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Atypical patterns of response to immunotherapy have been observed, including the abscopal effect and pseudoprogression. Although both are infrequent in head and neck squamous cell carcinoma, the synergism between radiation and checkpoint blockade therapy has generated excitement for exploitation of the abscopal effect. However, robust abscopal tumor regression observed in preclinical models has not translated to clinical experience. The optimal sequencing of radiotherapy with immunotherapy and dosage of radiation to target lesions to elicit this effect is being explored in clinical trials. Predictive markers of efficacy must be studied further to identify patients who may benefit from an abscopal effect and continued checkpoint inhibitor blockade beyond initial signs of radiologic progression. Given the rarity of pseudoprogression in head and neck squamous cell carcinoma, patients should be carefully selected to continue on immunotherapy, despite early radiologic signs of progression, given the risk of aggressive true progression and clinical deterioration that may result in missed opportunities for alternate treatments.

Psoriasis is known today as a T‑cell-mediated autoimmunological systemic disease. The chronic inflammatory processes involve neuroimmunological factors that are held responsible not only for various aspects of psychiatric-neurological comorbidities but also for neurosensory problems, primarily itching. Amongst other things, the significance of GABAFor lack of clinical safety data, preclinical tests for cutaneous cytotoxicity and calculations for systemic bioavailability after topical application have been performed.The present data cannot fully remove safety concerns for topical application of chloral hydrate in the formulation favoured by the NRF (Neues Rezepturformularium)-the so-called 1‑2-3-cream. A twice daily use of the 1‑2-3-cream on a maximum of 10% of the body surface can be regarded as safe. For a better assessment of harmlessness, tests for cutaneous bioavailability (concentration-time profile) on human skin and clinical studies would be necessary.

A 3D microtissues using T47D and JIMT-1 cells were generated to analyze tissue-like response of breast cancer cells after combined human epidermal growth factor receptor 2 (HER2)-targeted treatment and radiation. Following lentiviral knockdown of HER2, we compared growth rate alterations using 2D monolayers, 3D microtissues, and mouse xenografts. Additionally, to model combined therapeutic strategies, we treated HER2-depleted T47D cells and 3D microtissues using trastuzumab (anti-HER2 antibody) in combination with irradiation. Comparison of HER2 knockdown with corresponding controls revealed growth impairment due to HER2 knockdown in T47D 2D monolayers, 3D microtissues, and xenografts (after 2, 12, and ≥40days, respectively). In contrast, HER2 knockdown was less effective in inhibiting growth of trastuzumab-resistant JIMT-1 cells in vitro and in vivo. Combined administration of trastuzumab and radiation treatment was also analyzed using T47D 3D microtissues. Administration of both, radiation (5Gy) and trastuzumab, significantly enhanced the growth inhibiting effect in 3D microtissues. To improve the predictive power of potential drugs-as single agents or in combination-here, we show that regarding tumor growth analyses, 3D microtissues are highly comparable to outcomes derived from xenografts. Considering increased limitations for animal experiments on the one hand and strong need of novel drugs on the other hand, it is indispensable to include highly reproducible 3D microtissue platform in preclinical analyses to validate more accurately the capacity of future drug-combined radiotherapy.

For the development of medicinal products animal models are still indispensable to demonstrate efficacy and safety prior to first use in humans. Advanced therapy medicinal products (ATMP), which include cell-based medicinal products (CBMP), differ in their pharmacology and toxicology compared to conventional pharmaceuticals, and thus, require an adapted regime for non-clinical development. Developers are, therefore, challenged to develop particular individual concepts and to reconcile these with regulatory agencies. Guidelines issued by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA) and other sources can provide direction.The published approaches for non-clinical testing of efficacy document that homologous animal models where the therapeutic effect is investigated in a disease-relevant animal model utilizing cells derived from the same species are commonly used. The challenge is that the selected model should reflect the human disease in all critical features and that the cells should be comparable to the investigated human medicinal product in terms of quality and biological activity. This is not achievable in all cases. In these cases, alternative methods may provide supplemental information. To demonstrate the scientific proof-of-concept (PoC), small animal models such as mice or rats are preferred. During the subsequent product development phase, large animal models (i.e. sheep, minipigs, dogs) must be considered, as they may better reflect the anatomical or physiological situation in humans. In addition to efficacy, those models may also be suitable to prove some safety aspects of ATMP (e.g. regarding dose finding, local tolerance, or undesired interactions and effects of the administered cells in the target tissue). In contrast, for evaluation of the two prominent endpoints for characterizing the safety of ATMP (i.e. biodistribution, tumorigenicity) heterologous small animal models, especially immunodeficient mouse strains, are favourable due to their tolerance to the human cell therapy product. The execution of non-clinical studies under the principles of good laboratory practice (GLP) increases the acceptance of the results by authorities and the scientific community.

