Showing papers in "Drugs & Aging in 1994"

Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders.

Abstract: Trazodone is a triazolopyridine derivative, chemically and pharmacologically unrelated to other currently available antidepressants. It possesses antidepressant, and also some anxiolytic and hypnotic activity. Results from a small number of short term (4 to 6 weeks) comparative studies in a total of 320 evaluable elderly patients with major depression, suggest that trazodone at therapeutic doses is superior to placebo and as effective as amitriptyline, imipramine, fluoxetine and mianserin in relieving depressive symptoms. Trazodone has also been successfully used in a small number of patients with depression and pre-existing cardiovascular disease. More recently, trazodone has been used as a hypnotic for psychotropic-induced or other insomnias with some success. However, further clinical experience is needed to confirm these preliminary results. In the elderly, maximum tolerated doses of trazodone are 300 to 400 mg/day, although higher doses of up to 600 mg/day are tolerated by younger patients. Drowsiness is commonly reported, but the incidences of both anticholinergic and cardiovascular effects were notably lower in elderly patients treated with trazodone compared with older tricyclic antidepressants. However, undesirable effects such as orthostatic hypotension, arrhythmias and priapism need to be closely monitored. In comparison with other currently available agents, particularly the tricyclic antidepressants, trazodone is relatively safe in overdose. In terms of therapeutic efficacy, trazodone appears to confer little advantage over other available antidepressants. While limited data suggest that trazodone may be better tolerated than older tricyclic antidepressants, especially in the elderly, there is a paucity of data at present comparing trazodone with the secondary amine tricyclic agents, serotonin reuptake inhibitors or moclobemide. Bearing this in mind, trazodone may be of use in elderly patients in whom anxiety and insomnia are problematic, and in those patients who are unresponsive to or cannot tolerate therapy with other agents. Studies are also required to define the place of trazodone in long term prophylactic therapy for recurrent depression. Future trials comparing both its efficacy and tolerability with those of newer agents will ascertain whether trazodone becomes a first line agent within these subsets of elderly patients.

Polypharmacy in the aged. Practical solutions.

Abstract: Elderly patients use more medications than younger patients and the trend of increasing drug use continues through 80 years of age. Studies conducted in a variety of settings have shown that patients over 65 years of age use an average of 2 to 6 prescribed medications and 1 to 3.4 non-prescribed medications. Success of pharmaceutical and medical research has resulted in an abundance of effective drugs to treat acute and chronic conditions. Most research resulting in the development and marketing of these medications has been directed at proving the efficacy and safety of single drug products. Little research has been directed to determine the safety and efficacy of combining multiple medications to treat concurrent conditions in a single patient. It is known that the use of multiple medications increases the risks of adverse drug reactions, drug-drug interactions, and makes compliance with medication regimens more difficult. Numerous studies have been conducted to better understand factors that are associated with increased drug use in elderly people. Studies also have been conducted to identify interventions that can improve drug treatment for the elderly, and reduce polypharmacy. Multiple drug use is common in older people, and may give rise to drug related problems. Methods to reduce the risks of polypharmacy include patient education, physician education, such as education and feedback systems, and regulatory intervention. Continual drug and disease monitoring is essential.

Pharmacological manipulations of the alpha 2-noradrenergic system. Effects on cognition.

Abstract: Electrophysiological and neurosurgical lesion studies with experimental animals have implicated the ascending dorsal noradrenergic bundle of the locus coeruleus system in cognitive process such as memory, learning and selective attention. However, it has also been suggested that noradrenaline (norepinephrine) is crucial in certain cognitive functions associated with the frontal lobes, particularly the prevention of distractibility by irrelevant stimuli. The α2-receptors of the prefrontal cortex appear to be of particular importance in this respect. Studies with humans and experimental primates provide substantial support for this view. The aged primate brain is prone to degeneration of the locus coeruleus, as well as profound catecholamine depletion in the prefrontal cortex, and so is ideal for psychopharmacological investigation of the role of noradrenaline in frontal lobe function. Elderly monkeys show deficits in performance of the delayed response task, which can be reversed directly by both the mixed α1/(α2-agonist clonidine, the more specific α2-agonist guanfacine and also, indirectly, by the α2-antagonist yohimbine. It is suggested that these results can be explained by an attenuation of the distracting properties of irrelevant stimuli following stimulation of noradrenergic activity. Conversely, distractibility is magnified whenever noradrenergic activity is reduced. This is supported by similar findings in psychopharmacological studies of healthy humans. The exception to this is when the locus coeruleus is likely to be firing, e.g. in times of stress or when novel stimuli are encountered. Clonidine attenuates locus coeruleus firing on such occasions, and so counteracts any beneficial (or deleterious) effects of stress on task performance. α2-Adrenoceptor agents have little therapeutic value in patients with dementia of the Alzheimer’s type. However, they may have some clinical use in patients who have a cognitive symptomatology similar to that of patients who have received neurosurgical excisions to the frontal lobes, e.g. deficits in working memory, executive function or focused attention, with relative sparing of episodic short term memory. Patients with Korsakoff’s disease, attention deficit disorder or schizophrenia may benefit from treatment with α2-agents. In particular, idazoxan has putative therapeutic effects in patients with a neurodegenerative disorder, namely dementia of frontal type.

Tacrine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in Alzheimer's disease.

