Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality, Tacrine Study Group.

OBJECTIVE: To assess the possible association between tacrine (Cognex, manufactured by Parke-Davis, Morris Plains, NJ) dose and likelihood of nursing home placement (NHP) or death in patients with AD. DESIGN: A 30-week, randomized, double-blind, placebo-controlled, parallel-group multicenter clinical trial involving 663 patients, after which patients were treated openly and followed up a minimum of 2 years later. PATIENTS: At baseline, outpatients were at least 50 years of age, met criteria for probable AD, with baseline Mini-Mental State Examination scores between 10 and 26 (inclusive), were otherwise healthy, and had a caregiver who could provide assessments and ensure medication compliance. INTERVENTIONS: mandomized assignment to placebo or one of three ascending dosage regimens of tacrine over 30 weeks, followed by open label treatment for all patients who began the double-blind trial. OUTCOME MEASURES: NHP and death were examined using logistic regression. RESULTS: PATIENTS who remained on tacrine and were receiving doses > 80 mg/d or > 120 mg/d were less likely to have entered a nursing home than patients on lower doses (odds ratios > 2.7,2.8, respectively.) There was a trend for lower mortality for patients receiving > 120 mg/d (p = 0.063). CONCLUSIONS: Treatment with tacrine at doses > 80 mg/d was associated with a reduced likelihood of NHP. These data demonstrate that tacrine's 30-week effects on cognitive function and clinicians' global ratings may generalize to effects on a major milestone of AD. Future studies should attempt to replicate these findings prospectively.

A double-blind, randomized comparison of intramuscularly and intravenously administered parecoxib sodium versus ketorolac and placebo in a post-oral surgery pain model.

BACKGROUND: Parecoxib sodium is an injectable cyclooxygenase-2-specific inhibitor developed for the treatment of acute pain. The analgesic efficacy of IV and IM parecoxib has been demonstrated in previous pilot studies using the post-oral surgery pain model. OBJECTIVE: This study was conducted to characterize the analgesic efficacy of parecoxib in healthy adults after oral surgery while comparing the efficacy and tolerability of the IV and IM routes of administration. METHODS: This was a double-blind, randomized, parallel-group, placebo- and active-controlled, single-dose, single-center trial. Patients experiencing moderate to severe post-operative pain after the extraction of > or =2 impacted third molars were randomized to receive parecoxib sodium 20 mg IM, 20 mg IV, 40 mg IM, or 40 mg IV; ketorolac tromethamine 60 mg IM; or placebo. Patients assessed pain intensity and pain relief (PR) at baseline and at designated intervals for 24 hours after administration of study medication or until rescue medication was taken. Analgesic efficacy was assessed in terms of time-specific pain intensity difference (PID) and PR, time to onset of analgesia, and time to use of rescue medication. RESULTS: Three hundred four patients were randomized to treatment. Parecoxib sodium 20 and 40 mg IM or IV and ketorolac 60 mg IM were significantly superior to placebo in PID, PR, time to onset of analgesia, and time to use of rescue medication (P < or = 0.05). Equal IV and IM doses of parecoxib were comparable on these measures; however, time to use of rescue medication was longer with IM compared with IV administration. Both doses of parecoxib were comparable to ketorolac 60 mg IM in time to onset of analgesia, but parecoxib 40 mg had a significantly longer duration of action (P < or = 0.05). The few statistically significant differences in PID and PR between parecoxib 40 mg and ketorolac favored ketorolac versus parecoxib 40 mg IV at earlier time points and parecoxib 40 mg IM versus ketorolac at later time points (P < or = 0.05). All treatments were well tolerated. CONCLUSIONS: Parecoxib IV and IM provided effective analgesia. The 40-mg dose was comparable to ketorolac 60 mg on most measures of analgesia but had a longer duration of action.

Cardinal features of cognitive dysfunction in Alzheimer's disease: a factor-analytic study of the Alzheimer's Disease Assessment Scale.

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.

Bounds on life expectancy for the Rayleigh and Weibull distributions.

Bounds are presented for the life expectancy or the mean residual life of an individual whose lifetime is a random variable X following a Rayleigh distribution or more generally a Weibull distribution. Simple transformations of the variables give inequalities on the Mills' ratio and the incomplete gamma functions. Some numerical computations are also reported to compare the lower and upper bounds with the exact value of the life expectancy function for several values of the parameter. When the lifetime follows a Gompertz distribution, the problem becomes complicated, and it has not been possible to construct bounds on the life expectancy function. The importance of the Gompertz distribution in the dynamics of normal and tumor growth and in the embryonic and postnatal growth of birds and mammals is demonstrated, and life expectancy is evaluated by numerical methods for a number of parameter values.

Analysis of repeated measurements with dropouts among Alzheimer's disease patients using summary measures and meta-analysis.

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.

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.

The use of survival analysis techniques in evaluating the effect of long-term tacrine (Cognex) treatment on nursing home placement and mortality in patients with Alzheimer's disease.

