conventional release formulation used for comparison and as a consequence of Michaelis-Menten first pass metabolism it is possible to obtain relative bioavailability data showing superiority, equivalence or bioavailability loss with the slow release form. This may explain the discrepancies in bioavailability data for slow release drugs reported in the literature, (c) 'true' estimates of relative bioavailability of a slow release formulation can only be achieved if steady state conditions are present, and the dose and dosage interval of the slow and conventional release formulation are the same, (d) since a slower dissolution rate is 'ipso facto' associated with a lower bioavailability, slow release formulations of verapamil and nifedipine cannot be classified as being 'inferior' or of poorer quality on the basis of bioavailability alone.

Biological Availability↗
PubMed1988

[A model study of bioequivalence of dissolved nifedipine from soft gelatin capsules].

Oral absorption of nifedipine determined from plasma concentrations was studied in 20 healthy subjects aged 19 to 40 years following application of a single soft gelatin capsule as a generic preparation (P) and a reference preparation (R) containing 10 mg nifedipine. Nifedipine was measurable in plasma 15 min after application and maximal concentrations occurred after 0.44 and 0.64 h (mean), respectively. Maximal concentrations Cmax varied between 46.4 and 251.0 ng/ml (median 100.7, mean 112.6) after P and between 35.5 and 279.7 ng.h/ml (median 115.8, mean 125.2) after R. Mean areas under the curves (AUC0-infinity) were 173.6 (median 151.4 P) and 188.6 ng.h/ml (median 163.1, R). The minor differences in the AUC values and Cmax values were not statistically significant. The shorter tmax after the generic preparation (p less than 0.05) is clinically unimportant. Since the bioavailability of P is 97% the two preparations are bioequivalent.

Adult↗
PubMed1987

[Bioavailability of delayed-action and non-delayed-action preparations of isosorbide-5-nitrate].

In a randomized crossover study on twelve healthy test subjects, the plasma concentration of isosorbide-5-nitrate (IS-5-N) after oral administration of 40 mg IS-5-N daily from two standard preparations (two tablets Ismo 20 or Corangin 20) and two sustained release preparations with 40 mg or 60 mg IS-5-N (one tablet Corangin 40 or Corangin 60) once a day was determined. The concentrations were measured in the first and in the third dose interval (24 hours). The respective pharmacokinetic parameters (AUC, Cmax and tmax) of the first and the third day only differed slightly. The two standard formulations proved to be bioequivalent. With the two sustained release preparations, maximum plasma concentrations attained after five to six hours were measured which were lower by roughly the factor 2. The sustained release preparations showed a low loss of bioavailability of 13-19% as compared to the nonretarded standard formulations.

Adult↗
PubMed1987

Age-dependence and free fatty acid modulation of binding kinetics at the benzodiazepine binding site of serum albumin in neonates and adults determined using fast reaction methods.

Binding kinetics at the benzodiazepine binding site of albumin have been determined as a function of age and fatty acid concentration in serum from 32 neonates (umbilical cord blood), 28 adults aged 23-65 years and 24 adults aged 66-101 years using fluorescence-time curves obtained in a Durrum-Gibson stopped-flow apparatus and the specific marker ligand dansylsarcosine. The binding reaction can be described by a 2-step mechanism characterised by four constants: the association rate constant k2 and dissociation rate constant k-2 for the rate limiting step-2; the affinity constant KA' for the formation of an unstable intermediate complex in step-1; the affinity constant KA for the overall reaction. There were marked differences in k2 between the three groups of subjects with highest values occurring in neonates (mean: 296 s-1), intermediate values in adults aged 23-65 years (mean: 200 s-1, P less than 0.001) and lowest values in adults aged 66-101 years (mean: 144 s-1, P less than 0.001). The dissociation rate constants (k-2) averaged 18.5 s-1 overall, showed only minor changes with increasing age and corresponded to dissociation half-lives of 42 ms, 38 ms and 33 ms for neonates, adults 23-65 years and adults 66-101 years respectively. KA' in neonates and in the group of elderly subjects were lower than in adults aged 23-65 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

[Interval therapy in effective treatment of angina pectoris using nitroglycerin patch systems. A controlled study with determination of nitroglycerin plasma levels].

In ten patients with angiographically-documented coronary artery disease, stable angina pectoris and reproducible exercise-induced ST-segment depression, the extent and duration of antiischemic and antianginal effects of transdermal nitroglycerin patches delivering 10 mg/24 hours were investigated according to a double-blind, crossover, placebo-controlled protocol. Exercise testing and blood sampling for determination of nitroglycerin plasma concentrations were carried out at 2.5 and twelve hours after initial application, at 2.5, twelve and 24 hours after renewed application subsequent to a twelve-hour treatment pause as well as at 2.5 hours after application of a third patch (Figure 1). At 2.5 hours after initial application there was a reduction in exercise-induced ST-segment depression from 2.7 mm +/- 0.19 (SEM) to 0.75 +/- 0.2 (-72%; p less than 0.001) (Figure 2). The exercise capacity to onset of 1 mm ST-segment depression increased from 117 Watt X min +/- 34 (SEM) to 361 Watt X min +/- 84 (+210%; p less than 0.001) (Figure 3). At twelve hours, exercise-induced ST-segment depression was reduced only from 2.5 mm +/- 13 to 1.77 +/- 0.2 (-32%; p less than 0.01) and the increase in exercise capacity to onset of 1 mm ST-segment depression was narrowed from 136 Watt X min +/- 28.5 to 215 Watt X min +/- 43 (+59%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1987

[Bioequivalence of generic drugs and substitution: example of depot verapamil].

