Long-term tacrine treatment effects.
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Aged↗
Biomedical subjects
L Schneider
Publications and source records attributed to L Schneider.
Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer's disease.
We studied the effects of apolipoprotein E (APOE) genotype and gender on clinical response to tacrine in patients with mild to moderate Alzheimer's disease (AD). We analyzed data from a previously reported 30-week, double-blind, placebo-controlled trial of tacrine, in which APOE genotypes were determined from previously collected plasma samples. Patients were assigned to placebo or tacrine with daily dosages of 80, 120, or 160 mg/day. The outcome measures were Alzheimer's Disease Assessment Scale-Cognitive Component, Clinician Interview Based Impression, Mini-Mental State Examination, and the Caregiver-rated Clinical Global Impression of Change. An intent-to-treat (ITT) analysis of patients with available genotypes (n = 528) did not reveal response differences by genotype, although the effect size was twice as large in the epsilon2-3 as the epsilon4 group (-2.62 versus -1.25). The association of treatment effect with APOE genotype varied significantly according to gender (p < 0.002 for ITT; p < 0.05 for evaluables). The treatment effect was larger in the epsilon2-3 compared with epsilon4 women (ITT, 4.24 points, p = 0.03; evaluable, 7.20 points, p = 0.01). In contrast, treatment effect size was not different between epsilon2-3 and epsilon4 of men with AD. APOE genotype and gender may predict response to tacrine in patients with AD.
Aged↗
Optimal management of behavioural disorders associated with dementia.
Behavioural disorders occur with great frequency in patients with dementia. They are the major reason for admission of these patients to nursing homes. However, there have been few controlled trials of many of the commonly used drugs to guide therapy. To treat these conditions successfully, an adequate description of target symptoms of the behaviours to be corrected and a thorough investigation to identify precipitating causes are essential. Behavioural problems in dementia patients may results from physical illnesses, adverse drug effects, environmental changes, psychiatric syndromes (i.e. depression, delirium or psychosis) or the dementing illness itself. Therapeutic strategies should address the underlying cause whenever possible. Although pharmacological therapies are commonly employed, their efficacy is often modest and adverse effects can be quite significant. Ongoing reassessments are essential to maximise symptomatic benefits and minimise adverse effects. Several trials with different drugs are often necessary before an effective therapy is found. Anticholinergic adverse effects, which occur commonly with many antipsychotic and antidepressant medications, may worsen the cognitive and memory deficits that form the primary symptoms of dementia in these patients. This article summarises the use of the various psychoactive medications that target common behavioural disturbances, including agitation, psychosis, depression and sleep disturbances, in dementia patients. General guidelines regarding dosage, potential adverse effects and duration of therapy are discussed.
Aggression↗
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.
Aged↗
Multicenter evaluation of new instruments for Alzheimer's disease clinical trials: summary of results. The Alzheimer's Disease Cooperative Study.
The Instrument Development Project of the Alzheimer's Disease Cooperative Study (ADCS) evaluated new assessments in five domains: (a) cognitive function; (b) clinical global change; (c) activities of daily living; (d) behavioral symptoms, and (e) cognition in severely impaired patients. These new instruments demonstrate excellent discrimination between normal controls and patient groups and show adequate validity and reliability. Stability of measurement and sensitivity to longitudinal change were also demonstrated in each of these areas. Examination of several domain-specific questions also contributed new information on the measurement of cognitive function with different subtasks across AD severity levels, the stability of clinical ratings of global change, and the applicability of behavioral assessment across severity levels. The success of this project enhances the state of the art in the measurement of efficacy in AD clinical trials and also provides a basis for future research on improving AD outcome measures.
Activities of Daily Living↗
Clinical global measures of dementia. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines.
