Bioequivalence assumes, that two different formulations of drugs with comparable pharmacokinetics (PK) cause comparable pharmacodynamics (PD) or therapeutic effects. To compare the PK/PD relationship of different drug formulations, such approach is not established. The electroencephalogram (EEG) is widely used to investigate the effects of anesthetic drugs on the central nervous system. Therefore, we compared the PD of two different formulations of propofol on the bispectral index (BIS) of EEG. In a randomized double-blind two way cross-over study, twenty healthy volunteers received 2 mg/kg BW of 2% propofol (test) and disoprivan 2% (reference), respectively, on different days by a programmed infusion pump during one minute. The individual concentration-effect relationship of propofol where described using a sigmoidal Emax model. Test and reference where bioequivalent by standard pharmacokinetic measures. After start of infusion the BIS decreased rapidly within two minutes and returned to baseline after 15 minutes. No significant differences in pharmacodynamic parameters where observed: E0 95±2 vs. 96±3, Emax 40±13 vs. 46±15, and EC50 1191±311 vs. 1214±367 mcg/L (test vs. reference, mean±SD; n=17). In conclusion, two PK bioequivalent formulations of propofol where also not different in PK/PD comparison. In specific therapeutic areas, the use of PK/PD data may improve the generic drug development process but pharmacodynamic bioequivalence needs further characterization. Clinical Pharmacology & Therapeutics (2004) 75, P3–P3; doi: 10.1016/j.clpt.2003.11.010

A liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method with a rapid and simple sample preparation was developed for the determination of scopolamine in biological fluids. Scopolamine and the internal standard atropine in serum samples were extracted and cleaned up by using an automated solid phase extraction method. Microdialysis samples were directly injected into the LC-MS system. The mass spectrometer was operated in the multi reaction monitoring mode. A good linear response over the range of 20 pg/ml to 5 ng/ml was demonstrated. The accuracy for added scopolamine ranged from 95.0 to 104.0%. The lower limit of quantification was 20 pg/ml. This method is suitable for pharmacokinetic studies.

Scopolamine is a muscarinic receptor antagonist commonly used as a pharmacological model substance based on the “cholinergic hypothesis” of memory loss in senile dementia of the Alzheimer type. The objective of the study was to relate pharmacodynamic electroencephalogram (EEG) changes and scopolamine serum concentration using pharmacokinetic‐pharmacodynamic (PK‐PD) modeling techniques. This was a randomized, three‐way crossover, open‐label study involving 10 healthy nonsmoking young male volunteers who received either scopolamine 0.5 mg as an intravenous (IV) infusion over 15 minutes or an intramuscular (IM) injection oraplacebo. The pharmacodynamic EEG measure consists of the total power in delta, theta, alpha, and beta bands over frontal, central, and occipital brain areas. The values of the pharmacokinetic parameters of scopolamine after IV infusion were clearance (CL) 205 ± 36.6 L/h, volume of distribution (Vd) 363 ±66.7 L, distribution half‐life (t 1/2α ) 2.9±0.67 min, and terminal half‐life (t 1/2β ) 105.4 ±9.94 min (mean ± SEM). Mean peak serum concentrations (C max ) were 4.66 and 0.96 ng/ml after IV and IM administration, respectively (p < 0.05). The area under the serum concentration versus time curve (AUC) after IM administration (81.27±11.21 ng/ml/min) was significantly lower compared to the value after IV infusion (157.28 ±30.86 ng/ml/min) (mean ±SEM, p < 0.05). Absolute bioavailability of scopolamine after IM injection was 57% ±0.08% (mean ±SEM). After both IV and IM administration, scopolamine induced a decrease in EEG alpha power (7.50‐11.25 Hz) over frontal, central, and occipital brain areas compared to placebo (p < 0.05). The individual concentration‐EEG effect relationships determined after IV infusion of scopolamine were successfully characterized by a sigmoidal E max model. The averaged values of the pharmacodynamic parameters were E 0 = 0.58 μV 2 , E max = 0.29 μV 2 , EC 50 = 0.60 ng/ml, and γ = 1.17. No time delay between serum concentrations and changes in alpha power was observed, indicating a rapid equilibration between serum and effect site. The results provide the first demonstration of a direct correlation between serum concentrations of scopolamine and changes in total power in alpha frequency band in healthy volunteers using PK‐PD modeling techniques. As regards the effect on the EEG, 0.5 mg of scopolamine administered IV appears to be a suitable dose.

