Differences in the nyctohemeral secretion of TSH and PRL in healthy euthyroid men.

The circadian rhythm of TSH, PRL and cortisol was studied in 21 healthy euthyroid men in a normal sleep/wake cycle. Higher nyctohemeral (22.00 h till 6.00 h) levels of TSH as compared to diurnal (8.00 h till 22.00 h) levels were observed in 14 out of 21 men (Group A). In the remaining 7 volunteers the nyctohemeral and diurnal TSH-levels (Group B) were the same. In Group A, the nyctohemeral PRL-surge was also higher than in Group B (p < 0.01). The nyctohemeral area under the curve (AUC) of both TSH and PRL were significantly higher in Group A than in Group B (p < 0.05 and p < 0.001 respectively). The mean diurnal concentrations of TSH and PRL were, however, similar in both groups. Therefore, an impairment of the nyctohemeral TSH-surge can occur in healthy men usually combined with a reduced nyctohemeral PRL-surge. An impairment of nyctohemeral TSH-surge is thus not confined to patients with thyroid diseases.

The effects of a special Agnus castus extract (BP1095E1) on prolactin secretion in healthy male subjects.

The effects of three doses of a special Agnus castus extract (BP1095E1)--extracts from 120 mg, 240 mg and 480 mg of drug per day--were examined within the framework of a placebo-controlled clinical study of tolerance and prolactin secretion in 20 healthy male subjects during a period of 14 days. There was good tolerance during the study as regards the following: adverse effects, the effects on blood pressure and heart rate, blood count, Quick's test, clinical chemistry as well as testosterone, FSH and LH values. During each study phase the 24-hour prolactin secretion profile was measured from the penultimate to the final day, and the amount of prolactin release was monitored an hour after TRH stimulation on the last day. A significant increase in the 24-hour profile was registered with the lowest dose in comparison to placebo, the opposite being the case with the higher doses, i.e. a slight reduction. In contrast to the administration of placebo, the 1-hour AUC after TRH stimulation resulted in a significant increase with the lowest dose and a significant reduction with the highest dose. The results suggest effects of the special Agnus castus extract which are dependent on the dose administered and the initial level of prolactin concentration.

Absorption behavior of sulpiride described using Weibull functions.

Deconvolution absorption profiles of oral sulpiride formulations were calculated from plasma concentration-time data obtained in an open, 3-period study with a crossover of the 2 oral formulations in 12 healthy volunteers following single intravenous (100 mg) and oral (2 x 50 mg capsules, 200 mg tablets) application of sulpiride. A model based on 2 Weibull-functions, and applied using NONMEM, described the complex absorption profiles more satisfactorily than a first order absorption model or a model based on a single Weibull-function.

Transdermal nicotine in smoking cessation and involvement of non-specific influences.

The efficacy of a nicotine transdermal therapeutic system (TTS) (available size 10, 20 and 30 cm2; nicotine delivery rate = 0.7 mg/cm2/24 h) as an aid for smoking cessation, was evaluated in a randomized, single-blind, placebo-controlled, monocenter study using 160 heavy-smokers (> 20 cigarettes/day), male and female, who were divided into two matched parallel groups. The nicotine replacement treatment lasted for 3 months and was carried out according to the manufacturers recommendations. Abstinence was defined as smoking no cigarette during the last week of each month and COHb-levels < or = 1.2%. Efficacy was assessed using abstinence rates, withdrawal symptoms and cigarette consumption. Although at the commencement of the study all subjects expressed a high motivation to stop smoking, about a third were lost to follow-up at 4 weeks. This was attributed mainly to the lack of counselling and group dynamics. The greatest effect on smoking cessation and cigarette consumption was attributable to a non-specific aspect of treatment, i.e. the motivation to stop smoking on application of the first patch. On an intention-to-treat basis (all subjects), abstinence rates were 24% and 18% after 1 month, 24% and 14% after 2 months and 14% and 6% after 3 months for the nicotine-TTS and placebo-TTS, respectively. Nicotine-TTS was at least twice as effective as placebo in maintaining nicotine abstinence. The superiority of the nicotine-TTS was supported by the trend to a higher craving-for-cigarettes score and significantly higher blood COHb and cigarette consumption in the non-abstainers treated with placebo.

