Assessment of the value of therapeutic monitoring of tacrine in Alzheimer's disease

OBJECTIVES: The purpose of this study was to validate the lower end of the putative therapeutic range of serum tacrine concentrations of 7-20 ng ml(-1) in the treatment of Alzheimer's disease. METHODS: The relationship between dose, steady-state serum tacrine concentrations and change in MMSE score (a measure of cognitive function) was examined in 106 Alzheimer's disease patients who had been treated with the drug for 12 weeks. RESULTS: In all, 72% of patients showed some response, but there was no relationship between dose and the chance of a favourable outcome. The proportion of patients with serum concentrations above 7 ng x ml(-1) who improved (79%) was significantly greater than that of those with serum concentrations below this level (47%) (P < 0.02). Also, a significantly greater proportion of patients with serum concentrations above both 5 ng x ml(-1) and 9 ng x ml(-1) showed improvement in comparison to those with concentrations below these levels. CONCLUSIONS: This study indicates that therapeutic monitoring of serum tacrine concentrations might increase the possibility of responding to tacrine by some 68%. This represents an important contribution to the management of Alzheimer's disease patients with this drug, and may also be relevant to the use of the newer generation of cholinesterase inhibitors.     

Ethical concerns in the use of palliative drug treatment for Alzheimer's Disease

The cases of 3 patients with Alzheimer's disease (AD) who had varied outcomes from treatment with tacrine or other palliative drugs illustrate the need to consider the benefits of such agents for each case on an individual basis. In the absence of a cure, the most important factor in the care of AD patients may be the physician's attitude that irreversibility does not imply untreatability.     

Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology

Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer's disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer's Disease Assessment Scale -- Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer's disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer's disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer's disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with an incidence ranging between 7 to 30%. For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.     

Elucidation of mitochondrial effects by tetrahydroaminoacridine (tacrine) in rat, dog, monkey and human hepatic parenchymal cells

Tetrahydroaminoacridine (tacrine) causes morphological and functional changes in the endoplasmic reticulum, ribosomes, and mitochondria in the liver of humans and animals. In order to investigate species differences as well as to understand the morphological changes, we examined the effects of tacrine on respiration and electron transport in mitochondria isolated from rat, dog, monkey, and human liver. Tacrine produced significantly decreased respiratory control ratios (RCR) in all species at concentrations ranging from 5 to 25 microg/ml. Human mitochondria were more sensitive to tacrine effects with RCR decreased 24% at 5 microg/ml while other species were unaffected at this concentration. The tacrine effects were characterized by increased hepatic mitochondrial State 4 respiration in rats and decreased State 3 respiration in humans. Mitochondria from aged rats were more sensitive to the effects of tacrine than mitochondria from young animals, with significantly decreased RCR at 10 microg/ml in aged rats while mitochondria from young rats were unaffected at this concentration. Concomitant with the respiratory changes, mitochondrial DNA synthesis was impaired. Since tacrine undergoes extensive biotransformation, we also explored the possibility that metabolites could exert detrimental effects. The ranking order of potency for decreasing RCR caused by monohydroxylated metabolites was: tacrine > 4-OH and 7-OH > 2-OH, 1-OH, and velnacrine with the latter group of metabolites having no effect on mitochondrial respiration at concentrations up to 50 microg/ml. In vivo administration of 20 mg/kg tacrine to rats for up to 20 days caused a paradoxical increase in RCR and P/O on Day 1 and decreased RCR on Days 9 and 20, the later findings being consistent with in vitro data. From these data we propose that tacrine does not necessarily have to be metabolized to exert effects on mitochondria at different sites in the electron transport chain that differ among species. These effects are exacerbated in mitochondria from older animals and humans appear to be more sensitive than the laboratory animals studied.     

