Clinical chronopharmacology in the elderly

The behavior and effects of medications may be modified in the elderly. Factors contributing to such alterations may involve differences in drug pharmacokinetics and response and/or social and economic factors that affect nutrition and compliance to medications. Many studies have been devoted to such factors, but most of them have not taken into account chronopharmacologic data. Indeed, drug-administration time constitutes an additional factor of variability in drug response in the elderly. Biological rhythm-dependent differences in the kinetics and dynamics of medications seem to be diminished or altered with aging. Chronopathological (rhythmic aspects of disease) data in the elderly are of particular importance, taking into account frequently associated diseases, such as chronic obstructive pulmonary disease, cancer, diabetes, glaucoma, hypertension, and inflammatory conditions, among others. Although some chronobiological data are available, chronopharmacologic phenomena have yet to be extensively investigated in the elderly. Most of the sparse studies concern drug chronokinetics, but the data found in the literature do not reveal a clear trend in the age-related changes. Chronokinetic variations in the elderly, compared to young adults, suggest an amplification of the administration-time effects, as demonstrated for digoxin; dampening, as demonstrated for indomethacin; or detection of administration-time effects only in aged but not in young subjects, as found for others medications. Additional studies are needed to better understand the influence of age on the chronokinetics of medications. Moreover, the literature on possible administration-time differences in drug dynamics in the elderly is also very sparse. Altered receptor and/or post-receptor properties and impaired sensitivity of homeostatic mechanisms have yet to be studied from a chronopharmacological point of view. Thus, additional studies are needed to properly understand how drug responses in the elderly may vary in relation to the circadian timing of medications.     

Perspective on hypertension in the elderly.

More than half of elderly men and women have hypertension, leading to a significant risk of increased morbidity and mortality. The cause of hypertension in this age group is unknown. Left ventricular hypertrophy is frequently present, often associated with diastolic dysfunction. Systolic hypertension in the elderly increases the risk of cardiovascular disease, but there are no good data to show that the treatment of isolated systolic hypertension reduces the morbidity or mortality. Good evidence indicates that antihypertensive treatment in this group decreases cardiovascular morbidity and mortality up to age 80, so most elderly hypertensive patients should be treated. An empiric trial of nonpharmacologic therapy can be initiated in those with mild hypertension and no cardiovascular disease, but most patients will require drug therapy. Most elderly hypertensive patients have accompanying illnesses for which they may or may not be taking medications. Some antihypertensive drugs exacerbate coexisting diseases while others augment treatment regimens. Similarly, drugs may interact in a beneficial or adverse way. Finally, drug metabolism is altered by age, leading to problems with toxicity or diminished efficacy. The choice of medication should be based on all such considerations, including the cost and convenience of the drugs available.     

Effect of Age and Sex on Human Drug Metabolism

The capacity of inpatients in a geriatric hospital to metabolize drugs was measured. The mean plasma half-life values with antipyrine and with phenylbutazone were found to be 45% and 29% greater respectively in patients than in young controls. When women alone were considered the half-life of antipyrine was 78% longer in the elderly group. In a number of elderly individuals the rate of metabolism of these two drugs was found to be extremely slow. This decreased ability to metabolize drugs may contribute to the known high incidence of adverse drug reactions in the elderly.Within the control group a significant sex difference in the rate of antipyrine metabolism was found, the mean half-life being 30% longer in the males. It is clear from these results that the age and sex of subjects must be taken into account in studies of human drug metabolism.     

Connaître les particularités du traitement par antivitamine K chez le patient âgé ou comment minimiser leur iatrogénie ?

Elderly patients are commonly frail, due to a lot of comorbid conditions and numerous medications. These patients are at high risk of bleeding when treated with vitamin K antagonist (VKA). Special considerations on the choice of VKA drug, dosing and monitoring have to be taken into account in the elderly in order to avoid over-anticoagulation and to minimize the haemorrhagic risk which consequences may be dramatic or fatal in this age group. In these patients, INR monitoring is crucial, especially at the start of treatment. The use of dosing algorithms specifically developed for elderly patients allows to decrease over-anticoagulation during the initiation period. INR has to be monitored more frequently in case of acute illness or in case of modification of the associated drugs. Patient education is of great importance, even in geriatric patients and has been shown to improve the quality of anticoagulation. New oral anticoagulants with a wider therapeutic index seem to be of great interest.     