Biosimilars are currently a hot topic and there are many unsolved questions, misunderstandings and sometimes considerable uncertainty, especially among clinicians and patients. Regulatory agencies, such as the European Medicines Agency (EMA) issue guidelines for the development and approval of biosimilars, which are based on scientific principles.This article addresses some of the frequently noted misunderstandings and misperceptions. For example, why biosimilars are (or can only be) "similar" but not "identical" compared to the original pharmaceutical product, and aspects, such as the pharmaceutical quality of biosimilars, immunogenicity and the approval process for biosimilars are highlighted.

This article presents the design of clinical trials for the development of biosimilars in the European Union and the United States, with special focus on inflammatory diseases.All information available in PubMed and the Internet relating to the clinical development of biosimilars in inflammatory rheumatic conditions (e.g. rheumatoid arthritis, psoriasis, psoriatic arthritis and ankylosing spondylitis) was collated. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites were screened for guidelines on biosimilars.More than 10 years ago the EMA began to publish guidelines for the development of biosimilars and several biosimilars have now been approved. In the USA the FDA has published guidance for the nonclinical and clinical development of biosimilars but until early 2015 no biosimilar had been approved.Clinical trials aim to resolve uncertainties that may remain following nonclinical development regarding the similarity of the proposed biosimilar with the reference product. Pharmacokinetic and pharmacodynamic studies are essential for early clinical development and further phase 3 clinical studies. Factors to be considered in the clinical process include study population, design, endpoints, sample size, duration and analytical methods.

Due to the expiry of patents for biological pharmaceuticals, in forthcoming years there will be an increase in the approval of biosimilars by the international health authorities. This will bring potential savings in the range of 11.8-33.4 billion euros in the European Union (EU) in the year 2020.The aims are an understanding of the natural variability of biological substances and the clinical relevance of the diverse product attributes, proof of comparability (similarity) as a self-contained concept in the development and approval of biosimilars and importance of extrapolation to other indications when comparability is demonstrated by comprehensive analytical and functional studies.This study involved an assessment of the regulations of the European licensing authority, the European Medicines Agency (EMA), with respect to the approval of biosimilars, analytical, physicochemical and biological procedures for determination of comparability and the permissible deviation from the reference productApproved biological pharmaceuticals have a natural intrinsic variability, e.g. with respect to glycosylation. Furthermore, different batches in the manufacturing process can be different or the manufacturing process itself can be subject to change. Biosimilars are subject to specific and strict approval criteria with the aim of restricting the product attributes to lie within the variability range of the original biologics, can only show deviations from the original preparations within very narrow limits and must show proven safety, quality and effectiveness comparable to them.The development and approval concept of biosimilars has been proven for nearly 10 years. Strict requirements by the EMA guarantee the highest quality standards, which have led to significant savings in the healthcare system and an expansion of access to biological pharmaceuticals in many countries and for many patients.

To test the interchangeability of the commercially available (in Germany) latanoprost drugs and their generics respectively, the concentration of the active substance was tested. Guidelines of the European Medicines Agency postulate a sufficient bioequivalence, if the range of the agent is within 80-125% of the original drug.All compounds of latanoprost were procured registered. The concentration of latanoprost and benzalkoniumchloride was measured by high-performance liquid chromatography (HPLC) in a validated reference labroratory for 23 generics. In addition, the mean volume of drops and the pH of the formulation were measured. The packaging label and the readability of the enclosed information leaflet were checked.All products contained less than 50 μg/ml latanoprost. The deviating reduction of the active substance (mean: - 7.39%, ± 2.8%) was accompanied by fluctions of the eyedrops' mass (mean: 0.03 g, ± 0.002 g). The concentration of benzalkonium chloride was mostly increased (median: 5.45%, min: - 2.5%, max: 11.5%). The pH of the original drug and the generics (median 6.78, min: 6.62, max: 6.81) was similar to the original drug, but was significantly different from an unpreserved formulation (pH 7.18). Due to type size, the packaging leaflet was illegible for humans with impaired vision.Before prescribing generics in ophthalmology, different factors have to be considered, which might influence the amount of IOP lowering in effect. In the absence of healthcare research it is still unclear, how different bottle forms of eyedrops--such as appearance (e.g. Cyrillic characters) or pressure point (administration)--reduce the adherence of glaucoma patients.

