Gracon SI

References (12)

Title : Safety of tacrine: clinical trials, treatment IND, and postmarketing experience - Gracon_1998_Alzheimer.Dis.Assoc.Disord_12_93
Author(s) : Gracon SI , Knapp MJ , Berghoff WG , Pierce M , DeJong R , Lobbestael SJ , Symons J , Dombey SL , Luscombe FA , Kraemer D
Ref : Alzheimer Disease & Associated Disorders , 12 :93 , 1998
Abstract : The safety of tacrine (Cognex), a centrally active, reversible acetylcholinesterase inhibitor approved in 1993 for the treatment of mild to moderate dementia of the Alzheimer type, was evaluated in 2,706 patients with Alzheimer disease (AD) in clinical trials and in 9861 patients with AD in a treatment investigational new drug (TIND) program. More than 190,000 patients in the United States received tacrine during the first 2 years following marketing approval. The most common tacrine-associated adverse events were elevated liver transaminase levels [alanine aminotransferase (ALT) and, to a lesser degree, aspartate aminotransferase] and peripheral cholinergic events involving primarily the digestive system (nausea, vomiting, diarrhea, dyspepsia, anorexia, and weight loss). Based on clinical trial experience, potentially clinically significant (>3 x upper limit of normal) ALT elevations occurred in 25% of patients, requiring routine monitoring early in treatment. The elevations were almost always asymptomatic, rarely accompanied by significant increases in bilirubin, and related to time on drug rather than to dose (90% occurred within the first 12 weeks of treatment). Gastrointestinal events were related to dose and generally of mild to moderate intensity. Tacrine-associated events, including ALT elevations, were reversible. Cholinergic events were manageable with dosage adjustment. Tacrine was not associated with permanent liver injury in clinical trials or a TIND setting.
ESTHER : Gracon_1998_Alzheimer.Dis.Assoc.Disord_12_93
PubMedSearch : Gracon_1998_Alzheimer.Dis.Assoc.Disord_12_93
PubMedID: 9651138

Title : An enriched-population, double-blind, placebo-controlled, crossover study of tacrine and lecithin in Alzheimer's disease. The Tacrine 970-6 Study Group - Foster_1996_Dementia_7_260
Author(s) : Foster NL , Petersen RC , Gracon SI , Lewis K
Ref : Dementia , 7 :260 , 1996
Abstract : We studied the effects of 40 and 80 mg/day of tacrine on patients with probable Alzheimer's disease (AD) in an 8-week, randomized, double-blind, placebo-controlled crossover trial with an enriched-population design. In the initial dose titration phase, an intent-to-treat analysis showed significantly more improvement with 80 mg/day of tacrine than placebo. In the subsequent crossover trial that included only 'responders', no significant improvement was observed with tacrine, whether or not it was given with lecithin. We found that individualized dose titration and enrichment strategies were not helpful and had the effect of reducing the power of the study. In the dose titration phase of this study we found that more impaired subjects were as likely to improve as those who were less impaired, suggesting that tacrine should be further investigated in more severely demented AD patients.
ESTHER : Foster_1996_Dementia_7_260
PubMedSearch : Foster_1996_Dementia_7_260
PubMedID: 8872417

Title : Cardinal features of cognitive dysfunction in Alzheimer's disease: a factor-analytic study of the Alzheimer's Disease Assessment Scale - Talwalker_1996_J.Geriatr.Psychiatry.Neurol_9_39
Author(s) : Talwalker S , Overall JE , Srirama MK , Gracon SI
Ref : J Geriatr Psychiatry Neurol , 9 :39 , 1996
Abstract : Factor analysis methodology applied to Alzheimer's Disease Assessment Scale (ADAS) subtest profiles for patients in two large-scale clinical trials of the antidementia drug tacrine yielded three oblique factors interpreted as dysfunctions in memory, language, and praxis. The factor structures confirmed reliable assessment of primary dimensions of cognitive impairment in Alzheimer's disease that the original authors of the ADAS proposed to measure and that correspond well to that of the only previously reported factor analysis of the ADAS-COG. The presence of a strong general factor, supported by stable correlations among the oblique primary factors, justifies the recommendation to continue reliance on the ADAS-COG total score as a primary outcome measure in clinical trials, whereas the factor scores are recommended for evaluation of differential treatment effects on more specific aspects of the general cognitive decline. The stability of correlations across time appears to satisfy a primary requirement for application of repeated measures ANOVA to ADAS-COG total score and factor scores in longitudinal clinical trials.
ESTHER : Talwalker_1996_J.Geriatr.Psychiatry.Neurol_9_39
PubMedSearch : Talwalker_1996_J.Geriatr.Psychiatry.Neurol_9_39
PubMedID: 8679062

