Showing papers in "Drugs & Aging in 1998"

Epidemiology of Medication-Related Falls and Fractures in the Elderly

Abstract: About 30% of people aged over 65 years living in the community fall at least once a year; the fall rate is even higher in nursing homes. Many of these falls lead to fractures, the most serious type being hip fractures. Whether or not the use of various medications causes falls and fractures has been the subject of more than 50 observational epidemiological studies, most published after 1988. Few of these studies were specifically designed to investigate the associations between medication use and falls, so most have methodological limitations. Uncontrolled confounding factors are a particular problem. It is important to recognise these flaws in study design when reviewing the scientific literature on the link between medications and falls and fractures. Patients taking psychotropic medications appear to have about a 2-fold increased risk of falls and fractures, compared with individuals not taking these drugs. The strongest evidence is for antidepressants; nearly every relevant study has found an association with falls. The relative effect of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors and tricyclic antidepressants on falls is still unknown. The effect on the risk of falling of short-acting versus long-acting benzodiazepines is not straightforward: it may be the benzodiazepine dosage that matters, rather than the drug half-life. Whether or not any medications used to treat cardiovascular problems cause falls remains unclear. Current evidence suggests that diuretics, in general, do not cause falls and that thiazide diuretics, in particular, may help prevent fractures by slowing the development of osteoporosis. Some studies have found that use of nonsteroidal anti-inflammatory drugs is associated with falling; this deserves further study. Reducing the use of psychotropic drugs by residents of nursing homes should be a high priority for physicians, pharmacists and nursing staff. Psychotropic drug use should also be kept to a minimum among older people living in the community.

Important drug-drug interactions in the elderly.

Abstract: Although drug-drug interactions constitute only a small proportion of adverse drug reactions, they are important because they are often predictable and therefore avoidable or manageable. Their frequency is related to the age of the patient, the number of drugs prescribed, the number of physicians involved in the patient's care and the presence of increasing frailty. The most important mechanisms for drug-drug interactions are the inhibition or induction of drug metabolism, and pharmacodynamic potentiation or antagonism. Interactions involving a loss of action of one of the drugs are at least as frequent as those involving an increased effect. It is likely that only about 10% of potential interactions result in clinically significant events and, while death or serious clinical consequences are rare, low-grade, clinically unspectacular morbidity in the elderly may be much more common. Nonspecific complaints (e.g. confusion, lethargy, weakness, dizziness, incontinence, depression, falling) should all prompt a closer look at the patient's drug list. There are a number of strategies that can be adopted to decrease the risk of potential clinical problems. The number of drugs prescribed for each individual should be limited to as few as is necessary. The use of drugs should be reviewed regularly and unnecessary agents withdrawn if possible, with subsequent monitoring. Patients should be encouraged to engage in a 'prescribing partnership' by alerting physicians, pharmacists and other healthcare professionals to symptoms that occur when new drugs are introduced. Physicians with a responsibility for elderly people in an institutional setting should develop a strategy for monitoring their drug treatment. For those interactions that have come to clinical attention, it is important to review why they happened and to plan for future prevention. Clinicians should also report, via the appropriate postmarketing surveillance scheme, any drug-drug interactions they have encountered. Finally, multidisciplinary education about the nature of physiological aging and its effect on drug handling, and the possible presentations of drug-related disease in older patients, is an important element in reducing interactions in the elderly.

Rivastigmine: A review of its use in Alzheimer's disease

Abstract: UNLABELLED Rivastigmine (SDZ ENA 713) is a carbamylating, long-acting reversible and noncompetitive carbamate acetylcholinesterase inhibitor that is indicated as an oral treatment for patients with mild to moderately severe Alzheimer's disease. The drug has been evaluated for this use in 3 well designed, adequately powered, phase II/III, 26-week clinical trials that included a total of 1479 rivastigmine and 647 placebo recipients. Most of these patients had concomitant disorders that were being treated with numerous other drugs. Individual and pooled results of these trials indicate that rivastigmine 6 to 12 mg/day usually produces cognitive, global and functional changes that indicate significantly less deterioration than was observed with placebo in patients with mild to moderately severe Alzheimer's disease. Individual results of the 2 pivotal trials and pooled analysis also show that, compared with placebo recipients, significantly more rivastigmine 6 to 12 mg/day recipients respond to therapy. Indeed, after 26 weeks of therapy in the 2 pivotal trials, significantly more rivastigmine 6 to 12 mg/day than placebo recipients achieved clinically meaningful improvements as defined by 3 separate response criteria. The lower dosage range of 1 to 4 mg/day was not as effective as 6 to 12 mg/day, as measured using these criteria and other efficacy parameters. Rivastigmine causes adverse events that are generally those expected from an acetylcholinesterase inhibitor. They are usually mild to moderate, of short duration and responsive to dosage reduction. Unpublished data from 3989 patients indicate that rivastigmine and placebo were associated with similar incidences of serious adverse events and changes in laboratory parameters, ECG and cardiorespiratory vital signs. The most common events were gastrointestinal, central and peripheral nervous system and whole body adverse events. However, compared with placebo, rivastigmine more commonly caused adverse events resulting in treatment withdrawal. These events were most frequently gastrointestinal and were more common in women. CONCLUSION Rivastigmine is a useful option for the treatment of patients with mild to moderately severe Alzheimer's disease. Although only short term (6- month) comparisons with placebo are available, given the lack of established treatment options it should be considered for first-line use in this population.