Abrogation of autoimmune disease in Lyn-deficient mice by the mutation of the Btk gene

Alzheimer's disease (AD) is associated with a reduction in cholinergic activity as a result of specific neuronal loss. Current potential treatments for the disease include both cholinomimetic drugs and anticholinesterase inhibitors. One of the drugs approved by the FDA is tacrine (9-amine-1,2,3,4 tetrahydroacridine; THA), a strong acetylcholinesterase (AChE) inhibitor. We have studied the effects of tacrine on glial and neuronal cells in culture assessing cell survival and viability and morphology. Lactate dehydrogenase (LDH) activity and methylthiazol-diphenyl-tetrazolium (MTT) reduction were used as toxicity indicators. We found that tacrine toxicity on rat B12 glial cells and mouse Neuro 2A cells was strongly dependent on its concentration (up to 500 microM) and time of exposure. The toxic effect was not prevented by serum factors nor by bovine serum albumin. Fluorescein-conjugated phalloidin was used to examine the arrangement of actin filaments at substrate adhesion regions and cell-cell contacts. Primary events following exposure to tacrine included changes in cell morphology, disappearance of actin filament bundles, and disruption of focal adhesion contacts. At concentrations between 10 and 50 microM, tacrine induced neurite outgrowth in Neuro 2A cells, an effect that was not observed in B12 cells, suggesting that certain tacrine effects could be specific for neuronal cells. Although similar trends of response were observed for both cell types, some differences between undifferentiated and differentiated cells were apparent.     

Tacrine efficacy in Lewy body dementia

BACKGROUND: Response to tacrine varies among patients with Alzheimer's disease (AD). Lewy body dementia (LBD) could be a high responder subtype of AD. The aim of the study was to compare the effects of tacrine in LBD and AD. METHODS: Seventy-five consecutive outpatients with mild or moderate AD were screened. Tacrine was given at a dose of 40 mg/day during 6 weeks. During the next 6 weeks, the patients were treated with 80 mg/day and afterwards with 120 mg/day. Patients were assessed at baseline and treated with a dose of 120 mg/day tacrine for 2 weeks. RESULTS: Analysis was performed on 39 patients (AD, N = 20; LBD, N = 19). Eight patients were lost to follow-up, eight patients manifested with side-effects, six suffered from an intercurrent somatic disease during the study and 14 patients had poor compliance or were treated with incompatible drugs. Twenty-two patients (11 AD/11 LBD) increased their cognitive performances with tacrine. Among the 22 patients, the improvement differed between the AD and the LBD groups. In AD, conceptualization improved; in LBD, the improvements occurred in verbal initiation and digit span. CONCLUSION: This study emphasizes the importance of using appropriate tests to determine the positive effects of pharmacological treatments.     

Central cardiovascular effects of tacrine in the conscious dog: a role for catecholamines and vasopressin release

Centrally acting cholinergic agents are currently reported to increase blood pressure in various species through the stimulation of muscarinic cholinoceptors. Moreover, several cardiovascular adverse effects have been reported from clinical studies. The aim of this study was to investigate the effects of tacrine, an acetylcholinesterase inhibitor which has been reported to have therapeutic potential in Alzheimer's disease, on blood pressure and two vasopressor systems (sympathetic and vasopressinergic) in Beagle dogs. Intravenous (i.v.) tacrine (2 mg kg(-1)) induced, in conscious and anesthetized dogs, an increase in systolic and diastolic blood pressure, accompanied by bradycardia. This increase was dose-dependent with a peak effect at 1.5 min following administration. Tacrine also induced an increase in noradrenaline, adrenaline and vasopressin plasma levels. Pretreatment with the muscarinic receptor antagonist, atropine (2 mg kg(-1), i.v.), abolished the pressor response to i.v. injection of tacrine while pretreatment with the peripheral muscarinic receptor antagonist, methylscopolamine (0.2 mg kg(-1), i.v.), did not alter the increase in blood pressure. Similarly, noradrenaline and adrenaline changes in plasma levels were not modified by methylscopolamine but were abolished by atropine pretreatment. A similar tendency although not significant was observed for vasopressin plasma levels. The present results demonstrate that in dogs, tacrine (2 mg kg(-1), i.v.) stimulates central muscarinic cholinoceptors to increase blood pressure through activation of the two components of the sympathetic nervous system (i.e., neuroneuronal noradrenergic and the neurohormonal adrenergic pathways) as well as through increasing noradrenaline, adrenaline and vasopressin plasma levels.     

The management of cryptococcal meningitis in Papua New Guinea

The efficacy of tacrine for treatment of Alzheimer's has been demonstrated in several clinical trials but has not been assessed in cases complicated by medical and psychiatric comorbidities. Additionally, the benefit-risk ratio of tacrine is small, so it is best administered with carefully developed guidelines that specify this ratio for patients and families. On the basis of guidelines developed for the Johns Hopkins Dementia Research Clinic, tacrine treatment was offered to 162 patients with probable Alzheimer's. Only 35 accepted, and only 22 continued on tacrine beyond 3 months. The latter group declined by 1.36 points over 1 year on the Mini-Mental State Examination, significantly less than expected. The authors conclude that, if used in the context of clinical guidelines, tacrine is an effective treatment for Alzheimer's.     

