Balancing risk and benefit in venous thromboembolism trials: concept for a bivariate endpoint trial design and analytic approach.

Antithrombotic trials in venous thromboembolism treatment and prevention, including those evaluating the new oral anticoagulants, have typically evaluated thromboembolism risk as an efficacy endpoint and bleeding risk as a separate safety endpoint. Findings often occur in opposition (i.e. decreased thromboembolism accompanied by increased bleeding, or vice-versa), leading to variable interpretation of the results, which may ultimately be judged as equivocal. In this paper, we offer an alternative to traditional designs based on the concept of a bivariate primary endpoint that accounts for simultaneous effects on antithrombotic efficacy and harm due to bleeding. We suggest a bivariate endpoint as a general approach to the assessment of 'net clinical benefit' in recently published trials and to the design of future trials. Lastly, we illustrate the bivariate endpoint design using two examples: a recently published superiority trial of rivaroxaban (RECORD1) and an ongoing non-inferiority trial of the duration of anticoagulant therapy in children with venous thrombosis (Kids-DOTT).

Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit.

Cholinesterase (ChE) inhibition represents the most efficacious treatment approach for Alzheimer's disease (AD) to date. This multiple-dose study has examined the relationship between inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities in the cerebrospinal fluid (CSF) and cognitive change (measured by the Computerised Neuropsychological Test Battery [CNTB]) following administration of the ChE inhibitor, rivastigmine (Exelon). In 18 patients with mild to moderate AD, CNTB scores, activities of AChE and BuChE in the CSF, and plasma BuChE activity were determined prior to treatment with rivastigmine. Doses of rivastigmine were then titrated (1 mg b.i.d./week) to final doses of 1, 2, 3, 4, 5 or 6 mg b.i.d. (n = 3 per dose). Following treatment with the target dose of rivastigmine for at least 3 days, CNTB scores were re-determined. CSF samples were continuously collected together with plasma samples prior to and for 12 hours after the final dose of rivastigmine, and AChE and BuChE activities determined.AChE in CSF and BuChE in plasma were dose-dependently inhibited by rivastigmine treatment. The inhibition of BuChE in CSF was not clearly dose-dependent. A statistically significant correlation was observed between the change in CNTB summary score and inhibition of AChE activity (r = -0.56, p < 0.05) and BuChE activity (r = -0.65, p < 0.01) in CSF. Improvement in speed-, attention- and memory-related subtests of the CNTB correlated significantly with inhibition of BuChE but not AChE activity in CSF. Weak or absent correlation with change in cognitive performance was noted for inhibition of plasma BuChE. These results indicate that cognitive improvement with rivastigmine in AD is associated with central inhibition of ChEs and support a role for central BuChE in addition to AChE inhibition in modulating cholinergic function in AD.

Efficacy and safety of sibutramine for weight loss in obese patients with hypertension well controlled by beta-adrenergic blocking agents: a placebo-controlled, double-blind, randomised trial.

Sibutramine is a serotonin-noradrenaline reuptake inhibitor that is effective for long-term weight reduction and maintenance in obese patients when used as an adjunct to dietary and behavioural measures. Because the inhibition of noradrenaline reuptake may be expected to increase systolic and diastolic blood pressure (SBP and DBP) and pulse rate (PR), a 12-week multi-centre, placebo-controlled, double-blind study was designed to evaluate the efficacy and tolerability of sibutramine for weight loss in obese patients whose hypertension was well controlled (DBP < or = 95 mm Hg) by beta-adrenergic blocking agents (beta-blockers), with or without concomitant thiazide diuretics. Of the 61 patients randomised to sibutramine 20 mg once daily or placebo, 55 patients (90%) completed the study. After 12 weeks, sibutramine-treated patients lost significantly more weight than placebo-treated patients: mean weight reductions were 4.2 kg (4.5%) in the sibutramine group vs 0.3 kg (0.4%) in the placebo group (P<0.001). Greater weight reduction on sibutramine was accompanied by trends for greater mean reductions in serum triglycerides and very low density lipoprotein cholesterol. Sibutramine was well tolerated, and most adverse events were mild or moderate in severity. No sibutramine patient discontinued treatment because of an adverse event. Mean supine and standing DBP and SBP were not statistically significantly different between the sibutramine group and the placebo group at any post-baseline visit during the 12-week trial. At week 12, mean increases from baseline supine SBP and DBP, respectively, were 1.6 and 1.7 mm Hg for the sibutramine group vs increases of 0.4 and 1.3 mm Hg for the placebo group. At week 12, mean increases from baseline standing SBP and DBP, respectively, were 1.5 and 1.8 mm Hg for the sibutramine group vs an increase of 0.3 and a decrease of 0.8 mm Hg for the placebo group (P > 0.05 for treatment comparison). A statistically significant mean increase of 5.6 bpm (+/-8.25, s.d.) in supine PR from a baseline of 62 bpm was reported in sibutramine-treated patients at week 12, whereas placebo-treated patients had a mean supine PR decrease of 2.2 bpm (+/-6.43) (P < 0.001). In summary, sibutramine was well tolerated and effective in weight reduction. The addition of sibutramine did not result in an increase in BP in obese patients whose hypertension was well controlled by a beta-blocker. However, based on the potential for changes in BP and PR, obese patients being treated with sibutramine should be monitored periodically for changes in BP and PR and managed appropriately.

Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine.

In this randomized, double-blind, placebo-controlled, parallel-group study, patients received a single 50-mg oral dose of a 5-HT(1D) agonist, PNU-142633 (n = 34), or matching placebo (n = 35) during an acute migraine attack. No statistically significant treatment effects were observed at 1 and 2 h after dosing, even after stratifying by baseline headache intensity. At 1 and 2 h post-dose, 8.8% and 29.4% of the PNU-142633 group, respectively, and 8.6% and 40.0% of the placebo group, respectively, experienced headache relief; 2.9% and 8.8% of the PNU-142633 group and 0% and 5.7% of the placebo group were free of headache pain. Adverse events associated with PNU-142633 treatment included chest pain (two patients) and QTc prolongation (three patients). Results from this study suggest that anti-migraine efficacy is not mediated solely through the 5-HT(1D) receptor subtype, although this receptor may contribute, at least in part, to the adverse cardiovascular effects observed with 5-HT agonist medications.

Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer's disease.

Rivastigmine is a cholinersterase inhibitor approved recently for the treatment of Alzheimer's disease (AD). The objective of this study is to characterize the pharmacokinetics-pharmacodynamics of rivastigmine in patients with AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for about 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114-666, also called NAP 226-90), plasma, and cerebrospinal fluid (CSF) concentrations were determined together with the AChE activity and computerized neuropsychological test battery (CNTB) scores. Nonlinear mixed-effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivastigmine and its metabolite exhibited dose-disproportional pharmacokinetics. The apparent clearance and volume of distribution (plasma) of rivastigmine were estimated to be 120 L/h and 236 L, respectively. The relative bioavailability at the 6 mg dose was about 140%. The metabolite had a clearance of about 100 L/h and a volume of distribution of 256 L. The kinetics of the parent and metabolite in CSF showed an equilibration half-life of about 0.2 and 0.5 hours, respectively. The metabolite levels in CSF correlated very well with the acetylcholinesterase inhibition, with a ZNS 114-666 concentration of about 5.4 microg/L required for half-maximal inhibition of acetylcholinesterase activity. No statistically significant correlation of the CNTB scores with enzyme inhibition, parent or metabolite concentration (plasma/CSF), or rivastigmine dose could be established. The PK-PD model presented in this study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosing recommendations.

Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review.

The current approach to antimigraine therapy comprises potent serotonin 5-HT1B/1D receptor agonists collectively termed triptans. Sumatriptan was the first of these compounds to be developed, and offered improved efficacy and tolerability over ergot-derived compounds. The development of sumatriptan was quickly followed by a number of 'second generation' triptan compounds, characterised by improved pharmacokinetic properties and/or tolerability profiles. Triptans are believed to effect migraine relief by binding to serotonin (5-hydroxy-tryptamine) receptors in the brain, where they act to induce vasoconstriction of extracerebral blood vessels and also reduce neurogenic inflammation. Although the pharmacological mechanism of the triptans is similar, their pharmacokinetic properties are distinct. For example, bioavailability of oral formulations ranges between 14% (sumatriptan) and 74% (naratriptan), and their elimination half-life ranges from 2 hours (sumatriptan and rizatriptan) to 25 hours (frovatriptan). Clearly, such diverse pharmacokinetic properties will influence the effectiveness of the compounds and favour the prescription of one over another in different patient populations. This article reviews the pharmacological properties of the triptans (time to peak plasma concentration, half-life, bioavailability and receptor binding) and relates these properties to efficacy and time of onset. It also considers the effects of concomitant medication, food, age and disease on the pharmacokinetics of the compounds. In addition, the relative merits, such as headache recurrence, tolerability and route of administration, are discussed. Finally, the performance of the triptans is considered in the context of direct head-to-head comparative trials that have assessed the efficacy profile of the compounds.