Drug dosage in the elderly. Is it rational

Abstract: Pharmacotherapy in the elderly requires an understanding of the age-dependent changes in function and composition of the body Aging is characterised by a progressive loss of functional capacities of most if not all organs, a reduction in response to receptor stimulation and homeostatic mechanisms, and a loss of water content and an increase of fat content in the body The most important pharmacokinetic change in old age is a decrease in the excretory capacity of the kidney; in this regard, the elderly should be considered as renally insufficient patients The decline in the rate of drug metabolism with advancing age is less marked In addition, the volume of distribution and the oral bioavailability of drugs may be changed in the elderly compared with younger individuals Average dosage adjustments for the aged can be derived from simple equations and mean pharmacokinetic parameters from older and younger adults However, these average dose adjustment factors neglect the large variation in the decline in organ functions among the elderly Individual dose adjustment factors can be obtained from the drug clearance in a particular patient, where clearance/fractional bioavailability (CL/f) may be calculated from the area under the plasma concentration-time curve (AUC) of the drug in question Using pharmacokinetic guidelines for dose adjustments, the same plasma drug concentrations result in elderly as in younger adults However, we are frequently confronted with pharmacodynamic changes in old age which alter the sensitivity to drugs, irrespective of changes in drug disposition For instance, the sensitivity of the cardiovascular system to beta-adrenergic agonists and antagonists decreases in old age and the incidence of orthostatic episodes in response to drugs that lower blood pressure is increased The CNS is especially vulnerable in the elderly; agents that affect brain function (anaesthetics, opioids, anticonvulsants, psychotropic drugs) must be used very cautiously in this age group The increased responsiveness to drugs in the elderly renders the measurement of drug plasma concentrations an attractive method to monitor pharmacotherapy in this age group Sensitive technology to quantitatively determine plasma drug concentrations is available However, optimal therapeutic plasma concentrations have not been established for most drugs in the elderly Investigations concerning drug pharmacokinetic-pharmacodynamic relationships in the aged are an important area of future work in clinical pharmacology

Enhancing patient compliance in the elderly. Role of packaging aids and monitoring.

Abstract: Inadequate compliance with medications is a significant contributor to the costs of medical care in every therapeutic area. No matter how severe the consequence, there is no assurance that all patients will take their medications as prescribed. Elderly patients are a particular concern because of their common deficits in physical dexterity, cognitive skills and memory, and the number of medications that they are typically prescribed. To overcome problems of compliance in the elderly, healthcare providers are advised to prescribe a simple dosage regimen for all medications to be taken (preferably 1 or 2 doses daily), to help the patient select cues that assist them in remembering to take doses (time of day, meal-time, or other daily rituals), to provide devices to simplify remembering doses (medication boxes), and to regularly monitor compliance. A variety of compliance aids are available to help patients organise their medications (e.g. plastic boxes) or remember dose times (alarms). Medication packaged in standard pharmacy bottles should be identified with special labels, or dose charts can be provided to check the daily schedule. Single-unit doses, widely used in hospitals, may be cumbersome for elderly patients who have difficulty opening the foil-backed wrappers. Medication boxes with compartments that are filled weekly by the patient, family member or a home healthcare provider are useful organisers that simplify the patient's responsibilities for self-administration. Microelectronic devices can provide feedback that shows patients whether they have been taking doses as scheduled. Some systems are also designed to notify patients within a day if doses were omitted. No system is optimal for all patients, but elderly patients deserve a comprehensive assessment of their needs to enhance medication compliance.

Depression in Parkinson's disease. Pharmacological characteristics and treatment.

Abstract: Parkinson's disease (PD) is a common neurological illness and various degrees of depression frequently complicate its course. Risk factors for developing depression with PD include right-sided hemiparkinsonism, akinesia, increased severity of disability, anxiety and psychosis. Onset of parkinsonism at a younger age, female gender and the use of levodopa are arguable risk factors. Depression may be difficult to diagnose in patients with PD because the signs of the 2 disorders overlap. In addition, patients with atypical PD more commonly have depression than patients with classical PD presentations. Antidepressant response to antiparkinsonian treatment has been limited. Enhancement of catecholamine levels in the CNS by selegiline (deprenyl), a monoamine oxidase (MAO) type B inhibitor, has shown potential antidepressant as well as neuroprotective effects. Other MAO inhibitors have shown antidepressant efficacy in animal models but have not been well tolerated by patients with PD. A catechol-O-methyltransferase (COMT) inhibitor combined with an MAO inhibitor might synergistically maximise the levels of catecholamines in the CNS. Antidepressant medications used in patients without PD include tricyclic antidepressants (TCAs) and selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs), but only TCAs have been carefully studied for their antidepressant effects in PD. Electroconvulsive therapy has proven efficacy as antidepressant therapy in patients with PD, and transcranial magnetic stimulation has provided temporary relief of depression under experimental conditions. Adverse effects of polypharmacy in the attempted treatment of depression in patients with PD are common in the elderly. A 'serotonin syndrome' has occurred frequently enough to preclude the coadministration of selegiline with SSRIs or TCAs, and multiple interactions between antiparkinsonian and antidepressant medications further complicate treatment strategies in patients with PD. An algorithmic approach to the pharmacological treatment of depression is described in this article.

Brimonidine. A review of its pharmacological properties and clinical potential in the management of open-angle glaucoma and ocular hypertension.

Abstract: Brimonidine is a highly selective alpha 2-adrenoceptor agonist which reduces intraocular pressure (IOP) by reducing aqueous humour production and increasing aqueous humour outflow via the uveoscleral pathway. Brimonidine is indicated for the topical management of open-angle glaucoma or ocular hypertension. In 3 large comparative studies in patients with open-angle glaucoma or ocular hypertension, the ocular hypotensive efficacy of brimonidine was maintained during treatment periods of up to 1 year. Mean reductions in peak (measured 2 hours after the morning dose) and trough (measured 12 hours after the evening dose) IOP were 5.6 to 5.9 and 3.3 to 3.7 mm Hg, respectively, after 3 or 12 months of treatment with brimonidine 0.2% twice daily. The efficacy of brimonidine in this setting was similar to that of timolol 0.5% twice daily at peak only (-6.0mm Hg), and superior to that of betaxolol 0.25% twice daily at both peak (-3.5mm Hg) and trough (-2.7mm Hg). When added to topical beta-adrenoceptor antagonist therapy, initial results showed brimonidine 0.2% twice daily to have additive ocular hypotensive efficacy similar to that of pilocarpine 2% 3 times daily. Thus, brimonidine 0.2% may be a useful adjunct in this setting. According to combined data from 2 large comparative studies, the most frequent adverse events associated with brimonidine therapy were oral dryness (30.0% of patients), ocular hyperaemia (26.3%) and ocular burning and/or stinging (24.0%). Ocular allergic reactions including allergic blepharitis, blepharoconjunctivitis and follicular conjunctivitis occurred with an incidence of 9.6% in 1 study. In a third comparative study, the incidence of adverse events associated with brimonidine therapy was lower, with conjunctival hyperaemia (11.4%) the most frequently reported event. Changes in systolic and diastolic blood pressure and, to a lesser extent, heart rate have been reported in patients treated with therapeutic doses of topical brimonidine for up to 12 months, but these changes were not clinically significant. Unlike beta-adrenoceptor antagonists, brimonidine is not contraindicated in patients with cardiopulmonary disease, although it should be used with caution in individuals with severe cardiovascular disease. Thus, further studies are warranted to determine the efficacy of brimonidine when used in combination with other glaucoma medications and its efficacy relative to newer drugs such as dorzolamide and latanoprost. However, available data suggest that brimonidine is a promising alternative option for the lowering of IOP in the management of open-angle glaucoma and ocular hypertension, particularly in patients with cardiopulmonary disease in whom topical beta-adrenoceptor antagonist therapy is contraindicated.