De-Intensification of Diabetes Treatment in Elderly Patients with Type 2 Diabetes Mellitus

Objective: De-intensification of diabetes treatment is recommended in elderly patients with tight glycemic control at high risk of hypoglycemia. However, rates of de-intensification in endocrine practice are unknown. We conducted a retrospective study to evaluate the rate of de-intensification of antidiabetic treatment in elderly patients with type 2 diabetes mellitus (T2DM) and tight glycemic control.Methods: All patients with ≥2 clinic visits over a 1-year period at a major academic diabetes center were included. De-intensification of diabetes treatment was defined as a decrease or discontinuation of any antidiabetic drug without adding another drug, or a reduction in the total daily dose of insulin or a sulfonylurea drug with or without adding a drug without risk of hypoglycemia.Results: Out of 3,186 unique patients, 492 were ≥65 years old with T2DM and hemoglobin A1c (HbA1c) <7.5% (<58 mmol/mol). We found 308 patients treated with a sulfonylurea drug or insulin, 102 of whom had hypoglycemia as per physician note. Among these 102 patients, 38 (37%) were advised to de-intensify therapy. In a subgroup analysis of patients ≥75 years old with HbA1c <7% (<53 mmol/mol), we found that out of 23 patients treated with a sulfonylurea drug or insulin and reporting hypoglycemia, 11 (43%) were advised de-intensification of therapy. There were no significant predictors of de-intensification of treatment.Conclusion: Our study suggests that de-intensification of antidiabetic medications is uncommon in elderly patients with T2DM. Strategies may need to be developed to prevent the potential harm of overtreatment in this population.Abbreviations: ADA = American Diabetes Association; CGM = continuous glucose monitoring; HbA1c = hemoglobin A1c; T2DM = type 2 diabetes mellitus; UKPDS = United Kingdom Prospective Diabetes Study     

68例服胺碘酮的75岁以上老年心律失常患者甲功变化分析

目的：探讨口服小剂量胺碘酮对老年心律失常患者甲状腺功能的作用和影响。方法：回顾性分析老年器质性心脏病心律失常患者68例,记录胺碘酮治疗方案与疗效、甲状腺变化及随访干预措施情况。结果：老年人服用胺碘酮引起甲状腺疾病发生率为31．8％（22／68）,以甲状腺功能减退25．7％（18／68）为主,大致为甲状腺功能亢进（6．1％,4／68）的4倍。采用小剂量胺碘酮方案出现的甲状腺功能紊乱多数经过减量或停药逆转或恢复。结论：老年人服用胺碘酮甲状腺功能紊乱发生率高,但临床表现不典型,应更密切地监测甲状腺功能;甲状腺功能紊乱经胺碘酮及时减量或停药等措施多能逆转或恢复。     

Propuesta de desarrollo de una unidad de oncogeriatría. Tiempos de cambio: nuestra realidad

Age is one of the main risk factors for the development of cancer. It is expected that the progressive aging of the population will have an unprecedented impact on the incidence of various tumours. In fact, the management of elderly cancer patients is already a major public health problem in developed countries. However, elderly patients have systematically been excluded from cancer drug studies or protocol development. This has left health professionals in uncharted territory, without proper tools to address the multiple difficulties that arise in the treatment of these patients. A comprehensive geriatric assessment may serve as an ideal tool for the correct detection of hidden problems, facilitating treatment decisions in these complex patients, and integrating the care of patients with comorbidities.     

Can geriatrics survive?

Geriatrics has consistently failed to attract enough staff, and hence geriatric units often cannot provide a full service for the elderly. Meanwhile beds in general medical units may be blocked by elderly patients. This division between geriatric and medical units is arbitrary and wasteful. There are no clinical processes or techniques unique to geriatrics, which is probably why the specialty is unattractive; few doctors want to confine their attention only to the elderly. Geriatrics as a separate specialty should therefore be largely abandoned and the care of the elderly reintegrated into general medicine.     