The official experimental testing of biomedicinal products provides a very significant contribution to ensuring quality, safety and efficacy of these indispensable medicines. Already in the prelicensing phase or to elucidate clusters of increased adverse effects, official medicinal control laboratories are committed to perform experimental testing. The official batch release can be seen as external quality control of the manufacturer's release testing. For proficient performance in these tasks, scientific research is required, in particular on the development and refinement of test methods, and considering the continuous development of innovative biomedicinal products. This article is aimed at introducing the present thematic issue and in particular the regulatory basis of experimental product testing, and illustrates by means of several examples its great importance for the sake of the patients.

Many drugs have act differently in women and men. Biological differences between women and men lead to sex differences in pharmacokinetics, i.e., in drug absorption, distribution in tissues, metabolism by liver enzymes, and excretion via the kidney and intestine. In addition there are sex differences in pharmacodynamics, leading to a different efficacy of drugs in women and men. The biological differences between women and men may be caused by sex-specific gene expression, by sex-specific epigenetic modifications, and finally by the effect of sex hormones. In addition, gender plays a role in drug efficacy as a sociocultural dimension that may lead to differences between women and men. Frequently drugs are only tested on animals of one sex and thereby optimized for one sex. This is based on the notion that sex differences are not important for clinical drug effects. Furthermore, to date, sex and gender differences have been underestimated in clinical studies, and phase III studies were not prospectively designed to assess sex differences in drug effects. In addition, women and men use drugs differently with respect to compliance, adherence, and self-medication with over-the-counter drugs. Further, it is known that male and female physicians treat women and men as patients differently. In conclusion, drug therapy is not yet optimized for both genders. However, there is increasing awareness that differences between women and men should be respected in order to provide optimal drugs in optimal doses for both genders.

Cathepsin K, a cysteine protease, is an essential enzyme in degradation of collagen type I. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decades, efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. In contrast to balicatib and relacatib, whose drug development programmes were stopped due to cutaneous side-effects related to limited drug specificity, the more specific cathepsin K inhibitors odanacatib (ODN) and ONO-5334 have entered clinical trials. Odanacatib progressively increases bone mineral density (BMD) and decreases bone resorption markers in postmenopausal women with low BMD. Its clinical efficacy and safety was confirmed by several clinical studies but indicates that odanacatib is characterized by a resolution-of-effect with increases in bone resorption and rapid decreases in BMD following treatment discontinuation. A phase III fracture prevention study in postmenopausal women with osteoporosis is currently in the final phase.

Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.

Counterfeit drugs are often ineffective and are considered a problem with an immense risk potential especially in the treatment of infectious diseases. Emerging and developing countries are particularly affected. Little is known about the extent of counterfeit antibiotic drugs used in eye care. In the present study we investigated antibiotic eye drops purchased in two African countries with respect to the active substance and its concentration in the sample.A total of 33 antibiotic eye drops purchased in Kenya and the Democratic Republic of Congo were tested. The bottles were labeled to contain one of the following substances: the quinolones ciprofloxacin, levofloxacin and ofloxacin and the aminoglycosides gentamicin and tobramycin. Imported quality products as well as cheaper generic drugs were tested. Fluoroquinolones were determined by high pressure liquid chromatography (HPLC) and quantified by fluorescence measurement and aminoglycosides were tested by using a fluorescence polarization immunoassay.All samples were found to contain the declared drug. Nine samples (27%) showed an under-concentration by 10% or less and ten (30%) showed an increased concentration of 10% or more than indicated on the label. 75% of the original drugs but only 12% of the generic drugs had measured concentrations within the standard advisory ranges of ± 5% from the nominal value.Our results provide no evidence for significant criminal counterfeiting of eye drops in the studied countries. The frequent deviation from the stated concentration in the generic samples is cause for concern and justifies further investigation.

Involvement of metabotropic glutamate receptor subtype 5 (mGluR5) in physiological and pathophysiological processes in the brain has been demonstrated, and hence mGluR5 has emerged as an important drug target. [11C]-ABP688 is clinically the most successful mGluR5 positron emission tomography (PET) tracer to date and it allows visualization and quantification of mGluR5. Due to the short half-life of carbon-11, clinical use of [11C]-ABP688 is limited to facilities with an on-site cyclotron and a fluorine-18 (half-life 110 min) analogue would be more practical. Based on the [11C]-ABP688 structural motif, a novel derivative [18F]-PSS223 was prepared and evaluated as a PET tracer for imaging of mGluR5 in vitro and in vivo. Our results show favourable in vitro binding properties; however rapid defluorination of [18F]-PSS223 does not allow visualization of mGluR5 in the rat brain.