Abstract: Tacrine is a centrally acting cholinesterase inhibitor with additional pharmacological activity on monoamine levels and ion channels. It has been postulated that some or all of these additional properties may also be relevant to the mode of action of the drug. There are wide interindividual variations in pharmacological and clinical response to tacrine, possibly related to interindividual variation in bioavailability. Tacrine appears to improve cognitive function and behavioural deficits in a proportion of patients with Alzheimer's disease, at dosages of 80 to 160 mg/day. In the best designed trials, 30 to 51% of evaluable patients showed an improvement of at least 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale, versus 16 to 25% of placebo recipients. A similar proportion of tacrine recipients were judged to have improved when global assessment scales were used. There was a significant dose-response relationship up to 160 mg/day. However, large numbers of patients were withdrawn during the trials, many because of tacrine-associated increases in transaminase levels. Elevated liver enzyme levels occurred in about 50% of tacrine recipients (reaching clinical significance in about 25%). Cholinergic symptoms also occurred more often in tacrine recipients than in those receiving placebo. A gradual increase in tacrine dosage, at 6-week intervals, is recommended when initiating therapy, and weekly serum transaminase monitoring is required for 6 weeks after each dosage increase. Despite the limitations implied by the low proportion of responders and high incidence of hepatic adverse effects associated with therapy, tacrine appears to make a measurable difference in both cognitive and behavioural function in a proportion of patients with Alzheimer's disease--a welcome advance in an area previously devoid of acceptable treatment options.

Idebenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in age-related cognitive disorders.

Abstract: Idebenone is a benzoquinone compound which has been investigated in elderly patients with dementia. Its precise mechanism(s) of action remains unknown, but in vitro and in vivo studies suggest the drug may diminish nerve cell damage due to ischaemia, correct neurotransmitter defects and/or cerebral metabolism and facilitate memory and learning. In the small number of studies available for evaluation, idebenone was generally superior to placebo and comparable with bifemelane, oxiracetam and nebracetam on the basis of a number of objective and subjective tests and rating scales in patients with mild to moderate cognitive decline. Clinical trial results indicate that patients with mild dementia seem more likely to respond than those with greater functional decline. The degree of benefit conferred by idebenone is often difficult to determine, but in those who respond, improvement is generally mild to moderate. Therapy with idebenone appears well tolerated for up to 2 years, and no changes in vital signs or laboratory values have been seen in clinical trials. In view of the lack of a proven agent to limit or halt the progression of dementia in the elderly, idebenone may warrant consideration in patients with mild cognitive dysfunction on the basis of preliminary evidence of predominantly mild improvement of functional status in some patients and good tolerability. However, further well designed studies, including comparisons with newer and commonly used agents, such as tacrine, are required to better define the role of idebenone in this complex area of treatment.

Changes in the renin-angiotensin-aldosterone axis in later life.

Abstract: The renin-angiotensin-aldosterone system (RAAS) is one of the main systems involved in the regulation of blood pressure and sodium homeostasis. In animal experiments and in humans, the plasma renin activity and aldosterone levels are reduced with aging. The age-related differences in plasma renin activity and aldosterone are more pronounced in stimulated conditions (when sitting in an upright position, when salt intake is restricted and when plasma volume is depleted) than under basal conditions. Age-related alterations of the kidney (glomerulosclerosis, decreased number of functional nephrons) might account for the age-related differences in the active to inactive plasma renin ratio. In the same way, a diminished synthesis of angiotensinogen by the liver could contribute to the decrease in the activity of the RAAS in aging. This is partially compensated for by increases in the density of angiotensin II receptors reported in elderly patients. Furthermore, aging is associated with a reduced adrenal responsiveness to angiotensin II, contributing to lower production of aldosterone and alterations of sodium homeostasis. Estradiol and progesterone help stimulate the secretion of renin. Reduced levels of these hormones at menopause also lead to reduced plasma renin activity. In relation to these findings, several studies have shown that reductions in blood pressure, induced by short or long term treatment with angiotensin converting enzyme (ACE) inhibitors, were more pronounced in old than young hypertensive patients. An insertion/deletion polymorphism in the ACE gene has been described; the genotype deletion/deletion of this gene has been reported to be closely associated with longevity. This result was unexpected since the same deletion polymorphism was also shown to represent a potent risk factor for myocardial infarction.

The Role of Interleukin-6 in Certain Age-Related Diseases

Abstract: Interleukin-6 (IL-6) is a pro-inflammatory cytokine with a wide range of functions. Perhaps the most important physiologically is its role as a mediator of the acute phase inflammatory response. Normally, there is little measurable IL-6 in the circulation, but levels increase abruptly to nanogram amounts during an inflammatory process. During aging, it has been proposed that the tight regulation of IL-6 gene expression becomes less effective and levels are measurable even when there is no evidence for inflammation. Several investigators have identified this cytokine as being involved in the pathogenesis of various disease processes and we have suggested that certain age-associated diseases are directly related. Among these are late-life lymphoma and myeloma, osteoporosis and possibly Alzheimer’s disease.

Rational Use of Benzodiazepines in the Elderly

Abstract: In the 40 years since the introduction of benzodiazepines into clinical practice, considerable controversy has surrounded their use. While there is little evidence to suggest widespread abuse or long term use in most age groups, benzodiazepines continue to be widely prescribed to older adults in both community and long term care settings. Several studies have described an increased sensitivity to the clinical effects and toxicity of benzodiazepines in older adults. However, it is unclear whether these observations are attributable to age-related changes in benzodiazepine pharmacokinetics or pharmacodynamics. Benzodiazepines are the safest and most effective agents available for the pharmacological management of symptoms of anxiety and insomnia. However, the acute administration of benzodiazepines is associated with impairments in cognition, memory, coordination and balance, and long term use, even at therapeutic dosages, has been associated with symptoms of withdrawal upon abrupt discontinuation. Therefore, it is essential that the practitioner develop a treatment plan when utilising these agents to treat older patients. This plan may also involved the implementation of psychotherapy or other nonpharmacological modalities in the management of anxiety or insomnia. Although we recommend initiating benzodiazepines using the lowest available dosage, older patients should be treated with enough drug to produce a therapeutic response. For most clinical situations of anxiety or insomnia, we recommend prescribing limited quantities (e.g. a 2-week supply with a return visit for re-evaluation of effectiveness and adverse effects) of a drug with a short elimination half-life. Persistent anxiety or insomnia in the elderly may require a medical and possibly psychiatric evaluation. If benzodiazepines are used continuously for 6 weeks or longer, we recommend a gradual taper over 2 to 12 weeks with frequent follow-up to evaluate for signs of withdrawal or the return of symptoms.

