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PubMed2004

The application of the principles of clinical drug development to pharmacological challenge tests of the serotonergic system.

Pharmacological challenge tests of the serotonergic system have extensively been used during the past 20 years and new tests are in development. It is of crucial importance to standardize challenge tests to ascertain that observed variability is due to the state of the challenged system and not caused by variability of the test itself. This is even more important now that challenge tests increasingly are used in complex studies (e.g. in combination with neuroimaging and in large population studies with repeated tests over time). The Guideline for Good Clinical Practice may be of great help in the standardization of these tests. This is a recently developed guideline for pharmaceutical drug-development, which increasingly is used as a reference for all research in humans. To exemplify the possible usefulness of this approach, we apply it to meta-chlorophenylpiperazine, one of the most commonly used drugs in serotonergic challenge tests. We conclude that much can be learned from the development of this particular challenge. In the discussion, we address general issues that emerged from this review and their relevance to the development of future challenge tests.

Animals↗
PubMed2005

Molecular neurology of prion disease.

Prions are infectious pathogens principally composed of abnormal forms of a protein encoded in the host genome. They cause lethal neurodegenerative conditions including CJD, GSS, and kuru in humans and scrapie and bovine spongiform encephalopathy in domestic animals. Remarkably, distinct strains of prions occur despite absence of an agent-specific genome: misfolded proteins themselves may encode strain diversity--with wide implications in biology. The arrival of variant CJD, and the experimental confirmation that it is caused by infection with BSE-like prions, has focussed research on early diagnosis and treatment. Recent advances lead to considerable optimism that effective human therapies may now be developed. While several drugs have been tried in small numbers of patients, there is no clear evidence of efficacy of any agent and controlled clinical trials are urgently needed. Importantly, there is increasing recognition that fundamental processes involved in prion propagation--seeded aggregation of misfolded host proteins--are of far wider significance, not least in understanding the commoner neurodegenerative diseases that pose such a major and increasing challenge for healthcare in an ageing population.

Animals↗
PubMed2006

Current and future centrally acting antitussives.

The purpose of this review is to highlight some important issues regarding current centrally acting antitussive drugs as well as discuss the implications of these matters on the development of future cough suppressants. Drugs that act in the central nervous system to inhibit cough are termed centrally acting and this designation is based exclusively on evidence obtained from animal models. This classification can include drugs that act both at peripheral and central sites following systemic administration. These drugs are intended to reduce the frequency and/or intensity of coughing resulting from disorders of any etiology. There are a number of central cough suppressants identified by their efficacy in animal models and the most prominent of these are codeine and dextromethorphan. Although the exact neural elements on which these drugs act are currently unknown, they are thought to inhibit a functionally identified component of the central system for cough known as the gating mechanism. The efficacy of codeine and dextromethorphan in humans has recently been questioned. These drugs are less effective on cough induced by upper airway disorders than in pathological conditions involving the lower airways in humans. The reasons for this difference in antitussive sensitivity are not clear. We propose that sensory afferents from different regions of the airways actuate coughing in humans by antitussive sensitive and insensitive control elements in the central nervous system. This hypothesis is consistent with results from an animal model in which laryngeal and tracheobronchial cough had different sensitivities to codeine. Other factors that may be very important in the action of central antitussive drugs in humans include the role of sensations produced by a tussigenic stimulus as well as plasticity of central pathways in response to airway inflammation. Resolution of these issues in the human will be a challenging process, but one which will lay the foundation for the development of more effective cough suppressants.

Animals↗
PubMed1998

Neuroprotection for Parkinson's disease.

Levodopa is the most effective drug available for the treatment of Parkinson's disease (PD). As a precursor of dopamine, levodopa causes an increase in brain dopamine, which is depleted in PD. However, long-term levodopa therapy is associated with complications such as dyskinesias, motor fluctuations, and mental status changes. The treatment of these side effects is a major challenge for the clinician.

Antiparkinson Agents↗
PubMed2003

Adherence to research protocols in a clinical context: challenges and recommendations from behavioral intervention trials.

Conducting clinical interventions in a research setting poses numerous challenges to clinicians, researchers, supervisors, and research participants. These issues often reflect a tension between the rigorous demands of a research protocol needed to ensure internal validity of the research and clinical flexibility that is representative of an externally valid intervention. In this paper, we explore difficulties in defining the roles of clinicians and research participants, delineating the scope of the intervention, and problems encountered at the intersection of clinical intervention delivery and such methodological techniques as randomization, blinding, and incentive payments. We provide guidance for setting frames for the intervention and clinical relationship, conducting training and supervision of clinical staff, and structuring quality-assurance procedures in order to meet these challenges.

Biomedical Research↗