For more than 200 years, homeopathic doctors have been carrying out homeopathic drug provings (HDPs),which embodies the traditional self drug testing, an integral part of the homeopathic medical profession. However,according to national authorities, testing homeopathic drugs is a phase I clinical trial for which the German Federal Drug Law applies. Adapting a 200-year-old primary qualitative study design to modern drug law and Good Clinical Practice Guidelines generates several difficulties, in particular, blinding, informed consent and the classification of adverse events. In addition, in Germany naturopaths (German: ‘Heilpraktiker’) are excluded from leading HDP trials. The costs are climbing, and the organizational over heads for a HDP are enormous. Implications for the future are discussed.

In oncology, PET and PET/CT with tracers beyond FDG target more specific biological processes, such as proliferation (18F-3´-fluoro-3´-deoxy-L-thymidine; 18F-FLT), tumour hypoxia (18F-fluoromisonidazol; 18F-FMISO) and phospholipid metabolism (radioactively labelled choline derivates). FLT is a thymidine analogue which can be labelled with 18F. PET with 18F-FLT enables to non-invasively image and to quantify the proliferation fraction of tumours. Proliferation dependent accumulation of FLT has been demonstrated for a variety of solid and haematologic neoplasms including lung cancer, breast cancer, gastric cancer, colorectal cancer and malignant lymphoma. Furthermore, FLT has been suggested as surrogate marker for the assessment of response to treatment, especially when targeted drugs are utilized. PET imaging in particular has emerged as a promising non-invasive tool to accurately characterize tumour oxygenation. The great promise of PET/CT is its potential as a single imaging modality for whole body staging that provides anatomical and biological information on the disease as a whole. It allows a more precise estimation of the hypoxic tumour volume as well as comparisons on a voxel-by-voxel basis (parametric mapping). PET and PET/CT with hypoxia tracers thus offer the potential to optimize and individualize therapy for patients suffering from cancer. PET- and PET/CT-studies using 11C- or 18F-labeled choline derivates recently have shown promising results for re-staging prostate cancer in patients with biochemical recurrence and advanced prostate cancer. In patients with biochemical recurrence of prostate cancer after primary therapy the detection rate of 11C-choline-PET/CT shows a positive relationship with serum PSA-levels. In these patients 11C-choline PET/CT allows not only to diagnose but also to localize recurrent disease with implications on disease management (localised vs. systemic therapy).The clinical success of multimodal imaging with PET/CT is expected to promote the combination of MRI and PET in the future.

To establish precise diagnostic algorithms and standardised treatment of sarcomas in specialized centers, the interdisciplinary research group KoSar (sarcoma competence network) has been funded by German Cancer Aid. A sarcoma tissue repository and a diagnostic reference center have been set up, presently containing about 1000 accurately diagnosed sarcomas of different entities. Significant gene expression profiles for synovial sarcomas, leiomyosarcomas, myxoid liposarcomas and a small profile for myxofibrosarcomas as well as a new classification of angiosarcomas were defined. We systematically searched for activated signal transduction pathways in sarcoma cell lines and xenograft transplant models and candidate targets for molecular therapies were identified. Based on these results first clinical studies have been initiated by the German Interdisciplinary Sarcoma Study Group (GISG).

In 50% of all cases, bladder cancer patients develop tumor progression despite modern surgical methods such as radical cystectomy. A solution to the problem might be the identification and understanding of molecular biomarkers which could result in the development of advanced methods with better preventive, diagnostic, and therapeutic potential. One suitable approach is the identification of a bladder cancer-specific molecular marker in order to enhance patients' outcome. We and others have identified EMMPRIN as a prognostic biomarker in a variety of tumor diseases. EMMPRIN (CD147, extracellular matrix metalloproteinase inducer) is a cell surface protein that is expressed among other cell types, in particular in tumor cells. Since its first description in 1982 it is established that overexpression of EMMPRIN correlates with tumor progression and patient outcome. EMMPRIN expression levels can be used as an independent prognostic factor for survival. Recently, EMMPRIN has been defined as a potential target for tumor therapy in preclinical studies.

Biotechnological methods have become an important tool in pharmaceutical drug research and development. Today approximately 15 % of drug revenues are derived from biopharmaceuticals. The most relevant indications are oncology, metabolic disorders and disorders of the musculoskeletal system. For the future it can be expected that the relevance of biopharmaceuticals will further increase. Currently, the share of substances in preclinical testing that rely on biotechnology is more than 25 % of all substances in preclinical testing. Products for the treatment of cancer, metabolic disorders and infectious diseases are most important. New therapeutic approaches such as RNA interference only play a minor role in current commercial drug research and development with 1.5 % of all biological preclinical substances. Investments in sustainable high technology such as biotechnology are of vital importance for a highly developed country like Germany because of its lack of raw materials. Biotechnology helps the pharmaceutical industry to develop new products, new processes, methods and services and to improve existing ones. Thus, international competitiveness can be strengthened, new jobs can be created and existing jobs preserved.

