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Biomedical subjects

R N Tamura

Publications and source records attributed to R N Tamura.

At least 19 recordsLinked to original sources
PubMed2000

Comparing time to onset of response in antidepressant clinical trials using the cure model and the Cramer-von Mises test.

Currently available antidepressants have a delayed onset of action and there is considerable interest in developing new products which exhibit a shorter time to response. Previous authors have suggested using a cure model to characterize the time to response for the combination of the patients who respond and the patients who do not respond. In this paper, we use the cure model and propose a Cramer-von Mises statistic to compare the time to response distributions for patients who respond to therapy. The asymptotic null distribution of the statistic is derived. A bootstap procedure is also proposed for sample sizes typical in antidepressant clinical trials. Results of the simulation study suggest that for common designs and sample sizes used in such trials, the statistic has reasonable size and power properties as long as censoring is moderate.

Adrenergic beta-Antagonists↗
PubMed2000

Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.

BACKGROUND: Patients with Alzheimer disease (AD) commonly exhibit psychosis and behavioral disturbances that impair patient functioning, create caregiver distress, and lead to institutionalization. This study was conducted to assess the efficacy and safety of olanzapine in treating psychosis and/or agitation/aggression in patients with AD. METHODS: A multicenter, double-blind, placebo-controlled, 6-week study was conducted in 206 elderly US nursing home residents with AD who exhibited psychotic and/or behavioral symptoms. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/d of olanzapine. The primary efficacy measure was the sum of the Agitation/Aggression, Hallucinations, and Delusions items (Core Total) of the Neuropsychiatric Inventory-Nursing Home version. RESULTS: Low-dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo on the Core Total (-7.6 vs -3.7 [P<.001] and -6.1 vs -3. 7 [P =.006], respectively). Core Total improvement with olanzapine, 15 mg/d, was not significantly greater than placebo. The Occupational Disruptiveness score, reflecting the impact of patients' psychosis and behavioral disturbances on the caregiver, was significantly reduced in the 5-mg/d olanzapine group compared with placebo (-2.7 vs -1.5; P =.008). Somnolence was significantly more common among patients receiving olanzapine (25.0%-35.8%), and gait disturbance occurred in those receiving 5 or 15 mg/d (19.6% and 17.0%, respectively). No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. CONCLUSION: Low-dose olanzapine (5 and 10 mg/d) was significantly superior to placebo and well tolerated in treating agitation/aggression and psychosis in this population of patients with AD.

Aged↗
PubMed1999

Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol.

BACKGROUND: Tardive dyskinesia is important in the side-effect profile of antipsychotic medication. AIMS: The development of tardive dyskinesia was evaluated in patients treated with double-blind, randomly assigned olanzapine or haloperidol for up to 2.6 years. METHODS: Tardive dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS) and Research Diagnostic Criteria for Tardive Dyskinesia (RD-TD), it was defined as meeting RD-TD criteria at two consecutive assessments. The risk of tardive dyskinesia, the relative risk, incidence rate, and incidence rate ratio were estimated. RESULTS: The relative risk of tardive dyskinesia for the overall follow up period for haloperidol (n = 522) v. olanzapine (n = 1192) was 2.66 (95% CI = 1.50-4.70). Based on data following the initial six weeks of observation (during which patients underwent medication change and AIMS assessments as frequently as every three days), the one-year risk was 0.52% with olanzapine (n = 513) and 7.45% with haloperidol (n = 114). The relative risk throughout this follow-up period was 11.37 (95% CI = 2.21-58.60). CONCLUSION: Our results indicated a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol.

Antipsychotic Agents↗
PubMed1999

Changes in adverse events reported by patients during 6 months of fluoxetine therapy.

BACKGROUND: Although a period of 6 to 12 months of antidepressant therapy is recommended for most patients with depression, systematic examinations of the course of adverse events over time, the resolution of early-onset events, and the possible emergence of later-onset events are limited. We examined the safety of fluoxetine, 20 mg/day, in a large, prospective, long-term treatment trial, and we report a comparison of early- and late-onset adverse events and the course of adverse events over 26 weeks of treatment. METHOD: Adverse events were recorded at each visit in a uniform format by open-ended questioning, regardless of perceived causality. New or worsened events reported in either the first 4 weeks of treatment (early-reporting interval) or weeks 22 through 26 of treatment (late-reporting interval) were compared. RESULTS: Patients (N = 299) whose depression (DSM-III-R) remitted with 12 weeks of fluoxetine treatment entered continuation therapy, and 174 completed 26 weeks of therapy. All events that occurred in > or =5% of patients early in treatment decreased in frequency over time (p<.05), and no events occurred significantly more frequently during continuation therapy. No previously uncommon adverse events became common during long-term treatment. CONCLUSION: Common adverse events associated with initiating fluoxetine treatment in depressed patients, including nausea, insomnia, nervousness, and somnolence, resolve in the majority of patients and become significantly less frequent with continued treatment over a 6-month period. No adverse events present initially become more frequent late in treatment. Therapy with fluoxetine, 20 mg/day, is well tolerated over 6 months, and most adverse events observed early in treatment resolve.

