Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians.

In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients.Measurements of fluindione concentrations and international normalized ratio (INR ) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixed-effects modeling, and the parameters were estimated using MONOLI X 3.2. The pharmacokinetics (PK) of fluindione was monocompartmental, whereas the evolution of INR was modeled in accordance with a turnover model (inhibition of vitamin K recycling). Interindividual variability (II V) was very large. Clearance decreased with age and with prior administration of cordarone. Patients who had undergone surgery before the study had lower IC50 values, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione.

Early detection of patients in the pre demented stage of Alzheimer's disease: the Pre-Al Study.

OBJECTIVES: The aim of the Pre-Al study is to evaluate and compare the predictive value of different tools for an early identification of Alzheimer's disease. DESIGN AND PARTICIPANTS: Patients coming for consultation to memory clinics without dementia were included if they had an objective memory or attention trouble assessed by a MMSE score > 25 (with at least one missing item at the words recall) and / or an Isaac set test score < 28. All were examined by a neuropsychological battery (Free and Cued Selective Reminding Test, digit ordering test, WAIS-R digit symbol, Trail making test, Benton visual retention test, verbal fluency, confrontation naming and Baddeley's double task test). A subpopulation received an MRI and SPECT assessment. RESULTS AND DISCUSSION: 251 patients were included (mean age: 72.0 years; mean education duration: 10.9 years). Validation of the predictive tests will be based on the comparison of these tests in patients developing dementia and others, after a follow-up of at least 3 years. This paper presents methodology of the study and the population description.

Amnestic syndrome of the medial temporal type identifies prodromal AD: a longitudinal study.

OBJECTIVE: To compare the power of tests assessing different cognitive domains for the identification of prodromal Alzheimer disease (AD) among patients with mild cognitive impairment (MCI). BACKGROUND: Given the early involvement of the medial temporal lobe, a precocious and specific pattern of memory disorders might be expected for the identification of prodromal AD. METHODS: A total of 251 patients with MCI were tested at baseline by a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for verbal episodic memory; the Benton Visual Retention Test for visual memory; the Deno 100 and verbal fluency for language; a serial digit learning test and the double task of Baddeley for working memory; Wechsler Adult Intelligence Scale (WAIS) similarities for conceptual elaboration; and the Stroop test, the Trail Making test, and the WAIS digit symbol test for executive functions. The patients were followed at 6-month intervals for up to 3 years in order to identify those who converted to AD vs those who remained stable over time. Statistical analyses were based on receiver operating characteristic curve and Cox proportional hazards models. RESULTS: A total of 59 subjects converted to AD dementia. The most sensitive and specific test for diagnosis of prodromal AD was the FCSRT. Significant cutoff for the diagnosis was 17/48 for free recall, 40/48 for total recall, and below 71% for index of sensitivity of cueing (% of efficacy of semantic cues for retrieval). CONCLUSIONS: The amnestic syndrome of the medial temporal type, defined by the Free and Cued Selective Recall Reminding Test, is able to distinguish patients at an early stage of Alzheimer disease from mild cognitive impairment non-converters.

[Cholinesterase inhibitor therapy in long term care settings]. / Les anticholinestérasiques en soins de longue durée: analyse des pratiques actuelles à partir d'une étude observationnelle francoquébécoise.

PURPOSE: Cholinesterase Inhibitors (ChEIs) have proven efficacy in outpatients with mild to moderate Alzheimer's Disease (AD). The benefits of maintaining this treatment once patients are institutionalised remain controversial. The aim of this study was to present current therapeutic strategies regarding ChEIs use in long-term care settings (LTC). METHODS: A multicentric, retrospective, observational study was conducted on currently available ChEIs (donezepil, rivastigmine, galantamine) prescribed in LTC. Data were obtained from medical records. Judgement was based on three criteria: ChEIs indication, follow-up, and justification for maintenance of treatment. RESULTS: Among the 1,373 patients evaluated, 6% (N=81) were receiving ChEIs. They represented various stages of the disease, with cognitive and functional decline ranging from severe (18%) to very mild (10%). Among patients receiving ChEIs, 29% met neither the indication for which these drugs were approved, nor professional guidelines. Patient evaluation at entry was of high quality, with 90% of records including cognitive, functional and behavioural evaluation. Follow-up evaluations were weaker, with at least one assessment domain missing in 40% of the medical records. ChEIs treatment was maintained, although almost half of patients experienced a worsening of their clinical state. CONCLUSION: This study shows that follow-up of institutionalised patients receiving ChEIs could be improved. While treatment maintenance seems to be the rule, it should be questioned on ethical, efficacy, and economic grounds. The rationale for use and discontinuation of these therapeutic strategies in institutional settings requires urgent review.

