Is there a gender gap in clinical neurosciences? A cross-sectional analysis of female participation in academic neurology, neurosurgery, and psychiatry.

Gender equality or the lack thereof is a constantly recurring theme. Here, we sought to provide an overview of the status with respect to the participation and leadership of female doctors in clinical neuroscience analyzing different disciplines (neurosurgery, neurology and psychiatry). A total of 1910 articles published in six representative journals (07-12/2020) were reviewed. Of these, 1327 were original research papers, 145 invited publications and 303 letters/comments. Out of a total of 15,080 authors, 4365 (29%) were women. The percentage of female authors was found to differ significantly between the different specialties (19% in neurosurgery, 39% in neurology and 45% in psychiatry). Women were last authors in 9.5% of the papers in neurosurgery, 29% in neurology and 39% in psychiatry Based on these findings, it can be concluded that gender disparity in academic neuroscience is quite conspicuous. Our review seeks to address the reasons behind this phenomenon in the context of new publications as well as various cultural and historical underpinnings.

[The bioequivalence of a new amitriptyline tablet formulation in comparison with a reference preparation]. / Untersuchungen zur Bioäquivalenz einer neuen Amitriptylin-Tablettenformulierung im Vergleich zu einer Referenzzubereitung.

An investigation of the bioequivalence of a new tablet formulation (amitriptylin 25 von ct) with 28.3 mg amitriptyline hydrochloride (CAS 549-18-8) was performed in a two-way cross-over study with 18 subjects. The relative bioavailability with respect to a reference preparation for AUC related to amitriptyline (CAS 50-48-6) was 99.3% and for Cmax 100.4%. A positive decision for bioequivalence derived from the usual confidence intervals for both parameters related to amitriptyline and the metabolite nortriptyline (CAS 72-69-5), respectively tmax showed no difference. The new formulation was bioequivalent to the reference.

Safety, tolerability and pharmacokinetics of the new long-acting quinolone DW-116 after single and multiple dosing in healthy subjects.

The safety, tolerability and pharmacokinetics of DW-116, a new fluoroquinolone with a broad antibacterial spectrum, were evaluated in healthy male subjects after administration of single oral doses of 100, 200, 300 and 800 mg and after administration of multiple oral doses of 300 or 400 mg, respectively, for 7 days. DW-116 was well tolerated. Gastrointestinal symptoms and skin reactions were noted and considered to be possibly related to DW-116. The geometric means of the maximum plasma concentrations (Cmax) linearly increased with the dose administered from 1.19 mg/L to 8.73 mg/L after single dose administration. At steady state, the geometric mean minimum and maximum plasma concentrations were 2.14 and 5.65 mg/L, respectively, after the multiple 300 mg dose and 2.73 and 8.00 mg/L, respectively, for the multiple 400 mg dose. Tmax varied between 1 and 5 h. The terminal half-life ranged from 11.37 to 24.89 h. The geometric mean renal clearance was approximately 30 mL/min. Approximately 45% of the dose was excreted unchanged in urine within 60 h. There was no clinically relevant deviation from dose proportionality. The changes in steady-state pharmacokinetic parameters when DW-116 was taken before a high-fat breakfast were not clinically relevant. In conclusion, DW-116 was safe in this study, the first administration to human subjects. Its pharmacokinetics indicate that once-daily dosing may be possible.

[In vivo verification of in vitro release specifications of a theophylline sustained-release preparation]. / In-vivo-Verifizierung der In-vitro-Freisetzungsspezifikation eines Theophyllin-Retardpräparates.