Anxiety↗
PubMed1998

Analysis of homogeneity of treatment effect in adaptive multicenter clinical trials.

In this paper, an exact test for analyzing the homogeneity of treatment effect in adaptive multicenter clinical trials is proposed. Extensive simulation studies are performed to investigate the large sample behavior of a commonly used test statistic for testing homogeneity of treatment effect. When the sample size in each center is large relative to the number of centers, the asymptotic null distribution of the test statistic is reasonable. On the other hand, when the data are relatively sparse, the proposed exact test should be used to incorporate the adaptive nature of the design.

Algorithms↗
PubMed1998

Outcome assessment and clinical improvement in panic disorder: evidence from a randomized controlled trial of fluoxetine and placebo. The Fluoxetine Panic Disorder Study Group.

OBJECTIVE: Although panic attacks account for only a portion of the morbidity of panic disorder and panic attack frequency assessments are unreliable, studies of drug efficacy in panic disorder have generally used reduction in panic attack frequency as the primary measure of improvement. The authors studied the efficacy of fluoxetine treatment in panic disorder and measured the relative contributions of changes in symptoms to overall improvement. METHOD: Patients with a diagnosis of panic disorder (N = 243) were randomly assigned to treatment with 10 or 20 mg/day of fluoxetine or placebo. Primary outcome measures were change in panic attack frequency and clinician-rated Clinical Global Impression improvement scores. Other assessments included a panic attack inventory, clinician-rated and patient-rated versions of the Panic and Phobic Disorder Change Scale, a phobia rating scale, the Hamilton Anxiety Rating Scale, the 21-item Hamilton Depression Rating Scale, and the Sheehan Disability Scale. Correlations were determined between outcomes in individual symptom domains and overall clinical outcome. RESULTS: Fluoxetine, particularly the 20-mg/day dose, was associated with more improvement than was placebo in patients with panic disorder across multiple symptom measures, including global improvement, total panic attack frequency, phobic symptoms, and functional impairment. Global improvement was most highly correlated with reductions in overall anxiety and phobic symptoms and least correlated with reduction in panic attacks. Fluoxetine treatment for panic disorder was well tolerated, with a safety profile consistent with that observed for fluoxetine in other disorders. CONCLUSIONS: These data provide support for the efficacy and safety of fluoxetine treatment in reducing panic attacks, phobic symptoms, anxiety, and depressive symptoms in patients with panic disorder. Reductions in panic attack frequency in subjects given either fluoxetine or placebo were less closely related to overall clinical improvement than reductions in phobic avoidance, anxiety, depressive symptoms, and functional impairment, suggesting that outcome measures in this disorder should be more broadly based.

Adult↗
PubMed1997

Coating of titanium alloy with soluble laminin-5 promotes cell attachment and hemidesmosome assembly in gingival epithelial cells: potential application to dental implants.

The formation of a biological seal around the transmucosal portion of dental implants may be crucial for the long-term success of these therapies. Data to date suggest that the gingival epithelium attaches to dental implants through the formation of hemidesmosomes. Biochemical and genetic data indicate that the laminin isoform, laminin-5, a component of basement membranes, plays a crucial role in the assembly and maintenance of hemidesmosomes. We report the use of soluble laminin-5 as a biological coating of titanium-alloy to promote cell attachment of the gingival epithelial cell line, IHGK. Monoclonal antibodies reactive with laminin-5 depleted the coating solution of all cell attachment activity and blocked cell attachment to laminin-5-coated disks. Immunodepletion with antibodies to fibronectin had no effect. Finally, we demonstrate that IHGK cells assembled hemidesmosomes within 24 h of attachment to laminin-5-coated titanium alloy but not to the titanium alloy alone. These results suggest that soluble laminin-5 may have clinical applications as a dental implant coating to promote the formation of a biological seal.