Following is the report of the committee working on clinical global measures for antidementia drug guidelines. The concepts involved in global scales, the distinctions between change and severity scales, advantages and disadvantages of structured interviews, and anchoring of change scores are discussed, and selected existing clinical global scales are described. In addition, the committee assessed the utility of global scales in clinical trials for antidementia drugs. There was a consensus among the members of the working group on the following: (1) Clinical global scales are interview based; in most cases, they include information obtained from caregivers as well as directly from patients, but they can rely on information from the subject only. (2) Clinicians' global ratings are intended to assess clinically meaningful change based on multidimensional clinical assessment and take into account the clinical heterogeneity of dementia by assessing at least cognition, behavior, and functioning. (3) There are two distinct types of clinical global measures: (a) clinicians' interview-based global severity scales, which generally incorporate classification by stage or severity of illness and (b) clinicians' interview-based global change scales, which incorporate global assessment ratings of clinical change. The committee could not reach a consensus on whether global scales should be required in phase II and phase III clinical trials, or whether other specific assessments such as well-designed activities of daily living, cognition, and behavior measures could, when used in appropriate combinations, replace the global as assessments of clinical meaningfulness.
Activities of Daily Living↗
Prevention protocols for Alzheimer disease. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines.
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Aged↗
Simultaneous paclitaxel and radiotherapy: initial clinical experience in lung cancer and other malignancies.
This report summarizes results from a series of pilot trials using combined-modality chemoradiotherapy with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) as a radiosensitizing agent in patients with cancers of the lung, cervix, and bladder. In a phase I study of paclitaxel/radiotherapy in patients with locally advanced non-small cell lung cancer, five paclitaxel dose levels were evaluated in conjunction with simultaneous radiation (total dose, 59.4 Gy). A minimum of five patients were treated at each dose level; paclitaxel doses ranged from 45 mg/m2 over 3 weeks (level 1) to 65 mg/m2 for 7 weeks. Of 34 enrolled patients, 25 are evaluable for toxicity and response. Side effects were generally moderate for this combined-modality therapy, although two patients at level 5 developed dose-limiting toxicities (grade 4 esophagitis and grade 3 pneumonitis). Among 25 evaluable patients, complete and partial response rates were 4% (one patient) and 64% (16 patients), respectively; eight patients had a minor response. Median survival was 6 months (range, 1 to 20 months). Therapy was well tolerated, suggesting that the combined modalities offer a practical, effective therapy for patients with non-small cell disease. A paclitaxel dose of 55 mg/m2 is recommended for further study of combined-modality chemoradiotherapy in this clinical setting. In another trial, 33 women with inoperable, locally advanced cervical cancer received carboplatin 50 mg/m2 via intravenous infusion simultaneously with external-beam radiation therapy and vaginal brachytherapy, to define the regimen's toxicity and safety. Among the 33 women, 78% achieved a complete response to therapy. The investigators next conducted a trial of paclitaxel 50 mg/m2 given weekly over 3 hours with the previous carboplatin/radiotherapy regimen in four women and documented two partial responses, one near-complete response, and one minor response, with moderate, manageable toxicity. In a final case report on a patient with recurrent bladder cancer, simultaneous radiotherapy and weekly paclitaxel 50 mg/m2 intravenously over 3 hours yielded a partial remission, prompting the investigators to plan a phase I study to confirm the regimen's efficacy and safety. Additional planned studies include a phase I trial of simultaneous chemoradiotherapy in patients with cancer of the head and neck.
Adult↗
A prospective study of conservative surgery alone in the treatment of selected patients with stage I breast cancer.
