Cytochrome P450 2D6 phenotyping in an elderly population with dementia and response to galantamine in dementia: a pilot study.

BACKGROUND: The cytochrome P450 (CYP) 2D6 enzyme is involved in the metabolism of many drugs used by the elderly population. Variations in its activity can lead to altered drug response. However, few studies on the activity of this enzyme system have enrolled the elderly population. OBJECTIVE: The goal of this pilot study was to assess the feasibility of in vivo phenotyping of CYP2D6 in an elderly population with dementia and to determine if part of the variability in response to treatment with galantamine is attributable to CYP2D6 phenotype. METHODS: Patients with dementia attending geriatric clinics and receiving galantamine treatment for at least 6 months were enrolled in this case-control study. CYP2D6 phenotype was determined by analysis of the urinary concentrations of the probe drug dextromethorphan and its primary metabolite dextrorphan after ingestion of 30 mg of dextromethorphan. Patients were classified as robust responders to galantamine if their cognitive testing, as measured by using scores on the Mini-Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive subscale, had not changed or had improved after 6 months of treatment. RESULTS: Forty-three patients (23 men, 20 women; mean age, 78.4 years; 98% white) underwent phenotyping. The mean number of concomitantly prescribed medications was 5.7, and 16 patients (37%) were receiving other CYP2D6 substrate or inhibitor drugs. The distribution of CYP2D6 phenotype was similar to that seen in other white populations. There was no correlation between the phenotypic metabolic ratio and age, the number of routinely taken medications, whether patients were receiving other prescribed substrate or inhibitor drugs of CYP2D6 (P = 0.63), or whether they were a robust responder (P = 0.47). CONCLUSIONS: Urinary assays of CYP2D6 phenotype are technically feasible in older individuals with dementia who are taking multiple medications, and may be a useful clinical tool in this population. However, the study was unable to make inferences about an association between CYP2D6 phenotype and galantamine responsiveness.

A novel model of HPV infection in meshed human foreskin grafts.

The present study describes a novel meshing procedure that provided successful low-risk papillomavirus propagation and reproducible wart induction in human foreskin xenografts. The initial HPV6 and/or 11 inocula were collected from clinically excised human wart tissues and confirmed to be free of HPV16, 18 and 31 by PCR analysis. Human foreskin grafts were collected from a circumcision clinic, and pre-inoculated with HPV virions by scarification. Meshing was carried out with a Zimmer Skin Grafter Mesher. Grafts were cut to appropriate size (1cm x 1cm or 5mm x 5mm) for cutaneous or subcutaneous grafting to NIH-nu-bg-xid mice under halothane anesthesia. Cutaneous xenografts were dressed with antibiotics and protective band-aids for 3 weeks. In the paralleled experiment using the same viral stock containing both HPV6 and 11, and matched grafts, no visible papillomas were observed in non-meshed cutaneous xenografts (n = 4 up to 6 months). In comparison, six of eight cutaneous xenografts treated with the meshing procedure formed visible papillomas within 4 months. This high frequency of distinct papilloma induction over the surface of meshed xenografts were reproduced in subsequent experiments with viral stocks containing both HPV11 and 6 (8 out of 10 grafts), or with a single-type HPV11 inoculum (80-100%). In contrast, an initial viral stock of single-type HPV6 provided lower frequency and more delayed papilloma induction. Serial passage of HPV6 in the meshed xenograft appeared to improve both the induction frequency and growth rate up to the 3rd generation. Histology, in situ hybridization, and immunohistochemical analysis revealed similarity of xenograft warts to those observed in the clinic. The highly reproducible papilloma induction rate and successful viral stock propagation associated with the meshing procedure provide a novel feature in the HPV xenograft model.

Estimating the prevalence of renal insufficiency in seniors requiring long-term care.

BACKGROUND: Renal function declines with age, but little is known about the extent of renal insufficiency among the institutionalized elderly. The objective of this study was to estimate the prevalence of low glomerular filtration rate (GFR) in a large sample of elderly adults living in long-term care facilities, and to compare two commonly used methods for estimating GFR. METHODS: A total of 9931 residents aged 65 years and older participated in a retrospective cross-sectional study of 87 long-term care facilities in Ontario. GFR was estimated by the Cockcroft-Gault and Modification of Diet in Renal Disease Study (MDRD) equations. The prevalence of low GFR, using the Cockcroft-Gault equation (<30 mL/min), was compared with the MDRD equation (<30 mL/min/1.73 m2). RESULTS: A total of 17.0% (95% CI 15.6 to 18.5) of men and 14.4% (95% CI 13.6 to 15.3) of women had a serum creatinine concentration above the laboratory reported upper reference limit of normal. The prevalence of both elevated serum creatinine and low GFR were observed to increase with age (P < 0.0001). The Cockcroft-Gault equation produced a consistently lower estimate of GFR than did the MDRD equation, a discrepancy most pronounced in the oldest residents. Among all men, a low GFR was more prevalent using the Cockcroft-Gault (10.3%, 95% CI 9.2 to 11.5) than MDRD (3.5%, 95% CI 2.8 to 4.2) equation, with a similar difference also seen in women (23.3%, 95% CI 22.4 to 24.3 versus 4.0%, 95% CI 3.6 to 4.5, respectively). Of all residents whose Cockcroft-Gault estimated GFR was under 30 mL/min, 14.7% (95% CI 13.2 to 16.3) were found to have GFR greater than 60 mL/min/1.73 m2 according to the MDRD equation. CONCLUSION: Age-associated renal impairment is common among elderly long-term care residents, but there exists a clear discrepancy between the Cockcroft-Gault and MDRD equations in predicting GFR. Consideration should be given to medication dose adjustment, based on a practical estimate of GFR. However clarification is needed about which method, if either, is most valid among the frail elderly. Complex patient and societal issues surrounding advanced care directives, treatments associated with renal insufficiency, and, if and when to initiate dialysis, require further attention.

Renal impairment and medication use among psychogeriatric inpatients.

OBJECTIVES: To determine the prevalence of renal impairment and the dosage appropriateness of several medications for which dosing guidelines in the advent of renal impairment are available. METHOD: The authors assessed the renal function and medication use of 37 psychogeriatric patients (mean age of 75 years) living in a psychiatric hospital. Renal function was determined by serum creatinine (SCr) levels and creatinine clearance (CCr) data using the Cockcroft and Gault equation. RESULTS: Thirteen of 37 patients (35%) were found to have renal impairment according to CCr data but only two patients (6%) were considered impaired according to SCr levels (k=0.19). Of 44 medications for which dosing guidelines were available, only two (5%) were prescribed inappropriately. CONCLUSION: These data suggest that CCr data should be used over SCr levels to determine renal impairment and to support the monitoring of psychogeriatric patients for declines in renal function and required medication adjustments.