Objective: To study the effects of rifampicin, a potent inducer of the microsomal P 450 enzyme system and of specific isoforms of the uridine 5′-diphosphate(UDP)-glucuronyl-transferase enzyme system, and cimetidine, a known inhibitor of the hepatic microsomal cytochrome P 450 enzyme system, on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects.

OBJECTIVES:To investigate the effects of grapefruit juice on absolute bioavailability of scopolamine in healthy subjects and to evaluate differences in pharmacokinetics and pharmacodynamics between genders.SUBJECTS, MATERIAL AND METHODS:14 healthy subjects (7 men and 7 women) received scopolamine 0.5 mg as intravenous infusion, and as oral ingestion with and without grapefruit juice on separate occasions. Serum and urine samples were analyzed using gas chromatography-ion trap tandem mass spectrometry. Changes in subjective state were determined up to 24 hours after drug administration.RESULTS:After oral administration, pretreatment with grapefruit juice led to a 30% increase in systemic bioavailability of scopolamine (p = 0.005) and a significant increase in time to reach peak serum concentration (tmax) of scopolamine (p < 0.001). The Cmax value (6.61+/-0.63 ng/ml) of scopolamine after i.v. administration in male subjects was significant higher compared with the value in female subjects (3.93+/-0.04 ng/ml; geometric mean +/- SEM; p = 0.007). No differences were found in urinary excretion rate of scopolamine and scopolamine glucuronide across genders and between the three different routes of scopolamine administration. Scopolamine produced time-dependent decrements in subjective alertness while contentment and calmness were not influenced.CONCLUSIONS:Pretreatment with grapefruit juice delayed the absorption and increased the bioavailability of scopolamine, whereas elimination was not significantly affected. This study identified an influence of gender on Cmax of scopolamine after i.v. infusion.

Objective: Midazolam is a water-soluble benzodiazepine. Flumazenil is a potent antagonist of midazolam-induced sedation. Physostigmine has also been shown to reverse benzodiazepine sedation in anecdotal reports. The aim of this study was to quantitatively characterize the reversal of midazolam-induced changes in electroencephalogram (EEG) by physostigmine compared to flumazenil and placebo.Methods: Twelve healthy male subjects received 5 mg midazolam as an intravenous infusion over 15 minutes. Fifteen minutes after the end of infusion, single doses of either 0.4 mg flumazenil, 0.5 mg physostigmine, or placebo (physiologic saline solution) were administered as intravenous injections in a randomized crossover fashion. Midazolam serum concentrations were measured using liquid chromatography-tandem mass spectrometry, The time from the start of injection until awakening was noted and the EEG was measured.Results: Four subjects were excluded from further pharmacokinetic and pharmacodynamic analysis because no midazolam-induced changes on EEG alpha power could be observed in each of the three study periods. The pharmacokinetics of midazolam were not influenced by flumazenil or physostigmine. Midazolam induced a decrease in EEG alpha power (7.50 to 11.25 Hz) compared with baseline (P <.05). After injection of flumazenil and physostigmine, an increase in EEG alpha power was observed, whereas placebo did not affect alpha power Subjects opened their eves 25.2 +/- 1.1 minutes after the placebo injection was begun, whereas subjects awoke after 6.2 +/- 2.7 minutes and 15.4 +/- 3.4 minutes after they received flumazenil and physostigmine, respectively (mean +/- SEM; P < .001),Conclusion: Physostigmine and flumazenil antagonized midazolam-induced sedation. This suggests that a reversible central anticholinergic mechanism may be involved in the sedative action of midazolam.