Pramipexole. A review of its use in the management of early and advanced Parkinson's disease.

Abstract: UNLABELLED Pramipexole is an orally active non-ergoline dopamine agonist with selective activity at dopamine receptors belonging to the D2 receptor subfamily (D2, D3, D4 receptor subtypes) and with preferential affinity for the D3 receptor subtype. It is approved as monotherapy in early Parkinson's disease and as adjunctive therapy to levodopa in patients with advanced disease experiencing motor effects because of diminished response to levodopa. The potential neuroprotective effects of pramipexole have been shown in animal and in vitro studies. Data from relatively long term (10- or 31-week) studies suggest that pramipexole monotherapy (0.375 to 6.0 mg/day) can improve activities of daily living and motor symptoms in patients with early Parkinson's disease. Pramipexole (0.375 to 4.5 mg/day for 31 or 36 weeks), as an adjunct to levodopa in advanced disease, improved activities of daily living and motor symptoms, reduced the duration and severity of 'off' periods and allowed a reduction in levodopa dosage. Mentation, behaviour and mood [Unified Parkinson's Disease Rating Scale (UPDRS) part I], and timed walking test were not significantly improved. The extent of disability improved according to the UPDRS parts II and III but, when assessed by secondary efficacy parameters, it is unclear whether disability or the severity of disease improved. No significant differences were observed in patients randomised to pramipexole or bromocriptine according to a secondary hypothesis in a prospective study in which both drugs were better than placebo. Some quality-of-life measures improved with active treatment relative to placebo. Further studies comparing pramipexole with other dopamine agonists and levodopa in patients with early and advanced Parkinson's disease would be useful. In pramipexole recipients with early disease, the most commonly experienced adverse events were nausea, dizziness, somnolence, insomnia, constipation, asthenia and hallucinations. The most commonly reported adverse events in pramipexole recipients with advanced disease were orthostatic hypotension, dyskinesias, extrapyramidal syndrome (defined as a worsening of the Parkinson's disease), dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia and urinary frequency. The incidence of some adverse events did not greatly differ between pramipexole and placebo recipients. CONCLUSIONS Pramipexole is effective as adjunctive therapy to levodopa in patients with advanced Parkinson's disease. However, the potential beneficial effects of pramipexole on disease progression need to be confirmed in clinical studies. The efficacy of pramipexole monotherapy in patients with early disease has also been demonstrated, although the use of dopamine agonists in early Parkinson's disease remains controversial.

Osteoporosis in men: New insights into aetiology, pathogenesis, prevention and management

Abstract: Osteoporosis is increasingly recognised in men. Low bone mass, risk factors for falling and factors causing fractures in women are likely to cause fractures in men. Bone mass is largely genetically determined, but environmental factors also contribute. Greater muscle strength and physical activity are associated with higher bone mass, while radial bone loss is greater in cigarette smokers or those with a moderate alcohol intake. Sex hormones have important effects on bone physiology. In men, there is no abrupt cessation of testicular function or ‘andropause’ comparable with the menopause in women; however, both total and free testosterone levels decline with age. A common secondary cause of osteoporosis in men is hypogonadism. There is increasing evidence that estrogens are important in skeletal maintenance in men as well as women. Peripheral aromatisation of androgens to estrogens occurs and osteoblast-like cells can aromatise androgens into estrogens. Human models exist for the effects of estrogens on the male skeleton. In men aged >65 years, there is a positive association between bone mineral density (BMD) and greater serum estradiol levels at all skeletal sites and a negative association between BMD and testosterone at some sites. It is crucial to exclude pathological causes of osteoporosis, because 30 to 60% of men with vertebral fractures have another illness contributing to bone disease. Glucocorticoid excess (predominantly exogenous) is common. Gastrointestinal disease predisposes patients to bone disease as a result of intestinal malabsorption of calcium and colecalciferol (vitamin D). Hypercalciuria and nephrolithiasis, anticonvulsant drug use, thyrotoxicosis, immobilisation, liver and renal disease, multiple myeloma and systemic mastocytosis have all been associated with osteoporosis in men. It is possible that low-dose estrogen therapy or specific estrogen receptor-modulating drugs might increase BMD in men as well as in women. In the future, parathyroid hormone peptides may be an effective treatment for osteoporosis, particularly in patients in whom other treatments, such as bisphosphonates, have failed. Men with idiopathic osteoporosis have low circulating insulin-like growth factor-1 (IGF-1; somatomedin-1) concentrations, and IGF-1 administration to these men increases bone formation markers more than resorption markers. Studies of changes in BMD with IGF-1 treatment in osteoporotic men and women are underway. Osteoporosis in men will become an increasing worldwide public health problem over the next 20 years, so it is vital that safe and effective therapies for this disabling condition become available. Effective public health measures also need to be established and targeted to men at risk of developing the disease.