Transdermal nicotine substitution: pharmacokinetics of nicotine and cotinine.

The use of tobacco has resulted in major health related problems worldwide. Nicotine replacement is one of the most promising strategies in smoking cessation. The in vivo delivery rate and the pharmacokinetic properties of a recently developed transdermal nicotine system (TNS) was investigated in three separate studies. Two sizes (16 cm2 and 24 cm2) of the patches were tested. Mean daily nicotine delivery, expressed by a first order kinetic, varied between 0.9 and 1.0 mg/cm2 patch. The different sizes of the patches led to linearly dose-related nicotine plasma Cmax- and AUC-values. The nicotine levels achieved were in the same range with those of other nicotine patches and the chewing gum. As a result of multiple dose kinetic, no significant accumulation of nicotine was observed. Mean elimination half-life of nicotine after removal of the patches (3.5 +/- 1.8 h for the larger patch and 4.5 +/- 1.9 h for the smaller patch) was longer than reported values after i.v. administration, which was reported to vary between 40 and 120 min.

Steady state kinetics of a fatty alcohol-based slow-release nifedipine for once a day application.

The linearity of the relationship between dose and plasma concentration of nifedipine has been investigated in healthy male and female subjects under steady state conditions following application of a fatty alcohol matrix slow release nifedipine (Aprical long, CAS 21829-25-4) formulation at a dose rate of 60, 90 and 120 mg once daily. Plasma concentrations showed a broad plateau associated with mean residence times exceeding 20 h. On Day 4 mean pre-dose nifedipine concentrations were 20.5, 24.9, 31.8 ng/ml and Cmax values were 42.3, 51.7 and 93.9 ng/ml for the 60, 90 and 120 mg dose, respectively (n = 15). After dose normalisation there was no significant difference (Wilcoxon matched pair test) in the mean AUCs. Adverse reactions, mainly headache and flushes, were observed at all dose levels but the frequency was not dose-dependent. In view of the demonstrated proportionality between dose and AUC and the long duration of the plateau plasma concentrations it is concluded that this slow release formulation is suitable for once daily administration at dose rates up to 120 mg daily.

Lack of a pharmacokinetic interaction between carvedilol and digitoxin or phenprocoumon.

The possibility of a pharmacokinetic interaction between carvedilol and digitoxin (Study I) or phenprocoumon (Study II) has been evaluated in groups of 12 healthy volunteers. The bioavailability (Cmax, tmax, AUC) of digitoxin and phenprocoumon were assessed after a single dose, given once alone and once on day 6 of treatment with carvedilol 25 mg o.d. Cmax, tmax, AUC and Ut of carvedilol and desmethylcarvedilol were also investigated after the fifth dose of carvedilol and after the sixth dose given concomitantly with digitoxin or phenprocoumon. In Study I, the 95% confidence intervals of the ratio test versus the reference findings were; digitoxin Cmax 0.80-1.20, tmax 0.56-1.14, AUC 0.97-1.33, and for carvedilol Cmax 0.81-1.22; tmax 0.66-1.23; AUC 0.91-1.17. Formation of the active metabolite desmethylcarvedilol and the urinary recovery of carvedilol and desmethylcarvedilol were not influenced by digitoxin. In Study II Cmax and AUC of phenprocoumon were not changed after carvedilol. Cmax of carvedilol was decreased after phenprocoumon. The kinetic parameters of phenprocoumon were Cmax 0.80-1.05, tmax 0.47-2.00, AUC 0.78-1.05, and for carvedilol Cmax 0.59-1.06, tmax 0.71-1.73; AUC 0.80-1.08, respectively. The plasma levels of desmethylcarvedilol and the urinary recovery of carvedilol and desmethylcarvedilol were not influenced by phenprocoumon. The blood pressure and heart rate after carvedilol alone were not affected by concomitant administration of digitoxin or phenprocoumon.