Beta-amyloid therapies in Alzheimer's disease.

Neurones in the brain produce beta-amyloid fragments from a larger precursor molecule termed the amyloid precursor protein (APP). When released from the cell, these protein fragments may accumulate in extracellular amyloid plaques and consequently hasten the onset and progression of Alzheimer's disease (AD). A beta fragments are generated through the action of specific proteases within the cell. Two of these enzymes, beta- and gamma-secretase, are particularly important in the formation of A beta as they cleave within the APP protein to give rise to the N-terminal and C-terminal ends of the A beta fragment, respectively. Consequently, many researchers are investigating therapeutic approaches that inhibit either beta- or gamma-secretase activity, with the ultimate goal of limiting A beta; production. An alternative AD therapeutic approach that is being investigated is to employ anti-A beta antibodies to dissolve plaques that have already formed. Both of these approaches focus on the possibility that accrual of A beta leads to neuronal degeneration and cognitive impairment characterised by AD and test the hypothesis that limiting A beta deposition in neuritic plaques may be an effective treatment for AD.

The status of ongoing trials for mild cognitive impairment.

Mild cognitive impairment (MCI) is a term used to describe memory decline or other specific cognitive impairment in individuals who do not have dementia or significant impairment of other cognitive functions beyond that expected for their age or education. It has been suggested that as much as 38% of the elderly population would meet criteria for MCI and although the associated memory deficits are mild, the fact that up to 15% of MCI patients, particularly those with a particular type of memory impairment, convert to Alzheimer's disease (AD) annually has prompted serious attention. Despite the high conversion rate, MCI cannot be used synonymously with early or mild AD, as patients with AD are impaired not only in memory performance but in other cognitive domains as well; they meet diagnostic criteria for dementia. However, since there is a high conversion rate from MCI to AD, it is likely many with MCI have the underlying neuropathology of AD, though they do not yet meet clinical diagnostic criteria. Therefore, treatment strategies developed for AD, specifically acetylcholinesterase inhibitors and Cox-2 inhibitors, have been among the first employed to treat MCI. It is hoped that by impeding the progression of MCI in this manner, fewer patients will convert to AD. This article will give a brief overview of the condition of mild cognitive impairment and an account of trial methodology and current treatment strategies being employed for MCI.

Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients.

In clinical trials of dopamine-blocking antipsychotics, significant adverse events may occur in healthy volunteers at dose levels that are well tolerated by schizophrenic patients. Because of these differences in tolerability, bioequivalence and pharmacokinetic studies of antipsychotics should be performed in schizophrenic patients rather than in healthy volunteers. When clozapine is the drug being investigated, pharmacokinetic and bioequivalence studies should be carried out in real-life dosage conditions because the half-life of clozapine increases with multiple doses. Under real-life conditions, the evaluation of multiple doses of clozapine in a population of schizophrenic patients can provide direct therapeutic relevance to bioavailability findings. This article discusses patient recruitment and informed consent in pharmacokinetic trials of schizophrenia, issues in studying antipsychotic agents in healthy volunteers versus schizophrenic patients, and a bioequivalency study of Clozaril (Novartis Pharmaceuticals) and generic clozapine (Creighton [Sandoz]) in schizophrenic patients.

Review of the next generation of Alzheimer's disease therapeutics: challenges for drug development.