Vinorelbine. A review of its pharmacological properties and clinical use in cancer chemotherapy.

Abstract: Vinorelbine is a semisynthetic vinca alkaloid with a broad spectrum of antitumour activity. The drug is effective as a single agent in inoperable/advanced non-small cell lung cancer (NSCLC), producing objective response rates of about 15 to 30%, and as first-line or later chemotherapy for metastatic spread in advanced breast cancer. Combining vinorelbine with standard chemotherapeutic regimens improves response rates in these indications compared with vinorelbine monotherapy: in NSCLC response rates increase to 30 to 50% when vinorelbine is administered with cisplatin. Importantly, survival was prolonged by a further 9 weeks with this combination in a trial in > 600 patients with NSCLC. Comparative trials evaluating vinorelbine in women with advanced breast cancer are few at present. However, results suggest greater efficacy for vinorelbine than for melphalan as second-line chemotherapy, and similar efficacy for vinorelbine plus doxorubicin compared with doxorubicin plus 2 other drugs as first-line chemotherapy. Vinorelbine has tended to yield superior response rates when compared with vindesine, and appears to have greater haematological toxicity (i.e. granulocytopenia) but less neurological toxicity (peripheral neuropathy, constipation, loss of deep tendon reflexes) than this agent. Myelosuppression is the most frequent cause of vinorelbine treatment delay or dose reduction. Other consequences of vinorelbine therapy are those typically seen with antineoplastic agents, such as diarrhoea, nausea and vomiting, and alopecia. However, these are rarely severe. Early clinical investigations indicate that the antitumour effects of vinorelbine in other malignancies including ovarian carcinoma, lymphoma and head and neck cancer warrant further exploration, as does the efficacy of the drug relative to standard approaches and its possible beneficial effects on quality of life of cancer patients. Clarification is also required of the feasibility of an oral dosage form, which in preliminary investigations has shown some efficacy in NSCLC, but a variable response rate and high incidence of gastrointestinal disturbances in women with breast cancer. Thus, vinorelbine as a single agent or combined palliative therapy is effective against advanced NSCLC, and as first- or second-line chemotherapy in advanced breast cancer. This semisynthetic vinca alkaloid has a manageable tolerability profile and potential for use in other malignancies and as an oral formulation. With these attributes, vinorelbine is a valuable option which extends the range of treatments available for these difficult-to-treat malignancies.

Effects of antidepressants on cognitive functioning of elderly patients. A review.

Abstract: The influence of antidepressants on cognitive performance in elderly patients has been investigated in 18 studies More than 70 different psychological tests or batteries of tests could be identified in these studies The tentative conclusions that can be drawn are as follows Monoamine oxidase (MAO) inhibitors hardly influence cognitive performance Amitriptyline, dothiepin, mianserin and trazodone impair attention and ability to concentrate Drugs with anticholinergic properties, such as nortriptyline, maprotiline and amitriptyline, might impair aspects of memory For nortriptyline, higher plasma concentrations correlate with greater cognitive impairment Cognitive impairment induced by nortriptyline during treatment might not be a transient effect, but may last as long as treatment continues Data regarding the effects of selective serotonin (5-hydroxytryptamine) reuptake inhibitors on cognitive performance in the elderly indicate no detrimental effect A consensus on the use of instruments evaluating cognitive performance is needed to allow better comparison of future studies As these conclusions can only be provisional, more study is needed

Age-related changes in the gastrointestinal system. Effects on drug therapy.

Abstract: Although there are many changes in the gastrointestinal tract with aging, only those in the liver substantially influence blood concentrations and clearance of drugs. The liver mass, overall function, and blood flow decrease approximately 1% per year after age 40 to 50 years, and accordingly, the hepatic metabolism or clearance of drugs decreases in this proportion. The sensitivity of the gastrointestinal tract to usual concentrations of drugs is increased, and this, in part, accounts for the increased frequency of adverse drug reactions in elderly patients.

Cyproterone. A review of its pharmacology and therapeutic efficacy in prostate cancer

Abstract: Cyproterone (cyproterone acetate) is a steroidal antiandrogenic agent that inhibits the action of adrenal and testicular androgens on prostatic cells. Additionally, its progestogenic activity causes a centrally mediated reduction in testicular secretion of androgens. Studies have demonstrated the effectiveness of cyproterone monotherapy in patients with prostate cancer, and for those in whom orchiectomy is not an acceptable option cyproterone may be a useful alternative. In addition, the drug may be administered in combination with surgical or gonadotrophin-releasing hormone (GnRH) agonist-mediated castration to ensure ablation of adrenal androgens. However, the effectiveness of cyproterone in combination with these forms of testicular androgen deprivation remains to be fully established. Trials to date have not demonstrated prolonged survival in patients receiving the combination therapy. Importantly, however, cyproterone does prevent acute exacerbation of disease during initial treatment with a GnRH agonist. Furthermore, combination therapy tends to be associated with a lower incidence of hot flushes than GnRH agonist-mediated or surgical castration alone. Thus, cyproterone 200 mg/day has proven efficacy in preventing acute flare of disease and reducing the incidence of hot flushes associated with GnRH agonist therapy or orchiectomy. It may also facilitate maximal androgen deprivation in patients receiving GnRH agonist therapy. If this drug is used as monotherapy, dosages of 250 mg/day or greater will probably be required.

The Hypertension in the Very Elderly Trial (HYVET). Rationale, methodology and comparison with previous trials.