Clinical symptoms in acute intoxications are often nondescript and unspecific for a definite diagnosis. This makes laboratory investigations necessary in order to initiate supportive measures and to confirm or discard the diagnosis of an acute intoxication. For toxicological analyses immunoassays as well as chromatographic methods are applied. Unfortunately, not all potential toxic compounds can be detected by these methods, e.g. ethanol and metals (including lithium) cannot be seen. The sample materials for toxicological analyses are on one hand blood for the quantitative determination of a distinct compound and on the other hand urine for toxicological screening procedures. Whenever the clinical situation does not exclude intoxication, a toxicological screening should be carried out. The comprehensiveness of the toxicological screening is dependent on the anamnesis and the clinical symptoms of the patient and should also depend on the therapeutic options for the various differential diagnoses. A specific quantitative determination of the toxic compound is recommended for acetaminophen, lithium, amanitine (intoxications with death cap), colchicine, alcohols and glycols, carbon monoxide and cyanide.

Conventional therapeutic approaches to treat advanced renal cell carcinoma (RCC) are of limited benefit. Receptor tyrosine kinase inhibitors (RTKI) may open up novel treatment options. In the present study, the effects of the RTKI AEE788 on the growth and adhesion capacity of RCC cell lines were evaluated in vitro.RCC cells were treated with AEE788, and alterations of tumor growth and tumor cell interaction with vascular endothelium or extracellular matrix proteins were analyzed. Furthermore, the addition of interferon alpha (IFNalpha) was investigated to see whether it may enhance the anti-tumoral potential of AEE788.AEE788 significantly blocked RCC cell growth and adhesion. Analysis of alpha- and beta-integrins revealed distinct alterations of the receptor expression profile and downregulation of integrin-dependent signaling. Growth-blocking effects were further enhanced when the AEE788-IFNalpha combination protocol was applied. In addition, downregulation of integrin-dependent signaling was more intense in the presence of a combination of AEE788 and IFNalpha than with AEE788 monotherapy.AEE788 exerts significant anti-tumoral properties, particularly when combined with IFNalpha. AEE788 may therefore be an encouraging compound to treat advanced RCC.

The preclinical development of novel anticancer compounds mainly resembles the same principle as valid for other drug classes. New target structures on tumors are identified within academic or industrial fundamental research groups enabling a selective attack of cancerostatics. After the proof of principle in molecular or cellular systems, substance candidates are selected which undergo a stepwise preclinical testing. This procedure consists of cell culture models (in vitro) and animal experiments (in vivo) using suitable tumor models. With selected lead compounds the pharmaceutical formulation is prepared, and the legally required preclinical toxicological investigations are performed before initiation of clinical phase I studies. There is one special feature distinguishing cytostatics from all other drugs - their narrow therapeutic index. This constraint is to be considered already in early phases of anticancer drug development, and a special focus should be given to the revealing of potential side effects. This contribution especially gives attention to this aspect of preclinical anticancer drug development. Further on, focus is put on target-oriented compounds, whose preclinical development generates special challenges.

In the last few years, the therapy of cervical carcinoma has progressed substantially due to the use of simultaneous platinum- containing radiochemotherapy. However, there are no data which evaluate an individualized treatment adapted to tumor biology, in spite of the fact that patients show remarkably different responses to chemotherapy. Therefore this preclinical phase I study aims at finding therapeutic alternatives to the current cytostatic drugs to treat cervical carcinoma.In a tumor chemosensitivity assay, 8 drugs were tested on freshly isolated tumor cells of 16 patients [carbo- and cisplatin, topotecan, paclitaxel as well as the 2 tyrosine kinase inhibitors imatinib (Glivec) and gefitinib (Iressa (R) ) and the 2 monoclonal antibodies cetuximab (Erbitux) and trastuzumab (Herceptin (R) )].Overall the test was evaluable for 16 specimens (100%). Ten of 15 tumor samples (66.6%) were sensitive to imatinib. A sensitive therapeutic response could be demonstrated in all tested FIGO stages. An interindividual comparison could establish sensitivity to cetuximab in 12.5% of cases, to gefitinib in 6.25%, to trastuzumab in 6.6%, to cisplatin in 13.3%, to carboplatin in 7.6%, to paclitaxel in 93.8% and to topotecan in 25%.Imatinib seems to be an efficacious therapeutic option for patients with cervical carcinoma, independently of tumor subtype.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to death after 3 to 5 years. The glutamate antagonist Riluzole currently is the only drug with marginal therapeutic benefit, but its effect on survival is modest, with an average increase of only 3-4 months. Therefore symptomatic treatment still is the most important. Further neuroprotective agents are currently under investigation, both in transgenic animal models of ALS and clinical trials in ALS patients. This review summarizes the current state of clinical studies in ALS patients in the context of underlying therapeutic mechanisms.