NSAIDs and blood pressure. Clinical importance for older patients

Abstract: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensive medication increases with age to 26% and > 50%, respectively, among the elderly. Overall, 12 to 15% of elderly individuals take at least 1 NSAID and an antihypertensive medication concurrently. A large case-control study of older individuals demonstrated that recent users of NSAIDs had a 1.7-fold increase in risk of initiating antihypertensive therapy compared with non-users. A community-based epidemiological study revealed that NSAID use significantly predicted the presence of hypertension (odds ratio 1.4, 95% confidence interval 1.1 to 1.7) in the elderly. Furthermore, among those taking antihypertensive agents in the 65+ Rural Health Study, in Iowa, US, individuals also taking NSAIDs had a mean systolic blood pressure (BP) 4.9 mm Hg higher than non-users of NSAIDs. The hypertensive effect of NSAIDs varies depending on the specific NSAID used and the type of antihypertensive agent, if they are taken concurrently. While the results of randomised, controlled trials in the elderly have been conflicting, 2 meta-analyses involving younger adults have revealed that NSAID use produces a clinically significant increment in mean BP of 5.0 mm Hg, which is most marked in patients with controlled hypertension. Stratification by NSAID type has revealed that piroxicam and indomethacin had the greatest, and sulindac the least, pressor effect. While the mechanisms) of the pressor effect remain speculative, salt and water retention, caused by several factors operating in parallel, coupled with an increased total peripheral vascular resistance via increased renal endothelin-1 synthesis, are potentially important. A 5 to 6 mm Hg increase in diastolic BP maintained over a few years may be associated with a 67% increase in total stroke occurrence and a 15% increase in events associated with coronary heart disease. Clinicians should strive to avoid excessive use of NSAID treatment and consider alternative, well-tolerated therapeutic options, including simple analgesics and physical therapy. For patients who require concomitant NSAID and antihypertensive treatment, clinicians should be aware of the greater hypertensive effect of indomethacin and piroxicam compared with alternative NSAIDs, and the potential for relatively greater antagonism by NSAIDs of the BP-lowering effect of beta-blockers compared with other antihypertensives. Finally, the progress of each patient should be monitored by careful BP measurement particularly during the initiation of NSAID therapy.

Gout in the elderly. Clinical presentation and treatment.

Abstract: Gout in the elderly differs from classical gout found in middle-aged men in several respects: it has a more equal gender distribution, frequent polyarticular presentation with involvement of the joints of the upper extremities, fewer acute gouty episodes, a more indolent chronic clinical course, and an increased incidence of tophi. Long term diuretic use in patients with hypertension or congestive cardiac failure, renal insufficiency, prophylactic low dose aspirin (acetylsalicylic acid), and alcohol (ethanol) abuse (particularly by men) are factors associated with the development of hyperuricaemia and gout in the elderly. Extreme caution is necessary when prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of acute gouty arthritis in the elderly. NSAIDs with short plasma half-life (such as diclofenac and ketoprofen) are preferred, but these drugs are not recommended in patients with peptic ulcer disease, renal failure, uncontrolled hypertension or cardiac failure. Colchicine is poorly tolerated in the elderly and is best avoided. Intra-articular and systemic corticosteroids are increasingly being used for treating acute gouty flares in aged patients with medical disorders contraindicating NSAID therapy. Urate-lowering drugs are indicated for the treatment of hyperuricaemia and chronic gouty arthritis. Uricosuric drugs are poorly tolerated and the frequent presence of renal impairment in the elderly renders these drugs ineffective. Allopurinol is the urate-lowering drug of choice, but its use in the aged is associated with an increased incidence of both cutaneous and severe hypersensitivity reactions. To minimise this risk, allopurinol dose must be kept low. A starting dose of allopurinal 50 to 100mg on alternate days, to a maximum daily dose of about 100 to 300mg, based upon the patient's creatinine clearance and serum urate level, is recommended. Asymptomatic hyperuricaemia is not an indication for long term urate-lowering therapy; the risks of drug toxicity often outweigh any benefit.

Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone.

Abstract: Pamidronate (APD) is a potent inhibitor of bone resorption that is useful in the management of patients with osteolytic bone metastases from breast cancer or multiple myeloma, tumour-induced hypercalcaemia or Paget's disease of bone. After intravenous administration, the drug is extensively taken up in bone, where it binds with hydroxyapatite crystals in the bone matrix. Matrix-bound pamidronate inhibits osteoclast activity by a variety of mechanisms, the most important of which appears to be prevention of the attachment of osteoclast precursor cells to bone. In patients with osteolytic bone metastases associated with either breast cancer or multiple myeloma, administration of pamidronate together with systemic antitumour therapy reduces and delays skeletal events, including pathological fracture, hypercalcaemia and the requirement for radiation treatment or surgery to bone. Pamidronate generally improves pain control. Quality-of-life and performance status scores in pamidronate recipients were generally as good as, or better than, those in patients who did not receive the drug. Overall survival does not appear to be affected by pamidronate therapy. Tumour-induced hypercalcaemia also responds well to pamidronate therapy: 70 to 100% of patients achieve normocalcaemia, generally 3 to 5 days after treatment. Response durations vary, but are commonly 3 weeks or longer, In comparative studies, pamidronate produced higher rates of normocalcaemia and longer normocalcaemic durations than other available osteoclast inhibitors, including intravenous etidronate, clodronate and plicamycin (mithramycin). In most patients with Paget's disease of bone, intravenous pamidronate reduces bone pain and produces biochemical response. Serum alkaline phosphatase levels generally fall 50 to 70% from baseline 3 to 4 months after pamidronate treatment. Biochemical response may be prolonged. Pamidronate is well tolerated by most patients. Transient febrile reactions, sometimes accompanied by myalgias and lymphopenia, occur commonly after the first infusion of pamidronate. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcaemia and, rarely, ocular complications (uveitis and scleritis). Pamidronate should be considered for routine use together with systemic hormonal or cytotoxic therapy in patients with breast cancer or multiple myeloma and osteolytic metastases. At present, pamidronate is the drug of choice for first-line use in the management of patients with tumour-induced hypercalcaemia. It is an effective treatment for Paget's disease and is the treatment of choice where oral bisphosphonates are not an option.

Monoamine oxidase inhibitors. A perspective on their use in the elderly.