Abstract: The Hypertension in the Very Elderly Trial (HYVET) is a multicentre, open, randomised, controlled trial. The aim of this trial is to investigate the effect of active treatment on stroke incidence in hypertensive patients over the age of 80 years. Secondary end-points include total cardiovascular mortality and morbidity. Entry criteria include a sustained sitting systolic blood pressure of 160 to 219mm Hg plus a sustained sitting diastolic pressure of 95 to 109mm Hg. Also required is a standing systolic blood pressure of at least 140mm Hg. Patients must give their informed consent, and be free of congestive heart failure requiring treatment, gout, renal failure or a recent cerebral haemorrhage. Patients are to be randomised to 3 groups-(i) no treatment; (ii) treatment with a diuretic [bendroflumethiazide (bendrofluazide)]; or (iii) treatment with an angiotensin converting enzyme (ACE) inhibitor (lisinopril). Starting dosage for bendroflumethiazide and lisinopril is 2.5 mg/day. In order to achieve goal sitting systolic and diastolic blood pressures (< 150/80 mm Hg), a doubling of the dosage is allowed. Furthermore, slow release diltiazem (120 mg/day increasing to 240 mg/day if required) may be added to the medication of the actively treated groups. These drugs have been chosen as inexpensive and appropriate representatives of their therapeutic classes. 700 patients in each group (a total of 2100) will be sufficient to detect a 40% difference in cerebrovascular events between no treatment and active treatment (alpha = 0.01, 1-beta = 0.90). These numbers will also detect a difference in total mortality of 25% and in cardiovascular mortality of 35%. The pilot phase of the trial has been started with support from the British Heart Foundation. Centres which are interested in taking part should contact C.J. Bulpitt or any of the other authors.

Perspectives on quality of life of older patients with cancer.

Abstract: Cancer in older people is an increasingly common problem. Since survival benefits may decline and the risks of treatment progressively increase with age, preservation and improvement of quality of life (QOL) is a major goal of geriatric oncology. The concept of health-related QOL holds that the preservation of health and physical function is necessary to the maintenance and improvement of QOL, and encompasses several constructs, including physical, functional, emotional, social, and spiritual domains. Several instruments for the assessment of QOL have been validated, but none has been calibrated to the special problems of older people. Such problems involve diverse evolution of health and disease around variable models, potential age-related shifts in values and focus, and barriers to the use of questionnaires, such as poor visual and auditory function, easy fatiguability, slower reactions and dementia. Individualised questionnaires may represent the ultimate goal in the assessment of QOL in the elderly. The assessment of QOL in general oncology has provided new and important information related to the value of breast preservation in the management of breast cancer, to the value of sexual function in the management of prostate cancer, and to the effects of limb amputation on QOL. Also, QOL at the beginning of treatment has independent prognostic implications. In geriatric oncology, assessment of QOL may allow trade-off between QOL and survival, and may determine the choice among alternative forms of life-prolonging and palliative treatments.

Drug-Induced Parkinsonism in the Aged

Abstract: Drug-induced Parkinsonism is a frequent adverse effect of numerous drugs interfering with dopamine function at the basal ganglionic level. It accounts for 4% of all patients with Parkinsonism seen in neurology clinics. Pharmacological agents implicated in the production of this disorder have a wide range of applications in medicine, beyond the treatment of psychiatric illnesses. Antipsychotics, substituted benzamides and calcium channel blockers are the drugs most commonly involved. The aged population is at an increased risk of drug-induced Parkinsonism due to intrinsic factors and because they often receive multiple drugs, including those from self-medication. Lack of knowledge in the medical profession of the potential hazards involved in the use of certain drugs plays a contributory role in the development of drug-induced Parkinsonism. Physicians should be always alert in order to detect, as early as possible, the presence of extrapyramidal symptoms in patients exposed to medications with antidopaminergic properties. Whenever possible, withdrawal of the medication will help resolve symptoms; complete remission takes place within 6 to 18 months in the majority of patients. The use of anti-Parkinsonian drugs is only advisable if the symptomatology is disabling. The best available treatment is prevention.

Aniracetam. An overview of its pharmacodynamic and pharmacokinetic properties, and a review of its therapeutic potential in senile cognitive disorders.

Abstract: Aniracetam is a member of the nootropic class of drugs, which have possible cognition enhancing effects. It appears to positively modulate metabotropic glutamate receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive glutamate receptors, and may facilitate cholinergic transmission, effects which are possibly related to its mechanism of action. Results from trials in elderly patients with mild to moderate cognitive impairment due to senile dementia of the Alzheimer type suggest that aniracetam may be of benefit, with further trials required to confirm its efficacy profile and to define more precisely those patients most likely to respond to treatment. Aniracetam 1500 mg/day was significantly more effective than placebo in all tests at 4 and 6 months, and in a further 6-month trial was more effective than piracetam 2400 mg/day in 8 of 18 tests. Preliminary evidence in the treatment of patients with cognitive impairment of cerebrovascular origin suggests aniracetam may also be of benefit in this condition. Whilst incidence rates of adverse effects are not yet available, data from trials suggest aniracetam is well tolerated. In particular, aniracetam does not appear to cause increases in liver enzyme levels. The evaluation of drugs for patients with senile cognitive disorders is a difficult area and therapeutic options are currently limited. Preliminary evidence of the potential benefits and good tolerability profile of aniracetam support continued evaluation of its use in patients with mild to moderate senile dementia of the Alzheimer type.

Pimobendan. A review of its pharmacology and therapeutic potential in congestive heart failure.

