Cholinesterase inhibitors for Alzheimer's disease

New cholinesterase inhibitors capable of slowing the progression of Alzheimer's disease are being introduced at a rapid pace. In prescribing these drugs and setting realistic expectations for outcome, it is necessary to understand that they affect cholinergic activity in other tissues as well as the brain. They may be most effective when used in combination with other drugs.     

Cholinesterase inhibitors: Current pharmacological treatments for Alzheimer's disease.

Examines the use of cholinesterase inhibitors (ChEIs) for the pharmacological treatment of Alzheimer's disease (AD). Topics discussed include: (1) the pathophysiology of AD and the cholingergic hypothesis, (2) the development of the cholinesterase inhibitors, and (3) current issues and future directions for research and use of ChEIs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer's disease

Rivastigmine (ENA 713, or carbamoylatine) is an acetylcholinesterase (AChE) inhibitor with brain-region selectivity and a long duration of action. Both preclinical studies and studies in human volunteers have shown that rivastigmine induces substantially greater inhibition of AChE in the central nervous system (CNS) compartment than in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase in healthy volunteers). Moreover, rivastigmine preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer's disease (AD). Evidence from animal studies also suggests that rivastigmine is a more potent inhibitor of AChE in the cortex and hippocampus, the brain regions most affected by AD. Absorption of rivastigmine is rapid and almost complete (>96% of the administered dose). Extensive, saturable first-pass metabolism, however, leads to bioavailability of approximately 35% of the administered dose and nonlinear pharmacokinetics. The principal metabolite of rivastigmine has at least 10-fold lower activity against AChE compared with the parent drug. Rivastigmine is completely metabolized; the major route of elimination of the metabolites is renal. Although patients with AD demonstrate 30% to 50% higher plasma concentrations of rivastigmine and its principal metabolite than do healthy elderly patients, there is no evidence of drug accumulation, which is consistent with rivastigmine's short pharmacokinetic half-life. Distribution of rivastigmine into the CNS is extensive, and inhibition of AChE in the cerebrospinal fluid is detectable 1.2 hours after oral dosing in both healthy volunteers and patients with AD. Peak activity is reached somewhat more slowly in AD patients than in healthy subjects, and the inhibitory effects have a longer duration (6.0 vs 2.4 hours and 12.0 vs 8.5 hours, respectively). Rivastigmine is inactivated during the process of interacting with and inhibiting AChE, and, in contrast to other AChE inhibitors, the hepatic cytochrome P-450 (CYP-450) system is not involved in the metabolism of rivastigmine. This reduces its propensity to interact with drugs metabolized by specific CYP-450 isoenzymes. Consistent with rivastigmine's pharmacokinetic and pharmacodynamic profiles, Phase II and III trials have demonstrated that the drug is a well-tolerated and effective treatment for AD.     

General practitioners' perceptions of the tolerability of antidepressant drugs: a comparison of selective serotonin reuptake inhibitors and tricyclic antidepressants

OBJECTIVE: To examine inceptions and discontinuations of antidepressants in general practice. DESIGN: An observational study analysing data from an ongoing cross sectional postal survey. Every three months a representative sample of 250 doctors recorded prescribing activity for four weeks. This provided 4000 general practitioner weeks of recording per year. SETTING: A representative panel of general practitioners in England, Wales, and Scotland. SUBJECTS: Patients who began a new course of an antidepressant or had their treatment stopped or changed by the general practitioner between 1 July 1990 and 30 June 1995. MAIN OUTCOME MEASURES: Numbers of patients prescribed a new course of antidepressant; numbers discontinuing treatment; the ratio of antidepressant discontinuations to antidepressant inceptions; reasons for discontinuation; proportion of switches to another antidepressant. RESULTS: There were 13,619 inceptions and 3934 discontinuations of selective serotonin reuptake inhibitors and tricyclic antidepressants during the study. The number of newly prescribed courses of antidepressants increased by 116%, mostly due to an increase in prescribing of serotonin reuptake inhibitors. The ratio of total discontinuations to inceptions was significantly lower for serotonin reuptake inhibitors (22%) than for tricyclic antidepressants (33%). Differences persisted when controlled for age and sex of patients and severity of depression. However, there was more switching away from selective serotonin reuptake inhibitors when they failed (72%) than from tricyclic antidepressants (58%). CONCLUSIONS: Selective serotonin reuptake inhibitors are less likely than tricyclic antidepressants to be discontinued. A prospective study is needed in general practice to assess the implications of differences in discontinuation rates and switches on clinical and economic outcomes.     