老年与中青年患者下呼吸道感染病原菌的对比分析

目的对比分析老年与中青年患者下呼吸道感染病原菌的分布规律及其耐药性特点,以指导临床合理用药。方法将研究对象分为老年(≥60岁)和中青年(20～59岁)2组;采用API系统进行菌种鉴定;采用K-B法进行药敏试验;采用纸片扩散表型确证法进行超广谱β-内酰胺酶(ESBLs)测定;采用SPSS 13.0进行χ2检验。结果老年组的真菌分离率显著高于中青年组,以白色假丝酵母菌最多;中青年组的G-杆菌分离率显著高于老年组,以铜绿假单胞菌最多;老年组主要致病菌对多数药物的耐药率比中青年组有增高趋势,但差异多无统计学意义;老年组肺炎克雷伯菌的ESBLs阳性率显著高于中青年组。结论老年与中青年患者下呼吸道感染的病原菌分布及耐药性存在一定差异。     

Safety of treatment for subclinical osteomalacia in the elderly.

Forty one elderly patients admitted to hospital for acute illnesses were also found to have subclinical osteomalacia. Immediately before discharge, therefore, all were randomised to receive either vitamin D2 25 micrograms daily, alfacalcidol 0.5 micrograms daily, or placebo. Treatment was given for at least three months, those allocated to placebo then being switched to an active drug. Within the first three months of treatment with either of the active drugs most patients had exhibited a fall to normal in osteoid values. In only four treatment periods was there a mild increase in serum calcium concentration, and in no patient was this accompanied by deterioration in renal function. Any increase in serum creatinine concentration was invariably attributable to the underlying disease for which the patient had been admitted in the first place. Subclinical osteomalacia in the elderly may be corrected by relatively low doses of alfacalcidol (0.5 micrograms daily) or vitamin D2 (25 micrograms daily) given for three months. Such treatment is safe and not accompanied by a serious risk of hypercalcaemia or renal impairment.     

Estimación del filtrado glomerular en el paciente anciano. Implicaciones clínicas en el uso de antibióticos

IntroductionIn elderly, impaired kidney function may lead to relevant clinical implications, especially in drug dosage. There is no consensus on the best formula to estimate glomerular filtration rate (GFR) in this context. While the Cockcroft–Gault (CG) equation is the most used one in drug development, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is the most employed by clinical laboratories. The objective of this study is to analyze the differences and implications of using one or another equation when adjusting the dose of antibiotics.Material and methodsCross-sectional study performed in patients older than 80 years admitted to an acute geriatric unit for infectious disease. Socio-demographic, functional, clinic, assistance and laboratory variables were gathered, calculating GFR according to CG and CKD-EPI. A concordance study between both equations, bivariate analysis and multiple linear regression were carried out.Results100 patients were recruited, with mean age 88.5 ± 4.2 years, and 54% women. A relative overestimation of 13.63 mL/min was observed in GFR according to CKD-EPI, with a low-moderate concordance between both formulas. Greater need for dose adjustment of antibiotics with GC than with CKD-EPI was detected (38% vs. 23%; P < .001), as well as dosage discrepancies, especially with levofloxacin.ConclusionsBoth equations are not interchangeable in the elderly. When used to adjust antibiotic dose, CKD-EPI may overestimate GFR and may cause an increase in adverse reactions. Further studies should be carried out with the aim of reaching a consensus on the most appropriate equation for the elderly patient.     

Regulatory issues in aging pharmacology

Many current drugs increase the average lifespan by preventing fatal diseases or by slowing down the progressive degenerative diseases that increase mortality. The existing strategies and guidelines for the development and regulatory approval of new drugs are designed for such compounds. Rapid advances in understanding molecular mechanisms of aging make it possible to envisage future drugs that extend the lifespan by regulating aging mechanism outside of disease pathways. Strategies for development and regulatory approval of such drugs remain to be defined. Since the drug candidates will be given to healthy, elderly subjects, safety requirements will be extremely high. Clinical studies of many years' duration will be necessary to prove changes in longevity. These time intervals may exceed those of patent protection and thus minimize commercial incentives. Despite these challenges, two broadly defined pathways are feasible. First, it may be possible to obtain public funding for studies with voluntary participation of humans consuming existing drugs or natural compounds in the 'expected to be safe' category. Second, the development of novel drugs may proceed on the basis of well-defined biomarkers of aging that can serve as surrogate end points in clinical studies. The emerging approaches will prompt the regulatory agencies into taking the first steps towards regulatory guidance.     