Abstract: Pimobendan is a novel cardiotonic vasodilator (inodilator) which derives its inotropic activity from a combination of phosphodiesterase III inhibition and sensitisation of myocardial contractile proteins to calcium. The acute haemodynamic benefits of pimobendan (2.5 to 10mg orally; 5 to 10mg intravenously) seen in patients maintained on conventional diuretic, digitalis and vasodilator therapy for chronic heart failure (increases in cardiac output and stroke volume, and reductions in left ventricular preload and afterload) persisted on short term (1 month) therapy, and showed only limited evidence of attenuation on longer term (6 months) oral therapy with pimobendan 2.5 or 5mg twice daily. Adjunctive therapy with pimobendan 1.25 to 5mg twice daily for periods of 3 to 6 months improved exercise tolerance on symptom-limited exercise testing, New York Heart Association (NYHA) functional class, and quality of life, and additionally reduced the need for hospitalisation in patients with moderate to severe chronic heart failure. Pimobendan appears to be well tolerated at therapeutic doses (1.25 to 5mg twice daily) in patients with chronic heart failure, and preliminary indications suggest that it is largely devoid of the proarrhythmic effects of classical phosphodiesterase III inhibitors. Although information regarding the long term effects of pimobendan on mortality is currently lacking, the drug nevertheless shows potential benefit as an adjunctive therapy in patients with chronic heart failure.

Differential diagnosis of dementia, delirium and depression. Implications for drug therapy.

Abstract: Dementia, delirium and depression are the 3 most prevalent mental disorders in the elderly. While dementia and depression are prevalent in the community, hospitals and nursing homes, delirium is seen most often in acute care hospitals. Much of the management of these syndromes is undertaken by primary care physicians rather than psychiatrists. Therefore, it is imperative that generalist physicians be adept at recognising, evaluating and managing patients with these syndromes. Because no diagnostic tests are pathognomonic of these syndromes, the differential diagnosis hinges on a careful clinical evaluation. The first step is to recognise which of the syndromes is present. Dementia is defined by a chronic loss of intellectual or cognitive function of sufficient severity to interfere with social or occupational function. Delirium is an acute disturbance of consciousness marked by an attention deficit and a change in cognitive function. Depression is an affective disorder evidenced by a dysphoric mood, but the most pervasive symptom is a loss of ability to enjoy usual activities. It is important to recognise that these syndromes are not mutually exclusive, as dementia frequently coexists with delirium and depression. Furthermore, physical diagnoses, such as chronic obstructive lung disease, congestive heart failure, stroke and endocrine disorders, are frequently associated with depressive symptoms. Given this, a comprehensive evaluation is mandatory. Laboratory tests are necessary to exclude concurrent metabolic, endocrine and infectious disorders, and drug effects. Imaging studies should be obtained selectively in patients with signs and symptoms, such as focal neurological findings and gait disturbances, which are suggestive of structural lesions: stroke, subdural haematoma, normal pressure hydrocephalus and brain tumours. Appropriate management involving pharmacological and nonpharmacological measures will result in significant improvement in most patients with these syndromes. Potentially offending drugs should be discontinued. In delirious patients the underlying illness must be treated concomitantly with the use of psychotropics, if necessary. Although no current medications have been shown to have a significant effect on the functional status of patients with the 2 most common causes of dementia, Alzheimer's disease and multi-infarct dementia, the management of concomitant illness in these patients may result in improved function for as long as a year. Tacrine, an anticholinesterase inhibitor, improves cognitive function slightly in selected patients with Alzheimer's disease over short periods. Finally, the treatment of depression with medications or electroconvulsive therapy (ECT) results in significant reductions in mortality and morbidity.

Post-herpetic neuralgia in older patients. Incidence and optimal treatment.

Abstract: Post-herpetic neuralgia (PHN) is a disease caused by having had herpes zoster; it is not a continuation of shingles. Up to 50% of elderly patients who have had shingles may develop PHN. PHN is defined as pain recurring or continuing at the site of shingles, 1 or more months after the onset of the rash. Because many cases resolve spontaneously in the early stages, no claims of 'pharmacological cure' can be entertained before 3 months post-rash. In fact, some authorities will not accept claims made before 6 months. Antivirals administered systemically within the appropriate time-window greatly relieve the pain of acute shingles, and to a large extent prevent scarring. There is no evidence that they prevent the subsequent development of PHN. However, patients with PHN whose acute shingles were treated with aciclovir obtain pain relief with antidepressants in half the time required by those patients who did not receive aciclovir for their acute shingles. If patients with acute shingles are given low dose amitriptyline from the onset, only half as many are in pain at 6 months as a group not so treated, irrespective of the antiviral treatments given. The most effective treatment of established PHN to date consists of adrenergically active antidepressants. There is a strict correlation with the brevity of the interval between acute shingles and initiation of such treatment. 75% of patients starting treatment with antidepressants within 3 to 6 months after shingles obtain pain relief, whereas if antidepressants are not started for 2 years, only 25% obtain pain relief.(ABSTRACT TRUNCATED AT 250 WORDS)

Amantadine and rimantadine prophylaxis of influenza A in nursing homes. A tolerability perspective.

Abstract: Amantadine and rimantadine are recommended for the treatment and prophylaxis of influenza A infections, and constitute an integral component of influenza control measures in the nursing home setting. However, optimal use necessitates a thorough understanding of the toxicity profiles of these agents, as well as strategies to reduce the risk of adverse reactions. Adverse reactions of these compounds predominantly involve the gastrointestinal tract and the central nervous system (CNS), including hyperexcitability, slurred speech, tremors, insomnia, dizziness, mood disturbance, ataxia, psychosis and fatigue. Based on data from comparative trials, rimantadine appears to exhibit a lesser propensity to cause adverse CNS reactions than amantadine, but a similar propensity to cause adverse gastrointestinal reactions. Factors enhancing the risk of adverse reactions to these agents include reduced renal function (especially for amantadine), drug-drug interactions with cationic drugs, which inhibit amantadine renal tubular secretion (e.g. trimethoprim, triamterene, and possibly cimetidine and procainamide), elevated peak and trough plasma concentrations, and a history of seizures. Careful attention to published dosage adjustment guidelines for these compounds, avoidance of interacting drugs and avoiding these agents in patients with a history of seizures may be the best means to reduce the risk of toxicity in elderly patients. Rimantadine may have an advantage over amantadine in the elderly population in light of its lesser propensity to cause adverse reactions, less complex dosage adjustment in the case of renal impairment and probable lack of drug-drug interaction potential with cationic drugs.