Title : Evaluation of tacrine hydrochloride (Cognex) in two parallel-group studies - Gracon_1996_Acta.Neurol.Scand.Suppl_165_114
Author(s) : Gracon SI
Ref : Acta Neurologica Scandinavica Supplementum , 165 :114 , 1996
Abstract : The efficacy of tacrine hydrochloride (Cognex) for the treatment of Alzheimer's disease (AD) has been confirmed in two randomized, double-blind, placebo-controlled, parallel-group studies. More than 1100 patients with mild to moderate, probable AD were randomized to receive placebo or tacrine for 12 or 30 weeks. Outcome measures included objective assessments of cognitive function, qualitative assessments of treatment response from the caregiver and clinician perspective, and assessments of activities of daily living. Statistically significant treatment effects favoring tacrine were demonstrated in each domain. These results suggest several considerations for clinicians. Because response to treatment is dose related, patients should be titrated to their maximum tolerated dose. Response may be subtle and may range from improvement to stabilization or slowed decline. A minimum treatment period of 6 months is recommended to evaluate a response and treatment should be continued depending on patient tolerability.
ESTHER : Gracon_1996_Acta.Neurol.Scand.Suppl_165_114
PubMedSearch : Gracon_1996_Acta.Neurol.Scand.Suppl_165_114
PubMedID: 8740998

Title : Long-term tacrine treatment in patients with Alzheimer's disease -
Author(s) : Solomon PR , Knapp MJ , Gracon SI , Groccia M , Pendlebury WW
Ref : Lancet , 348 :275 , 1996
PubMedID: 8684234

Title : A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group - Knapp_1994_JAMA_271_985
Author(s) : Knapp MJ , Knopman DS , Solomon PR , Pendlebury WW , Davis CS , Gracon SI
Ref : Jama , 271 :985 , 1994
Abstract : OBJECTIVE: To evaluate the efficacy and safety of high-dose tacrine hydrochloride over 30 weeks in patients with probable Alzheimer's disease. DESIGN: A 30-week randomized, double-blind, placebo-controlled, parallel-group trial. SETTING: Outpatients at 33 US centers. PATIENTS: Men and women at least 50 years of age with mild to moderate Alzheimer's disease and otherwise in good health. INTERVENTIONS: Group 1 received placebo; group 2 received 40 mg/d of tacrine for 6 weeks, then 80 mg/d for 24 weeks; groups 3 and 4 received 40 mg/d of tacrine for 6 weeks, 80 mg/d for 6 weeks, and 120 mg/d for 6 weeks. Group 3 remained on a dosage of 120 mg/d for a total of 18 weeks; after 6 weeks at 120 mg/d, group 4 titrated to 160 mg/d for the last 12 weeks. PRIMARY OUTCOME MEASURES: Clinician Interview-Based Impression (CIBI), Alzheimer's Disease Assessment Scale--Cognitive subscale (ADAS-Cog), and Final Comprehensive Consensus Assessment (FCCA).
RESULTS: A total of 663 patients entered the study; 653 patients were included in an intent-to-treat (ITT) analysis; 263 had evaluable data at 30 weeks. The results of the ITT analysis revealed significant (P < or = .05) dose-response trends and between-group comparisons on CIBI and ADAS-Cog. In evaluable patients, significant dose-response trends were observed for all three primary measures (P < or = .001). Significant differences in favor of 160 mg/d of tacrine vs placebo were observed on the CIBI (P < or = .002) and ADAS-Cog and FCCA (P < or = .001), as well as caregiver-global and quality-of-life assessments (P < or = .05). On the CIBI, 23% and 42% of tacrine-treated patients in the ITT and evaluable-patient populations, respectively, were rated improved compared with 17% and 18% of placebo patients, respectively. The primary reasons for withdrawal of tacrine-treated patients were asymptomatic liver transaminase elevations (28%) and gastrointestinal complaints (16%). These adverse events were reversible on discontinuation of treatment, and many patients were able to restart tacrine.
CONCLUSIONS: Tacrine produced statistically significant, dose-related improvements on objective performance-based tests, clinician- and caregiver-rated global evaluations, and measures of quality of life. There was no evidence that the large number of patient withdrawals biased the overall conclusions of the study.
ESTHER : Knapp_1994_JAMA_271_985
PubMedSearch : Knapp_1994_JAMA_271_985
PubMedID: 8139083