Abstract: Monoamine oxidase inhibitors (MAOIs) are mainly used in psychiatry for the treatment of depressive disorders and in neurology for the treatment of Parkinson's disease. While the classical, nonselective and nonreversible MAOIs, such as phenelzine and tranylcypromine, are characterised by the risk of inducing a hypertensive crisis when dietary tyramine is ingested, the selective monoamine oxidase-B (MAO-B) inhibitor selegiline (deprenyl) and, even more so, the selective and reversible monoamine oxidase-A (MAO-A) inhibitor moclobemide, are free from this potential interaction. Drug tolerability data for the elderly show that moclobemide is one of the most well tolerated compounds. Selegiline, especially when used in combination with levodopa, can cause anorexia, dry mouth, dyskinesia and, most problematic, orthostatic hypotension. For the traditional MAOIs, phenelzine and tranylcypromine, published data are insufficient to be able to give a conclusive tolerability statement regarding the use of these compounds in elderly people. Although orthostatic hypotension occurs in most patients treated with traditional MAOIs, the incidence in elderly patients with depression does not appear to be greater than that reported with tricyclic antidepressants.

Paclitaxel. An update of its use in the treatment of metastatic breast cancer and ovarian and other gynaecological cancers.

Abstract: The antitumour agent paclitaxel has proved to be effective for the treatment of patients with metastatic breast or ovarian cancer, and limited data also indicate its clinical potential in patients with cervical or endometrial cancer. The regimen of paclitaxel administration has varied in clinical trials, the most common including a dosage of between 135 and 250 mg/m2 administered over an infusion period of 3 or 24 hours once every 3 weeks. Promising results have been achieved in phase I/II trials of a weekly regimen of paclitaxel (60 to 175 mg/m2). The objective response rate in patients with metastatic breast cancer (either pretreated or chemotherapy-naive) is generally between 20 and 35% with paclitaxel monotherapy, which compares well with that of other current treatment options including the anthracycline doxorubicin. Combination therapy with paclitaxel plus doxorubicin appears superior to treatment with either agent alone in terms of objective response rate and median duration of response. However, whether combination therapy also provides a survival advantage remains unclear; recent results of a phase III study indicate that it does not. Paclitaxel is also a useful second-line option in some patients with anthracycline-resistant disease. Combination therapy with paclitaxel and cisplatin has proved highly effective as first-line therapy for patients with advanced ovarian cancer, showing superior efficacy to cyclophosphamide/cisplatin in terms of progression-free survival time and median duration of survival. Combination therapy with paclitaxel and carboplatin has also shown promising results. Paclitaxel monotherapy is a useful second-line option for patients with platinum-refractory metastatic ovarian cancer (objective response rates have ranged from 15 to 48%). The major dose-limiting adverse events associated with paclitaxel include myelotoxicity and peripheral neuropathy. Paclitaxel has acceptable tolerability in most patients, although adverse events are common. Conclusion Paclitaxel generally appears to be as effective as other antineoplastic agents used in the treatment of metastatic breast cancer, including doxorubicin. Importantly, it is a useful second-line option for some patients with anthracycline-resistant disease. Combination therapy with both paclitaxel and doxorubicin is a highly effective first-line option for metastatic breast cancer; however, recent results indicate no survival advantage versus monotherapy. Paclitaxel is a valuable agent for second-line treatment of patients with platinum-refractory metastatic ovarian cancer and, when combined with cisplatin or carboplatin, is recommended as first-line therapy for this disease.

Age-related changes in cobalamin (vitamin B12) handling. Implications for therapy.

Abstract: Cobalamin (vitamin B12) deficiency is more common in the elderly than in younger patients. This is because of the increased prevalence of cobalamin malabsorption in this age group, which is mainly caused by (autoimmune) atrophic body gastritis. Cobalamin supplementation is affordable and nontoxic, and it may prevent irreversible neurological damage if started early. Elderly individuals with cobalamin deficiency may present with neuropsychiatric or metabolic deficiencies, without frank macrocytic anaemia. An investigation of symptoms and/or signs includes the diagnosis of deficiency as well as any underlying cause. Deficiency states can still exist even when serum cobalamin levels are higher than the traditional lower reference limit. Cobalamin-responsive elevations of serum methylmalonic acid (MMA) and homocysteine are helpful laboratory tools for the diagnosis. The health-related reference ranges for homocysteine and MMA appear to vary with age and gender. Atrophic body gastritis is indirectly diagnosed by measuring serum levels of gastrin and pepsinogens, and it may cause dietary cobalamin malabsorption despite a normal traditional Schilling's test. The use of gastroscopy may also be considered to diagnose dysplasia, bacterial overgrowth and intestinal villous atrophy in healthy patients with atrophic body gastritis or concomitant iron or folic acid deficiency. Elderly patients respond to cobalamin treatment as fully as younger patients, with complete haematological recovery and complete or good partial resolution of neurological deficits. Chronic dementia responds poorly but should, nevertheless, be treated if there is a metabolic deficiency (as indicated by elevated homocysteine and/or MMA levels). Patients who are at risk from cobalamin deficiency include those with a gastrointestinal predisposition (e.g. atrophic body gastritis or previous partial gastrectomy), autoimmune disorders [type 1 (insulin-dependent) diabetes mellitus and thyroid disorders], those receiving long term therapy with gastric acid inhibitors or biguanides, and those undergoing nitrous oxide anaesthesia. To date, inadequate cobalamin intake has not proven to be a major risk factor. Intervention trials of cobalamin, folic acid and pyridoxine (vitamin B6) in unselected elderly populations are currently under way.

The role of nitric oxide in neurodegeneration. Potential for pharmacological intervention.

Abstract: Nitric oxide (NO) is involved in important physiological functions of the CNS, including neurotransmission, memory and synaptic plasticity. Depending on the redox state of NO, it can act as a neurotoxin or it can have a neuroprotective action. Data suggest that NO may have a role in the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease. Additionally, these data indicate that inhibitors of the NO-synthesising enzyme, NO synthase, may be useful as neuroprotective agents in these diseases. In animal models, NOS inhibitors have been shown to prevent the neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other dopaminergic toxins. However, the clinical effects of NOS inhibitors remain unknown.