The use of monoclonal antibodies has led to new therapeutic possibilities for many clinical conditions. However, their application also bears risks, as demonstrated by the acute occurrence of a cytokine storm following administration of TGN1412, an anti-CD28 superagonist, in March 2006. This article highlights the principles of the Paul-Ehrlich-Institut (PEI) for the scientific assessment of first-in-man clinical trial applications for monoclonal antibodies. These principles are implemented as a standard operating procedure in the PEI Quality Management System and are intended as a supplement specific to monoclonal antibodies to the published general guideline issued by the Committee for Medicinal Products for Human Use (CHMP). Central aspects are the identification of risk factors for monoclonal antibodies based on defined criteria, since not every novel monoclonal antibody represents a risk per se. Furthermore, a PEI expert group that supports the scientific assessment procedure has been founded.

The concept for the medical treatment of vertigo has changed over the last 30 years due to recognition of the dependence of the vertiginous sensation on vestibular compensation and the dependence of vestibular compensation on the state of vigilance.In this systematic review, experimental studies of the influence of the special ginkgo extract EGb 761 on vestibular compensation in animals and randomized, double-blind clinical studies of EGb 761 in vestibular and non-vestibular vertigo are described and critically evaluated.The beneficial effect of EGb 761 on vestibular compensation has been demonstrated in preclinical and clinical studies.Evidence of the efficacy of EGb 761 for the treatment of vertiginous syndromes is presented in the available studies.

A variety of approaches (in vitro-/ex vivo studies, animal models, human studies and clinical trials) are available to assess compounds with potential antipsoriatic properties. Over the past few years various rodent models that mirror aspects of psoriasis phenotypes and/or pathogenesis have been created (e. g. knockout rodents, xenotransplantation models). Unfortunately these animal models do not reflect the complete pathogenesis of psoriasis. Therefore, screening procedures involving psoriatic lesions in humans are necessary. Even in the era of biologicals, the psoriasis plaque test (PPT) remains an important in vivo tool. In addition to screening potential antipsoriatic substances, the PPT can help answer other questions (frequency of use, dose-response relationship). A prerequisite for correct performance of PPT is knowledge of the toxicological and pharmacological data of the investigational compounds. The PPT is relatively simple, not time-consuming and allows the simultaneous testing of multiple substance. All the results from PPT must be confirmed by controlled clinical trials.

Nowadays immunoassays are used for the rapid screening of drugs world-wide. Despite the fact that they are a highly valuable tool for the test of legal and illicit drugs, there is a non-negligible risk of false positive and false negative findings, and many pitfalls must be taken into account when using these tests in an uncritical manner and without valid confirmation procedures. In accordance with the committee for "problems of threshold values for medical and addictive drugs" set up by German scientific societies (in particular GTFCh, DGRM and DGVM), immunoassays are recommended as a useful tool for screening. But confirmation analysis with conclusive methods (GC/MS or LC/MS) is indispensable for valid substance identification, discrimination between active and inactive metabolites, detection of escort substances and accurate determination of concentrations in body fluids.

Intoxicated patients make up 5-10% of all patients seen at emergency departments. The management of these patients is not always simple. Many of them are seen after ingestions of relatively non-toxic substances that require minimal medical care, intentional poisoning however often requires the highest standards of medical and nursing care and therefore the admission to an emergency department is mandatory. At admission, the involved substances are often not known since some of the patients are comatose. In such cases, the information from relatives and friends can be very crucial but to get hold of these sometimes essential "hints" is not always easy. Knowledge of the specific toxic agent allows the physician to plan a rational approach to the definitive management of the intoxicated patient after the vital functions have been stabilised. In some cases, very rare intoxications but with typical clinical signs do occur (e.g scromboid fish poisoning, coprinus-syndrome), which needs special diagnostic and therapeutic steps and a great deal of clinical experience. In most cases it is preferable to contact the Poison Control Center for additional advice.