Following oral administration of 240 mg Verapamil-HCl as Isoptin RR, Veramex SR 240 and durasoptin SR 240, plasma concentration time curves of Verapamil and ECG changes were determined in 14 healthy subjects. There was a linear correlation between maximal plasma concentration and prolongation of PQ-intervals of the ECG. No hysteresis was observed when the changes in PQ-interval were plotted against plasma concentration. Comparison of concentration and effect profiles showed that the three formulations were not equivalent and a change in therapy from one to the other cannot be recommended.

Blood Pressure↗
PubMed1987

[Concentration-time profile of isosorbide dinitrate and its metabolites in plasma following percutaneous resorption of a transdermal therapeutic system].

Percutaneous absorption of isosorbide dinitrate (ISDN), determined from plasma concentrations of ISDN and its metabolites isosorbide 2-mononitrate (IS-2-MN) and isosorbide 5-mononitrate (IS-5-MN), was studied in 8 healthy subjects aged 19 to 25 years following application of a single plaster containing 40 mg ISDN to the hairless skin on the left side of the chest for 72 h. ISDN and mononitrates were measurable in plasma 2 h after application and maximal concentrations for ISDN and mononitrates occurred after 12-16 h and 16 h, respectively. Mean areas under the curves values corrected for the body surface (BS) (AUC0-72 h.BS of 1074, 815 and 3584 nmol.m2.h/l for ISDN, IS-2-MN and IS-5-MN are equivalent to area ratios of 1, 0.8 and 3.3. ISDN metabolism following transdermal application is less extensive than after oral application. The molar nitrate concentration including metabolites, however, is comparatively low reaching approximately 60-80 nmol/l.

Administration, Cutaneous↗
PubMed1987

[Postprandial delay of drug absorption in a gitoformate model].

Oral absorption of gitoformate (Dynocard), a non-renal-dependent cardiac glycoside, was investigated in 8 healthy subjects aged 23-45 years. Plasma concentration-time profiles were obtained once following a 12-h period of fasting, then after intake of a standard high protein meal. The half-life of absorption t1/2a, Cmax and tmax, half-life of elimination t1/2z, and area under the curve (AUC) were compared to evaluate the influence on the bioavailability of gitoformate. t1/2a in the fasting condition (0.36 +/- 0.43 h) is increased when gitoformate is applied after a high protein meal 1.12 +/- 1.12 h). Correspondingly, fasting maximum concentrations are already achieved after 1.4 +/- 1.2 h, but only after 4.8 +/- 1.8 h following the intake of a standard meal. Comparison of AUC (0-168 h) showed that the bioavailability was reduced by 25% after meals.

Absorption↗
PubMed1986

[Pharmacokinetics of glycerol trinitrate].

The absorption, distribution and elimination of glyceryl trinitrate (GTN) in the human are extremely rapid processes. Enzymatic denitration occurs not only in the liver, but also in blood and other organs. The terminal half-life is 2-6 minutes, and clearance about 30 l/min. A large distribution volume indicates that GTN is taken up by peripheral tissues with the consequence that the concentration at the site of action is greater than in blood. The denitrated and glucuronidated metabolites make only a minor contribution to the anti-anginal effect. Within the therapeutic range there is a linear relationship between the applied dose and concentration in blood and this relationship is independent of the mode of application. GTN plasma concentration may fluctuate during prolonged infusions and transdermal application. GTN measurement on multiple plasma samples collected during the dosage interval are therefore required to obtain a reliable estimate of the steady state concentration. Individual dosage regimens are necessary to optimize therapy.

Animals↗
PubMed1985

[Bioavailability of isosorbide dinitrate and isosorbide-5-mononitrate under steady-state conditions].

The relative bioavailability of isosorbide dinitrate (ISDN) and its mononitrate metabolites (IS-2-MN, IS-5-MN) was determined under repetitive dose conditions in 8 healthy volunteers using a randomised, crossover design. Reference drugs were non-sustained release ISDN (Isoket 20) and IS-5-MN (Ismo 20). The relative bioavailability of ISDN after Iso Mack Retard was 69%, for two development products 78% and 79%, and 87% for Isoket Retard. The bioavailability of IS-2-MN and IS-5-MN in sustained release preparations was 6-16% and 1-17% lower, respectively. Whereas the sum total for the area under the concentration-time curve (ISDN and metabolites) for Iso Mack Retard 20 mg was also significantly lower, there was no significant difference in this parameter between Isoket retard 20 and Isoket 20. Taking IS-5-MN non-retard as reference, the bioavailability of IS-5-MN and total nitrate in all ISDN preparations examined was significantly lower.

Adult↗
PubMed1985

[Serum concentration of glyceryl trinitrate (GTN) in transdermal application of GTN dressings of various origins].

Serum levels of glyceryl trinitrate have been determined in eight healthy subjects following transdermal application of four different glyceryl trinitrate plasters using a randomised crossover design. The plasters investigated were Deponit 10, Nitradisc 10, Nitroderm TTS 10 and Nitro-Pflaster-ratiopharm 10. The medians of serum concentrations arranged in decreasing order were 0.17-0.23 ng/ml for Nitroderm TTS 10, 0.13-0.21 ng/ml for Nitradisc 10, 0.08-0.13 ng/ml for Deponit 10, and 0.04-0.09 ng/ml for Nitro-Pflaster-ratiopharm 10. Corresponding areas under the concentration-time curves (AUC 0-24) were 23.15 nmol . h/l (Nitroderm TTS), 20.32 nmol . h/l (Nitradisc), 10.39 nmol . h/l (Deponit), and 5.7 nmol . h/l (Nitro-Pflaster-ratiopharm).

Administration, Topical↗