Mechanisms of Drug-Induced Diarrhoea in the Elderly

Abstract: In the rapidly increasing elderly population, diarrhoea as a result of drug therapy is an important consideration. The elderly consume a disproportionately large number of drugs for multiple acute and chronic diseases. Drugs can compromise both immune and nonimmune responses. Aging decreases the quality and proportion of T cells which in turn reduces the production of secretory IgA, the primary immune response of the gut. Acid production in the stomach decreases with increasing age and this compromises its vital ‘self-sterilising’ function, thus increasing the risk of diarrhoea due to viral, bacterial and protozoal pathogens. Other nonimmune defence mechanisms include the motility of the small intestine and the host—protective commensal bacteria of the colon. Drug induced hypomotility may result in bacterial overgrowth, deconjugation of bile salts and diarrhoea. Less commonly, diarrhoea may occur due to hypermotility because of a cholinergic-like syndrome. In the colon the host-protective commensal bacteria provide a powerful defence against pathogens. Disruption of this commensal population by antibiotic therapy may result in Clostridium difficile supra-infection which causes diarrhoea through toxin production. This is especially important in the elderly patient on chemotherapy for malignancy and those with multiple diseases. The organism responds to vancomycin, metronidazole and bacitracin. Metronidazole is the suggested drug of choice, with vancomycin reserved for relapses. Drugs also cause diarrhoea by interfering with normal physiological processes. Drugs impair fluid absorption by activating adenylate cyclase within the small intestinal enterocyte which increases the level of cyclic AMP. This causes active secretion of Cl− and HCO3 −, passive efflux of Na+, K+ and water and inhibition of Na+ and Cl− into the enterocyte. Examples of these drugs (secretagogues) are bisacodyl, misoprostol and chenodeoxycholic acid (used to dissolve cholesterol gallstones). Drugs may also affect a second mechanism that regulates water and electrolyte transport, the Na+,K+ exchange pump. The energy for this pump is provided by the ATPase mediated breakdown of ATP. ATPase may be inhibited by digoxin, auranofin, colchicine and olsalazine. A number of drugs cause osmotic diarrhoea including antacids containing magnesium trisilicate or hydroxide. Lactulose is being used increasingly in compensated liver disease to increase protein tolerance and prevent hepatic encephalopathy. Sorbitol, an osmotic laxative agent also used in some liquid pharmaceutical preparations, induces diarrhoea by virtue of its osmotic potential. Another mechanism by which drugs cause diarrhoea is by mucosal damage of the small and large bowel. In the small intestine mucosal damage causes diarrhoea and fat malabsorption, as may occur with neomycin and colchicine. In the colon, for example, gold salts and penicillamine cause colitis of varying severity. Though the causes of diarrhoea are diverse, a drug-associated aetiology should always be considered and actively sought and addressed to prevent the complications of dehydration, electrolyte imbalance and undernutrition.

Midodrine. A review of its therapeutic use in the management of orthostatic hypotension.

Abstract: Midodrine is a prodrug which undergoes enzymatic hydrolysis to the selective alpha 1-adrenoceptor agonist desglymidodrine after oral administration. Oral midodrine significantly increases 1-minute standing systolic blood pressure compared with placebo. The drug also improves standing time and energy level and clinical symptoms of orthostatic hypotension including dizziness, light-headedness and syncope. Comparative studies have shown midodrine to have similar efficacy to dihydroergotamine mesylate, norfenefrine, fludrocortisone and etilefrine, and to be more effective than dimetofrine and ephedrine in patients with orthostatic hypotension. Midodrine is well tolerated, with the most commonly reported adverse events being piloerection, pruritus, paraesthesias, urinary retention and chills. The risk of supine hypertension, which is associated with midodrine therapy in up to 25% of patients, can be reduced by taking the final daily dose at least 4 hours before bedtime. Thus, oral midodrine is an effective therapeutic option for the management of various forms of orthostatic hypotension. This well-tolerated agent is likely to be useful in conjunction with standard nonpharmacological care.

Cytokines in rheumatoid arthritis. Potential targets for pharmacological intervention.

Abstract: The ingress of inflammatory leucocytes into the synovium is a crucial step in the pathogenesis of rheumatoid arthritis (RA). Cytokines are mediators involved in the inflammatory events, adhesive mechanisms, angiogenesis and osteopenia associated with RA. Pro- and anti-inflammatory cytokines, growth factors and chemokines all have an important role in these processes. Because the efficacy of currently used antirheumatic therapy is often limited, there is a need for more specific intervention strategies. Anticytokine therapy may include the use of monoclonal antibodies, antagonistic cytokines, soluble cytokine receptors, cytokine receptor antagonists, somatic gene transfer or other approaches. Hopefully, the study of cytokines and their interactions will lead to the development of new immunomodulatory strategies that will benefit patients with RA.

Common Cancers in the Elderly

Abstract: The proportion of elderly persons (65 years or older) has increased in most countries during the last few decades, and will increase further in the coming years. Annual age-standardised cancer incidence rates per 100,000 elderly persons (1988 to 1992) were calculated based on data from cancer registries in 51 countries in 5 continents kept by the International Agency for Research on Cancer (IARC) and International Association of Cancer Registries (IACR). The proportions of all cancers among elderly men and women were 61 and 56% respectively. All cancers combined (except nonmelanoma skin cancer) were, based on the standardised rates, almost 7-fold more frequent among elderly men (2158 per 100,000 person-years), and around 4-fold more frequent among elderly women (1192 per 100,000 person-years) than among younger persons (30 to 64 years old). However, large variations exist between different cancer sites. Contrary to the pattern in younger age groups, in which annual cancer rates are almost equally distributed among the 2 genders, elderly men have an almost double cancer incidence rate compared with elderly women. For all major specific cancer sites except testicular cancer, the incidence rate is significantly higher among the elderly than among any groups of younger and middle-aged persons. Among elderly men, cancer of the prostate (451 per 100,000), the lung (449 per 100,000) and the colon (176 per 100,000) make up around half of all diagnosed cancers. Prostate cancer is around 22 times more frequent among elderly men than among younger men. The corresponding most frequent cancers among elderly women, making up 48% of all malignant cancers, are breast (248 per 100,000), colon (133 per 100,000), lung (118 per 100,000) and stomach cancer (75 per 100,000). For most cancers, marked geographical variations in incidence rates are found among the elderly, reflecting socioeconomic differences, particularly between the developing and the developed countries. In contrast with other major causes of death among the elderly, cancer incidence and mortality have not in general declined, indicating that primary prevention (especially cessation of tobacco smoking) remains a most valuable approach to decrease mortality; for most of the major cancers (prostate, colon, breast) the causes remain almost unknown. Thus, research into potential causes is urgently needed for future prevention. Since the mortality rates for female cancer in general are declining, and since the incidence is increasing more steeply than the mortality among the men, the number of living elderly ever diagnosed with a cancer will further increase during the next years. Therefore, it is important to emphasise the increasing need for research into the prevention of cancer and the planning of treatment and care in the elderly.