Title : The Clinician Interview-Based Impression (CIBI): a clinician's global change rating scale in Alzheimer's disease - Knopman_1994_Neurology_44_2315
Author(s) : Knopman DS , Knapp MJ , Gracon SI , Davis CS
Ref : Neurology , 44 :2315 , 1994
Abstract : Global assessments are Food and Drug Administration-required primary outcome measures in trials of putative antidementia drugs. Global ratings are intended to provide an index of clinical importance of change that cannot be obtained from quantitative assessment measures such as mental status examinations. We examined the performance of a global assessment of change instrument, the Clinician Interview-Based Impression (CIBI), in the placebo group of a 30-week, randomized, double-blind clinical trial of tacrine in patients with Alzheimer's disease. Initially there were 184 placebo patients, of whom 125 completed the 30-week study. Descriptive statistics, correlations with changes on other assessment instruments, and test-retest reliability were determined for the CIBI. At week 30, clinicians rated more than 40% of patients on the CIBI as unchanged. The CIBI ratings were weakly but significantly correlated, in the expected direction, with change scores on the quantitative cognitive assessments. The CIBI was modestly reliable on test-retest at weeks 22 and 24 but less reliable compared with other quantitative outcome measures. Modifications of the CIBI that might improve its reliability and acceptance include (1) no restrictions on the form of the bedside mental status assessment, (2) inclusion of caregiver input, and (3) better definition of ratings on the global scale. Global instruments, if properly constructed, can provide an index of clinically important change for the assessment of dementia patients.
ESTHER : Knopman_1994_Neurology_44_2315
PubMedSearch : Knopman_1994_Neurology_44_2315
PubMedID: 7991118

Title : Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease - Watkins_1994_JAMA_271_992
Author(s) : Watkins PB , Zimmerman HJ , Knapp MJ , Gracon SI , Lewis KW
Ref : Jama , 271 :992 , 1994
Abstract : OBJECTIVE: To characterize the hepatic effects of tacrine treatment in patients with Alzheimer's disease. DESIGN: Controlled trials of tacrine therapy consisting of two blinded, parallel-group trials; three blinded, enrichment-design trials; and their respective open-label extensions. SETTING: Multicenter clinical trials in the United States, France, and Canada. PATIENTS: A total of 2446 men and women at least 50 years of age with a diagnosis of probable Alzheimer's disease of mild to moderate severity and in good health without significant hepatic, cardiovascular, or renal disease. INTERVENTION: Administration of tacrine vs placebo, with weekly measurement of serum hepatic enzymes. MAIN OUTCOME MEASURES: Incidence, maximum severity, and timing of event for serum alanine aminotransferase (ALT) elevation.
RESULTS: Among the 2446 patients who received tacrine in clinical trials, ALT levels greater than the upper limit of normal (ULN) occurred on at least one occasion in 1203 patients (49%), ALT levels greater than three times the ULN occurred in 621 patients (25%), and ALT levels greater than 20 times the ULN occurred in 40 patients (2%). The elevated ALT levels were generally asymptomatic and occurred more frequently in women than men. The mean time from initiation of tacrine treatment to first ALT level greater than three times the ULN was 50 days, and 90% of all initial ALT levels greater than three times the ULN occurred during the first 12 weeks of treatment. Of 145 patients who discontinued tacrine treatment because of an ALT level greater than three times the ULN and were rechallenged, 127 (88%) were able to resume long-term therapy with the drug. In all instances, discontinuing tacrine completely reversed elevations in ALT levels, and no deaths related to hepatotoxicity occurred.
CONCLUSIONS: These data suggest that the potential for serious hepatic toxicity can be reduced through careful monitoring of ALT levels in patients who may benefit from tacrine therapy.
ESTHER : Watkins_1994_JAMA_271_992
PubMedSearch : Watkins_1994_JAMA_271_992
PubMedID: 8139084

Title : Tacrine in Alzheimer's disease -
Author(s) : Gracon SI
Ref : N Engl J Med , 328 :808 , 1993
PubMedID: 8437605