1. AD is believed to stem from dysfunctional cholinergic signaling in the regions of the brain associated with memory and cognition. 2. The occurrence of AD in afflicted individuals correlates with an increase in the accumulation of A beta-rich senile plaques and neurofibrillary tangles in the brain. 3. Currently, the only FDA-approved AD therapies are a group of acetylcholinesterase inhibitors which slow the turnover of the neurotransmitter acetylcholine in the synapse. 4. Many other compounds which target other aspects of the disease, such as reducing neuronal damage and limiting oxidation, are in clinical trials. These include monoamine oxidase (MAO-B) inhibitors, NSAIDs, antioxidants and estrogen, among others. 5. Recent research discoveries have more completely defined the molecular nature of AD, and are generating new approaches for treatment. One idea is to limit the ability of the protein tau to become phosphorylated in hopes that this will limit the formation of neurofibrillary tangles in the brain. 6. A separate approach that is being pursued is to prevent formation and accumulation of A beta plaques. This may be accomplished by either regulating gamma-secretase activity, or using anti-beta-amyloid antibodies to reduce the size of existing plaques. 7. Employing improved procedural and technological approaches during clinical trials, such as bridging studies, dynabridge studies and PET analysis, promises to streamline the drug development process. 8. The use of biomarkers and MRI analysis may be an effective means by which to identify the disease early. Consequently, early intervention treatment therapies may be an effective way of delaying onset of the disease. 9. Long term AD studies, particularly those focusing on the MCI population, are likely to provide statistically valid results using a smaller study population.

Pharmacokinetics and tolerability of buspirone during oral administration to children and adolescents with anxiety disorder and normal healthy adults.

A 21-day, open-label, multisite, dose escalation study comprising three demographic groups (children, adolescents, and adults) was performed to determine the pharmacokinetics and tolerability of orally administered buspirone. Thirteen children and 12 adolescents with anxiety disorder and 14 normal healthy adults were escalated from 5 to 30 mg buspirone bid over the 3-week study. Pharmacokinetic analysis revealed that buspirone was rapidly absorbed in all study groups, reaching peak levels at about 1 hour after administration. Peak plasma buspirone concentrations (Cmax) were highest in children and lowest in adults at all three dose levels (7.5, 15, 30 mg bid). However, 1-pyrimidinylpiperazine (1-PP), the primary metabolite of buspirone, exhibited a different plasma concentration-time profile; Cmax was significantly higher in children than in either adolescents or adults at all concentrations. In addition, TAUC0-T for 1-PP was significantly higher in the children cohort relative to adolescents and adults. Buspirone was generally safe and well tolerated at doses up to 30 mg bid in adolescents and adults and most of the children. The most frequently reported adverse events in children and adolescents were lightheadedness (68%), headache (48%), and dyspepsia (20%); 2 children withdrewfrom the study at the higher doses (15 mg and 30 mg bid) due to adverse effects. In adults, the most common adverse effect was somnolence (21.4%); lightheadedness, nausea, vomiting, and diarrhea were also reported, although these were mild in intensity.

Women's health care during the perimenopause.

OBJECTIVE: To review the perimenopause, its associated symptoms, and current management options. DATA SOURCES: Published articles identified through MEDLINE (1966-2000) using the search terms perimenopause and treatment. Additional articles and books were identified from the bibliographies of the retrieved articles. DATA SYNTHESIS: The perimenopause is the transition period from normal ovulatory cycles to menopause. It is associated with erratic fluctuations in reproductive hormone levels, often leading to irregular menstrual cycles, vasomotor symptoms, changes in mood or cognition, and sexual dysfunction. The perimenopause is an ideal time to evaluate a woman's health risks for such common chronic midlife conditions as heart disease, osteoporosis, and some cancers, and to initiate appropriate preventive health measures. Low-dose oral contraceptives and other hormonal therapies are often effective in managing perimenopausal symptoms. CONCLUSION: The transition to menopause is an important time in the female life span that is associated with varied physical and psychological symptoms. Pharmacists should be prepared to provide education about the perimenopause and counsel women on the benefits and risks of various pharmacologic and nonpharmacologic treatments that can ease their passage through this often difficult transition. Pharmacists also are well-positioned to educate and encourage perimenopausal women to initiate lifestyle changes that can enhance their health for the rest of their lives.

Ongoing trials in Alzheimer's disease.

Researchers have sought to understand the underlying pathophysiology of Alzheimer's disease (AD) ever since Dr A Alzheimer first described the condition in 1907. Unfortunately however, until recently, they have done so with limited success. This lack of clarity has deterred advancements in therapeutic drug research beyond all but the purely symptomatic treatment relief currently available. However, through spatio-temporal analysis of the two types of cerebral lesions that characterise the disorder (senile plaques and neurofibrillary tangles) and the compilation of genetic data concerning familial AD, there now exists the foundation for a more comprehensive understanding of the disease. Although symptomatic cholinergic strategies have beneficial effects, their benefits are modest and current research has turned to the development of other promising strategies, including oestrogen replacement, anti-inflammatory agents, free radical scavengers, anti-oxidants and monoamine oxidase-B (MAO-B) inhibitors. Many of these strategies may have some merit, however further analysis and structured research are necessary before a definitive decision can be made about their efficacy and possible role in AD therapy. Strategies that are directed at halting the underlying biochemical changes in AD are nearing clinical testing and offer the promise for meaningful therapeutic outcomes.