Survival analysis techniques using Cox proportional hazards regressions with time-dependent covariates, life table survival plots, and Kaplan-Meier estimates were used to evaluate the effect of long-term tacrine hydrochloride (Cognex) treatment on nursing home placement (NHP) and mortality in patients with Alzheimer's disease. Patients with probable Alzheimer's disease (NINCDS criteria) who were randomized in a 30-week double-blind, placebo-controlled, parallel-group, high-dose study of tacrine (1) were subsequently allowed to receive long-term, open-label treatment during which they could receive doses up to 160 mg/day. Using last tacrine dose, the analyses demonstrated a dose-response relationship where patients on higher tacrine doses were less likely to enter a nursing home or die than patients on lower doses. The Cox proportional hazards regression approach with time-dependent covariates is also compared to logistic regression, which looks only at the crude proportions of patients having the event. Since logistic regression does not allow for the use of time-dependent covariates, it provides somewhat less conservative estimates of the magnitude of the treatment effect.

Satranidazole: experimental evaluation of activity against anaerobic bacteria in vitro and in animal models of anaerobic infection.

Satranidazole, a 5-nitroimidazole derivative, was tested for its activity against reference strains and clinical isolates of anaerobic bacteria in vitro and in two murine models of anaerobic infection in comparison with metronidazole, tinidazole, ornidazole and clindamycin. The MIC90 of satranidazole against 50 clinical isolates of anaerobes was 0.25 mg/l which was four-fold lower than the MIC90 of metronidazole, tinidazole and ornidazole (MIC90 = 1.0 mg/l). In a fatal murine infection with Fusobacterium necrophorum, ATCC 27852, the ED50 of satranidazole was 2.1 +/- 0.62 mg/kg while for metronidazole, ornidazole, tinidazole and clindamycin, the values were 11.31 +/- 1.99, 8.70 +/- 2.21, 13.19 +/- 2.39 and 7.10 +/- 1.73 respectively. In a subcutaneous Bacteroides fragilis abscess in mice, satranidazole alone produced a three log reduction in cfu of the infecting organism at 10 mg/kg, the lowest dose tested. At 100 mg/kg, only satranidazole and clindamycin effected a complete sterilization of abscesses.

The injectable cyclooxygenase-2-specific inhibitor parecoxib sodium has analgesic efficacy when administered preoperatively.

Preoperative administration of analgesics may prevent or reduce hyperalgesia and inhibit inflammation and pain by reducing the synthesis of prostaglandins in response to surgical injury. We evaluated in this placebo-controlled study the analgesic efficacy and safety of single doses of parecoxib sodium (20, 40, and 80 mg IV) when administered before oral surgery. Efficacy assessments were recorded during the 24-h period after completion of surgery. All doses of parecoxib sodium were consistently and significantly superior to placebo as measured by time to rescue medication, proportion of patients requiring rescue medication, patient's global assessment, and pain intensity. There were no significant differences between the Parecoxib Sodium 40- and 80-mg groups, suggesting that the analgesic effect of preoperatively administered parecoxib sodium reaches a plateau at 40 mg in this model. Forty-eight percent of the Parecoxib Sodium 40-mg group required rescue medication in the 24-h study period, compared with 93% of patients in the Placebo group. Overall, there were fewer adverse events in parecoxib sodium-treated patients compared with placebo. These findings suggest that preoperative administration of parecoxib sodium, the injectable prodrug of the cyclooxygenase-2 specific inhibitor valdecoxib, is effective, safe, and well tolerated for treating postoperative pain.

Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects.

OBJECTIVE: To investigate the efficacy and safety of SC-58635 (celecoxib), an antiinflammatory and analgesic agent that acts by selective cyclooxygenase 2 (COX-2) inhibition and is not expected to cause the typical gastrointestinal (GI), renal, and platelet-related side effects associated with inhibition of the COX-1 enzyme. METHODS: Four phase II trials were performed: a 2-week osteoarthritis efficacy trial, a 4-week rheumatoid arthritis efficacy trial, a 1-week endoscopic study of GI mucosal effects, and a 1-week study of effects on platelet function. RESULTS: The 2 arthritis trials identified SC-58635 dosage levels that were consistently effective in treating the signs and symptoms of arthritis and were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, 19% of subjects receiving naproxen (6 of 32) developed gastric ulcers, whereas no ulcers occurred in subjects receiving SC-58635 or placebo. The study of platelet effects revealed no meaningful effect of SC-58635 on platelet aggregation or thromboxane B2 levels, whereas aspirin caused significant decreases in 2 of 3 platelet aggregation measures and thromboxane B2 levels. In all 4 trials, SC-58635 was well tolerated, with a safety profile similar to that of placebo. CONCLUSION: SC-58635 achieves analgesic and antiinflammatory efficacy in arthritis through selective COX-2 inhibition, without showing any evidence of 2 of the toxic effects of COX-1 inhibition associated with nonsteroidal antiinflammatory drugs.