Caffeine and the Elderly

Abstract: The most common source of dietary caffeine among the elderly is coffee, with consumption averaging about 200 mg/day. Because of the greater proportion of adipose tissue to lean body mass in older humans, and because caffeine is distributed essentially only through lean body mass, a dose of caffeine expressed as mg/kg total bodyweight may result in a higher plasma and tissue concentration in elderly compared with younger individuals. The metabolism of, and physiological responses to, caffeine is similar in elderly and younger individuals. However, there is a limited amount of evidence that responses to caffeine in some physiological systems may be greater in the elderly at doses in the 200 to 300 mg range. Although caffeine consumption increases urinary calcium levels similarly in both younger and older individuals, the preponderance of data suggest that caffeine has a greater impact on calcium metabolism and bone in older people. Evidence also suggests that increasing age is associated with increasing sensitivity to the pressor effects of caffeine. Caffeine appears to affect metabolic and neurological responses similarly in both young and elderly individuals, when differences in baseline performance are taken into account.

Anastrozole. A review of its use in the management of postmenopausal women with advanced breast cancer

Abstract: UNLABELLED Anastrozole is a new oral nonsteroidal aromatase inhibitor indicated for the second-line endocrine treatment of postmenopausal women with advanced breast cancer. In postmenopausal women, anastrozole significantly reduces plasma estrogen levels; maximal suppression is achieved at dosages > or = 1 mg/day and levels remain suppressed during long term therapy. In two phase III clinical trials, anastrozole 1 or 10 mg/day showed similar clinical efficacy to that of oral megestrol (megestrol acetate) 160 mg/day in postmenopausal women with advanced breast cancer. Primary end-points [including time to disease progression (120 to 170 days) and overall response rates (complete and partial response and stable disease lasting > or = 24 weeks: 29 to 37%)] and secondary end-points [time to treatment failure (115 to 168 days) and duration of response (257 to 261 days)] did not differ significantly between treatment groups. However, a significant survival advantage was observed in patients treated with anastrozole 1 mg/day compared with megestrol in a follow-up combined analysis of patients enrolled in both studies (median time to death 26.7 vs 22.5 months). Quality of life parameters were generally improved to a similar extent in all treatment groups. Anastrozole is generally well tolerated in the majority of patients, the most common adverse events being gastrointestinal (GI) disturbances (incidence 29 to 33%). These events are generally mild or moderate and transient. Other adverse events reported with anastrozole include headache (< or = 18%), asthenia (< or = 16%), pain (< or = 15%), hot flushes and bone pain (both < or = 12%), back pain and dyspnoea (both < or = 11%) and peripheral oedema (< or = 9%). GI disturbance tended to be more common with anastrozole than megestrol, particularly at the 10 mg/day dosage; however, compared with megestrol, anastrozole is less frequently associated with weight gain. CONCLUSIONS Anastrozole, with its apparent survival advantage versus megestrol (demonstrated in a combined analysis of phase III studies), convenient once daily oral administration and acceptable short term tolerability profile, is a second-line treatment option for postmenopausal patients with tamoxifenrefractory advanced breast cancer. The results of ongoing comparative trials with tamoxifen will determine the relative efficacy of anastrozole as first-line endocrine therapy for advanced breast cancer and as adjuvant therapy for early disease. In addition, direct comparative studies are required to determine the efficacy of anastrozole relative to that of other oral aromatase inhibitors such as letrozole and vorozole.

New Atypical Antipsychotics Experience and Utility in the Elderly

Abstract: The atypical antipsychotics are a new class of agents with great promise for use in the elderly because of their reduced propensity to cause acute extrapyramidal adverse effects. Treatment of older patients with these agents, however, needs to take into consideration age-related changes in pharmacokinetics and the risks of drug-drug interactions. Additionally, current evidence of their efficacy in late-life psychoses is derived largely from case series and from the extrapolation of results obtained in studies of younger patients with schizophrenia. Controlled clinical studies of atypical antipsychotics in elderly patients are urgently needed.

Choosing appropriate antidepressant therapy in the elderly. A risk-benefit assessment of available agents.

Abstract: This article discusses the advantages and disadvantages of tricyclic antidepressants (TCAs), tetracyclic antidepressants (i.e. mianserin), selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), triazolopyridines (i.e. trazodone), phenylpiperazines (i.e. nefazodone), serotonin and noradrenaline (norepinephrine) reuptake inhibitors (i.e. venlafaxine), and aminoketones [i.e. amfebutamone (bupropion)] in the treatment of late-life depression. A limitation of the existing literature is that most data regarding drugs are derived from studies that have involved medically stable outpatients who do not have dementia and who are less than 80 years of age. There is a paucity of data on the use of antidepressants in very elderly individuals, patients who have significant medical comorbity and patients with dementia or other neurological problems. No one class of antidepressant has been found to be more effective than another in the acute treatment of geriatric major depression. However, given design short-comings in many of these studies, the possibility of a real difference in efficacy between drugs (especially in the treatment of severe or melancholic depression) cannot be excluded. With respect to adverse effects, drug interactions, and dosage and administration, each class of antidepressant has its benefits and limitations. There is no one 'first-line' antidepressant for elderly patients with depression. Selection of an antidepressant should be made on a case by case basis, taking into account each patient's characteristics.

Highly precise peripheral quantitative computed tomography for the evaluation of bone density, loss of bone density and structures. Consequences for prophylaxis and treatment.

