How to Interpret an Investigator's Brochure for Meaningful Risk Assessment: Results of an AGAH Discussion Forum.

Purpose: A discussion forum was hosted by the Association for Applied Human Pharmacology (AGAH e.V.) to critically debate how to interpret and optimise the Investigator's Brochure (IB) for meaningful risk assessment of early clinical trials.

Unintended drug exposure during pregnancy in clinical trials - a survey in early drug development.

Purpose: To collect information on unintended drug exposure during pregnancy in early clinical drug development.

Materials And Methods: Questionnaire mailed in autumn 2015 to members of human pharmacology societies in Europe for anonymous responses via the online tool SurveyMonkey.

Results: 53 of the ~ 700 addressees participated in the survey.

European Federation for Exploratory Medicines Development Lyon Conference 2019: The Changing Landscape of Early Medicines Development-Be Prepared.

The second biennial conference of the European Federation for Exploratory Medicines Development (EUFEMED) was the result of a continued effort of EUFEMED to gather all stakeholders of exploratory clinical drug development to evaluate and discuss recent developments in the field. The conference focused on how the landscape around early clinical development is changing and how clinical pharmacologists might prepare for these changes. A preconference workshop gave consideration to the impact that modeling and simulation, including physiology-based pharmacokinetic strategies, is having on the practice of clinical development.

The New First-in-Human EMA Guideline: Disruptive or Constructive? Outcomes From the First EUFEMED Discussion Forum.

The European Federation for Exploratory Medicines Development (EUFEMED) organized a meeting in Leuven, Belgium entitled 'The new FIH EMA guideline: Disruptive or constructive?' to provide a forum for stakeholders to discuss the guideline's operational impact. The revised EMA Guideline on strategies to identify and mitigate risks for first-in-human (FIH) and early clinical trials with investigational products was published on 20 July 2017. The revision gave guidance on sentinel dosing/staggering of subjects within a multiple-ascending dose (MAD) clinical trial, permissible maximum exposure/investigation of supra-therapeutic doses and dose escalations above the no-observed adverse effect level.

Use of integrated clinical trial protocols - A survey in early medicines development .

Purpose: To collect information on the use of integrated protocols in early clinical medicines development.

Materials And Methods: The questionnaire was mailed in fall 2014 to members of human pharmacology societies in Europe for anonymous responses via the online tool SurveyMonkey.

Results: 97 respondents reported on 164 integrated protocols overall.

EUFEMED London Conference 2017: Exploratory Medicines Development: Innovation and Risk Management.

The first formal conference of the EUropean Federation for Exploratory MEdicines Development (EUFEMED) held in London was the result of a collaborative effort of its founding associations: the Association for Applied Human Pharmacology (AGAH; Germany), the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI; UK), the Belgian Association of Phase-I Units (BAPU; Belgium), and Club Phase-I (France). The conference focused on innovation and risk management in early clinical drug development. Among other innovations, immunotherapy in oncology and inflammatory diseases were discussed as well as the importance of adaptive trial designs in early clinical drug development.

Who is a 'healthy subject'?-consensus results on pivotal eligibility criteria for clinical trials.

Introduction/methods: A discussion forum was hosted by the German not-for-profit Association for Applied Human Pharmacology (AGAH e.V.) to critically review key eligibility criteria and stopping rules for clinical trials with healthy subjects, enrolling stakeholders from the pharmaceutical industry, contract research organisations, academia, ethics committees and competent authority.

A systematic review of available clinical evidence - filgrastim compared with lenograstim.

Background: Filgrastim (Neu-pogen®, Amgen) and lenograstim (Granocyte®, Chugai Pharma) are chemically different granulocyte colony-stimulating factors (G-CSFs). Based on receptor-binding studies and in vitro potency assessment, a clinical superiority of lenograstim versus filgrastim has been postulated together with potential cost savings favouring lenograstim over filgrastim.

Objectives: To compare the clinical efficacy of filgrastim and lenograstim based on current Summaries of Product Characteristics (SPCs) for both products taking into account published clinical trials in patients and healthy volunteers.

Amoxicillin/clavulanic acid (875/125): bioequivalence of a novel Solutab tablet and rationale for a twice-daily dosing regimen.

A new amoxicillin/clavulanic acid tablet formulation (Solutab tablet, Forcid Solutab) containing amoxicillin/clavulanic acid (875/125) has been developed. The aim of the present study was to demonstrate bioequivalence between the new tablet formulation (test), taken as an intact tablet and after prior dispersal, versus the originator product viz. Augmentan film-coated tablet (875/125) used as reference.

Severe tardive dyskinesia in affective disorders: treatment with vitamin E and C.

Tardive dyskinesia caused by antipsychotic treatment is a severe problem not only in the management of schizophrenia, but also of affective disorders. Vitamin E monotherapy has been used in schizophrenic patients with tardive dyskinesia. Pharmacologists warn against high dosage of vitamin E because of its pro-oxidative effects on low-density lipoprotein with consecutive cardiac risks.

Comparison of talinolol and atenolol effects on blood pressure in relation to lipid and glucose metabolic parameters. Results from the TALIP study.

Aims: The primary objective of this double-blind, randomized, parallel-group study was to compare the influence ofthe selective beta1-receptor antagonists talinolol (100 mg) and atenolol (50 mg) on the lipid metabolism in hyperlipemic patients with mild to moderate hypertension after 12 weeks of treatment. As a secondary endpoint, the influence of the drug on blood pressure, pulse rate as well as glucose metabolism were examined. Furthermore, pharmacokinetic parameters were assessed.

Bioequivalence study of a novel Solutab tablet formulation of amoxicillin/clavulanic acid versus the originator film-coated tablet.

