Gene-trap mutagenesis: past, present and beyond.

Although at least 35,000 human genes have been sequenced and mapped, adequate expression or functional information is available for only approximately 15% of them. Gene-trap mutagenesis is a technique that randomly generates loss-of-function mutations and reports the expression of many mouse genes. At present, several large-scale, gene-trap screens are being carried out with various new vectors, which aim to generate a public resource of mutagenized embryonic stem (ES) cells. This resource now includes more than 8,000 mutagenized ES-cell lines, which are freely available, making it an appropriate time to evaluate the recent advances in this area of genomic technology and the technical hurdles it has yet to overcome.

Phase II study of patients with metastatic nonsmall cell carcinoma of the lung treated with paclitaxel by 3-hour infusion.

BACKGROUND: Single-agent chemotherapy produces partial responses in the range of 7-27% in patients with Stage IV nonsmall cell lung carcinoma (NSCLC). Cisplatin-based combination regimens have achieved higher response rates but with significant toxicity. Two prior studies employing 24-hour infusions of paclitaxel showed responses of 21% and 24%. The purpose of this Phase II study was to determine the effects of paclitaxel administered by short duration infusions on response rate, toxicity, and quality of life (QOL) in patients with NSCLC. METHODS: Twenty patients with histologically proven Stage IV NSCLC were enrolled in this study. All were treated on an outpatient basis with standard premedication followed by paclitaxel 200 mg/m2 infused intravenously over 3 hours. Treatments were repeated every 21 days for a maximum of 6 cycles. RESULTS: The objective response rate was 6/19 (32%; 95% confidence interval, 13-57%). The median duration of response was 6.0 months (range, 2-13 months). The median survival of the entire group was 6.0 months (range, 2-24+ months), and the 1-year survival rate was 22%. Toxicity was mild, with only one hospitalization required for treatment of catheter-related thrombosis. Nonresponding patients were found to have worsening Functional Assessment of Cancer Therapy (FACT)-G and FACT-L scores. Because this was a small clinical study, it did not demonstrate consistent improvement in FACT-G or FACT-L in responding patients. CONCLUSIONS: Paclitaxel given as a 3-hour infusion is a well-tolerated, active single agent in the treatment of Stage IV NSCLC, worthy of further study. Baseline QOL scores predicted those more likely to respond to treatment, but changes in QOL status did not correlate well with objective response status.

Airway reactivity induced reversible voice dysfunction in singers.

As the power source for vocalization, the lower respiratory tract plays a key role in voice production. This is particularly true with sustained singing, where continued high ventilatory demands are present. Changes in pulmonary function that are insignificant with normal speech have been shown to lead to performance impairment. The purpose of this study was to examine and characterize this problem in a large group of singers. Systematic evaluation of a defined population, along with inhalational and singing challenge, was the design. The demographic characteristics, history, pulmonary function, and response to treatment were evaluated in 20 professional or serious amateur singers with voice problems, who did not have causal laryngeal pathology, whose history and evaluation suggested increased airway reactivity, and who responded to anti-asthma therapy. An additional patient was challenged by the exercise of singing in the office, with pulmonary function measurements before and after. This group of serious singers demonstrated vocalization complaints referable to bronchodilator responsive airway obstruction. They responded to treatment for asthma, with improvement in their performance-related difficulties. An additional subject demonstrated a small decline in expiratory flow rates with only 20 minutes of singing in the office. This was readily reversed by an inhaled bronchodilator. Singers who present with complaints of impaired vocalization, such as vocal fatigue, decreased control, and excessive muscular tension, should be evaluated for increased airway reactivity as a possible cause of their complaints.

The oral dose-effect relationship for fluvoxamine: a fixed-dose comparison against placebo in depressed outpatients.

This 7- to 8-week, multicenter, randomized, double-blind, placebo-controlled study was performed to determine the dose-effect relationship and minimum effective dose for fluvoxamine maleate in a titrated fixed-dose study of major depressive disorder. Gradual titration over 2 weeks to fixed maintenance doses was employed to minimize dropout due to initial side effects. The study enrolled 600 outpatients, male and female, age 18-65, meeting DSM-III-R criteria for major depressive disorder. A 13-item subscore of the standard 21-Item Hamilton Depression Scale was used to minimize the possible contribution of known side effects from serotonin reuptake inhibitors to the overall HAM-D score. Secondary efficacy assessments included the HAM-D retardation factor, HAM-D depressed mood item, CGI-severity of illness item, and SCL depression factor. Fluvoxamine (50-150 mg/day) was therapeutically effective and well tolerated during 6 weeks of therapy. Based on the HAM-D depressed mood item, efficacy was dose dependent. The minimum effective dose was 50 mg/day. Fluvoxamine maleate shows dose-related effectiveness in the acute treatment of major depressive disorder.