Phase I clinical trials are of particular importance in drug research. In this phase, a new chemical entity is applied for the first time to humans, normally to young healthy volunteers. The primary aims are safety and tolerability, the pharmacokinetic, and as far as possible the pharmacodynamic behaviour of the new substance in the human body. The effects of age, gender, race, drug interactions, food intake and organ damage are examined in studies of later phase I. This article deals mainly with "first into human" studies during early phase I. We describe the processes before, as well as the technical, medical and regulatory requirements during, the conduct of a "first into human" trial. Furthermore, the choice of galenic formulation, route of application, and study population, and the risks at trial participation are addressed. In addition to different dose escalating schemes, which serve for the identification of the maximum tolerated dose, and other common study designs for "first into human" trials, this article reviews the literature on the determination of the first dose.

Medical conduct relies on the efficacy and tolerability of a given pharmacotherapy. On the basis of an experimental comparison of different treatment options, a clinical trial provides the foundation for an evidence-based medicine that complies with state-of-the-art scientific practice. The quality of the data assessment determines the clinical relevance of the study results. Clinical trials are classified into Phases I-IV to ensure the development of an effective and safe pharmaceutical. The investigator is responsible for being experienced in the relevant area of expertise, for conducting the study according to the investigational plan, and for complying with ethical guidelines and drug safety.

Now-a-days immunoassays are world wide used for the rapid screening of drugs. Despite the fact that they are a highly valuable tool for the test of legal and illicit drugs, there is a non-negligible risk of false positive and false negative findings and many pitfalls must be taken into account when using these tests in an uncritical manner and without valid confirmation procedures.

To improve the transition from research to development a critical evaluation of the individual project by research and disease area teams is required to include input from pharmacology, toxicology, pharmacokinetics, galenics, clinical pharmacology, clinical as well as regulatory experts and marketing. Decisions on the individual development strategy should be made prior to the start of development and all projects should be reviewed at predefined stages throughout the product development life cycle. This ensures consistency of decision-making not only during the development of individual products but throughout the entire development pipeline. Studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials in the confirmatory stage that require power for proof-of-safety and proof-of-efficacy. The more thorough and profound studies have been carried out during this exploratory stage of drug development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success rate of the project in the later confirmatory effectiveness trial with an adequate number of subjects receiving the new therapy under typical conditions of use. Strategies which may be helpful to improve the quality of decisions in drug discovery and drug development are: discovery experiments should be done to critically evaluate the compound, the "killer" experiments should be done as early as possible, continuous effort on preclinical disease models is necessary to improve predictability of efficacy in patients ("humanized" research): genomic technology should be used to identify novel, disease-related targets and to characterise preclinical test systems, improvement of knowledge and experience concerning the relevance of new technologies for the clinical picture, genotyping of clinical trial patients to select patient groups which are likely to respond to treatment (pharmacogenomics), modelling and simulation of preclinical and clinical trials, integration of pharmacokinetic and pharmacodynamic principles into drug development, assessment of the interaction potential (CYP-450, trasporter proteins and others), increasing use of biomarker/surrogate marker for rapid clinical feedback, involvement of the target population as soon as possible, applying statistical data analysis techniques for proving effectiveness, co-operation with high quality centers. To reach this goal clinical pharmacology must be fully integrated in the whole process from the candidate selection to its positioning within the market.

To improve the transition from research to development a critical evaluation of the individual project by research and disease area teams is required to include input from pharmacology, toxicology, pharmacokinetics, galenics, clinical pharmacology, clinical as well as regulatory experts and marketing. Decisions on the individual development strategy should be made prior to the start of development and all projects should be reviewed at predefined stages throughout the product development life cycle. This ensures consistency of decision-making not only during the development of individual products but throughout the entire development pipeline. Studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials in the confirmatory stage that require power for proof-of-safety and proof-of-efficacy. The more thorough and profound studies have been carried out during this exploratory stage of drug development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success rate of the project in the later confirmatory effectiveness trial with an adequate number of subjects receiving the new therapy under typical conditions of use. Strategies which may be helpful to improve the quality of decisions in drug discovery and drug development are: discovery experiments should be done to critically evaluate the compound, the "killer" experiments should be done as early as possible, continuous effort on preclinical disease models is necessary to improve predictability of efficacy in patients ("humanized" research): genomic technology should be used to identify novel, disease-related targets and to characterise preclinical test systems, improvement of knowledge and experience concerning the relevance of new technologies for the clinical picture; genotyping of clinical trial patients to select patient groups which are likely to respond to treatment (pharmacogenomics), modelling and simulation of preclinical and clinical trials, integration of pharmacokinetic and pharmacodynamic principles into drug development, assessment of the interaction potential (CYP-450, trasporter proteins and others), increasing use of biomarker/surrogate marker for rapid clinical feedback, involvement of the target population as soon as possible, applying statistical data analysis techniques for proving effectiveness, co-operation with high quality centers. To reach this goal clinical pharmacology must be fully integrated in the whole process from the candidate selection to its positioning within the market.