Especially in drugs with a narrow therapeutic range, "within product bioequivalence" i.e. "batch-to-batch bioequivalence" should be scrutinized. Therefore, pharmacokinetics and bioavailability of to batches at the upper and lower in vitro specification range as well as a batch representing the middle of the specification range was evaluated in an in vivo bioequivalence study. An open, randomized, 3-way crossover, multiple dose study in 18 healthy, male volunteers was selected for this purpose. Bioequivalence regarding rate (Cmax ss; t75%Cmax) and extent (AUCss) of absorption could be established for both extreme batches at the lower and upper in vitro specification range. Additionally both batches proved to be bioequivalent compared to the batch in the middle of the in vitro specification range. As a result, reproducible concentration-time profiles can be guaranteed for all batches of this sustained release theophylline (CAS 58-55-9) preparation. Furthermore, pharmacokinetic characteristics of all three batches meet the quality criteria defined for sustained release theophylline preparations, guaranteeing optimal concentration/time profiles for the therapy of asthma.

[Pharmacokinetics of a theophylline sustained-release formulation after single and twice daily dosage]. / Pharmakokinetik einer Theophyllin-Retardformulierung nach einmal und zweimal täglicher Mehrfachdosierung.

Sustained release theophylline (CAS 58-55-9) preparations may be dosed once or alternatively twice-a-day, depending on the intention of a theophylline therapy. A once-a-day dosage regimen is considered appropriate in patients with nocturnal asthma attacks, whereas a twice-a-day regimen is advantageous for guaranteeing bronchodilatation and to control the underlying inflammatory disease. Therefore, pharmacokinetic characteristics of both modes of administration were evaluated in a randomised, two-way crossover study in 18 female and male elderly volunteers under multiple-dose conditions. The shape of the pharmacokinetic profiles showed the expected and pronounced differences, while the extent of absorption was bioequivalent. Twice daily administration decreased the nocturnal maximum concentration and at the same time increased the minimum concentration. At the expense of the nocturnal excess, the peak-trough fluctuations (PTF) were reduced from 92.1% to 39.5%. Plateau times of 11.4 h and 20.2 h were achieved with both modes of administration. As for theophylline with its narrow therapeutic range, high quality sustained release preparations distinguish themselves by long plateau times and small peak-trough fluctuations such as those observed with the preparation under investigation. When using this preparation, therapeutic concentrations necessary for safety and efficacy are assured under either a once- or a twice-daily dosing regimen.

Bioavailability and pharmacokinetics of a fixed combination of delapril/indapamide following single and multiple dosing in healthy volunteers.

The study objective was to obtain detailed information on the bioavailability and pharmacokinetics of the new fixed combination of delapril and indapamide following single and multiple dosing. For this reason, the study was performed in two parts, separated by a medication-free period of at least 7 days. In the single dose part, one tablet, containing 30 mg delapril and 2.5 mg indapamide, was administered to 12 male volunteers; in the multiple dose part, the volunteers received one tablet of the test preparation, once daily over 7 days. Following single and on the last day of the multiple dosing regimen, blood samples were withdrawn and serum concentrations of delapril and its metabolites M1, M2 and M3 and whole blood concentrations of indapamide were quantified by means of HPLC methods. In addition, urine samples were collected following single and multiple dosing for evaluation of the cumulative amount of delapril and its metabolites M1-M3 excreted in urine. For the area under the curve, calculated from time 0 to infinity (AUC(0-infinity)) the study revealed, following single dosing, mean values of delapril and its metabolites M1, M2 and M3 of 281, 2178, 739 and 716 h.ng/ml, respectively; for indapamide the mean value was 1597 h.ng/ml. The corresponding mean values found after multiple dose administration were 272, 2071, 857 and 598 h.ng/ml for delapril and its metabolites, respectively and 1536 h.ng/ml for indapamide. Evaluation of the cumulative amount of delapril and its metabolites M1-M3 excreted in urine (Ae) demonstrated mean values following single dosing (observation period 36 h) of 705, 4521, 454 and 4203 micrograms, respectively; the corresponding values after multiple dose administration (observation period 24 h) of the test preparation were 655, 4679, 469 and 4801 micrograms, respectively. The most important pharmacokinetic parameters AUC(0-infinity) and Ae were statistically compared by analysis of variance (ANOVA) and 90% confidence intervals were calculated. It may be concluded from the results of this study, that the bioavailability and pharmacokinetic parameters of the test preparation after single dosing and after multiple doses correspond well. The undesired side effects observed are known to occur after administration of the test preparation. The occurrence was a little more frequent after multiple dose application in comparison with the single dose administration.