Review of the acetylcholinesterase inhibitor galanthamine.

Galanthamine (or galantamine, Reminyl) is a tertiary alkaloid acetylcholinesterase inhibitor (AChEI) which has been approved in several countries for the symptomatic treatment of senile dementia of the Alzheimer's type. Derived from bulbs of the common snowdrop and several Amaryllidaceae plants, (-)-galanthamine (GAL) has long been used in anaesthetics to reverse neuromuscular paralysis induced by turbocurarine-like muscle relaxants and more recently, has been shown to attenuate drug- and lesion-induced cognitive deficits in animal models of learning and memory. GAL directly inhibits acetylcholinesterase activity, while demonstrating much weaker activity on butyrylcholinesterase (BuChE). GAL also stimulates pre- and postsynaptic nicotinic receptors, although the clinical significance of this finding is yet unclear. Numerous variants and analogues of GAL have also been developed, with varying potency in inhibiting AChE activity. GAL is readily absorbed after oral administration, with a t(max) of 52 min and a plasma elimination t(1/2) of 5.7 h. The efficacy of GAL administered to Alzheimer's disease (AD) patients has been well demonstrated by large-scale clinical trials. Typical of AChEIs, the most common adverse events associated with GAL are nausea and vomiting. In conclusion, evidence to date suggests galanthamine to be similar to other AChEIs in improving cognitive function in AD patients.

Mild cognitive impairment: emerging therapeutics.

OBJECTIVE: To present a general overview of the etiology, definition, and prevalence of mild cognitive impairment (MCI), as well as outline possible treatment strategies. DATA SOURCES: A MEDLINE search was conducted for relevant references generated from 1990 to 2000 concerning MCI, mild to moderate Alzheimer disease (AD), and therapeutic strategies. Several books were also used in the compilation of data for this review, as well as the authors' experience in designing and conducting MCI trials. DATA EXTRACTION: All of the references listed were assessed, and all relevant information was included in this review. DATA SYNTHESIS: Forgetful individuals most likely to develop AD have a condition known as MCI previous to their development of dementia. This condition is hallmarked by memory impairment that is abnormal for the individual's age and educational level. While not all individuals with MCI develop AD, it is apparent that the condition can serve as a potential marker for early onset of AD. CONCLUSIONS: As many clinicians can attest, occasional forgetfulness is a common aspect of the aging process. Eventually, however, a large portion of forgetful individuals, especially those with MCI, will be diagnosed with AD or some other form of dementia. Indeed, many researchers have suggested that MCI should be regarded as incipient AD and that these individuals would benefit from drug therapy. Thus, MCI screening may be beneficial in terms of both early AD intervention and perhaps even AD prevention.

Gender differences in depression and antidepressant pharmacokinetics and adverse events.

OBJECTIVE: To review data generated by studies examining gender differences in the prevalence of depression, as well as in antidepressant pharmacokinetics, pharmacodynamics, and adverse events. DATA SOURCES: Published articles and abstracts were identified through MEDLINE (January 1966-April 1999) using the following search terms: antidepressant, response, gender, pharmacokinetic, pharmacodynamic, female, side effect, and adverse events. All articles that assessed gender differences in antidepressant response, pharmacokinetics, and adverse events, as well as articles that evaluated postulated mechanisms for these differences, were reviewed. Additional articles were identified from bibliographies of retrieved articles. STUDY SELECTION AND DATA EXTRACTION: All relevant abstracts, studies, and review articles were evaluated. DATA SYNTHESIS: Gender differences in the prevalence of depression have been reported and may result from the interaction of several factors. Women have been shown to have a higher incidence of depression, which may be due to artifact, social, or biologic reasons. Studies suggest that the pharmacokinetic disposition of popular antidepressants varies between men and women, and women taking antidepressants may exhibit a different adverse event profile. Only one study specifically evaluated gender differences in antidepressant treatment response. CONCLUSIONS: Further research elucidating gender differences in response to antidepressant treatment and on depression prevalence is needed. Some studies report that the pharmacokinetics of antidepressants may vary between men and women. Therefore, clinicians should be aware that potential differences in antidepressant pharmacokinetics may exist, and a dosage adjustment may be necessary for women to ensure a favorable drug response, compliance, and decreased incidence of adverse events.