A fixed-dose study of adinazolam-SR tablets in generalized anxiety disorder.

1. This four-week, randomized, double-blind, multicenter study compared the efficacy and safety of adinazolam-SR, at three dosage levels, with placebo. Forty (40) patients were randomized at our site: 10 to adinazolam 30 mg/day, 10 to 60 mg/day, 10 to 90 mg/day, and 10 to placebo. All patients were moderately anxious with Hamilton Anxiety Scale (HAM-A) scores of > or = 21 at baseline. 2. The data were analyzed by pooling the three adinazolam groups and comparing them with the placebo group using t-tests. HAM-A scores decreased significantly more in the pooled adinazolam-SR treatment group than in the placebo group at both Week one (p < .02) and at Week two (p < .01), as well as at endpoint (p < .03). 3. At endpoint the adinazolam-treated group included 8 "responders" (> or = 50% reduction on the baseline HAM-A score) while none of the placebo patients were responders (p < .05). Dose-response effects were evaluated and relationships were not statistically significant. 4. The results indicate that adinazolam-SR was clearly superior to placebo for the treatment of patients suffering from Generalized Anxiety Disorder.

A double-blind, placebo-controlled study comparing mianserin and amitriptyline in moderately depressed outpatients.

We report on the results of a study comparing mianserin with amitriptyline and placebo, in outpatients with major depression (DSM-III 296.2 or 296.3). One hundred and forty-nine patients were randomized to mianserin (n = 50), amitriptyline (n = 50) or placebo (n = 49). Medication was taken in a nightly (qhs) dose. During Week 1, the maximum dose was 60 mg mianserin, 120 mg amitriptyline or two placebo capsules. Beginning at Day 7 (through Day 42) maximum dosages were 150 mg mianserin, 300 mg amitriptyline or five placebo capsules. At multiple weeks and endpoint, statistically significant reductions in the Hamilton Depression Scale (HAM-D) 17- and 21-item scores were recorded for both active drugs compared with placebo. Positive results with the HAM-D were corroborated by other measures of efficacy. There were no statistically significant differences between mianserin and amitriptyline in terms of efficacy; however, the results do suggest a more rapid therapeutic response for mianserin compared with amitriptyline, in terms of percentage of patients showing > or = 50% improvement at Weeks 2 (30% vs 23%) and 4 (61% vs 44%). The most common adverse experiences were somnolence (amitriptyline and mianserin 60%, placebo 31%) and dry mouth (amitriptyline 76%, mianserin 30% and placebo 20%). Our results indicate that mianserin is clearly superior to placebo, compares favorably with amitriptyline, and is a safe, well-tolerated, effective medication in the treatment of depressed outpatients.

A study comparing paroxetine placebo and imipramine in depressed patients.

These data provide evidence for the antidepressant efficacy of paroxetine. Paroxetine- and imipramine-treated patients were significantly different from placebo-treated patients, but little different to each other, on all depressive outcome measures. However, paroxetine appeared to have a possibly greater and earlier beneficial effect on anxiety symptoms associated with depression, when compared with imipramine. Both active therapies were effective in treating patients with severe depression. Side effects for paroxetine were typical of other serotonin (5-HT) uptake inhibitors but different from those of imipramine. In particular, anticholinergic and cardiovascular symptoms were reduced, and premature withdrawal less likely.

Antidepressant efficacy and cardiac safety of trimipramine in patients with mild heart disease.

The antidepressant efficacy and cardiac safety of trimipramine were evaluated in 22 depressed patients with mild heart disease (New York Heart Association class I, II, or III) who received doses of 50 to 200 mg/day for 28 days. Efficacy was evidenced by a significant decrease from baseline in Hamilton Rating Scale for Depression scores. The only significant change from baseline in electrocardiographic, Holter monitor, myocardial function, or vital sign evaluations was a transient prolongation of the mean QRS interval. None of the adverse reactions involved the cardiovascular system. The results demonstrate that trimipramine is effective in the treatment of depression and is not likely to produce serious or harmful cardiovascular side effects in patients with mild heart disease.

Paroxetine in major depression: a double-blind trial with imipramine and placebo.

Paroxetine is a selective serotonin reuptake inhibitor which is being developed as an antidepressant. Previous studies suggest it is effective in the treatment of depression and has a low incidence of side effects. The authors report on a 6-week, randomized, prospective trial of paroxetine, imipramine, and placebo in 120 outpatients with major depression. The results showed that paroxetine was significantly superior to placebo in relieving depression. There were no significant differences in antidepressant efficacy between paroxetine and imipramine. However, paroxetine was also significantly superior to placebo on several measures of anxiety. Imipramine either was not superior on these measures or took longer to show a significant difference. Paroxetine lacked the typical anticholinergic side effects that accompanied imipramine therapy. The results show that paroxetine is an effective antidepressant that may have value especially when depression is accompanied by significant anxiety.