Alloys↗
PubMed1997

Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial.

OBJECTIVE: This international, multicenter double-blind trial was designed to compare the therapeutic profile of an atypical antipsychotic, olanzapine, with that of a conventional dopamine D2 antagonist, haloperidol. METHOD: A total of 1,996 patients at 174 sites in Europe and North America were randomly assigned to treatment with olanzapine (N = 1,336) or haloperidol (N = 660) over 6 weeks. The primary efficacy analysis involved the mean change from baseline to endpoint in total scores on the Brief Psychiatric Rating Scale (BPRS). Secondary analyses included comparisons of the mean change in positive and negative symptoms, comorbid depression, extrapyramidal symptoms, and overall drug safety. RESULTS: Olanzapine demonstrated clinical results superior to those of haloperidol on overall improvement according to the BPRS and on every secondary measure, including depression. Olanzapine was also associated with significantly fewer discontinuations of treatment due to lack of drug efficacy or adverse events. Substantially more olanzapine-treated patients (66.5%) than haloperidol-treated patients (46.8%) completed 6 weeks of therapy. Statistically significant advantages of olanzapine treatment were related to 1) change in negative symptoms, 2) extrapyramidal symptom profile, 3) effect on prolactin levels, and 4) response rate. CONCLUSIONS: Olanzapine shows a superior and broader spectrum of efficacy in the treatment of schizophrenic psychopathology, with a substantially more favorable safety profile, than haloperidol. It meets several of the criteria for a novel atypical antipsychotic agent.

Adolescent↗
PubMed1997

Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol.

OBJECTIVE: Tardive dyskinesia is a serious and common complication of neuroleptic treatment. Olanzapine is a novel antipsychotic agent exhibiting regional mesolimbic dopaminergic selectivity and a broad-based pharmacology encompassing serotonin, dopamine, muscarinic, and adrenergic receptor binding affinities. The authors' goal was to compare the incidence of tardive dyskinesia among patients receiving olanzapine and those receiving the conventional dopamine 2 antagonist haloperidol. METHOD: Data were analyzed from three actively controlled and blind long-term responder studies of subjects meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder treated with olanzapine (N = 707, up to 20 mg/day, 237 median days of exposure) or haloperidol (N = 197, up to 20 mg/day, 203 median days of exposure) who did not have evidence of tardive dyskinesia at baseline. All of the subjects had a chronic disease course (mean greater than 10 years), and there were no significant between-treatment group differences in demographic or disease characteristics. The Abnormal Involuntary Movement Scale and research diagnostic criteria for tardive dyskinesia were used to define the comparative incidence rates of long-term treatment-emergent tardive dyskinesia. RESULTS: The incidence of newly emergent tardive dyskinesia at any visit after baseline, at the final visit, and at the final two clinical assessments was statistically significantly lower among olanzapine-treated patients than among haloperidol-treated patients. CONCLUSIONS: These findings support an atypical extrapyramidal symptom profile and the potential of a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol among patients requiring maintenance antipsychotic treatment.

Adult↗
PubMed1996

Using the proportional odds model to assess the relationship between a multi-item and a global item efficacy scale in a psychiatric clinical trial.

The proportional odds model is illustrated in the analysis of two efficacy scales used in a phase II clinical trial involving 81 schizophrenic patients. The proportional odds model preserves the discrete, ordinal nature of one of the scales. The analysis of this data suggested that the relationship between the two scales is not captured by a linear proportional odds model. A linear model and a piecewise linear model for the explanatory variable were therefore compared using likelihood-based analyses. Residuals from both models were compared. Predicted probabilities for the ordinal categories were constructed from the estimated model. Extensions and limitations of the model for interpretation of other trials and for the planning of future trials are discussed.

Antipsychotic Agents↗
PubMed1995

Rapid spreading and mature hemidesmosome formation in HaCaT keratinocytes induced by incubation with soluble laminin-5r.

