piperidines and rofecoxib

Mild cognitive impairment (MCI) is an operational definition for a cognitive decline in individuals with a greater risk of developing dementia. The amnestic subtype of MCI is of particular interest because these individuals most likely progress to Alzheimer's disease (AD). Currently hypothesised therapeutic approaches in MCI are mainly based on AD treatment strategies. Long term secondary prevention randomised clinical trials have been completed in amnestic MCI populations, encompassing agents with various mechanisms of action: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), antioxidants (vitamin E), anti-inflammatories (rofecoxib), and nootropics (piracetam). The design of clinical trials in MCI is influenced by study objectives and definition of primary end points: time to clinical diagnosis of dementia, and AD in particular, or symptom progression. As none of the drugs previously shown to have clinical efficacy in AD trials or benefit in everyday practice have met the primary objectives of the respective trials, design of future clinical trials in MCI should be further developed particularly as regards the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes.

Topics: Aged; Alzheimer Disease; Anti-Inflammatory Agents; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Lactones; Neuropsychological Tests; Phenylcarbamates; Piperidines; Rivastigmine; Severity of Illness Index; Sulfones; Vitamin E

Topics: Antipsychotic Agents; Cyclooxygenase 2 Inhibitors; Dibenzocycloheptenes; Evidence-Based Medicine; Heterocyclic Compounds, 4 or More Rings; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoindoles; Isoxazoles; Lactones; Lurasidone Hydrochloride; Piperidines; Psychotic Disorders; Pyridines; Serotonin Receptor Agonists; Sulfones; Thiazoles

Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.

Topics: Animals; Arthritis; Chronic Disease; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Freund's Adjuvant; Lactones; Male; Nitric Oxide Synthase Type II; Pain; Phenols; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Stifle; Sulfides; Sulfones; Time Factors; Weight-Bearing