The regulation of apoptosis is an important potential target for anticancer therapy. The mitochondrial Bcl-2 protein inhibits apoptosis and is therefore an important mediator of resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy and monoclonal antibody therapy. Oblimersen (Genasense, Aventis Pharmaceuticals / Genta Inc) is a 18mer antisense-oligonucleotide (ASO), which specifically binds to the first 6 codons of the human bcl-2 mRNA, resulting in degradation and destruction of the mRNA by RNAse H. Subsequently there is a significant decrease of bcl-2 translation. A growing number of preclinical and clinical studies suggests that the combination of cytotoxic therapy with Oblimersen results in synergistic anticancer efficacy in many hematologic and solid tumors. Due to its low toxicity profile, oblimersen is an ideal combination partner with conventional chemotherapy. Three randomized phase-III trials (malignant melanoma, chronic lymphocytic leukemia, multiple myeloma) have recently finished recruitment. The results of these studies will be available by the end of 2003. Based on preclinical data, a lot of nonrandomized phase-II studies on several different tumor types like AML, CML, NHL, prostate cancer and breast cancer are underway. The manipulation of proapoptotic and antiapoptotic factors in favor of proapoptotic factors by inhibition of the bcl-2 protein translation in order to enhance the efficacy of anticancer treatments represents a promising new treatment concept in oncology.

Considerable advances in the fields of molecular biology and pain research during the last decade has led to the identification of a wide range of pharmacological targets for new analgesics. Genes of interesting targets may be regulated either upwards or downwards under pathophysiological, i. e. inflammatory or neuropathic pain conditions. Targets exclusively expressed in terms of tissues relevant for pain transmission, are potential promising candidates for the generation of analgesics devoid of serious side-effects. Especially those targets that are expected to be essential for the development and maintenance of a number of pains offer the opportunity to define courses of treatment for patients with a variety of different symptoms and causes. Modern drug-development is based on the identification of compounds directed against these specific targets. In a high throughput screening procedure, all substances of our drug library (about 1 million) are examined for their effects on this specific molecular mechanism. Predicted pain-relieving effects are then identified by a screening cascade where selected drugs are tested for their activity in in-vitro assays on isolated neurons, tissues or recombinant cell lines. The final validation of a drugs' antihyperalgetic or antiallodynic properties is carried out in the relevant animal models of chronic pain, which mirror the clinical situation as much as possible. Compounds being more efficient or having an improved side effect profile in these models than medications currently available (and which are toxicologically harmless) are interesting candidates for clinical development.

Systemic adjuvant chemotherapy achieves unsatisfactory results for inoperable liver tumors and metastases. Various clinical studies have shown that locoregional chemotherapy increased the survival rate by a few months. The aim of this study was to investigate tumor targeting of the most frequently used cytostatic 5-fluouracil by modifying systemic and locoregional therapy by liposome encapsulation. The tumor concentration of 5-FU encapsulated in SUV-PEG liposomes increases by a factor of 27 in systemic therapy and a factor of 90 in locoregional therapy. The tumor concentration of 5-FU increases by a factor of 8000, if the blood flow is additionally slowed by starch microspheres (Spherex) during locoregional therapy with liposome-encapsulated 5-FU.

In clinical reality the drugs used for H1/H2-prophylaxis are not restricted to the combination of dimetinden/cimetidine, also only for this combination the effectiveness for preventing severe cardiorespiratory disturbances is proven in a randomised controlled clinical trial. However, it is almost impossible to conduct such an extended clinical trial in order to check all possible combinations. Instead of this, we developed a complex animal model featuring clinical variability and the principles of a well conducted randomised controlled clinical trial (CMRT = clinic modelling randomised trials), to evaluate different H1/H2 combinations. In this CMRT in pigs (four groups of 15 animals), the H1/H2 combination of dimetinden/cimetidine and dimetinden/famotidine showed an effectiveness similar to the randomised clinical trial. With dimetinden/ranitidine no significant prophylactic effect was observed. Two conclusions can be drawn: (1) CMRTs in animals are able to answer relevant clinical and research questions that otherwise only could be solved by clinical studies and may be a successful intermediate between basic research and clinical trials. (2) Drugs, even of the same substance class, may not be simply exchangeable. Hence, before changing a proven medication, trials in an adequate complex animal model (CMRT) should be mandatory.