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Hampel H.,University Pierre and Marie Curie | Schneider L.S.,University of Southern California | Giacobini E.,University of Geneva | Kivipelto M.,Karolinska Institutet | And 7 more authors.
Expert Review of Neurotherapeutics | Year: 2014

Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis-and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre-and asymptomatic at-risk stages of AD. © Informa UK, Ltd.

Eckstein N.,Federal Institute of Drugs and Medical Devices | Haas B.,Federal Institute of Drugs and Medical Devices
European Journal of Clinical Pharmacology | Year: 2014

Introduction: GnRH (gonadotropin-releasing hormone) analogues are long-term known to be safe and effective in the clinical management of hormone-dependent advanced prostate cancer. However, their unusual mechanism of action of de-sensitizing pituitary receptors makes generic market entry challenging. In addition, safety aspects like initial flare-up, breakthrough escape, and miniflares render planning and organization of clinical registration trials a complex project. Regulatory requirements: therapeutic equivalence: Regulatory requirements are high as these medicines are compared to bilateral surgical castration with a 100 % success rate. GnRH analogues will be used probably even wider in the near future due to demographic development and extension of indications. However, they are challenged by their antagonistic counterparts, which are avoiding flare-up phenomena. The following article deals with regulatory requirements of GnRH analogues in regard to their clinical characteristics. © 2014 The Author(s).

Vellas B.,French Institute of Health and Medical Research | Vellas B.,University Paul Sabatier | Vellas B.,Toulouse University Hospital Center | Carrillo M.C.,Alzheimers Association | And 23 more authors.
Alzheimer's and Dementia | Year: 2013

An international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met in Monte Carlo, Monaco, on October 31, 2012, to review lessons learned from the recent bapineuzumab and solanezumab trials, and to incorporate insights gained from these trials into future clinical studies. Although there is broad consensus that Alzheimer's disease (AD) should be treated during its earliest stages, the concept of secondary prevention has evolved to be described more accurately as treatment of preclinical, presymptomatic, or early AD. There continues to be a strong emphasis on biomarkers and a need for new biomarkers; however, there has also been a realization, based on completed trials, that the most reliable indicator of clinical efficacy across the entire spectrum of disease from asymptomatic to AD dementia is likely a measure of cognition. The task force made many recommendations that should improve the likelihood of success in future trials, including larger phase 2 or combined phase 2/phase 3 studies, clear evidence of target engagement in the central nervous system, evidence of downstream effects on biomarkers before initiating phase 3 studies, consideration of adaptive and targeted trial designs, and use of sensitive measures of cognition as the most robust indicator of treatment benefit. © 2013 The Alzheimer's Association. All rights reserved.

Hicks J.K.,Cleveland Clinic | Bishop J.R.,University of Minnesota | Sangkuhl K.,Stanford University | Muller D.J.,Campbell Family Mental Health Research Institute | And 13 more authors.
Clinical Pharmacology and Therapeutics | Year: 2015

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org). © 2015 American Society for Clinical Pharmacology and Therapeutics.

Eckstein N.,Federal Institute of Drugs and Medical Devices | Eckstein N.,Kaiserslautern University of Applied Sciences | Haas B.,Federal Institute of Drugs and Medical Devices | Hass M.D.S.,Federal Institute of Drugs and Medical Devices | Pfeifer V.,Federal Institute of Drugs and Medical Devices
Orphanet Journal of Rare Diseases | Year: 2014

Cushing's disease (CD) in a stricter sense derives from pathologic adrenocorticotropic hormone (ACTH) secretion usually triggered by micro- or macroadenoma of the pituitary gland. It is, thus, a form of secondary hypercortisolism. In contrast, Cushing's syndrome (CS) describes the complexity of clinical consequences triggered by excessive cortisol blood levels over extended periods of time irrespective of their origin. CS is a rare disease according to the European orphan regulation affecting not more than 5/10,000 persons in Europe. CD most commonly affects adults aged 20-50 years with a marked female preponderance (1:5 ratio of male vs. female). Patient presentation and clinical symptoms substantially vary depending on duration and plasma levels of cortisol. In 80% of cases CS is ACTH-dependent and in 20% of cases it is ACTH-independent, respectively. Endogenous CS usually is a result of a pituitary tumor. Clinical manifestation of CS, apart from corticotropin-releasing hormone (CRH-), ACTH-, and cortisol-producing (malign and benign) tumors may also be by exogenous glucocorticoid intake. Diagnosis of hypercortisolism (irrespective of its origin) comprises the following: Complete blood count including serum electrolytes, blood sugar etc., urinary free cortisol (UFC) from 24 h-urine sampling and circadian profile of plasma cortisol, plasma ACTH, dehydroepiandrosterone, testosterone itself, and urine steroid profile, Low-Dose-Dexamethasone-Test, High-Dose-Dexamethasone-Test, after endocrine diagnostic tests: magnetic resonance imaging (MRI), ultra-sound, computer tomography (CT) and other localization diagnostics. First-line therapy is trans-sphenoidal surgery (TSS) of the pituitary adenoma (in case of ACTH-producing tumors). In patients not amenable for surgery radiotherapy remains an option. Pharmacological therapy applies when these two options are not amenable or refused. In cases when pharmacological therapy becomes necessary, Pasireotide should be used in first-line in CD. CS patients are at an overall 4-fold higher mortality rate than age- and gender-matched subjects in the general population. The following article describes the most prominent substances used for clinical management of CS and gives a systematic overview of safety profiles, pharmacokinetic (PK)-parameters, and regulatory framework. © 2014 Eckstein et al.; licensee Biomedcentral Ltd.

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