Cerebrospinal fluid MR dynamics and risk of falls in the elderly.

RATIONALE AND OBJECTIVES: To investigate the relationship between CSF dynamics and risk of falls of unknown origin in the elderly. POPULATION AND METHODS: Phase contrast MR studies allowed CSF aqueductal flow quantification on 23 community-dwelling older people initially explored for mild cognitive impairment. Mobility assessment included report of falls, talking walking test, stance test, one leg standing test, up and go test, and measurement of fast gait speed. RESULTS: History of falls was associated with larger aqueduct, steeper diastolic slopes higher ratios RDV/SD of diastolic volume/CSF systole duration (p

[Cutaneous lymphangitic carcinomatosis and acquired ichtyosis associated with prostatic carcinoma]. / Lymphangite carcinomateuse et ichtyose acquise associées à un adénocarcinome prostatique.

BACKGROUND: Prostatic adenocarcinoma is exceptionally associated with cutaneous lesions. We describe a patient with cutaneous lymphangitis and paraneoplastic ichtyosis related to prostatic cancer. CASE REPORT: A 92 year-old man had been treated for five years for a prostatic carcinoma. An angiomatous lesion developed with in 3 months near the right breast. Physical examination revealed axillary node enlargement, a large skin angiomatous lesion, and ichtyosis. The skin biopsy of the angiomatous skin lesion demonstrated its prostatic origin with carcinomatous metastases in the lymphatic vessels. The ichtyosis was considered as paraneoplastic. DISCUSSION: Cutaneous metastases from prostatic carcinoma are rare. Less than 1 p. 100 of cutaneous metastases are of prostate origin despite the high frequency of this cancer in the general population. The clinical aspects - angiomatous lesion and paraneoplastic ichtyosis - are exceptional.

[Transpupillary thermotherapy for treatment of choroidal melanomas]. / Thermothérapie transpupillaire dans le traitement du mélanome de la choroïde.

PURPOSE: To report the results of transpupillary thermotherapy (TTT) for selected posterior pole choroïdal melanomas. MATERIAL AND METHODS: Prospective study including 56 patients (mean age of 61 years) with choroidal melanoma treated with TTT. All treated tumors had either documented growth or clinical risk factors for future growth and for metastasis. The injection of infracyanine green (I CG) was randomized. RESULTS: The mean initial tumor basal diameter was 7.8 mm and tumor thickness was 3 mm. Twenty-seven tumors (48%) touched the optic disc and sixteen (29%) were under the fovea. Among these 56 patients with choroidal melanoma, 47 patients (84%) presented with primary choroidal melanoma. 9 tumors (16%) were late recurrences after conservative treatment. A mean of three treatment sessions was delivered. After a mean follow-up of 30 months, tumor regrowth was documented in 4 patients (7%) and the visual acuity was the same than the pretreatment acuity in 26 eyes (47%). The mean final thickness was 1.8 mm (percent reduction of tumor thickness was 39%). Intraocular complications included retinal fibrosis and/of retinal striae in 12 eyes (22%) and vascular occlusion in 14 eyes (25%). No statistical impact of ICG administration on the tumor regression was demonstrated. CONCLUSIONS: This series confirms the efficacy of transpupillary thermotherapy in the management of selected posterior pole choroïdal melanomas.

[Heart insufficiency in the elderly]. / Insuffisance cardiaque du sujet âgé.

Congestive heart failure in the elderly differs from the one in the younger. The ageing of the cardiovascular system makes the organism weaker. When a myocardial infarction or an other cardiovascular disease happens, the occurrence of congestive heart failure is precipitated. The symptoms which are often misleading and the polypathologies make the assumption of relationship difficult between a symptom like dyspnea and congestive heart failure. Further examinations are limited because of the reduced physical performances in the elderly (stress test) or because of an increased risk of side-effects (coronary angiogram). The echocardiography has a central role in the exploration of congestive heart failure. The medical treatment has the same principles than in the younger but with cautions especially regarding the renal insufficiency and the multiple treatments that an elderly patient has.