BACKGROUND: Randomized clinical trials have clearly demonstrated that the use of radiation therapy (RT) following breast-conserving surgery (CS) substantially reduces the risk of local recurrence. However, the low rate of local recurrence after CS and RT for patients without known risk factors, and the recent increase in the detection of smaller cancers due to mammographic screening have led to the speculation that a subgroup of patients who have a low risk of local recurrence without RT might be identified. In 1986, we initiated a one-arm, prospective clinical trial of CS alone for treatment of highly selected breast cancer patients without known risk factors for local recurrence. METHODS: The study had a sequential design with a planned accrual of 90 patients. Criteria for entry into the trial were: a unicentric, clinical TI infiltrating ductal, mucinous or tubular carcinoma without an extensive intraductal component or lymphatic vessel invasion; a wide excision with a pathologically-documented negative margin of at least 1 cm; and histologically negative axillary lymph nodes. No adjuvant RT or systemic therapy was administered. Seventy-six per cent of the lesions were detected by mammography alone. The median gross pathologic tumor size was 0.9 cm. The median patient age was 67 years. RESULTS: Eighty-seven patients were enrolled in the trial before it closed prematurely in 1992 because the predefined stopping boundary was crossed (i.e., the sixth local recurrence was observed). At that time, the average annual local recurrence rate was 4.2%. With a median follow-up of 56 months, there are now 14 patients (16%) with local recurrence as their site of first failure (average annual local recurrence rate: 3.6%). Four patients without local recurrence developed distant metastases. Three patients have died, one of metastatic breast cancer and two of unrelated causes. CONCLUSIONS: Even in a highly selected group of patients with early-stage breast cancer, there is a substantial risk of early local recurrence for those treated with wide excision alone.
Adenocarcinoma, Mucinous↗
Conscious sedation: a multidisciplinary team approach.
The administration of intravenous conscious sedation for patients undergoing minor procedures has increased in many settings throughout health care. Recognizing this, managers are challenged to develop policies to standardize the quality of patient care delivery. Consumer interest and knowledge in health care has increased dramatically in the last few years. Their demands for decreased cost, increased technology, and quality of care have compelled health care organizations to adopt quality management models. Quality improvement teams were developed to look at processes crossing departmental boundaries. Teams facilitate dialogue, understanding, and knowledge, and use the scientific method to design, streamline, and improve processes. The authors share strategies for policy development using a 7-step quality improvement process with a multidisciplinary team approach.
Clinical Competence↗
Managing asthma with the adolescent.
Adolescents are at high risk for poor outcomes from asthma owing to lifestyle and developmental changes. Not only are its prevalence, morbidity, and mortality steadily increasing, but asthma is the most common chronic disease of adolescents and it can have a profound impact on every aspect of their lives. However, through a management approach based on education, environmental modification, self-monitoring, and medication, adolescents can take control of a disease that otherwise controls them. Step therapy based on the National Heart, Lung, and Blood Institute asthma severity classification scale indicates the use of inhaled anti-inflammatory agents as maintenance medications and bronchodilators as rescue medications, thus preventing exacerbations and intervening when they occur. Through clinician-patient comanagement, asthma can be controlled and adolescents' lives normalized.
Adolescent↗
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.
Aged↗
Experimental autoimmune nigral damage in guinea pigs.
An animal model of experimental autoimmune nigral damage (EAND) has been developed in guinea pigs by immunization with hybrid dopaminergic cells (MES 23.5). In such animals, loss of 40% of the substantia nigra (SN) neurons and damage to an additional 10% of SN neurons was associated with a 37-43% decrease of tyrosine hydroxylase (TH) activity and a 36% decrease of dopamine (DA) content in the nigral-striatum. Eight of the thirteen animals developed significant hypokinesia. The EAND model suggests that degeneration of dopaminergic neurons in SN can be caused by immune-mediated processes, which may help our understanding of the pathogenesis in Parkinson's disease.
Animals↗
[Thrombophilia and thrombogenic orthopedic surgery].
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Aged↗
[Salvaging of drained blood in orthopedic surgery].
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Blood Loss, Surgical↗
A single isocenter three-field breast irradiation technique using an empiric simulation and asymmetric collimator.