A new method for evaluation of motor deficits in 3-acetylpyridine-treated rats

BACKGROUND: approximately one-third of patients with Alzheimer's disease (AD) respond favourably to the anticholinesterase tacrine, but the drug's usefulness is marred by a high incidence of side-effects. OBJECTIVE: to discover if AD patients with white matter low attenuation (WMLA) represents a subgroup that responds differently to tacrine from those with no WMLA. DESIGN: the results come from a combination of double-blind and open studies. Seventy-two AD patients prescribed tacrine in our centre were divided into two groups according to the presence or absence of WMLA on brain CT scans. We compared the rate of response to and withdrawal from tacrine between the groups. Response was defined as an improvement in the Mini-Mental State Examination score of three or more points at 3 months. RESULTS: 18 of the 72 patients were found to have WMLA. There was no significant difference in the proportion of patients responding to tacrine in each group (28.5% in those with WMLA and 31% in those without), but the rate of withdrawal from tacrine did differ: 11 patients with WMLA (61%) had to be withdrawn prematurely, compared with 14 patients (26%) in the group without evidence of WMLA (P = 0.015). CONCLUSION: AD patients with WMLA can still respond to tacrine, although the rate of withdrawal from treatment is much higher in such patients.     

Tacrine and donepezil attenuate the neurotoxic effect of A beta(25-35) in rat PC12 cells

The effect of the cholinesterase inhibitors tacrine and donepezil on A beta(25-35)-induced toxicity was investigated in rat pheochromocytoma PC12 cells by measuring the mitochondrial activity. Tacrine and donepezil was found in clinical relevant concentrations (10(-7)-10(-6) M) to attenuate A beta(25-35)-induced toxicity in PC12 cells. The neuroprotective effect of tacrine was blocked in the presence of the nicotinic antagonists mecamylamine (10(-5) M) and tubocurarine (10(-5) M), suggesting an interaction via nicotinic receptors. This study demonstrates that tacrine and donepezil can exert neuroprotective properties which might be of importance and contribute to the clinical efficacy of cholinesterase inhibitors in the treatment of Alzheimer's disease.     

Reversibility of the effect of tacrine on the secretion of the beta-amyloid precursor protein in cultured cells

The amyloid beta-protein (A beta) of Alzheimer's disease is derived from a family of large integral membrane glycoproteins, beta-amyloid precursor proteins (beta APP). Two secretory proteolytic pathways are involved in the metabolism of beta APP. The major pathway involves cleavage within the A beta sequence and generates carboxyl-truncated derivatives of beta APP which are secreted into the conditioned medium of cells. The minor 'amyloidogenic' pathway results in the production of A beta. Here, cell cultures were used to examine the metabolism of beta APP by tacrine, a centrally active cholinesterase inhibitor reported to improve cognitive deficits. Treatment with tacrine in cells resulted in the drastic inhibition of secretion of the major isoforms of beta APP into the medium. The effect of tacrine can be reversed by washing away the drug from the cells. Treatment with tacrine did not change the level of either HSP-70 or LDH. Thus, the inhibitory effect of tacrine on the secretion of beta APP was not due to the permanent damage or loss of cells as normal release of beta APP could be restored when the drug was washed away.     

Treating Alzheimer's disease. Pharmacologic options now and in the near future

Treatment of Alzheimer's disease has in the past been limited to empirical trials of psychotropics for relief of behavioral complications. At present, tacrine and doneprezil are the only FDA-approved antidementia agents available. In the very near future, however, other cholinesterases inhibitors (e.g., ENA 713, metrifonate, long-acting physostigmine) are expected to be approved for clinical use. The evidence at this point suggests that they have modest but meaningful clinical effects and possible long-term benefits. Clinical use of the newer agents is likely to be influenced by their side-effect profiles, which consist largely of cholinergic effects, although without the hepatotoxic effects associated with tacrine. To what extent these agents are accepted by patients and physicians remains to be seen. On the one hand, benefits are modest; on the other, these medications are increasingly safe. Continuing research is clarifying the role of cholinergic therapy in relieving behavioral symptoms, as well as the possible side effects on rates of illness progression, institutionalizaton, and even mortality. In the not-too-distant future, physicians can expect to see a variety of medications, now in early stages of development, that are intended to affect cholinergic systems in other ways. Further down the road, a host of mechanism-based therapeutic strategies, which hope to deal with the first cause of this devastating illness, will have been assessed in clinical trials.     