With amoxicillin/clavulanic acid Solutab tablet, a new tablet formulation of amoxicillin/clavulanic acid (500/125), was developed. The aim of the present study was to demonstrate bioequivalence between the new tablet formulation, taken as an intact tablet and after prior dispersal, versus the originator product viz. Augmentan film-coated tablet.

KA 672-HCl, a neuronal activator against dementia: tolerability, safety, and preliminary pharmacokinetics after single and multiple oral doses in healthy male and female volunteers.

In vitro and animal experiments have characterized KA 672-HCl as a potent functional antagonist of excitatory amino acid-induced convulsions and mortality. In receptor-binding studies, the compound displayed high affinities to several serotoninergic, adrenergic, and dopaminergic receptors and to the sigma receptor. The potential for short- and long-term toxicity of KA 672-HCl in rats and dogs was found to be low.

Pharmacokinetic profile of cefaclor.

Cefaclor is a well-absorbed oral cephalosporin antibiotic. Peak concentrations in serum are attained within 30-60 minutes. Food intake reduces the rate, but not the extent of absorption.

Pharmacokinetic and pharmacodynamic evaluation of triamcinolone acetonide after intravenous, oral, and inhaled administration.

Triamcinolone acetonide (TCA) is a corticosteroid that is frequently used in the treatment of asthma. After inhalation, TCA can become systemically available when the inhaled formulation is swallowed, causing undesirable systemic effects. A clinical study was conducted to determine the systemic side effects of TCA after intravenous (2 mg as phosphate ester), oral (5 mg), and inhaled (2 mg) administration.

Pharmacokinetics of triamcinolone acetonide after intravenous, oral, and inhaled administration.

The pharmacokinetics of triamcinolone acetonide were studied after intravenous (2 mg), oral (5 mg), and inhaled (2 mg) administration. Triamcinolone acetonide concentrations were measured in plasma by high-performance liquid chromatography/radioimmunoassay. After intravenous administration, triamcinolone acetonide was eliminated with a total body clearance of 37 L/h and a half-life of 2.

Influence of the xanthine derivative denbufylline and the anti-inflammatory agent nabumetone on microsomal free radical production and lipid peroxidation in rat liver.

The influence of denbufylline, nabumetone and its main metabolite BRL 10,720 on iron stimulated lipid peroxidation (LPO), cytochrome P 450 dependent H2O2 and chemiluminescence (CL) production was investigated in rat liver microsomes in vitro (10(-5)-10(-3) M) and in vivo after treatment of rats (5-300 mg/kg b.m. orally on three consecutive days).

Influence of 3,5-dimethyl-3'-isopropyl-L-thyronine on thyroid state and gestational outcome in the Wistar rat.

3,5-Dimethyl-3'-isopropyl-L-thyronine (DIMIT, CAS 26384-44-1), a non-halogenated, artificial analogue of the thyroid hormone T3, was administered once daily by intragastric gavage to pregnant Wistar rats on days 17-20 of gestation to elucidate the effects of DIMIT on maternal and foetal thyroid state and gestational outcome under the influence of low iodine or iodine excess nutrition. Doses of 20 micrograms.kg-1.

Ultrastructure of fetal pars-tuberalis-specific secretory cells under the influence of propylthiouracil and thyroxine.

The rat pituitary pars tuberalis (pt) is a functional and morphological unique component of the adenohypophysis. It mainly consists of specific secretory cells whose morphological and functional characterization is far from being complete. In this study the ultrastructure of fetal secretory pt cells developing under hypo- and hyperthyroid conditions was examined.

Changes in TSH-immunoreactivity in the pars tuberalis and pars distalis of the fetal rat hypophysis following maternal administration of propylthiouracil and thyroxine.

The pars tuberalis (pt) of the adenohypophysis is unique in its close spatial relationship to the neurohemal contact area of the median eminence. The morphology of pt-specific secretory cells does not resemble cell types of the pars distalis (pd); the functional role of these cells within the endocrine system is still unknown. One group of young mature female Wistar rats received propylthiouracil (PTU), a second group thyroxine (T4) (10 mg/l each in drinking water) from about 3 weeks prior to the expected pregnancy and throughout the experiment.

Inhibition by certain plant extracts of the binding and adenylate cyclase stimulatory effect of bovine thyrotropin in human thyroid membranes.

The present studies were undertaken to explore the mechanism by which, as previous studies have shown, freeze-dried aqueous extracts (FDE) of plants of the species Lycopus virginicus and Lycopus europaeus, Melissa officinalis (Laminaceae), and Lithospermum officinale (Boraginaceae) have the ability to inhibit at least many of the effects of exogenous and endogenous TSH on the thyroid gland. To this end, we have examined the in vitro effects of FDE from these plants on the ability of bovine TSH (bTSH) to both bind to human thyroid plasma membranes (TPM) and activate adenylate cyclase therein. FDE of these four species produced a dose-related, ultimately complete, inhibition of the binding of 125I-labeled bTSH when studied at 4 C in a 20 mM Tris-HCl-0.

Antihormonal effects of plant extracts. Pharmacodynamic effects of lithospermum officinale on the thyroid gland of rats; comparison with the effects of iodide.

The antithyrotropic activity of freeze-dried-extracts from Lithospermum officinale (Lith. off. FDE) was investigated in the rat.

T4 levels in methylxanthine-treated premature newborns.

The respiratory stimulants caffeine and theophylline are able to control apneic spells in premature newborns. However both substances have goitrogenic properties in rats on low-iodine diet. They lower T4 serum levels and inhibit TSH- and GH-release probably by enhancing hypothalamic somatostatin secretion.