Background: Drug information centers (DICs) were established in Europe more than two decades ago. The majority of German DICs were created in the 90s. The regional University hospital-based DIG, which offers services to physicans, is now in operation for three and a half years. Objective: To evaluate the types of enquiries received and the profile of the users of a drug information service. Methods: The working procedure at a regional center in Dresden, Germany, is described. The topics for consultation (adverse reactions, pharmacokinetics, etc.) are presented, and the types of drugs involved are classified according to the Anatomical Therapeutic Chemical. (ATC) classification. Users are grouped by medical specialty. Future plans for the DIC are discussed. Results: A total of 516 enquiries were received. Questions concerning therapeutic use (34%), adverse drug reactions (28%), pregnancy/lactation (16%), and pharmacokinetics/dosage (15%) were asked most frequently. Cardiovascular drugs (20%), systemic antiinfectives (19%) as well as drugs targeting the central nervous system (15%) and alimentation/metabolism (9%) were the predominant foci of enquiries. The major users of the DIC were internists (19%), general practitioners (19%), pediatricians (18%), and gynecologists (11%). Conclusions: The types of questions and users of this service were generally similar to those recorded at many other European DICs. The service has begun producing educational bulletins on drug-related topics of clinical relevance.

OBJECTIVE:Captopril and enalapril have been reported to influence cognitive functions and quality of life in hypertensive patients.METHODS:The effects of captopril (12.5 mg and 25 mg) and enalapril (5 mg and 10 mg) administered during 7-day periods on electroencephalogram (EEG), cognitive functions, and subjective assessments were investigated in healthy males.RESULTS:Neither captopril nor enalapril influenced EEG and cognitive functions compared with placebo. Captopril 12.5 mg decreased subjective activity compared with placebo. Enalapril did not alter subjective ratings. Both systolic and diastolic blood pressure were significantly lower after administration of captopril 25 mg, whereas blood pressure was unaffected by enalapril compared with placebo.CONCLUSION:Our results suggest that central effects of captopril and enalapril were minor and not constant in young healthy men.

Background and Objectives. With increasing age, there are physiologic changes that could affect pharmacokinetics of drugs. More elderly patients are undergoing routine dental procedures for which local anesthesia could be required. The goal of the present study was to evaluate the effect of age on pharmacokinetics of the local anesthetic agent articaine. Methods. The submucosal infiltration anesthesia from two different dosages of 4% articaine without epinephrine was compared in healthy elderly and young volunteers. High performance liquid chromatography has been used to determine concentrations of articaine in serum. Basic pharmacokinetic parameters were calculated according to standard procedures using a two-exponent equation. Results. The clearance and volume of distribution (Vdss) of articaine after infiltration anesthesia were significantly lower in elderly volunteers compared with young volunteers. The area under the serum concentration-time curve and maximum drug concentration (Cmax) values did not differ significantly with age; however, both parameters tended to be higher in elderly volunteers. No changes in terminal half-life and time to reach maximum serum concentration (tmax) were observed. The Cmax and tmax values of the metabolite articainic acid were similar in young and elderly volunteers. Conclusions. The results show that the metabolism of articaine is ageindependent in healthy male volunteers. The smaller Vdss in the elderly results in a trend to higher serum levels after a given dose of articaine. No change of dosage of articaine in elderly patients should be necessary.