Structural alterations in synaptosomal membrane-associated proteins and lipids by transient middle cerebral artery occlusion in the cat

We have previously reported that ischemia reperfusion injury results from free radical generation following transient global ischemia, and that this radical induced damage is evident in the synaptosomal membrane of the gerbil. [Hall et al, (1995) Neuroscience 64: 81-89]. In the present study we have extended these observations to transient focal ischemia in the cat. We prepared synaptosomal membranes from frontal, parietal-temporal, and occipital regions of the cat cerebral cortex with reperfusion times of 1 and 3 hours following 1 hour right middle cerebral artery occlusion. The membranes were selectively labeled with protein and lipid specific paramagnetic spin labels and analyzed using electron paramagnetic resonance spectrometry. There were significant motional changes of both the protein and lipid specific spin labels in the parietal-temporal and occipital regions with 1 hour reperfusion; but, both parameters returned to control values by 3 hours reperfusion. No significant changes were observed in the normally perfused frontal pole at either reperfusion time. These results support the argument that free radicals play a critical role in cell damage at early reperfusion times following ischemia.     

The difference in mean costs as a pharmacoeconomic outcome variable: power considerations

Significant changes in cholinergic neurotransmission have been described in Alzheimer's disease (AD). These findings led to consider cholinergic deficit as the main disturbance in AD, due to degeneration of presynaptic cholinergic neurons, and that replacement of acetylcholine could restore the cognitive alterations characteristic of AD. Although it was soon demonstrated that cholinergic deficit was not the only change, cholinergic hypothesis has allowed to set several possible therapeutic strategies for these severe disease, the most promising is administration of acetylcholinesterase inhibitors. Of all the compounds investigated, tacrine (tetrahydroamineacridine) has shown in several clinical trials a positive effect on memory in patients with symptoms of slight to moderate severity. Although not all studies have given successful result, probably due to methodological differences, global clinical impression has justified the introduction of tacrine as the first palliative therapy in AD.     

Cytotoxicity study of tacrine, structurally and pharmacologically related compounds using rat hepatocytes

Tacrine is the first drug approved for the treatment of Alzheimer's disease. Approximately 50% of patients treated with tacrine develop elevated serum aminotransferase levels, as an indication of potential hepatotoxicity. However, acute and chronic studies with a limited number of animal models have not demonstrated hepatotoxicity. The present study compared the cytotoxicity in hepatocyte cultures of tacrine with structurally (proflavine and 9-aminoacridine) or pharmacologically similar compounds (physostigmine), as well as structurally modified tacrine to determine if there was a structure activity relationship with regards to toxicity. Cytotoxicity was assessed by determination of extra- and intracellular amounts of lactate dehydrogenase. Cytotoxicity was assessed after a four-hour exposure over a test compound concentration range of 0 to 3 mM. Concentration-dependent cytotoxicity occurred with tacrine and all structurally related compounds. Physostigmine which is pharmacologically similar, but structurally different, did not induce cytotoxicity. Cytotoxic potency did not appear to be related to acetylcholinesterase inhibitory activity, while compounds with acridine structures induced cytotoxicity. Thus, in this in vitro model, cytotoxicity appears to be related to structure and not pharmacological action. Results of this study indicate that compounds structurally related to tacrine are cytotoxic because of the heterocyclic ring structure. Neither unsaturation of an aromatic ring of the heterocyclic compound, amino substitution of the heterocyclic rings, N-hydroxylation of the amino group, nor ring hydroxylation dramatically alter cytotoxicity.     

Ethanol disordering of GM1-enriched short-sleep synaptosomal plasma membranes

The Long-Sleep (LS) and Short-Sleep (SS) mouse synaptosomal plasma membranes differ in ethanol sensitivity at superficial membrane regions, which corresponds with the behavioral response of the mice to ethanol hypnosis. The only significant difference between these synaptosomal plasma membranes is the synaptosomal monosialoganglioside (GM1) content, LS > SS. Here, GM1 was examined as a parameter for increasing membrane sensitivity to ethanol effects in the ethanol-resistant SS membranes. Synaptosomal plasma membranes from SS mice were allowed to incorporate exogenous GM1. Membrane order was then studied at the surface, intermediate, and interior regions of the membranes by delayed Fourier transform proton NMR in the presence and absence of perdeuterated ethanol. Differences in membrane order were observed in all three membrane regions with increasing perdeuterated ethanol concentrations depending on the synaptosomal GM1 content.     