Steady state investigation of possible pharmacokinetic interactions of moxonidine and glibenclamide.

The aim of the study presented here was to determine possible pharmacokinetic interactions of moxonidine and glibenclamide at steady state in 18 healthy male volunteers. Multiple oral doses of 0.2 mg of moxonidine b.i.d. (q. 12 h) and of 2.5 mg of glibenclamide o.i.d. (q. 24 h) were administered alone and in combination in an open, non-randomized, three-treatment design. The preparations were given for 5 days in each of the 3 periods. The results of this multiple dose study did not indicate substantial pharmacokinetic interactions of the drugs. Regarding the influence of glibenclamide on the pharmacokinetics of moxonidine, no significant changes were seen at all. In the presence of moxonidine, a minor decrease of bioavailability of glibenclamide was detectable, as could be derived from the AUC and clearance data. The actual differences were small and not considered to be of clinical significance.

[Plasma and urine kinetics of amitriptyline oxide and its metabolites. Comparison of intravenous infusion and oral administration in volunteers]. / Plasma- und Urinkinetik von Amitriptylinoxid und seiner Metaboliten. Vergleich einer intravenösen Infusion mit einer oralen Einmalgabe bei Probanden.

The study objective was to obtain detailed information on the plasma and urine kinetics of amitriptylinoxide (CAS 4317-14-0) and its metabolites. For this reason, 60 mg of amitriptylinoxide was administered to 12 subjects, both by intravenous infusion and by oral dosage, in a study performed according to a randomized two-way cross-over design. In plasma, we succeeded in analyzing the metabolites amitriptyline and nortriptyline in addition to the parent substance amitriptyloxide. The tests for the parent substance amitriptylinoxide revealed maximum plasma levels of 721 and 686 ng/ml at 1.96 h (i.v. infusion) and 0.82 h (oral formulation), respectively. Mean values of 2331 (infusion) and 1714 h.ng/ml (oral formulation) were determined for the area under the curve from time 0 to infinity AUC (0-infinity). We also produced a comprehensive evaluation of amitriptyline, however, this was not possible for the metabolite nortriptyline. In urine, we succeeded in a reliable quantification of 4 metabolites, namely cis-OH-amitriptylinoxide, trans-OH-amitriptylinoxide, amitriptyline and OH-nortriptyline, in addition to the parent substance amitriptylinoxide. In individual samples, nortriptyline, cis-OH-amitriptyline and trans-OH-amitriptyline were additionally identified. In the course of the study, there were no reports or observations of any adverse reactions in addition to the side effects known for amitriptylinoxide from literature. There were no clinically relevant differences in tolerability observed between these two preparations.

Multiple peaks and low bioavailability of furosemide correlate with the volume of fluid ingested.

Two different single dose cross-over bioavailability studies were performed comparing a new oral furosemide preparation (test preparation = preparation A) with a marketed standard with a marketed standard preparation (reference preparation = preparation B). Test and reference preparation contained 40 mg of furosemide each. Into both studies, 18 healthy male volunteers were included; 4 volunteers participated in both studies. In study 1, the volunteers ingested the tested preparations together with 300 ml of an electrolyte solution in order to substitute volume and electrolyte deficits. Additional 200 ml were given 30 min post dose, 500 ml during the next 30 min and 1000 ml during the second hour after drug intake. In study 2, the tested preparations were ingested together with 200 ml of water without any additional volume substitution. The plasma concentration curves of study 1 showed a double peaking with a first maximum of furosemide levels at 1 h and a second peak at 3 h and 4 h, respectively, on average. The concentration-time curves of study 2 showed a single peak 1 h p.a. in the mean for both preparations. The relative bioavailability of preparation A was about 67% in study 1 compared to study 2. Preparation B showed a relative bioavailability of 59% in study 1 compared to study 2.