Emergency hospitalization in the elderly in a French university hospital: medical and social conditions and crisis factors precipitating admissions and outcome at discharge.

Emergency admissions of elderly patients constitute a major management issue due to the complexity of their problems. The aim of this retrospective observational study was to identify medical and social characteristics and crisis factors for emergency department (ED) hospitalization in elderly patients, and to evaluate the influence of these factors on the length of stay and outcome at discharge. During a 4-month period, 396 patients aged 70 years and older were referred to the ED of a University Hospital (Hjpital Edouard Herriot) in Lyon, France. A questionnaire specifically designed for the study was completed for each patient using the information in the patients' files previously filled in by the "Rapid Geriatric Assessment Team" of the ED. We described civil and marital status, living conditions, reason for admission to ED and other associated pathologies according to the ICM-9, crisis factors, length of stay (LOS) and outcome at discharge. The mean age was 81.9 years (SD 6.5); two thirds (66.7%) of the study subjects were female, and 46.7% were widowed; the majority (68.7%) lived in their own homes. The main reasons for admission were cardiopulmonary diseases in 31.6% of cases, followed by neuropsychiatric disorders in 28.2%, and falls in 8.3%; a final category (31.8%) included subjects admitted for general, non-specific symptoms. Among the crisis factors observed, 49.4% presented an acute episode of a chronic illness, 33.6% lived alone, and 20.9% had been hospitalized during the 6-month period preceding the study. The average LOS was 3.15 days. The multivariate model showed that falls increase LOS by 74%, dementia by 65%, and depression by 21%. Upon discharge, 13% returned to their residence before hospitalization, 55% were transferred to a medical speciality ward, and 4% to other facilities, whereas only 19% were transferred to a geriatric ward, and 9% died during their stay in the ED. The multinomial model showed that outcome at discharge was influenced by functional dependency, dementia, depression, and acute episodes of a chronic illness. For many elderly, the ED remains a critical point of access to more complete managed care. This elderly population is comprised of polypathological, frail persons whose morbid state requires multidisciplinary management in geriatric units. The findings of this study suggest that interventions of multidisciplinary networks, such as home health care programs aimed at detecting crisis factors and establishing early prevention of crisis states, may improve unfavorable medical and social conditions and reduce hospitalization in geriatric patients.

Dehydroepiandrosterone replacement administration: pharmacokinetic and pharmacodynamic studies in healthy elderly subjects.

Dehydroepiandrosterone (DHEA; 50 and 25 mg) and placebo tablets were orally administered daily to 24 healthy aging men and women (67.8 +/- 4.3 yr) for 8 days according to a balanced incomplete block design. Nine blood tests on both the first and eighth days allowed the measurement of DHEA, its sulfate DHEAS, and metabolites: testosterone, 5alpha-androstan-3alpha,17beta-diol glucuronide, estradiol, and estrone. Relatively low background levels of DHEA(S) were observed, and with the reestablishment of "young" levels, four important results were obtained. 1) Blood DHEA had an apparent terminal half-life of more than 20 h, the same order of magnitude as that of blood DHEAS, a result explainable by back-hydrolysis of the large amount of DHEAS formed after oral administration of DHEA, a mechanism providing long-lived unconjugated DHEA and metabolites. 2) The metabolic conversion of DHEAS to DHEA was significantly greater in women than in men. 3) No accumulation of steroids was observed. 4) No worrying transformation to androgen and estrogen was recorded; indeed, the limited increased estradiol in aged women could be predicted to be beneficial. These results suggested that daily oral administration of DHEA (25/50 mg) is safe in elderly subjects. The 50-mg dose was chosen for a 1 yr, double blind, placebo-controlled trial of daily oral administration of DHEA in 60- to 80-yr-old individuals (DHEAge).

Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue.