Die Anwendung zytotoxischer Substanzen während einer Schwangerschaft kann für das Überleben der Mutter - trotz der Gefahr für den Fetus - unvermeidlich sein. Wir recherchierten 268 in der Literatur von 1983 - 1994 publizierte Einzelfallbeschreibungen sowie zwei eigene Beobachtungen einer Zytostatikaanwendung während der Schwangerschaft, wobei die angewandte Substanz, die Dosis und der Zeitraum ihrer Anwendung hinsichtlich des Ausganges der Schwangerschaft (Teratogenität, Totgeburten, Spontanaborte, Frühgeburt) berücksichtigt wurden. Ein Drittel aller Geburten waren gesunde reife Neugeborene, über 60 % der Kinder wiesen keine Fehlbildungen auf. Nur bei 20 Neugeborenen waren Fehlbildungen unterschiedlichen Schweregrades und bei 3 Kindern chromosomale Anomalien nachweisbar. 12 Kinder wurden tot geboren oder verstarben kurz nach der Geburt. Spontanaborte traten in 16 Fällen auf, wobei diese meist nach Anwendung von Methotrexat beschrieben wurden. Aufgrund der Vielzahl der applizierten Zytostatika ist es unmöglich, die Substanz bei einer Kombinationstherapie zu identifizieren, die bei den Fallbeschreibungen mit kindlichen Fehlbildungen letztlich als ursächlich anzusehen ist. Weiterhin muß berücksichtigt werden, daß eine endgültige Einschätzung, ob die zytostatische Therapie oder die zugrunde liegende Erkrankung die kindliche Fehlbildung letztlich hervorgerufen hat, schwierig erscheint. Das Vorgehen bei schwangeren Patientinnen, die mit zytotoxischen Substanzen behandelt werden müssen, hängt vor allem von der Prognose der Erkrankung, der Schwangerschaftswoche, in der die Therapie erfolgen muß, und dem Kinderwunsch ab. Fehlbildungen sind bei Anwendung von Zytostatika während der Embryogenese am wahrscheinlichsten, obwohl es zahlreiche Literaturangaben gibt, die zeigen, daß auch nach einer Therapie in diesem Zeitraum gesunde Kinder geboren wurden.

The aim of this study was to evaluate receptor-mediated mechanisms of action of histamine in the human skin using histamine iontophoresis. 10 healthy volunteers (4 male) took single oral doses of the Hi-receptor antagonist cetirizine (CET; 10 mg), CET plus the H-2-receptor antagonist cimetidine (CIM; 400 mg) or placebo in a randomised cross-over design. Three hours after medication, subjects received six increasing doses of histamine by transcutaneous iontophoresis on forearm skin. Histamine iontophoresis caused dose-dependent vasodilation. Maximum vasodilation (Emax) was not affected by CET or CIM. CET shifted the histamine dose response curve to the right (ED50; geometric mean; 208 mu A . sec vs. 343 mu A . sec; p<0.05). The combination of CET and CIM caused an additional increase of ED50 (551 mu A . sec; p<0.05 compared to GET). The study shows that histamine acts through its H-1- and H-2-receptors to cause vasodilation in human skin.

The effects of physostigmine on scopolamine-induced changes were investigated in a randomized, double-blind cross-over study utilizing quantitative electroencephalogram (qEEG) and cognitive tasks. Ten healthy male volunteers received scopolamine 0·6 mg subcutaneously. After 90 min, single doses of either 0·5, 1·0 and 2·0 mg physostigmine salicylate or placebo were administered subcutaneously in randomized order. qEEG, cognitive function and the visual analogue scale were recorded before and at 1, 2, 3, 4, 6, and 8 h after scopolamine administration; that was 0·5, 1·5, 2·5, 4·5, and 6·5 h after physostigmine administration. Scopolamine produced an increase in delta (1·25–4·50 Hz) and theta power (4·75–6·75 Hz) in qEEG 1 h after administration compared to baseline, while physostigmine decreased the spectral delta power density in qEEG compared to placebo. The maximal effect of physostigmine was seen up to 1·5 h after injection. A dose-dependent reversal of the scopolamine induced decrements in cognitive performance was found 0·5 h after administration of physostigmine. Psychometric tests sensitively discriminated between the doses of physostigmine, and showed dose- and time-dependent effects. The results suggest that physostigmine may reverse the scopolamine-induced changes in both qEEG and cognitive function. This reversal was temporary and of short duration. © 1998 John Wiley & Sons, Ltd.

The effects of subcutaneously administered scopolamine on quantitative electroencephalogram (qEEG) and cognitive performance were evaluated and correlated with pharmacokinetic parameters in a randomized, double‐blind placebo‐controlled crossover study of 10 healthy male volunteers. Changes in qEEG and cognition were determined for 8 hours after drug administration. Scopolamine produced dose‐ and time‐dependent impairments of attention and memory and a time‐dependent increase in delta power (1.25‐4.50 Hz) and a decrease in fast alpha power (9.75‐12.50 Hz) on qEEG compared with placebo. Maximum serum concentrations of scopolamine occurred 10 to 30 minutes after drug administration. Mean peak serum concentrations (free base) were 3.27, 8.99, and 18.81 ng/mL after administration of 0.4, 0.6 mg, and 0.8 mg scopolamine, respectively. Elimination half‐life was approximately 220 minutes. The findings indicate temporary changes in qEEG and psychometric tests, and support the possible use of such a testing model for impaired cognitive functions such as age‐related memory disturbances.