Bioequivalence and pharmacodynamics of a modified glibenclamide formulation in healthy volunteers.

A glibenclamide preparation (Glycolande N) with a modified galenic formulation was compared with a marketed standard preparation for bioequivalence and hypoglycaemic action after single oral administration of 3.5 mg. Twelve healthy male volunteers participated in this open two-way cross-over study. The confidence intervals around the mean values of the standard preparation were all in the range of +/- 20%. No significant differences were found between both formulations for Cmax, Tmax, AUC1 and AUC3. The glucose profiles were virtually equal. Both preparations are regarded as bioequivalent and therapeutically equivalent.

Improved orthostatic dysregulation record after administration of a sustained-release form of urapidil.

The efficacy and safety of urapidil has been demonstrated in a long-term treatment. However, a relatively good record of side effects has been marred by reports of orthostatic dysregulation. This study was designed to examine the blood pressure lowering effect, tolerability and pharmacokinetics of a sustained-release formulation of urapidil. Twelve patients received either 60 mg of sustained-release urapidil (Ebrantil 60) or 50 mg urapidil for experimental reference as a fast-release tablet in single or multiple doses in a randomized, double-blind fashion. To ensure the double blind-character of the study, the tablets were encapsulated. Blood samples for the determination of urapidil (HPLC) were drawn before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h post application. Blood pressure was measured at 0.5, 1.5, 3, 8, 10 and 12 h post application. An orthostatic test was performed before and at 1, 2, 4 and 6 h post application. Twelve h after the first application, patients received a second capsule or encapsulated tablet and continued medication for two days. On day four, the same procedure as on day one was repeated, except that patients received no evening medication and blood samples and blood pressure were measured at 24, 28 and 32 h post application on the fifth day. The Cmax of sustained-release urapidil was 44% lower than for the single tablet dose and 37% lower after multiple dosing. The peak-trough fluctuation of the steady-state serum concentrations was 29% lower for the sustained-release capsule (138 +/- 45%) compared to the tablet (195 +/- 83%).(ABSTRACT TRUNCATED AT 250 WORDS)

[Bioavailability and pharmacokinetics of a new nifedipine preparation in healthy volunteers]. / Untersuchungen zur Bioverfügbarkeit und Pharmakokinetik einer neuen Nifedipin-Zubereitung an gesunden Freiwilligen.

In the course of this trial the bioavailability and the essential pharmacokinetic parameters of a newly developed 10 mg nifedipine preparation were to be determined in comparison to a marketed reference preparation after single oral administration. For this purpose, the test and the reference preparation were examined in 16 healthy volunteers according to a randomized 2-way cross-over design (latin square), blood samples were withdrawn up to 16 h p.a. and plasma concentrations of nifedipine and NPO (primary metabolite of nifedipine) were quantified by a HPLC method. Both preparations led to mean maximum concentrations of nifedipine in plasma of 110 mg/ml about 0.5 h p.a.; the mean termial half-lives were 1.8 h (test preparation) and 1.7 h (reference preparation). The data found for the metabolite NPO largely corresponded to those of the parent substance, thus equal metabolisation and adequate pharmaceutical quality of the two galenics may be presumed. Statistical comparison (ANOVA, Pratt-Wilcoxon test) did not reveal any significant differences between the test and reference preparation and, apart from a minor deviation, confidence intervals according to Westlake were sufficiently small, such that the two formulations may be considered bioequivalent. No differences of clinical relevance were detected between the two preparations in assay. The undesired side effects/concomitant symptoms known after nifedipine administration were observed.

Quantitative determination of verapamil and metabolites in human serum by high-performance liquid chromatography and its application to biopharmaceutic investigations.