The secretion and the blood levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) decrease profoundly with age, and the question is posed whether administration of the steroid to compensate for the decline counteracts defects associated with aging. The commercial availability of DHEA outside the regular pharmaceutical-medical network in the United States creates a real public health problem that may be resolved only by appropriate long-term clinical trials in elderly men and women. Two hundred and eighty healthy individuals (women and men 60-79 years old) were given DHEA, 50 mg, or placebo, orally, daily for a year in a double-blind, placebo-controlled study. No potentially harmful accumulation of DHEAS and active steroids was recorded. Besides the reestablishment of a "young" concentration of DHEAS, a small increase of testosterone and estradiol was noted, particularly in women, and may be involved in the significantly demonstrated physiological-clinical manifestations here reported. Bone turnover improved selectively in women >70 years old, as assessed by the dual-energy x-ray absorptiometry (DEXA) technique and the decrease of osteoclastic activity. A significant increase in most libido parameters was also found in these older women. Improvement of the skin status was observed, particularly in women, in terms of hydration, epidermal thickness, sebum production, and pigmentation. A number of biological indices confirmed the lack of harmful consequences of this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects of aging, but does not create "supermen/women" (doping).

[Characteristics of pain and pain management in the elderly]. / Particularités de la douleur et de sa prise en charge chez les personnes âgées.

A COMMON SYMPTOM: Pain is a common and underestimated problem in older people who are likely to suffer from many acute and chronic conditions. DIFFICULT ASSESSMENT: Clinical assessment of pain often depends on the patient's ability to communicate his or her experience. If self-assessment of pain is not possible, behavioral hetero-evaluation instruments have been built for easy pain assessment by caregivers. ADJUSTED PAIN MANAGEMENT: As for younger patients, the most common strategy for pain management is the use of analgesic drugs. Special care should be taken however when such drugs are initiated in the elderly because increased sensitivity, prolonged drug half-life and adverse effects and drug interactions are more likely.

Digital necrosis revealing ovarian cancer.

We describe a 57-year-old woman who developed permanent acrocyanosis of all fingers rapidly leading to distal necrosis, revealing an ovarian cancer (OC). Seven similar published cases are reviewed. Digital ischaemia was bilateral, severe and frequently complicated by digital necrosis. OC was of epithelial origin and disseminated at the time of diagnosis. Initial treatment of OC usually resulted in improvement of digital ischaemia. A possible OC should be looked for in women aged 45 years or more presenting with severe digital ischaemia of recent onset.

The aging process modifies the distensibility of elastic but not muscular arteries.

Aging decreases the distensibility of large elastic arteries; however, the effects of age on the functional parameters of muscular, medium-sized arteries are not well determined. This study evaluated the consequences of aging on the functional parameters of the carotid and radial arteries in normotensive men. A total of 62 elderly subjects (aged 74+/-2 years) were compared with 87 young subjects (aged 35+/-3 years). Internal diameter and intima-media thickness (IMT) were measured by a high-resolution echo-tracking system to calculate distensibility and incremental elastic modulus (Einc). Although in the normal range, systolic and diastolic blood pressure levels were statistically different in the 2 groups at 128+/-19 and 74+/-13 mm Hg versus 121+/-27 and 71+/-18 mm Hg in the young and elderly subjects, respectively (P<0.05). At the carotid artery level, elderly subjects exhibited a greater IMT (742+/-144 versus 469+/-132 microm; P<0.01) and internal diameter (7067+/-828 versus 6062+/-1026 microm; P<0.01) than young subjects; elderly subjects also had lower distensibility (12+/-2 versus 21+/-2 kPa(-1) x 10(-3); P<0.01) and higher Einc (0.9+/-0.2 versus 0.7+/-0.3 kPa x 10(3); P<0.01). At the radial artery level, both IMT (240+/-42 versus 218+/-51 microm; P<0.01) and internal diameter (2685+/-432 versus 2491+/-444 microm; P<0.01) were greater in elderly subjects, but no differences in distensibility and Einc were observed between the 2 groups. All differences remained significant, even after adjusting for mean blood pressure. These results indicate that the increase of the internal diameter and IMT observed during the aging process can have opposite effects on the functional parameters of large elastic or medium-sized muscular arteries.

[Antihypertensive treatment can normalize the geometry and the arterial function in the aged patient]. / Le traitement antihypertenseur peut normaliser la géométrie et la fonction artérielle chez le sujet âgé.