Trophic factors in aging. Should older people receive hormonal replacement therapy

Abstract: The aging process is associated with significant declines in the levels of many hormones and trophic factors including estrogen, testosterone, growth hormone (somatropin, somatotropin) and insulin-like growth factor-1 (IGF-1, somatomedin-1, somatomedin-C). Since the classic age-related changes resemble the signs and symptoms of endocrine deficiency, it has been hypothesised that some of the negative effects of aging are due to these hormonal deficits. Consequently, the potential role of hormonal replacement in reversing the deleterious effects of aging deserves investigation.

Etidronic acid. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease.

Abstract: Etidronic acid is an orally and intravenously active bisphosphonate, which is believed to inhibit resorption of bone via a number of cellular mechanisms, including alteration of osteoclastic activity. In studies of patients with symptomatic Paget's disease, etidronic acid 5 to 20 mg/kg/day administered orally rapidly decreased the biochemical indices of bone turnover. Mineralisation defects in forming bone may be avoided by the use of an initial dosage of 5 mg/kg/day for up to 6 months; dosages above 10 mg/kg/day should be limited to 3 months' duration, and dosages greater than 20 mg/kg/day should be avoided. Although 3-day intravenous therapy with etidronic acid 7.5 mg/kg/day has shown superior efficacy to rehydration and forced diuresis in the management of hypercalcaemia of malignancy, the efficacy of the drug is lower than that of the newer bisphosphonates, pamidronic acid and clodronic acid. Clinical studies involving postmenopausal women with established osteoporosis have indicated that oral etidronic acid 400 mg/day for 14 days as part of a 90-day cycle, repeated for up to 3 years, increases the bone mineral density (BMD) of the lumbar vertebrae and appears to reduce the incidence of vertebral fracture. Published data suggest that etidronic acid shows similar efficacy to hormone replacement therapy (HRT) in these respects. The above dosage also appears to be effective in preventing corticosteroid-induced osteoporosis when administered as part of an intermittent, cyclical regimen. Etidronic acid in higher dosages (10 to 20 mg/kg/day orally) is effective in reducing the incidence of heterotopic ossification and its ensuing complications in both neurological and post-surgical patients. Etidronic acid is well tolerated by the majority of patients, with gastrointestinal complaints reported most commonly, but tends to delay the normal mineralisation of forming bone when administered continuously at higher dosages for prolonged periods. This is of little consequence where short term treatment is involved, but may be detrimental to those patients receiving longer courses of therapy. This effect may be minimised or avoided by using the lowest effective dosage for as short a time as possible (as in the above recommendations for Paget's disease), or by the use of intermittent cyclical therapy (as in the management of osteoporosis). Etidronic acid therefore retains a role in the management of resorptive bone disease, particularly in the treatment of Paget's disease, the prevention of heterotopic ossification, and as a second-line option in postmenopausal osteoporosis. However, the development of newer bisphosphonates requires that these compounds be continually compared and re-evaluated.

Acquired immunodeficiency syndrome in the elderly.

Abstract: Recent data from the US show that since 1990 the number of paediatric patients with AIDS is decreasing while the number of patients with AIDS over age 50 years is increasing. To date, little attention has been given to understanding AIDS risk-taking behaviours, clinical presentations, and therapeutic needs of middle-aged and older HIV-infected individuals. Older HIV-infected individuals deteriorate more rapidly than younger patients due to an accelerated loss of CD4+ helper T cells. Despite recognised age-related physiological differences between voung and elderly individuals, scant information about drug optimisation for the treatment of AIDS in older individuals is available. More data need to be collected about this group of AIDS patients, and appropriate treatment strategies designed for their special needs.

Rational Approach to the Antibiotic Treatment of Pneumonia in the Elderly

Abstract: The incidence of pneumonia is highest among the aged compared with other adult populations, and causes significant morbidity and mortality among this group. Most episodes of pneumonia are caused by aspiration of oropharyngeal flora into the lungs and failure of lung defence mechanisms to eliminate the aspirated bacteria.

Transdermal estradiol/norethisterone. A review of its pharmacological properties and clinical use in postmenopausal women.