Supermolecular inclusion of piroxicam with beta-cyclodextrin: pharmacokinetic properties in man.

Piroxicam beta-cyclodextrin is a novel inclusion complex in which the piroxicam molecule has higher wettability and faster dissolution characteristics than plain piroxicam. Pharmacokinetic studies comparing piroxicam beta-cyclodextrin with plain piroxicam have been carried out in both patients and healthy subjects. The absorption rate of piroxicam from the complex, determined using tmax, absorption rate constant (Ka) and plasma concentrations at 15 min and 30 min post-dose, is considerably faster than that for plain piroxicam. This difference, that can be demonstrated with both tablet and sachet formulations, is still present during repeated dose administration and when the drugs are administered after food. After absorption from piroxicam beta-cyclodextrin formulations, the kinetic disposition of piroxicam and bioavailability parameters are identical to those for plain piroxicam. The more rapid rise in piroxicam plasma concentrations and the reduced contact time of piroxicam in the upper gastrointestinal-tract may be reasons for the reduced incidence of gastrointestinal complaints and gastrointestinal bleeding and the rapid attainment of pain relief with piroxicam beta-cyclodextrin. The most rapid relief of pain will be achieved using piroxicam beta-cyclodextrin sachets administered in the fasting state, since piroxicam is immediately bioavailable in this formulation and the onset of action is similar to that for injectable piroxicam.

[Biological availability and pharmacodynamics following single oral administration or three different sustained-release isosorbide-5-mononitrate dosage forms]. / Bioverfügbarkeit und Pharmakodynamik nach oraler Einmalgabe drei verschiedener retardierter Isosorbid-5-mononitrat-Darreichungsformen.

The bioavailability of 3 different commercial available isosorbide mononitrate (IS-5-MN; CAS 16051-77-7) 40 mg slow-release preparations (A, B and reference formulation C) was determined after oral application to 18 healthy volunteers in a randomized cross-over study. The AUC after C (26.9 mumol/l x h) was not significantly different from that for A (25.1 mumol/l x h) and B (26.0 mumol/l x h). The corresponding 95% confidence intervals were within the limits of 80-120%. Maximal plasma concentrations (Cmax) for C (1.90 mumol/l), A (1.91 mumol/l), and B (2.05 mumol/l) were obtained at (tmax) 5.72 h, 4.94 h and 4.72 h, respectively. The 95% confidence intervals for Cmax and tmax were within the prescribed limits of 70-130%. Mean residence times (MRT) 10.5 h (C), 10.3 h (A), and 10.1 h (B) and plateau-times (duration over which the plasma concentration greater than 0.524 mumol/l) 17.8 h (C), 17.1 h (A), and 17.0 h (B) were not significantly different. It is concluded that the test preparations A and B are bioequivalent to reference C. Systolic blood pressure and heart rate, easily measurable indeces of the pharmacodynamic effects, showed no significant differences between the 3 preparations. In agreement with recently published data, plasma concentrations above 1.5 mumol/l did not result in a further reduction of systolic blood pressure, but were associated with a further marked elevation in heart rate.

[Biologic availability and hemodynamic actions following administration of sublingual glycerol trinitrate. A new delivery system]. / Bioverfügbarkeit und hämodynamische Wirkungen nach Applikation von sublingualem Glyceroltrinitrat. Ein neues Freisetzungssystem.