RBC cholinesterase inhibition: a useful surrogate marker for cholinesterase inhibitor activity in Alzheimer disease therapy?

Red blood cell (RBC) acetylcholinesterase (AChE) inhibition has been used as a peripheral surrogate marker for the activity of centrally acting AChE inhibitors (AChEIs) in the treatment of Alzheimer disease. As a valid peripheral surrogate marker, RBC AChE inhibition should reflect the central pharmacodynamic activity of the compound and should demonstrate a relation with cognitive or global improvement in patients with Alzheimer disease. As a useful clinical tool, RBC AChE inhibition should also provide an advantage in dose optimization. However, the application of surrogate markers in research and clinical use is controversial (Prentice, 1989; Gotzsche, 1996; Colburn, 1997; De Gruttola et al., 1997). For instance, surrogate markers that have been identified or applied inappropriately can lead to erroneous conclusions, slowing the drug development process (Colburn, 1997). Also, the validation of surrogate markers for the pharmacodynamic activity of central nervous system drugs is not always possible because samples of brain tissue cannot be analyzed in humans. Finally, although validation of peripheral markers for central nervous system drugs has been approached via analysis of cerebrospinal fluid (Cutler et al., 1998a), few markers have been subjected to such rigorous evaluation in clinical studies. The extent to which measures of peripheral AChE inhibition accurately model central drug activity and therapeutic effectiveness of AChEIs, both as individual agents and as a drug class, is the focus of this review. AChEIs comprise a group of structurally diverse compounds with a wide range of relative specificities for the various molecular species of cholinesterase found in plasma, RBCs, and the brain. Studies of RBC AChE inhibition after administration of AChEIs in animals are of limited utility because of the differential sensitivity of AChEIs for human versus animal forms of AChE, the poor correlation between effective doses in animals and humans, and the lack of standardized measurements of effectiveness. Although clinical studies of donepezil, metrifonate, and eptastigmine have suggested the potential use of RBC AChE inhibition as a predictor of clinical response, the degree of inhibition yielding maximum cognitive improvements was highly variable from compound to compound (30-80%). Further, investigators did not prove a relation between central and peripheral pharmacodynamics or demonstrate an advantage over dose in the ability of RBC AChE inhibition to predict clinical response. A study of rivastigmine in patients with Alzheimer disease revealed that cerebrospinal fluid AChE inhibition correlated well with cognitive performance, whereas peripheral inhibition did not. Therefore, RBC cholinesterase inhibition is not a reliable surrogate marker for the activity of AChEIs as a class of drugs, and its usefulness as a dose optimization tool for individual agents has yet to be demonstrated clearly.

Recent developments in the drug treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder with an impact on public health which continues to increase with the increasing longevity of the population. The disease is characterised clinically by a progressive loss of cognitive and behavioural function. These deficits are thought to result from decreased cholinergic transmission; therefore, restoring cholinergic function has been the main focus in the development of drugs for AD. Several pharmacological approaches to enhancing cholinergic function have been developed for symptomatic or palliative therapy of AD. Although these strategies have resulted in modest cognitive and behavioural improvements in patients with AD, they do not address the underlying progression of the disease. New strategies will be required to slow, stop or reverse the effects of neurodegeneration in AD. A number of potential therapies are currently under investigation, including estrogen replacement, anti-inflammatory agents, free radical scavengers and antioxidants, and monoamine oxidase-B (MAO-B) inhibitors. The evidence for a protective effect of estrogens or nonsteroidal anti-inflammatory drugs (NSAIDs) is controversial, and largely based on retrospective studies. More controlled prospective studies are needed to definitively demonstrate the benefits of long term estrogen or NSAID use in the prevention of AD. Free radical scavengers/antioxidants such as idebenone, and selective prevention MAO-B inhibitors such as lazabemide are well tolerated, but require additional studies in order to demonstrate preventative effects. In addition, other approaches, such as anti-amyloid treatments that affect beta-amylase secretion, aggregation and toxicity, appear promising; treatments that hinder neurofibrillary tangle construction and nerve growth factor (NGF) induction are in the very early stages of development.