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Pharmacotherapy, clinical pharmacology and biomarker research in geriatric patients

By S.V. Frankfort

Abstract

Evaluation of pharmacotherapy and diagnosis and treatment of dementia are important subjects within geriatric medicine. Geriatric patients are more vulnerable for adverse events and pharmacokinetic interactions. Polypharmacy should be reduced, however, undertreatment of conditions or illnesses is also recognised in geriatric populations. Pharmacotherapy was evaluated in geriatric patients attending the diagnostic day-clinic and the geriatric ward of a general hospital. Vitamin supplementation, treatment of urinary tract infections and proton-pump-inhibitor therapy were the most frequently started therapies after evaluation. Although less frequent, medication was discontinued mostly because diagnoses were not longer relevant. Patients aged above 65 years are often excluded from clinical pharmacological research. We showed selected polymorphism in exon 12, 21 and 26 of the ABCB1 gene, encoding for the efflux pump P-glycoprotein, to be unrelated to the steady-state digoxin clearance in geriatric patients. Rivastigmine, an acetylcholinesterase inhibitor, is registered for the indication mild-to-moderate severe Alzheimer's Disease. In clinical practice patients discontinue therapy because of adverse events and only a subset of patients is identified as a responder to therapy. Rivastigmine was primarily discontinued within the first 6 months of therapy because of adverse events, after 6 months mainly for therapy ineffectiveness. Absence of nurse support and not tolerating the minimal effective daily dose of twice daily 3 mg resulted in an increased risk for discontinuation of rivastigmine within 6 months after starting therapy. Rivastigmine shows a modest effect on cognition, activities of daily living and memory-related behaviour. Rivastigmine does not have clinically relevant treatment effects on disruptive behaviour, and depressive behaviour worsened during the first 6 months of treatment. Patients with a baseline Mini Mental State Examination score ?19 showed significant and larger responses to rivastigmine therapy. Differences in pharmacokinetics were not related to treatment outcome in Alzheimer’s disease patients and could not explain treatment variability in individuals. With the future possibilities of disease-modifying therapies it is becoming important to diagnose dementia preferably in a pre-clinical stadium or as early as possible in the clinical process, when pathological mechanisms have already been started. We showed that selected genotypes in exon 12, 21 and 26 of the ABCB1 gene, encoding for the efflux drug-transporter P-glycoprotein, are not useful as biological markers for different types of dementia. These ABCB1 single nucleotide polymorphism were not significantly different between dementia patients and age-matched non-demented control patients, or between different types of dementia. Furthermore, we used Surface-Enhanced Laser Desorption/Ionisation-Time of Flight Mass Spectrometry (SELDI-TOF MS) to investigate amyloid ? profiles in cerebrospinal fluid and serum of patients with Alzheimer’s disease, vascular dementia and non-demented control patients. Certain peaks in cerebrospinal fluid, as obtained with SELDI-TOF MS, were significantly different between those patient groups. In serum, however, no significantly different peaks intensities were obtained between the three patient groups. Investigations in serum showed that the ABCB1 polymorphism in exon 21 (G2677T/A) was significantly related to the peak intensity of amyloid ?-40 and the SNP in exon 12 (C1236T) was significantly related to a peak at molecular mass 3891, corresponding to an unidentified amyloid-peptide

Topics: Farmacie, rivastigmine, Alzheimer's disease, biomarkers, P-glycoprotein, ABCB1, polypharmacy, medication evaluation, pharmacokinetics, pharmacogenetics, elderly
Publisher: Utrecht University
Year: 2007
OAI identifier: oai:dspace.library.uu.nl:1874/19078
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