A specific and sensitive high-performance liquid chromatographic method for the quantitative analysis of verapamil and N-desmethylverapamil in human serum is described. The analytes were extracted from serum using diethylether under alkaline conditions, followed by back extraction into dilute hydrochlorid acid for chromatographic analysis on a reversed-phase column with a mobile phase consisting of acetonitrile, water and perchloric acid at a flow rate of 1 l/min. The analytes were detected by fluorescence detection, the influence of temperature on retention is discussed. The method is linear, quantitative and reproducible for two calibration ranges in serum (2.5 ng/ml-100 ng/ml and 12.5 ng/ml-500 ng/ml) using peak area ratios analyte/internal standard for quantification. At ultimate sensitivity, concentrations down to 250 pg/ml could be assayed. The method was selective to 6 other metabolites of verapamil and common exogenous interferences. It was applicated to the serum samples of a comparative 120 mg - verapamil hydrochloride tablet single dose two-way cross-over study comprising 18 volunteers. The pharmacokinetic data for both formulations are presented.

Improved high-performance liquid chromatographic method for the determination of tiotixene in human serum.

The problem of accurate determination of tiotixene in body fluids is still challenging. Several methods have been published but most of them require a tedious, time-consuming sample preparation, are not specific enough and lack the necessary sensitivity or require highly sophisticated analytical devices. As carefully validated analytical methods represent the basis of conclusive clinical trials (e.g. evaluating bioavailability/bioequivalence), an assay was developed to fulfill these needs. The method present employs an HPLC system combined with a UV-detector and uses perazine as an internal standard. The achieved lower limit of detection in serum was 0.05 ng/ml and the calibration curves were linear in the range of 0.5-20 and 0.1-2.0 ng/ml, respectively. The chromatographic peaks were well resolved and the cis-/transisomers well separated. The imprecision and inaccuracy data typically ranged from 2 to 7%; the recovery from serum was always better than 80%. The assay has been successfully used for the determination of very low tiotixene serum levels during several clinical studies.

High-performance liquid chromatographic determination of trans-doxepin and desmethyldoxepin.

An improved high performance liquid chromatographic (HPLC) assay for the quantitative determination of trans-doxepin (I) and desmethyldoxepin (II) in body fluids is presented. This HPLC assay, employing a UV-detector and perazine (III) as an internal standard, provides a very sensitive and selective determination in the low ng/ml range. The lower limit of quantification was 0.426 ng/ml (I) and 0.50 ng/ml (II); respectively. The calibration curve was linear in the measured range of 0.426-34.08 ng/ml (I) and 0.50-40 ng/ml (II). In combination with the excellent precision and accuracy data (c.v. values typically lower than 5%) and a recovery exceeding 90% for both compounds, the method is well suited for quantitative determinations of plasma samples generated during clinical studies, eg. evaluating the pharmacokinetics and/or bioavailability/bioequivalence as well as evaluations of clinical response.

Determination of methyldopa in plasma using high-performance liquid chromatography with electrochemical detection. Application to pharmacokinetic/bioavailability studies.

The problem of quantitatively measuring methyldopa (a-methyldopa) in biological matrices after applying therapeutic doses to humans is still challenging. Numerous methods have been published but most of them require a tedious, time-consuming sample preparation, are not specific enough or lack the necessary sensitivity. As the basis of conclusive human pharmacokinetic and bioavailability/bioequivalence studies is a validated analytical method, which is reliable, selective, sensitive and able to proceed hundreds or even thousands of samples in a limited time, an assay to fulfill these needs was developed. The present method employs a hiph-performance liquid chromatographic system consisting of a pump, an ODS column, an autosampler and an electrochemical detector. The assay is sensitive down to 50 ng/ml plasma, the calibration curves are linear in a range of 50-2000 ng/ml, the chromatographic peaks are well resolved and the precision and accuracy are excellent. The assay has been successfully used for the determination of very low methyldopa plasma levels during several clinical studies.