Title : A controlled trial of tacrine in Alzheimer's disease. The Tacrine Study Group - Farlow_1992_JAMA_268_2523
Author(s) : Farlow M , Gracon SI , Hershey LA , Lewis KW , Sadowsky CH , Dolan-Ureno J
Ref : Jama , 268 :2523 , 1992
Abstract : OBJECTIVE: To compare efficacy and safety of tacrine hydrochloride with placebo in patients with probable Alzheimer's disease. DESIGN: A 12-week, double-blind, placebo-controlled, parallel-group study. SETTING: Outpatients at 23 centers. PATIENTS: Men and women with probable Alzheimer's disease, at least 50 years old, mildly to moderately impaired, without other significant medical conditions. INTERVENTIONS: In the initial 6 weeks, patients received placebo, 20 mg/d of tacrine, or 40 mg/d of tacrine. In the second 6 weeks, half received the same treatment and half increased tacrine dose: those receiving placebo increased to 20 mg/d, those receiving 20 mg/d increased to 40 mg/d, and those receiving 40 mg/d increased to 80 mg/d. PRIMARY OUTCOME MEASURES: Alzheimer's Disease Assessment Scale (ADAS) cognitive component and clinician-rated Clinical Global Impression of Change (CGIC).
RESULTS: Four hundred sixty-eight patients entered. After 12 weeks, dose-related improvement was significant on the ADAS cognitive (P = .014), clinician-rated CGIC (P = .014), and caregiver-rated CGIC (P = .006). Comparison of 80 mg/d with placebo showed significant improvement on the ADAS cognitive (P = .015), clinician-rated CGIC (P = .016), and caregiver-rated CGIC (P = .028). Significant effects appeared as early as 6 weeks on the ADAS cognitive and caregiver-rated CGIC. Among patients receiving 80 mg/d of tacrine, 51% achieved a four-point or greater improvement of the ADAS cognitive component after 12 weeks of treatment. Reversible asymptomatic transaminase elevations greater than three times normal occurred in 25% of patients. Other treatment-related events included nausea and/or vomiting (8%), diarrhea (5%), abdominal pain (4%), dyspepsia (3%), and rash (3%).
CONCLUSIONS: These results confirm the efficacy and safety of tacrine in some patients with Alzheimer's disease. After 12 weeks, the magnitude of the treatment effect is clinically important and recognized by the physician and caregiver. Liver toxicity is reversible and easily detected by weekly alanine aminotransferase determinations.
ESTHER : Farlow_1992_JAMA_268_2523
PubMedSearch : Farlow_1992_JAMA_268_2523
PubMedID: 1404819

Title : A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. The Tacrine Collaborative Study Group - Davis_1992_N.Engl.J.Med_327_1253
Author(s) : Davis KL , Thal LJ , Gamzu ER , Davis CS , Woolson RF , Gracon SI , Drachman DA , Schneider LS , Whitehouse PJ , Hoover TM , et al.
Ref : N Engl J Med , 327 :1253 , 1992
Abstract : BACKGROUND: In Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease.
METHODS: Of 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living.
RESULTS: At the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P < 0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment.
CONCLUSIONS: In this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients.
ESTHER : Davis_1992_N.Engl.J.Med_327_1253
PubMedSearch : Davis_1992_N.Engl.J.Med_327_1253
PubMedID: 1406817

Title : Steady-state pharmacokinetics of tacrine in patients with Alzheimer's disease - Cutler_1990_Psychopharmacol.Bull_26_231
Author(s) : Cutler NR , Sedman AJ , Prior P , Underwood BA , Selen A , Balogh L , Kinkel AW , Gracon SI , Gamzu ER
Ref : Psychopharmacol Bull , 26 :231 , 1990
Abstract : Neurochemical studies of Alzheimer's disease (AD) suggest deficiencies in the cholinergic system. We evaluated the steady-state pharmacokinetics of tacrine (Cognex), an oral cholinesterase inhibitor, in 12 patients with AD. Patients sequentially received nine doses of 10 mg, 20 mg, and 30 mg of tacrine every 6 hours. Blood samples were collected until 24 hours after the final dose. Plasma tacrine concentrations were measured using a validated high-performance liquid chromatographic method. Mean maximum plasma concentrations (Cmax) were 5.1 ng/ml, 20.7 ng/ml, and 33.9 ng/ml following administration of 10 mg, 20 mg, and 30 mg doses, respectively. Corresponding mean values for steady-state area under the curve (AUC) were 19.7 ng/ml, 82.9 ng/ml, and 139 ng/ml.hr. Dose-normalized Cmax and AUC values after administration of the 20 mg and 30 mg doses of tacrine were comparable to each other but were significantly greater (p less than .05) than those after the 10 mg doses. The apparent elimination half-life was approximately 3.4 hours for all dosing regimens. Dose-dependent increases in Cmax and AUC values in patients with AD were similar to those previously reported in normal volunteers. The mechanism of the nonlinearity in tacrine pharmacokinetics is unknown.
ESTHER : Cutler_1990_Psychopharmacol.Bull_26_231
PubMedSearch : Cutler_1990_Psychopharmacol.Bull_26_231
PubMedID: 2236461