HaCaT cells, an immortalized keratinocyte line, incubated in plastic wells in the presence of conditioned medium from 804G cells adhered and spread rapidly in less than 30 min. In contrast, cells plated in fibroblast or keratinocyte conditioned medium adhered poorly and remained rounded at 30 min. Immunodepletion of 804G conditioned medium with polyclonal antisera to laminin-5r, but not control antisera, abolished rapid cell spreading. Electron microscopy of HaCaT cells spread by incubation in 804G conditioned medium, but not control medium, revealed mature hemidesmosomes after 24 h. Rapid spreading was also observed in wells precoated with 804G conditioned medium or 804G cell-deposited matrix, but not with fibronectin, vitronectin, or laminin-1. Immunoblotting of 804G conditioned medium with anti-laminin-5r antibodies unveiled polypeptides of 150, 140, 135, and 100 kDa, identical by electrophoretic mobility to immunoreactive polypeptides in 804G deposited matrix. Our results suggest that addition of laminin-5r in a soluble form is sufficient to promote rapid spreading and hemidesmosome assembly in keratinocytes. The mechanism of soluble laminin-5r action may include efficient surface "priming" for cell adhesion. Soluble laminin-5r may have a physiologic role in morphogenesis and repair of the epidermis and may be of use for therapeutic applications.

Animals↗
PubMed1994

Quantitative measurement of alpha 6 beta 1 and alpha 6 beta 4 integrin internalization under cross-linking conditions: a possible role for alpha 6 cytoplasmic domains.

In epithelial cells integrins are segregated on discrete domains of the plasma membrane. Redistribution may also occur during migration or differentiation. However, little is known about the mechanisms that control such redistribution. Receptor internalization may be a part of one such mechanism. We developed a quantitative assay and measured internalization of two epithelial integrin heterodimers, alpha 6 beta 1 and alpha 6 beta 4, induced by cross-linking with specific antibodies. alpha 6 beta 1 is a receptor for EHS laminin, while alpha 6 beta 4 is a receptor for a component of the basement membrane. alpha 6 beta 4 plays an important role in the establishment of hemidesmosomes, and becomes redistributed on the epithelial cell surface when cells are in a migratory phase. We report that alpha 6 beta 4 is efficiently internalized in human keratinocytes. More than 25% of cell surface alpha 6 beta 4 was internalized at 30 minutes, after cross-linking with A9, an anti-beta 4 monoclonal antibody. alpha 6 beta 1 is also internalized, in melanoma and teratocarcinoma cells, with maximum values of 20% of total receptors expressed at the cell surface. No significant difference was observed between the alpha 6 isoforms A and B in these assays. To determine whether alpha 6 cytoplasmic domains could influence integrin endocytosis, we prepared chimeric constructs with the extracellular domain of a reporter protein (CD8), and the cytoplasmic domains of either alpha 6 A or alpha 6 B. Both alpha 6 cytoplasmic domains but not a control cytoplasmic domain promoted internalization of the chimeric proteins, after cross-linking with antibody. Internalization of alpha 6 integrins may have a role in redistributing these receptors at the cell surface. Furthermore, the cytoplasmic domains of alpha 6 may be involved in regulating integrin internalization.

Animals↗
PubMed1993

Constrained randomization in a therapeutic efficacy trial.

The use of valid constrained randomization is presented for a therapeutic efficacy trial. The construction and evaluation of randomization schemes are studied for two treatment replicates per block and for hypothesized linear gradients. Two different isomorphism classes of designs are compared using the variance of the mean squared error criterion. The results indicate that valid constrained randomization schemes can be constructed that are superior to ordinary randomization. A mastitis efficacy trial provided the specific problem to be solved.

Animals↗
PubMed1991

Cell type-specific integrin variants with alternative alpha chain cytoplasmic domains.

The integrin heterodimers composed of the alpha 6 subunit with the beta 1 or beta 4 subunit (alpha 6 beta 1 and alpha 6 beta 4) are receptors for laminin and basement membrane components, respectively. The alpha 3 beta 1 integrin recognizes laminin, collagen, fibronectin, or epiligrin. We report the identification of structural variants (A and B) of the alpha 6 and alpha 3 subunits, containing distinct cytoplasmic domains. The expression of one cytoplasmic domain or the other, based probably on alternative exon usage, is cell-type dependent. Most transformed cell lines express both alpha 6A and alpha 6B isoforms, as determined by mRNA amplification or antibody immunoprecipitation. In contrast, embryonic fibroblasts express exclusively alpha 6A, and embryonic stem cells express exclusively alpha 6B. In most normal tissues, both alpha 6 isoforms are detectable, but several tissues express either alpha 6A or alpha 6B. The alpha 3B mRNA was amplified from heart and brain, while all other tissues and cell lines tested contained only alpha 3A mRNA. Alternative cytoplasmic domains may provide a means for varying the cellular responses to the ligands of alpha 6 and alpha 3 integrins according to the cell type.