Two combined, multicenter double-blind studies of paroxetine and doxepin in geriatric patients with major depression.

Depressive illness among the elderly is an important public health concern. However, treatment of the elderly may be complicated by age-related changes in physiology, general medical status, and susceptibility to side effects. There is therefore a need for improved treatment modalities for depressed elderly patients. Paroxetine is an antidepressant that acts through selective inhibition of serotonin reuptake. It lacks the anticholinergic and cardiovascular side effects of most first- and second-generation antidepressants. The authors present the combined data from two similarly designed comparisons of paroxetine and doxepin in outpatients over 60 years of age with major depression. The results show that paroxetine was an effective as doxepin in alleviating depression as measured on the Hamilton Rating Scale for Depression (HAM-D) total score, the Montgomery and Asberg Depression Rating Scale (MADRS), and the Hopkins Symptom Checklist (SCL) depression factor score. Paroxetine was significantly superior to doxepin on the Clinical Global Impressions (CGI) scale for severity of illness, the HAM-D retardation factor, and the HAM-D depressed mood item. Doxepin produced significantly more anticholinergic effects, sedation, and confusion. Paroxetine was associated with more reports of nausea and headache. These results suggest that paroxetine may be a valuable tool for the treatment of major depression in the elderly.

Predictors of placebo response: a retrospective analysis.

This retrospective evaluation involved 197 patients from independent clinical investigations of four antidepressant medications. Six variables were analyzed for their discriminative utility in predicting placebo response rates: gender; marital status; age; education; duration of illness; and severity of depressive symptomatology, as measured by Hamilton Rating Scale for Depression (HAM-D or HDRS) scores. Men were slightly more responsive to placebo than were women (29.8%, n = 94 vs. 24.3%, n = 103). Married patients demonstrated the highest probability of a positive placebo response (38.15%, n = 76), as compared with widowed/separated/divorced (21.9%, n = 73) or single (16.7%, n = 48) patients. A trend toward an increased probability of placebo response was detected for patients aged 60 and above (35.7%, n = 14). Educational level achieved and duration of illness were not predictive. Severity of illness proved most noteworthy, with the placebo response rate higher in the more mild patients (40.8%, n = 27 vs. 23.4%, n = 77).

Use of buspirone in patients with generalized anxiety disorder and coexisting depressive symptoms. A meta-analysis of eight randomized, controlled studies.

This report presents the results of a retrospective analysis of pooled efficacy data from eight studies in which buspirone was compared to placebo in 520 patients with generalized anxiety disorder (GAD). In addition to evaluating overall efficacy in the composite patient data base, four criteria were used to identify subsets of patients with GAD who had coexisting depressive symptoms of at least moderate intensity: (1) a score of > or = 2 on the Hamilton Anxiety (HAM-A) Rating Scale item 6 (depressed mood), (2) a score of > or = 2 on the Hamilton Depression (HAM-D) Rating Scale item 1 (depressed mood), (3) a HAM-D total score of > or = 18, or (4) a HAM-D Retardation Factor value (items 1, 7, 8, and 14) greater than the median for the group. Overall, patients treated with buspirone demonstrated significant (p < or = 0.001) improvement over baseline in total HAM-A scores compared to patients who received placebo. Buspirone also produced significant (p < or = 0.001) global improvement compared to placebo as assessed by the attending physician. Of the GAD patients stratified according to the four criteria for coexisting depressive symptoms, a substantial percentage (44-64%) of the total patient sample exhibited significant depressive symptoms as part of their anxiety disorder. Patients with GAD and coexisting depressive symptoms of at least moderate intensity exhibited significantly greater improvement with buspirone compared to placebo treatment regardless of the stratification criterion used. They also responded at least as well or better to buspirone therapy as did those with GAD who had less intense depressive symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of paroxetine, imipramine and placebo in depressed out-patients.

To compare the safety and antidepressant efficacy of paroxetine, imipramine, and placebo, data from six centres using the same protocol were pooled. A double-blind parallel-group design was used, with therapy lasting six weeks. From week 2 onwards, both the 240 paroxetine-treated and the 237 imipramine-treated patients were significantly different from the 240 placebo-treated patients, but no different from each other. Side-effects with paroxetine were less likely to lead to drop-out than with imipramine. Paroxetine had a possible earlier antidepressant effect than imipramine, and a possible earlier beneficial effect on anxiety symptoms associated with depression.