The aging process and the elevation of arterial blood pressure (BP) have synergistic effects on the modifications of the arterial system. The effects of the treatment on these modifications are unknown. Our objective was to study the consequences of anti-hypertensive treatment on the geometry and function of the arteries in men over 70 years old. In 89 men aged 74 +/- 2 years, we measured internal diameter and intima-media thickness (IMT) of carotid and radial arteries using high resolution echography (WALL TRACK SYSTEM and NIUS-02), and carotid-femoral pulse wave velocity (PWV) by COMPLIOR. The BP was measured in supine position by Dinamap. In 28 subjects the BP was more than 140/90 mmHg (poor controlled hypertensives-HTpc); in the subjects where BP < 140/90 mmHg, 44 were normotensives (NT) without treatment and 17 were well controlled hypertensives (HTwc) on use of at least one antihypertensive. [table: see text] The PWV was increased in HTpc (20.1 m/s) in comparison with NT (14.6 m/s) and HTwc (16.1 m/s) (p < 0.05). The operational distensibility of radial artery was similar in the three groups. In conclusion, in elderly men aged more than 70 years, the anti-hypertensive treatment can normalize the functional properties and the geometry of muscular and elastic arteries. These results indicate that the arterial modifications observed in elderly hypertensives are consequence of the high blood pressure per se and not only consequent the modifications due to the aging.

Is the LDL receptor-related protein involved in Alzheimer's disease?

LDL-related protein receptor (LRP) is the main receptor in the brain for apolipoprotein E. Moreover, the LRP gene is located on chromosome 12, the site of a potential Alzheimer's disease (AD) locus. We explored the association between the LRP gene and AD in 600 French Caucasian patients (37.8% men, mean age 72.0+/-8.0 years, mean age at onset 68.7+/-8.1 years) and age-matched controls (n=646, 37.0% men, mean age 72.5+/-8.2 years) and observed an association between a (TTTC) repeat at the 3' end of an Alu sequence in the LRP gene and the risk of developing AD. Three alleles were detected in this population [corresponding to 83, 87, and 91 base pairs (bp)], the 91-bp allele being associated with an increased risk of developing AD [all patients: odds ratio (OR) 1.6, P<0.01; late-onset AD: OR 1.8, P<0.01]. This suggests an association between the LRP locus and AD. However, in the light of studies related to the exon 3 LRP polymorphism and given the low strength of the association reported here, a biologically active variant may exist on chromosome 12, either in the LRP gene itself or in another gene in the vicinity.

Peripheral antioxidant enzyme activities and selenium in elderly subjects and in dementia of Alzheimer's type--place of the extracellular glutathione peroxidase.

Defenses against free radical damage were determined in red blood cells and plasma from 40 patients with dementia of the Alzheimer-type (DAT) and 34 aged control subjects with normal cognitive function. No crude significant difference in erythrocyte copper-zinc superoxide dismutase (E-CuZnSOD), seleno-dependent glutathione peroxidase (E-GSH-Px), glutathione reductase (E-GSSG-RD) activities, and selenium (Se) concentration was found between DAT cases and control subjects. The peroxidation products evaluated in plasma by the thiobarbituric-reactive material (TBARS) were at the same level in the DAT group as compared to controls. In the DAT group, plasma GSH-Px (P-GSH-Px) activity and plasma Se (P-Se) were negatively correlated with age (r = -0.58; p < 0.001 and r = -0.63; p < 0.001 respectively). Moreover, erythrocyte GSH-Px activity and Se were also negatively correlated with age (r = -0.40; p < 0.01 and r = -0.46; p < 0.01, respectively). No significant correlation with age was observed in the controls. When controlling for age, a significant increase for P-GSH-Px activity and P-Se was observed in DAT patients as compared to controls. These significant differences mostly appeared in DAT subjects under 80 years. Some correlations were only observed in the DAT group such as P-GSH-Px and E-GSH-Px (r = +0.68; p < 0.001); P-GSH-Px and E-Se (r = +0.79; p < 0.001). Correlations between P-GSH-Px and P-Se, E-GSH-Px and P-Se, and P-Se with E-Se are greater in the DAT group (r = +0.84; p < 0.001; r = +0.76; p < 0.001 and r = 0.75; p < 0.001) than in the control group (r = 0.54, pI < 0.01; r = 0.43, p < 0.01 and r = +0.34, p < 0.05 respectively). The fact that first -- a significant increase in P-GSH-Px and P-Se, second -- some modifications in the relationships between antioxidant parameters, and third -- age-dependent decreases of glutathione-peroxidase activities and their cofactor, appeared only in the DAT group suggest that DAT is associated with an oxidative stress due to an imbalance between reactive oxygen species and the peripheral antioxidant opposing forces.