Abstract: The combined transdermal estradiol/norethisterone therapeutic system is designed to deliver both estradiol and norethisterone into the systemic circulation at a constant rate for up to 4 days when affixed to the skin. Transdermal administration avoids hepatic first- pass metabolism, allowing therapeutic concentrations of the progestogen and estrogen to be maintained in postmenopausal women following low dose administration. Transdermal norethisterone does not appear to alter the potentially beneficial effects of transdermal estradiol on total cholesterol low- density lipoprotein (LDL) or triglyceride levels, or metabolic parameters of bone resorption or vaginal cytology. Protection of the endometriumfrom the effects of unopposed estradiol is achieved by sequential treatment with transdermal estradiol/norethisterone for 2 weeks of each 28- day cycle, and the majority of patients experience a regular vaginal bleeding pattern with this treatment regimen. Menopausal symptoms are improved to a similar extent during the transdermal estradiol- only and combined estradiol/norethisterone treatment phases. The transdermal therapeutic system has been well accepted by patients in clinical trials. It is generally well tolerated, the most common adverse effect being local irritation at the site of application. Estrogen- and progestogen- related systemic adverse events are reported in a small proportion of patients. Thus, the combined estradiol/norethisterone transdermal delivery system offers a more convenient and consistent method of progestogen administration. Together with its therapeutic efficacy when administered at lower dosages than oral therapy, it is likely to further improve patient compliance during hormone replacement therapy. The combined estradiol/norethisterone therapeutic system is designed to deliver 0.05 mg/day estradiol and 0.25 mg/day norethisterone (given as the acetate) at a constant rate for up to 4 days. Following application of the delivery system to intact skin, steady-state plasma concentrations of norethisterone (the active gestogen), were between 1.6 and 3.2 nmol/L 2 days after the first application. Steady-state concentrations of estradiol of 0.15 to 0.18 nmol/L were reached within 24 hours, and were similar to estradiol levels in the early follicular stage of the ovulatory cycle in premenopausal women. Estradiol is rapidly cleared from the circulation following transdermal administration, with a plasma elimination half-life (t½) of about 1 hour. The t½ of norethisterone varies between 6 and 8 hours. Metabolism of both estradiol and norethisterone occurs mainly in the liver, the major metabolites being estrone, estriol and their conjugates, and the 5β,3α-norethisterone derivative, respectively. Metabolites are mainly excreted as sulphate and glucuronide conjugates in the urine, although some enterohepatic recirculation may occur. Plasma concentrations of estradiol and norethisterone return to pretreatment values within 24 and 48 hours of patch removal, respectively. Transdermal estradiol therapy appears to have a positive effect on cardiovascular disease risk factors in postmenopausal women, which may be mediated in part by the beneficial changes in lipid and lipoprotein profiles observed in patients receiving transdermal estradiol for ≥ 3 months. Addition of sequential transdermal norethisterone does not appear to significantly affect the reduced plasma levels of total and low density lipoprotein (LDL) cholesterol induced by estradiol, and triglyceride levels are reduced by a similar extent during both the estrogen-only and combined estrogen/norethisterone treatment phases. Transdermal estradiol appears to have a favourable effect on carbohydrate metabolism and no net adverse effect is observed following coadministration of transdermal norethisterone. The effects of combined transdermal estradiol/norethisterone on haemostatic factors and arterial status have yet to be determined. During transdermal estradiol/norethisterone therapy, vaginal cytology is converted to a pattern similar to that found in premenopausal women, with increased numbers of superficial and decreased numbers of basal and parabasal cells. Transdermal estradiol inhibits bone resorption, as evidenced by a reduction in the urinary ratios of calcium and hydroxyproline to creatinine, and stabilisation of, or small increases in, bone mineral density in postmenopausal women receiving long term treatment. Concomitant progestogen therapy does not appear to impair, and may enhance, the bone conserving effects of estrogens; however, further investigation is necessary to confirm the latter findings. The clinical efficacy of the combined transdermal estradiol/norethisterone delivery system in preventing endometrial hyperplasia and controlling climacteric symptoms has been investigated in noncomparative clinical trials of up to 3 years’ duration. In most studies, transdermal estradiol 0.05 mg/day was administered for the first 2 weeks of a 28-day cycle, followed by combined transdermal estradiol/norethisterone 0.05/0.25 mg/day for the last 2 weeks. The combined transdermal estradiol/norethisterone delivery system provided endometrial protection from unopposed estradiol. Biopsy samples from more than 400 treated women showed proliferative endometrium in 1.5 to 7% and secretory endometrium in 57 to 100%. The incidence of hyperplasia in women receiving this treatment regimen was less than 2%. Sequential transdermal norethisterone induced a regular vaginal bleeding pattern in about 80% of women. Regular bleeding episodes occurred in 80 to 90% of cycles, with irregular episodes in about 5 to 11%. Amenorrhoea occurred in about 6 to 9% of cycles during therapy. In 2 small studies in which 30 women received continuous transdermal estradiol/norethisterone, the incidence of amenorrhoea was 53 and 100% after 6 months. Climacteric symptoms including hot flushes, sweating, sleep disturbance, vaginal discomfort, poor concentration and irritability were significantly improved compared with baseline in patients receiving transdermal estradiol with sequential transdermal norethisterone. The most frequently reported adverse effects in women using transdermal estradiol or combined transdermal estradiol/norethisterone delivery systems are dermatological reactions. Transient mild erythema and itching at the site of application are the most common events. However, severe cutaneous irritation necessitating withdrawal of treatment is experienced by about 6% of patients using the estradiol-only or combined delivery systems. The occurrence of skin reactions can be minimised by selection of new sites when applying patches. Adverse systemic events associated with estrogen or progestogen therapy occurred in a small proportion of women and included breast tenderness, vaginal spotting or bleeding, fluid retention, headache, nausea, gastrointestinal disturbances, bodyweight gain and depression. Of these events, unacceptable vaginal bleeding was the most common reason for patients discontinuing combined estradiol/norethisterone therapy (affecting 6 to 10%). Transdermal estradiol did not stimulate hepatic metabolism and therefore no increases in plasma levels of renin substrate, sex hormone-, thyroxin-, and cortisol-binding globulins or clotting factors were observed; however, a slight decrease in sex hormone-binding globulins was observed during combined transdermal estradiol/norethisterone treatment. For treatment of postmenopausal symptoms and symptoms of estrogen deficiency due to surgical menopause, and for prevention of postmenopausal osteoporosis in women with an intact uterus, transdermal estradiol 0.05 mg/day is recommended for the first 14 days of a 28-day cycle, followed by 14 days of combined transdermal estradiol 0.05/norethisterone 0.25 mg/day. The transdermal delivery system should be applied to clean dry intact skin and should be changed twice weekly. Contraindications to the use of estradiol include carcinoma of the breast or endometrium, vaginal bleeding of unknown origin, previous estrogen-associated, or active thromboembolic disease or thrombophlebitis. Caution is advised in patients with past or present endometriosis, uterine leiomyomata, impaired hepatic or renal function, conditions likely to be influenced by fluid retention, or a history of depression or pregnancy-associated jaundice.