Bioavailability and Hemodynamic Properties of Sublingually Applied Glyceryl Trinitrate/A new delivery system Bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) was investigated in 16 healthy subjects after sublingual application of 0.8 mg GTN from either a reference product (B) where GTN release is effected by fluorochlorohydrocarbon (FCH) or a test product (A) (Corangin Nitrospay) where GTN release is effected FCH-independently by a pumping system. Plasma concentrations of GTN and hemodynamic effects (digital plethysmography) were measured until 30 min after application. There was no significant difference (Wilcoxon's matched pairs signed rank test) in AUCo-t (A: 8.9 +/- 7.3 ng x h/ml; B: 8.3 +/- 7.6 ng x h/ml) and Cmax (A: 1.43 +/- 1.26 ng/ml; B: 1.13 +/- 1.06 ng/ml), but tmax was significantly shorter after application of the test product (A: 4.6 +/- 1.0 min; B: 6.7 +/- 2.7 min, p less than 0.01). Nonparametric confidence limits (90%) were 0.80-1.89 for AUCo-t (point estimator of the median 1.14), 0.92-2.78 for Cmax (point estimator 1.06) and 0.61-0.90 for tmax (point estimator 0.75). EC50-values obtained from the individual concentration/effect-curves were linked with the concentration/time-curves to establish the time of reaching EC50 (tEC50). GTN response did not differ for both preparations (EC50A: 0.25 +/- 0.24 ng/ml; EC50 B: 0.34 +/- 0.36 ng/ml), coincident with tmax, tEC50 was significantly shorter after administration of (A) (A: 1.8 +/- 0.3 min, B: 2.7 +/- 1.0 min). With respect to the variability of GTN pharmacokinetics, the test preparation shows superior bioavailability and a faster onset of hemodynamic action.

Pharmacokinetics of nicotine after application of a 30 cm2 nicotine patch under steady-state conditions.

Transdermal nicotine systems (Nicotinell 30) were applied daily to the skin of healthy nicotine-dependent smokers for 4 days. Blood samples were taken for the measurement of nicotine and cotinine in plasma using capillary gas chromatography with nitrogen detection. The plasma concentration-time profiles of nicotine and cotinine and the pharmacokinetic parameters cmax, tmax, AUC and the elimination half-life were determined under steady-state conditions. Nicotine levels after application of the 30 cm2 patch were in accord with published values for 10, 20 and 2 x 20 cm2 patches. The elimination half-life of nicotine after removal of the patch was longer than reported values obtained after i.v. application.

Bioaequivalence of sublingual glycerol trinitrate. Bioavailability and haemodynamic effects after application of a fluorochlorohydrocarbons-dependent spray and a new pumping system.

Bioaequivalence of glycerol trinitrate (GTN, CAS 55630) was investigated in 16 healthy volunteers after sublingual application of 2 x 0.41 mg GTN from two different spray-formulations (A: fluorochlorohydrocarbons (FHC)-dependent formulation; B: FHC-free pumping system). Plasma concentrations of GTN (measured by a gas chromatographic method) and haemodynamic effects (measured by digital plethysmography) were monitored 30 min after application. EC50 of the individual concentration-effect curves were calculated and linked to the individual concentration-time curves to establish the time of reaching EC50 (tEC50). AUC0-infinity, Cmax, tmax and the haemodynamic parameters were compared intraindividually (Wilcoxons matched pairs sign rank test), bioequivalence of B to A was tested on the basis of nonparametric 95%-confidence intervals (Tukey). There was no significant difference in the AUC0-infinity (A: 14.2 ng min/ml, B: 16.3 ng min/ml), but significant differences were obtained in Cmax (A: 1.41 ng/ml, B: 2.77 ng/ml, p less than 0.01) and tmax (A: 6.8 min, B: 3.9 min, p less than 0.01). The confidence intervals of the ratio B/A were 0.81-1.56 for AUC0-infinity, 1.3-3.13 for Cmax and 0.50-0.58 for tmax. The GTN-response did not differ after both formulations (EC50 A: 0.441 ng/ml, EC50 B: 0.421 ng/ml), but significant differences were observed for tEC50 (A: 2.82 min, B: 1.05 min, p less than 0.01). Preparation B exhibits a superior bioavailability and a more rapid onset of haemodynamic efficacy.

[Bioavailability of isosorbide dinitrate and isosorbide-5-mononitrate under steady-state conditions]. / Bioverfügbarkeit von Isosorbiddinitrat und Isosorbid-5-mononitrat unter Steady-state-Bedingungen.

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.