The treatment of abutting fields presents multiple difficulties, including problems of field overlaps or gaps, complexity of simulation, and the difficulties of daily setup and variation. Multiple techniques have been described for the treatment of the breast/chest wall and supraclavicular nodes using tangents and a matched supraclavicular field. The techniques described have used collimator angles, couch angles, and/or corner blocks in an attempt to match these fields with no overlap or gap. Some of these techniques required complex calculations or treatment devices to achieve a geometric match between fields. We describe a technique for treatment of breast and supraclavicular nodes that uses a single isocenter and requires asymmetric collimator jaws to give half-blocked fields. The simulation and setup are done empirically, with no complex calculations required. The daily setup and treatment can be done rapidly and reliably, with no extra equipment required. Custom blocks may be used to conform to the chest wall contour and decrease the amount of lung in the treatment fields.
Breast Neoplasms↗
20-year experience in childhood craniopharyngioma.
PURPOSE: The management of craniopharyngioma is controversial, and surgery alone is frequently advocated. The purpose of this study was to assess the long-term impact of various treatments in childhood craniopharyngioma. METHODS AND MATERIALS: Sixty-one children < or = 21 years of age at diagnosis were treated for craniopharyngioma at Children's Hospital and the Joint Center for Radiation Therapy in Boston from 1970 to 1990. The median age was 7.5 years (range 10 months-21 years). There were 33 females and 28 males. The median follow-up was 10 years (range 2-20.5 years). Neuroimaging was available for detailed review in 53. Nine children were treated with radiotherapy alone, 15 were treated with surgery alone, and 37 were treated with both surgery and radiotherapy. All patients in the radiotherapy and surgery plus radiotherapy groups were treated with megavoltage radiation with a median dose of 5464 cGy. RESULTS: All nine of the children treated with radiation therapy alone are alive; none have recurred. Nine of the 15 children treated with surgery alone have recurred (p = 0.007 Fisher exact test). Two are alive with disease, and seven are alive without disease after treatment at relapse with radiation therapy, surgery, or both. Seven of the 37 patients treated with surgery plus radiotherapy have recurred. Three of the seven patients are dead of disease, three patients are alive with disease, and one patient is alive without disease after further treatment. The 10-year actuarial overall survival was 91% for all patients. The 10-year actuarial freedom from progression for the surgery group was 31% compared with 100% for patients treated with radiation therapy only (log rank p = 0.01), and 86% for patients treated with surgery plus radiotherapy at diagnosis (p = 0.001). There were two treatment related deaths, both in the surgery plus radiotherapy group. A higher incidence of visual loss and diabetes insipidus was associated with the use of aggressive surgery. The size of the tumor at presentation correlated with an increased risk of recurrence; 5 of 6 patients with tumors > or = 5 cm experienced recurrences while only 6 of 30 recurred when the tumor was < 5 cm. CONCLUSIONS: Overall survival in childhood craniopharyngioma is excellent. However, patients treated with surgery alone have a significantly worse freedom from progression when compared to patients treated with surgery and radiation therapy or radiation therapy alone.
Actuarial Analysis↗
Perceptual and conceptual cueing in implicit and explicit retrieval.
Subjects saw or heard words in a list (e.g. limerick) and then took two successive tests. The first was a yes/no recognition test in which auditory/visual modality of test words was manipulated orthogonally to the study modality. The second test varied with experimental conditions: subjects produced words to either perceptual (fragment) cues (l- -e-ick) or conceptual cues (What name is given to a lighthearted five-line poem?), under either explicit or implicit retrieval instructions. The major findings were: (a) that regardless of the type of retrieval cue (perceptual or conceptual) the degree of dependency between recognition and cued recall was greater than that between recognition and implicit retrieval; and (b) that modality shifts adversely affected perceptually cued explicit and implicit retrieval, whereas they had no effect either on conceptually cued retrieval or on recognition. These results suggest that the memory system subserving, and the processes involved in, conceptual priming differ from those underlying recognition and perceptual priming.
Analysis of Variance↗