Pharmacological Advances in the Treatment of Glaucoma

Abstract: Glaucoma is a potentially blinding disease. The goal of glaucoma therapy is to reduce intraocular pressure to a predetermined target level. There are currently 5 classes of compounds used for the medical management of glaucoma. Four classes that appear promising for the long term management of glaucoma are in different phases of clinical investigation, and include the topically active carbonic anhydrase inhibitors, selective α2-adrenergic agonists, prostaglandins and ethacrynic acid. The topically active carbonic anhydrase inhibitor dorzolamide (MK-507) is effective and well tolerated in clinical trials of up to 1 year’s duration. Animal studies have demonstrated that this drug lowers intraocular pressure by reducing aqueous humour formation. The selective α2-adrenergic agonists, brimonidine and apraclonidine, have been shown to be effective in reducing intraocular pressure in the short term. Long term effectiveness of these agents is under investigation. Prostaglandins (PG) of the PGF2-α isopropylester series caused marked reductions of intraocular pressure in laboratory and clinical trials. The newest prostaglandin analogue, latanoprost (PhXA41), effectively lowered intraocular pressure and was well tolerated in clinical trials of up to 4 weeks’ duration. Prostaglandins reduce intraocular pressure by enhancing uveoscleral outflow. Ethacrynic acid enhanced traditional outflow facility and lowered intraocular pressure when applied topically or intracamerally in laboratory studies and clinical trials. Corneal adverse effects of ethacrynic acid have been noted. Reformulation of ethacrynic acid ointment may resolve this problem. These 4 classes of compounds will enhance our options for the medical management of glaucoma. They may be used instead of or in combination with some of the drugs currently in use, and may be better tolerated.

Physiological changes due to age. Implications for the prevention and treatment of thrombosis in older patients.

Abstract: The risk of venous thromboembolism increases with age. This increasing risk is associated with a concurrent enhancement of coagulation activation and gradual development of a ‘prethrombotic state’. This is reflected by increased levels of coagulation activation peptides in the elderly, as well as decreased activity of the fibrinolytic system. Moreover, with increasing age there is an increased incidence of comorbid conditions, which may, in themselves, be associated with an increased risk for the development of thrombosis. Accurate diagnostic techniques and strategies for treatment and prevention of deep vein thrombosis (DVT) are mandatory in order to prevent potentially fatal complications of DVT, such as pulmonary embolism. The feasibility of validated diagnostic techniques for detecting DVT, such as real-time B-mode ultrasonography, impedance plethysmography and contrast venography, is not significantly hampered in elderly patients. The same applies to strategies for prophylaxis and treatment of DVT, which are similar to those for younger patients, although formal studies in elderly patients with DVT are lacking.

Ciprofloxacin. A review of its pharmacological profile and therapeutic use in the elderly.

Abstract: Ciprofloxacin belongs to the fluoroquinolone class of antimicrobial agents which primarily inhibit bacterial DNA gyrase. It is effective after oral or intravenous administration, demonstrating potent antibacterial activity against most Gram-negative, and many Gram-positive bacteria. Although most bacterial strains have remained susceptible to the drug, low rates of resistance have been observed in some strains of Pseudomonas aeruginosa and enterococci and higher rates in methicillin-resistant Staphylococcus aureus. Ciprofloxacin attains concentrations in most tissues and body fluids sufficient to inhibit the majority of susceptible pathogens. Its pharmacokinetic profile in the elderly (> or = 65 years) is broadly similar to that reported in younger persons, although plasma concentrations are higher, and renal clearance is decreased in elderly persons. Ciprofloxacin is an effective treatment for those infections most common in elderly patients, including infections of the urinary tract, lower respiratory tract, skin and soft-tissues, and bone and joints, and is an effective agent for prophylaxis in transurethral surgery. Orally administered ciprofloxacin appeared to be at least as effective as alternative orally administered antimicrobial agents (trimethoprim, cotrimoxazole [trimethoprim/sulfamethoxazole], amoxicillin, amoxicillin/clavulanic acid) and also as effective as various parenteral agents (ceftriaxone, cefamandole, ceftazidime, cefotaxime) in a small number of comparative clinical trials. However, further studies are needed to clarify the comparative efficacy of ciprofloxacin with that of other oral and parenteral agents in the elderly. Initial trials have also indicated therapeutic efficacy of oral ciprofloxacin in malignant external otitis and bacterial prostatitis. Nevertheless, with its good tolerability profile and potent antimicrobial activity following oral administration, ciprofloxacin appears to offer a valuable alternative for treating various acute and chronic infections in elderly patients. Causative pathogens are frequently multiresistant in this patient group, and ciprofloxacin avoids or minimises the need for parenteral therapy.

Distinguishing Between the Fit and Frail Elderly, and Optimising Pharmacotherapy

Abstract: Frail older patients are at risk for adverse consequences from medications or other external stresses. No single marker, such as age or physical disability, or laboratory test can identify this group of patients. As a result, screening questionnaires have been developed and successfully used by nurses to help identify frail older patients upon admission to a hospital. A very short, 7-item screen with questions concerning cognitive ability, physical mobility, nutrition, number of medications used and hospitalisation within the previous month, was able to identify those patients who were more likely to be discharged to a nursing home, die, or incur a large hospitalisation cost for the institution. While the number of medications used was not an independent predictor of the outcome measures studied (e.g. discharge to a nursing home), data from the literature show that the number of medications prescribed is related to iatrogenic complications in older patients, and specific impairments in mobility and cognition. The proper choice and prescribed dose of a medication is extremely important in frail older patients who, for instance, are at increased risk from hip fracture with some benzodiazepines, and who have markedly diminished clearance of some drugs. A systematic approach is suggested for the prescription of medications in frail older persons which will help achieve optimal pharmacotherapy by using a limited number of medications, thoughtfully selecting medications which will not impair function, and prescribing an appropriate dose based on pharmacodynamic and pharmacokinetic changes that occur with age.