Gender differences and the interpretation of genetic instability in Alzheimer's disease.

The neuronal degeneration and death which characterize Alzheimer's disease (AD) may stem from a constitutive genetic instability related to DNA repair deficits. To test this hypothesis, we treated peripheral blood lymphocytes from persons with AD, age-matched controls, and young controls with two drugs that induce chromosome breakage. Bleomycin, a radiomimetic antineoplastic drug, causes single- and double-stranded DNA breaks through the generation of activated oxygen radicals. Methyl methane-sulfonate (MMS) is a monofunctional alkylating agent that binds covalently to DNA. Cells were grown in culture for 72 h, with drug treatments for 4 h (bleomycin) or 24 h (MMS) prior to harvest. Fifty cells per subject per drug were scored for chromosome breakage. Breakage rates for both drugs in AD women were significantly higher than those in age-matched control women. This was not the case in men, due to the very high induced breakage rates seen in the age-matched normal control men. Because the induced breakage rates in AD women and AD men are equivalent, it seems likely that an independent factor may be contributing to genetic instability in the normal control men. Our findings indicate that the interpretation of the response of AD lymphocyte chromosomes to DNA-damaging chemicals can be strongly confounded by the effects of gender ratio in the control population sampled. These findings have important implications for the design of future studies of Alzheimer's disease, as well as for the assessment of health risks in unaffected elderly populations.     

老年肝硬化并发自发性腹膜炎临床特点及病原学分析

目的探讨老年肝硬化并发自发性腹膜炎(SBP)患者的临床特点及腹水病原菌分布及其耐药情况,指导临床合理用药。方法回顾性分析老年肝硬化并发SBP患者的临床特点,并对118例腹水病原菌培养结果阳性的120株病原菌进行鉴定和耐药分析。结果365例SPB患者治愈113例(31.0%),好转99例(27.1%),病情恶化自动出院及死亡153例(41.9%)。发病隐匿164例(44.9%),急性发病201例(55.1%)。365例SBP患者腹水病原菌培养阳性118例(32.3%),共分离出病原菌120株,其中大肠埃希菌检出率最高,占40.0%(48/120),其次为肺炎克雷伯菌,占12.5%(15/120)。分离菌株的耐药情况比较严重,特别是大肠埃希菌对多种抗菌药物的耐药率60%。结论老年肝硬化并发SBP患者病情复杂,病死率高,且细菌耐药比较严重,应尽早进行腹水培养,依据药物敏感试验结果合理选用抗菌药物。     

Oncocytic nodule. An unusual case of a submaxillary gland mass in an elderly patient

A submaxillary gland mass in an elderly woman was diagnosed as an oncocytic nodule by cutting needle biopsy and was followed with serial fine needle aspiration (FNA) biopsy for seven years. All specimens showed pure populations of oncocytes. Oncocytic nodules of the salivary gland are unusual lesions that may represent hyperplastic proliferations or true neoplasms. Although oncocytic metaplasia is commonly identified in the salivary glands of elderly patients, oncocytes rarely form masses that are targets for needle biopsy. This case suggests that FNA biopsy may be a useful method of evaluating salivary gland lesions in elderly patients who are not candidates for surgery.     

Clinical Trial of Emepronium Bromide in Nocturnal Frequency of Old Age

A double-blind cross-over trial of emepronium bromide (Cetiprin) in nocturnal frequency of micturition in a group of elderly women living in their homes showed that the drug was superior to placebo in diminishing urinary frequency, though not every person benefited. It is suggested that the drug may alter the established habit of rising at night to pass urine. Side-effects were negligible.