Hypnotic efficacy of estazolam compared with flurazepam in outpatients with insomnia.

Estazolam is a new benzodiazepine hypnotic agent with an intermediate half-life of 12 to 15 hours. The authors designed an investigation to compare its hypnotic efficacy to that of flurazepam, generally considered the reference standard. The hypnotic efficacy of estazolam at two doses (1 mg and 2 mg) was compared with that of flurazepam (30 mg) in a double-blind, placebo-controlled, multicenter, 7-night study that involved 223 outpatients with insomnia. On subjective assessments of the patients, no differences were noted between estazolam 2 mg and flurazepam 30 mg on any of six sleep parameters. Patients who were receiving estazolam 1 mg rated their sleep significantly better than did patients who were receiving placebo on all parameters except sleep latency. Global evaluation of the physicians indicated significant improvement in quality of sleep, sleep depth, sleep duration, and nocturnal awakenings in all three active treatment groups; estazolam 2 mg and flurazepam also decreased sleep latency significantly. The percentage of patients who reported any adverse experience was 68% for flurazepam, 58% for estazolam 2 mg, and 54% for estazolam 1 mg; the incidence of adverse events in the placebo group was 43%. In conclusion, estazolam 2 mg was found to be as effective a hypnotic as flurazepam 30 mg. Estazolam 1 mg is also effective in the treatment of outpatients with insomnia, but to a lesser degree.

Development of an "early" detection battery for dementia of the Alzheimer type.

1. To develop a diagnostic battery sensitive to and specific for the early detection of Alzheimer disease (AD) dementia, the authors reviewed over 400 journal articles dealing with the diagnosis of A.D. or senile dementia and cognitive assessment in organic brain dysfunction and closed head injury. 2. We culled those studies that met our criteria for solid, reliable and statistically significant results and recommend the testing paradigms that most often produced good discrimination of mild AD dementia from normal senescence. 3. These include tests of language, verbal and non-verbal memory, perception, praxis, attention and reasoning. 4. The battery we assembled takes less than 1 hour to administer, requires no special equipment, and was designed as an early screen for use by psychologists, psychiatrists and other trained health care professionals; it is not intended for repeated administration, as in pharmacological or longitudinal studies.

Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients.

Two hundred forty-one elderly depressed patients entered the 8-week, double-blind phase of this parallel-group, multicenter study; 161 patients were randomized to receive sertraline (50-200 mg/day) and 80 were randomized to receive amitriptyline (50-150 mg/day). Among evaluable patients, there were no statistically significant differences between treatments in any of the primary efficacy variables: change in total Hamilton Rating Scale for Depression (HAM-D) score (17 items), percentage change in HAM-D score, change in HAM-D Item 1, change in Clinical Global Impressions (CGI) Severity score, change in the Depression Factor of the 56-item Hopkins Symptom Checklist, and the CGI Improvement score at the last visit. Similar results were obtained using data from all patients (intention-to-treat analysis), except that amitriptyline was superior in HAM-D Total score (p = .044). The two drugs produced a similar degree of response: on the basis of the HAM-D criterion, 69.4% of sertraline patients and 62.5% of amitriptyline patients responded, and, on the basis of CGI criterion, 79.5% of sertraline and 73.4% of amitriptyline patients responded. Twenty-eight percent of the sertraline patients withdrew from the study because of a treatment-related side effect and 2.5% (4) because of a laboratory abnormality. In comparison, 35% of the amitriptyline patients withdrew because of treatment-related side effects. Sertraline was associated with a statistically lower frequency of somnolence, dry mouth, constipation, ataxia, and pain and a higher frequency of nausea, anorexia, diarrhea/loose stools, and insomnia; thus, anticholinergic effects were less common and gastrointestinal effects were more common with sertraline than with amitriptyline.(ABSTRACT TRUNCATED AT 250 WORDS)

Allelic association of human dopamine D2 receptor gene in alcoholism.

In a blinded experiment, we report the first allelic association of the dopamine D2 receptor gene in alcoholism. From 70 brain samples of alcoholics and nonalcoholics, DNA was digested with restriction endonucleases and probed with a clone that contained the entire 3' coding exon, the polyadenylation signal, and approximately 16.4 kilobases of noncoding 3' sequence of the human dopamine D2 receptor gene (lambda hD2G1). In the present samples, the presence of A1 allele of the dopamine D2 receptor gene correctly classified 77% of alcoholics, and its absence classified 72% of nonalcoholics. The polymorphic pattern of this receptor gene suggests that a gene that confers susceptibility to at least one form of alcoholism is located on the q22-q23 region of chromosome 11.