The cardinal features of cognitive and noncognitive dysfunction and the differential efficacy of tacrine in Alzheimer's disease patients

The Alzheimer's Disease Assessment Scale (ADAS), frequently used in clinical trials to assess overall pathology of Alzheimer's disease (AD), comprises two subscales. The cognitive subscale (ADAS-COG) consists of 11 items, and the noncognitive subscale consists of 9 items. Factor analyses were carried out on ADAS-COG and ADAS-NONCOG item scores from the most recent and largest (n = 663) placebo-controlled, multicenter, 30-week study (970-61) of tacrine in patients with AD conducted by the clinical research group at Parke-Davis Pharmaceutical Research. Through factor analyses the primary dimensions of variation in the ADAS-COG and ADAS-NONCOG were defined. Obliquely rotated three principal factors of ADAS-COG and three principal factors of ADAS-NONCOG have been interpreted as three cardinal features of cognitive function corresponding to memory, language, and praxis, and three cardinal features of noncognitive function corresponding to agitation, depression, and lack of concentration. Reliably defined factors of ADAS-COG enabled comparisons of longitudinal changes in cognitive dysfunction. Factor scores at week 30, adjusted to baseline factor scores, were used to compare the effects of tacrine with those of placebo on cognitive cardinal features. Additionally, the effect of concurrent depression on cardinal features of cognitive dysfunction was evaluated by gender.     

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.     

Human globin chain separation by capillary electrophoresis in acidic isoelectric buffers

The potency of a series of anticholinesterase (anti-ChE) agents and serotonin-related amines as inhibitors of the aryl acylamidase (AAA) activity associated with electric eel acetylcholinesterase (AChE) (EC 3.1.1.7) and horse serum butyrylcholinesterase (BuChE) (EC 3.1.1.8) was examined and compared with the potency of the same compounds as ChE inhibitors. Neostigmine, physostigmine, BW 284C51, (+/-)-huperzine A, E2020, tacrine, edrophonium and heptyl-physostigmine were, in that order, the most potent in inhibiting eel AChE-associated AAA activity, their inhibitor constant (Ki) values being in the range 0.02-0.37 microM. The rank order of the same compounds as AChE inhibitors basically paralleled that of AAA, although they were in general stronger on AChE (Ki = 0.001-0.05). The peripheral anionic site inhibitors propidium and gallamine were inactive on AChE-associated AAA. Serotonin and its derivatives were slightly stronger on AAA (Ki = 7.5-30 microM) than on AChE (Ki = 20-140 microM). Tacrine (IC50 = 0.03 microM), diisopropylfluorophosphate (IC50 = 0.04 microM), heptyl-physostigmine (IC50 = 0.11 microM), physostigmine (IC50 = 0.15 microM) and tetra-iso-propylpyrophosphoramide (iso-OMPA) (IC50 = 0.75 microM) were the most potent in inhibiting horse serum BuChE-associated AAA activity. Serotonin and related amines were very weak on BuChE-associated AAA activity. These results indicate that the inhibitory potencies of the active site anti-ChE agents on the AAA activity associated with eel AChE and horse serum BuChE are closely correlated with their action on the respective ChE. In addition, the efficacy of tacrine, E2020, heptyl-physostigmine and (+/-)-huperzine A in the treatment of Alzheimer's disease is unlikely to be related to the action of these drugs on ChE-associated AAA.     

Peroxynitrite reaction with carbon dioxide/bicarbonate: kinetics and influence on peroxynitrite-mediated oxidations

A method of stratifying the data according to the patterns of missing observations, summarizing each subject's repeated measurements by a summary measure and then comparing the treatment groups with the help of a distribution-free test based on the summary measure, is used here to compare the efficacy of tacrine dose regimens with that of placebo in a recent trial in Alzheimer's disease patients. The usefulness of the method of meta-analysis for comparing the treatment groups, in the presence of missing data, is also investigated.