Advances in the treatment of Alzheimer's disease

Management of the most common type of dementia--Alzheimer's disease--is becoming increasingly sophisticated. Differentiation of Alzheimer's disease from vascular dementia has become therapeutically important, since the choice of treatments depends on the diagnosis. Two cholinesterase inhibitors, donepezil and tacrine, are labeled for use in patients with Alzheimer's disease. Other therapies, such as estrogen, nonsteroidal anti-inflammatory drugs and vitamin E, are sometimes used and show promise in delaying the progression of this dementia. Behavior problems, which often accompany the disease, can be managed using environmental modification, alterations in caregiving and medication. In the terminal phase of the illness, quality care involves implementing advance directives, communicating with the family, individualizing care and attending to patient comfort.     

Medical treatment of Alzheimer's disease

OBJECTIVE: To review the drugs commercially available at present and in the near future in relation to the evolution of Alzheimer disease, bearing in mind the possible psychiatric disorders which may be associated with the disease. DEVELOPMENT: The therapeutic approach is planned according to the different phases of the disease. In the preclinical phase, anti-inflammatory drugs and estrogens in post-menopausal women have been effective. In the initial phase current recognition therapy is directed basically towards correcting the break-down of acetylcholine (tacrine, donepezil, SB202026, SDZ ENA 713). For depressive symptoms serotonin levels are corrected using selective inhibitors of serotonin uptake. CONCLUSIONS: Drug treatment should be considered with the association of drugs which activate the malfunctioning circuits and/or pathways. It would also be useful to design clinical studies using pharmacological combinations of cholinergic agonists, estrogens, anti-inflammatory drugs, seligiline and/or new anti-cholinesterase drugs amongst others.     

Pharmacological treatment of Alzheimer's disease: present situation and perspectives

Alzheimer's disease (AD) is the commonest cause of dementia. Although its ethology is unknown, there is increasing evidence in support of the view that an abnormal degradation of the amyloid precursor protein (APP), perhaps influenced by a number of genetic, tisular or environmental factors, may be the primary cause of the many biochemical and morphological disorders that exist in the associative areas of the brain of these patients. Histopathologically it can be shown by the presence of extracellular senile plaques, intraneuronal fibrilar tangles and neuronal loss. There is no specific pharmacological treatment at present to prevent the disease or its development, in spite of the numerous and diverse drugs studied. Many of these studies are methodologically inadequate. The attempt of activating the cholinergic system has deserved special attention. A reversible inhibitor of acetylcholinesterase, tacrine, has been approved in the United States and other countries for the symptomatic treatment of mild to moderate AD, but its use still arises many questions. Different drug and non drug related interventions may be of great value in the care of these patients, and may influence the specific pharmacological treatments. The complexity and heterogeneity of AD and the multiple factors which may take part in its evolution make it necessary to place special attention on the methodological aspects of the clinical trials with new drugs for the treatment of this disease.     

A comparison of category and letter fluency in Alzheimer's disease and Huntington's disease.

44 patients with dementia of the Alzheimer type (DAT), 44 elderly normal control (ENC) Ss demographically matched to the DAT group, 42 patients with Huntington's disease (HD), and 42 middle-aged normal control (MNC) Ss demographically matched to the HD group were administered letter and category fluency tasks. DAT patients showed an overproportional impairment on category than on letter fluency tasks, whereas HD patients were equally impaired. Analyses based on receiver operating characteristic curves revealed that category fluency correctly classified significantly more DAT and ENC Ss than did letter fluency, whereas the 2 fluency tasks did not differ in this respect for HD and MNC Ss. Results suggest that HD patients' failures on fluency tasks are caused by impaired initiation/retrieval capacities. In contrast, DAT patients' greater category than letter fluency deficits are primarily due to a breakdown in the structure of semantic knowledge. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Efficacy and tolerability of moclobemide in comparison with placebo, tricyclic antidepressants, and selective serotonin reuptake inhibitors in elderly depressed patients: a clinical overview