Objective: To compare the venodilator potencies of the phosphodiesterase (PDE) III inhibitors amrinone and enoximone with the unspecific PDE inhibitors theophylline and pentoxifylline in human hand veins in vivo.

Background Memory and cognitive functions are known to decline with advancing age. Studies have suggested that this may be due to a decrease in cholinergic function in the brains of elderly people. This review aims to assess studies documented in the literature dealing with the 'scopolamine model' of dementia.Methods Sources included MedLine searches from the last 10 years (search for 'scopolamine model', 'dementia', 'electroencephalogram', 'cognition') and references from original and review articles. The aim was to include human and animal studies occupying the cholinergic hypothesis in cognitive dysfunction. Electroencephalographic (EEG) and cognition findings were considered.Results Scopolamine influences delta, theta, alpha and beta activity in EEG and partially mimics the EEG changes found in patients with senile dementia or dementia of the Alzheimer type. Effects on different cognitive functions have been extensively documented.Conclusion Scopolamine produces similar memory deficits seen in the elderly, but the drug cannot induce the full range of deficits seen in patients with Alzheimer's disease. Various aspects of memory were unaffected by scopolamine administration. Memory improvements in elderly subjects can be achieved after cholinergic stimulation.

The use of cytotoxic agents during pregnancy may be unavoidable in order to ensure maternal survival—despite the dangers to the developing fetus. We review 217 such cases published between 1983 and 1995, classifying them into 5 groups according to whether the cytotoxic drugs were used to treat leukaemias, malignant lymphomas, severe rheumatic diseases, gynaecological/breast neoplasms, or other grave conditions. Various factors, such as the drug type, dose, and timing to exposure to gestational age, are analysed with respect to the outcome of these pregnancies (teratogenicity, stillbirths, spontaneous abortions, prematurity, etc.). These results are then integrated in order to determine whether one can predict the individual risk of abnormality for the newborn when cytotoxic agents must be administered to pregnant women faced with a malignancy or other serious condition.

Although the influence of thyroid dysfunction on the effectiveness and disposition of drugs has been extensively studied, the pharmacokinetic/pharmacodynamic interactions between cardiac glycosides and antithyroid drugs have not been investigated. This possibility arose following the clinical observation of relatively lower digoxin plasma levels in 1 patient concomitantly treated with Carbimazole. We therefore examined the influence of a single oral dose of 60mg Carbimazole or placebo on the steady-state serum levels and haemodynamic effects of digoxin (0.375mg maintenance dose) in 10 healthy subjects according to a double-blind randomised crossover design. Serum digoxin levels were measured by the fluorescence polarisation immunoassay technique; haemodynamic parameters, cardiac output and stroke volume were determined by Doppler echo-aortography. Peak serum levels (Cmax) of digoxin were significantly lowered (1.72 ± 0.33 vs 1.33 ± 0.29 µtg/L, p = 0.0275) in 9 out of 10 subjects when digoxin was combined with Carbimazole. The mean time to reach peak levels (tmax) and area under the serum concentration-time curve (AUC0-24) were not significantly affected. However, serum digoxin levels rose considerably in 1 subject upon administration of Carbimazole (Cmax 1.08 to 2.38 µg/L and AUC0-24 12.75 to 23.85 µg/L·h). Systolic blood pressure was significantly lowered (p < 0.05) for 3 hours with digoxin alone, but not when Carbimazole was added. Diastolic blood pressure was also significantly (p < 0.05) reduced up to 12 hours with digoxin, but for for 6 hours with combination treatment. Despite the fact that the investigated drugs are structurally and functionally unrelated, these results suggest the need to monitor digoxin plasma levels when concomitantly administering antithyroid drugs.