Amino Acid Sequence↗
PubMed1991

Comparison of the immunogenicity of recombinant and pituitary human growth hormone in rhesus monkeys.

The relative concentrations of antibodies produced in monkeys against three forms of human growth hormone (hGH) were determined using an antigen-specific avidin/biotin ELISA assay. Monkeys were treated in two separate 90-day studies with recombinant methionyl-hGH (met-hGH) and pituitary-derived hGH (pit-hGH) (Study 1) and recombinant natural sequence hGH (Study 2). The lowest dose was equal to the expected therapeutic dose of 0.1 IU/kg. Sixty-nine percent of monkeys treated with pit-hGH and 81% of those treated with met-hGH developed detectable anti-hGH responses. The magnitudes of the responses exhibited wide animal to animal variability, were not markedly related to dose or sex, and were lower than levels obtained in monkeys immunized with hGH in Freund's adjuvant. In contrast, the incidence of antibody responses in monkeys treated with natural sequence hGH was lower (23% in one experiment and 5% in a replicate experiment) and took longer to develop. Antibody concentrations were lower, on average, than in those animals treated with met- or pit-hGH. These results are in accord with those observed clinically, thus supporting the use of the monkey model to predict the relative immunogenicity of some proteins in humans.

Animals↗
PubMed1991

Cardiovascular and adrenal proliferative lesions in Fischer 344 rats induced by long-term treatment with type III phosphodiesterase inhibitors (positive inotropic agents), isomazole and indolidan.

Male and female Fischer 344 rats were treated with the positive inotropic agents, isomazole or indolidan, in the diet for 104 weeks. The doses were 0.0, 11.5, 23.5, or 48.0 mg/kg and 0.0, 0.12, 0.40, or 1.3 mg/kg, respectively. Only 17% of the males treated with 48.0 mg/kg isomazole survived the duration of the study. The male component of the indolidan study was terminated at 22 months, with only 18% of the high-dose males surviving. Sixty-five percent of the males treated with 48.0 mg/kg isomazole and 70% of the males treated with 1.3 mg/kg indolidan were found to have severe periarteritis, often with thrombi located mainly in the mesenteric arteries. Fifty-four percent of the male rats treated with 48.0 mg/kg isomazole and 55% of the male rats treated with 1.3 mg/kg indolidan died from cardiovascular disease compared to 1-2% among the control males. Animals in the low- and middle-dose groups of both studies had a lower incidence of cardiovascular disease than did those in the high-dose group. Additional lesions associated with the long-term administration of both drugs were markedly increased incidence of adrenal medullary proliferative lesions (both hyperplasia and pheochromocytomas) and increased incidence of chronic progressive glomerulonephrosis. These lesions, like those in the cardiovascular system, occurred in a dose-dependent manner and were more frequent in males than in females. Treatment-related effects in these studies were judged to be related to the pharmacologic action of these compounds.

Adrenal Gland Neoplasms↗
PubMed1991

Target organ toxicity and leukopenia in Fischer 344 rats given intravenous doses of vinblastine and desacetyl vinblastine.

The toxicity and leukopenia produced by vinblastine or desacetyl vinblastine were established in 1-month studies in rats. Groups of male Fischer 344 rats were given weekly intravenous doses of vinblastine or desacetyl vinblastine at doses of 0.08, 0.16, 0.32, 0.64, or 1.28 mg/kg. The target organ toxicity was similar for both compounds. Decreased cell production in the thymus, testes, and bone marrow was produced in the animals of the two highest dose groups for both compounds with the degree of severity greater in the highest dose group. All high dose rats (1.28 mg/kg) given desacetyl vinblastine and three rats given vinblastine died prior to study termination. Body weight loss was more pronounced in high dose rats given desacetyl vinblastine, but at lower doses there were no significant differences in body weight reduction for rats receiving either compound. Leukopenia occurred at all dose levels of 0.32 mg/kg and higher. During the first 2 weeks of the study, rats given 1.28 mg/kg of desacetyl vinblastine had a greater leukopenic response than rats given 1.28 mg/kg of vinblastine. It is concluded that both compounds produced similar target organ toxicity and leukopenia without deaths at doses of 0.32 and 0.64 mg/kg given once a week for 4 weeks. At the high dose (1.28 mg/kg) desacetyl vinblastine was more toxic than vinblastine resulting in greater mortality and body weight reduction.

Animals↗