OBJECTIVE: To review the efficacy and safety of moclobemide in comparison with TCAs (for our purposes, "TCAs" will represent tricyclic and tetracyclic antidepressants, including maprotilin and mianserin) and selective serotonin reuptake inhibitors (SSRIs) in elderly depressed patients. METHODS: The efficacy data reviewed were obtained from the following sources: 1) results of published studies in the elderly; 2) data on patients aged > or = 60 years extracted from all available controlled trials in adults (> or = 18 years) in which moclobemide was compared with TCAs or SSRIs; and 3) the adverse events were extracted for patients aged > or = 60 years from the safety data base of all available comparative short-term studies with moclobemide versus TCAs, SSRIs, or placebo and of long-term studies with moclobemide. RESULTS: The data show that moclobemide is an effective antidepressant in depressed patients aged > or = 60 years. The response rate to moclobemide was 50% to 55% in this population. Moclobemide was more effective than placebo and was of similar efficacy to the TCAs and the more recently introduced SSRIs. The tolerability of moclobemide was rated as "very good" or "good" in almost 90% of these patients, which was better than the tolerability of TCAs and similar to that of SSRIs. Patients without any adverse events were more frequently found in the moclobemide group than in those treated with TCAs (P < 0.01) or SSRIs (P < 0.01). Adverse events of the anticholinergic type were more frequent with TCAs than with moclobemide (P < 0.001), and nausea was found 3 times more frequently with SSRIs than with moclobemide (P < 0.01). CONCLUSIONS: Moclobemide is an effective and well-tolerated antidepressant for the treatment of elderly depressed patients.     

Bisphosphonates: pharmacology and use in the treatment of osteoporosis

Bisphosphonates are attractive antiresorptive drugs for osteoporosis. The only compound available in Japan is the first-generation bisphosphonate, etidronate. Etidronate adsorbes to the surface of hydroxyapatite crystals, and can slow bone mineralization and inhibit bone resorption. It has a narrow therapeutic window between these two actions, so that long-term continuous administration is not feasible. The intermittent use of etidronate produces a positive effect on bone mass. But the response varies directly with the rate of bone turnover at baseline. In high turnover osteoporosis there could be a gain in bone mass, but it reaches a plateau after 2 to 3 years. In normal or low turnover osteoporosis bone mass is stabilized but does not increase. However, the long-term effect of bisphosphonates on bone strength is not known.     

A comparison of the efficacy, tolerability and safety of azithromycin and co-amoxiclav in the treatment of sinusitis in adults

The efficacy, tolerability and safety of azithromycin and co-amoxiclav in the treatment of non-severe acute maxillary/ethmoidal sinusitis were compared in a randomized, open clinical trial in 254 adult patients. The predominant pathogens were Streptococcus pneumoniae and Haemophilus influenzae (83 patients). Azithromycin was administered orally to 165 patients at a single daily dose of 500 mg for 3 days, and co-amoxiclav (4:1) to 89 patients, at a dose of 500 mg three times daily for 10 days. The overall clinical response rates were 87.5% for azithromycin and 83.7% for co-amoxiclav at follow-up (day 21-28). Microbiological responses to both drugs were good, with only five patients in each group having a persistent infection after treatment. Both drugs were well tolerated and produced similar incidences of adverse events, which were mostly gastrointestinal. Azithromycin was as effective, and as well tolerated as co-amoxiclav, and its shorter simpler dosing regime may offer advantages in compliance and cost.     

Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer's disease

Neurodegeneration and cell death in Alzheimer's disease might be associated with aberrant proliferative mechanisms and activation of cell-cycle related events. We reported previously on the elevated expression of the cyclin dependent kinase inhibitor p16INK4a in Alzheimer's disease closely associated with neurofibrillary degeneration. In the present study, we demonstrate that other members of the INK4-family of cyclin dependent kinase inhibitors such as p15INK4b, p18INK4c and p19INK4d that bind directly to cdk4/6 or to complexes of cdk4/6 with D-type cyclins are all elevated. In contrast, no indication of altered expression of the cyclin dependent kinase inhibitors p21Cip1 and p27Kip1 were observed. Inhibitors of the INK4-family were strongly expressed in tangle-bearing neurones and neuritic components of plaques. A much lower expression was also seen in astrocytes. These findings add further evidence to the suggestion that a dysfunction of cell cycle regulation is of critical importance in the pathomechanism of Alzheimer's disease.     

Nutritional pharmacology and malignant disease: a therapeutic modality in patients with cancer

It is now established that certain nutrients have a significant effect on cellular metabolism and growth, tissue repair and regeneration, and modulation of host defences. So far, however, potential clinical benefits have been difficult to demonstrate. Nevertheless, the use of nutrients in combinations seems to have promise and may be associated with a reduction in infectious complications and length of hospital stay. Nutritional pharmacology in the future may be able to improve tumour response to chemotherapy and may minimize the metabolic effect of cachexia.