Abstract: The importance of serial examinations over time with peripheral quantitative computed tomography (pQCT) is that they enable the detection of patients at high risk of osteoporosis, and the individualisation of prophylaxis and treatment. We have shown that postmenopausal patients with high bone turnover evaluated by biochemical markers are identical to fast bone losers as determined by pQCT. As a consequence, we use agents that inhibit bone resorption in patients who are fast bone losers and agents that stimulate bone formation in patients who are slow bone losers. To visualise bone microarchitecture, and to evaluate bone density and the rate of bone loss, we used a highly sensitive pQCT system (DENSISCAN 1000, reproducibility of 0.3% in a mixed population of normal individuals and patients with osteopenia or osteoporosis). This system enabled us to separately assess trabecular and cortical bone density in the radius and tibia, and to differentiate between fast and slow bone losers within a few months (threshold: 3% loss of trabecular bone density in the radius per year). We have shown that the lower the trabecular bone density in the distal radius, the higher the relative bone loss. To classify patients as slow and fast losers in the future, we may need only one measurement. With this highly precise measurement method, we have shown that calcitonin and etidronate are more effective in fast than in slow bone losers, and that vitamin D metabolites (calcitriol or 1 α-calcidol) and estrogens can halt fast bone loss. In conclusion, highly sensitive pQCT enables us to adapt the treatment to different forms of osteoporosis and bone turnover, resulting in an increase in the number of patients successfully treated and also in patient compliance. Because our treatment is based on precise, objective measurements, treatment modifications — especially in those who change from a slow to a fast bone-loser state — can be easily justified.

Glucocorticoids in Alzheimer's disease. The story so far.

Abstract: The inflammatory hypothesis of Alzheimer’s disease states that specific inflammatory mechanisms, including the cytokine-driven acute-phase response, complement activation and microglial activation, contribute to neurodegeneration. If the hypothesis is correct, anti-inflammatory treatment aimed at suppression of these mechanisms could slow the rate of disease progression. Towards this goal, a multicentre trial of prednisone in Alzheimer’s disease is under way and pilot studies of other anti-inflammatory regimens are being conducted.

Fast and slow bone losers: Relevance to the management of osteoporosis

Abstract: A low bone mineral density (BMD) is presently regarded as the most important risk factor for the development of osteoporosis. BMD is a function of peak bone mass attained during growth and subsequent age-related bone loss. BMD can be measured accurately and precisely, although the rate of bone loss is more difficult to assess. When axial BMD was measured, the rate of bone loss was shown to increase by 2- to 4-fold at the menopause. Although this rate varies markedly between individuals, it is symmetrically distributed, which argues against the existence of a subpopulation of fast bone losers. Levels of biochemical markers of bone turnover (e.g. osteocalcin, bone specific alkaline phosphatase, deoxypyridinoline) also increase markedly at the menopause, and individuals with a high turnover tend to lose bone more rapidly. Moreover, since increased bone resorption also results in qualitative changes regardless of BMD, a high bone turnover constitutes an independent risk factor. Currently, large intra-individual variations (10 to 40%) in levels of biochemical markers and assay errors still limit our ability to correctly classify individual patients as fast or slow bone losers. The routine use of these markers as a screening tool to predict the risk of osteoporosis in individuals is of limited value, although their selective use in therapeutic decision-making is more promising.

Propionyl-L-Carnitine

Abstract: Propionyl-L-carnitine stimulates energy production in ischaemic muscles by increasing citric acid cycle flux and stimulating pyruvate dehydrogenase activity. The free radical scavenging activity of the drug may also be beneficial. Propionyl-L-carnitine improves coagulative fibrinolytic homeostasis in vasal endothelium and positively affects blood viscosity. Improvements in maximum walking distance (MWD) correlated positively with increased mitochondrial oxidative adenosine triphosphate (ATP) synthesis in a study in patients with peripheral arterial disease. Oral propionyl-L-carnitine 1 to 3 g/day significantly improved mean MWD compared with placebo in patients with peripheral arterial obstructive disease (Fontaine Leriche stage II) in double-blind multicentre phase III studies (mean improvements ranged from 21 to 50% with placebo and from 33 to 73% with propionyl-L-carnitine). In one phase III study, propionyl-L-carnitine 1 to 3 g/day significantly improved mean MWD (measured by treadmill) compared with placebo (by 73 vs 46% after 24 weeks) in patients with intermittent claudication. Oral propionyl-L-carnitine therapy was associated with significant improvements in quality of life compared with placebo in patients with a baseline MWD < 250m. Propionyl-L-carnitine appears to be well tolerated, showing a similar incidence of adverse events to that reported in placebo recipients.

Assessment and Treatment of Bipolar Disorder in the Elderly

Abstract: The aetiology of late-onset bipolar disorder is heterogeneous because the disease is more likely to have a secondary (i.e. a medical disorder or medication-induced) cause in older than in younger patients. Elderly patients with bipolar disorder typically require lithium dosages that are 25 to 50% lower than those used in younger individuals. Information on the use of valproic acid (sodium valproate) in elderly patients with bipolar disorder is limited but encouraging. In contrast, there is virtually no information regarding the use of carbamazepine or other drugs in this patient group. Electroconvulsive therapy is well tolerated by older people and can be useful for these patients.

Age-associated alterations in calcium current and its modulation in cardiac myocytes

Abstract: The calcium current is one of the most important components in cardiac excitation-contraction coupling. During aging, the magnitude of L-type Ca++ channel current (ICa,L) is significantly increased in parallel with the enlargement of cardiac myocytes, resulting in unaltered ICa,L density. Since the inactivation of ICa,L is slowed and the action potential duration is prolonged, the net Ca++ influx during each action potential is likely to be increased in senescent hearts relative to young ones. This augmentation of Ca++ influx may be important for the preserved cardiac function of the older heart in the basal state. However, it increases the risk of Ca++ overload and Ca++-dependent arrhythmias in the senescent heart. During stress, the response of ICa,L to β-adrenergic receptor stimulation is markedly reduced, which may be an important cause of the age-related decrease in cardiac reserve function. These age-dependent changes in ICa,L and its modulations are similar to those observed in the enlarged myocytes of the hypertrophied and failing heart.