Patient satisfaction with eletriptan in the acute treatment of migraine in primary care.

OBJECTIVE: The efficacy of triptans for acute migraine has been well established in clinical trials but not in primary care, where they are most commonly prescribed. The aim of this open-label study was to evaluate the effectiveness of eletriptan 40 mg in primary care, using a patient-weighted satisfaction scale. METHODS: Eligible patients met International Headache Society criteria for migraine, with 1-6 attacks per month. Patients completed questionnaires at screening and following a single eletriptan-treated attack. Treatment satisfaction was evaluated using a six-item Medication Satisfaction Questionnaire (MSQ). MSQ item scores were weighted, based on the important score ratings, to yield individualised satisfaction scores. The primary end-point was the difference in weighted satisfaction scores between the patient's previous treatment and eletriptan 40 mg. Secondary end-points assessed quality of life (QOL), functioning and efficacy of treatment. RESULTS: Of 590 patients screened, 437 completed the study. Degree (95.2%), time (88.8%) and duration (83.8%) of headache pain relief were rated as most important by patients. The mean (+/-SD) total satisfaction score on the MSQ was higher for eletriptan than previous therapy (2.2 +/- 3.0 vs. 0.6 +/- 2.4; p < 0.001). The high level of satisfaction with eletriptan vs. previous treatment reflects the improvements in QOL and functioning observed, and the high headache and pain-free response rates. CONCLUSIONS: Patient-weighted satisfaction with eletriptan 40 mg was higher than with previous treatment for all items. The use of patient-weighted importance ratings of satisfaction is a promising approach for establishing effectiveness of treatment in primary care.

Eletriptan in the early treatment of acute migraine: influence of pain intensity and time of dosing.

This double-blind, placebo-controlled study was designed to evaluate the efficacy and tolerability of early treatment of a single migraine attack, when headache pain was mild, with two doses (20 mg and 40 mg) of eletriptan. Patients (N = 613; female 79%; mean age 39 years) meeting International Headache Society criteria for migraine were encouraged, but not required, to utilize early treatment, thus providing an opportunity to assess the relative contribution to efficacy of pain severity and timing of dose. For the total patient sample (mild-to-severe headaches), 2-h pain-free rates were significantly higher than placebo (22%) on both eletriptan 20 mg (35%; P < 0.01) and eletriptan 40 mg (47%; P < 0.0001). For the cohort of patients who treated their headache when the pain intensity was mild, the 2-h pain-free rate on eletriptan 40 mg was 68% compared with 25% on placebo (P < 0.0001). Pain intensity at the time of taking eletriptan appeared to influence outcome more than the timing of the dose relative to headache onset. Eletriptan was well-tolerated, with adverse event rates similar to placebo when mild headaches were treated.

Comparative efficacy of eletriptan and zolmitriptan in the acute treatment of migraine.

Eletriptan 40 mg and 80 mg have shown greater efficacy in acute migraine than oral sumatriptan 100 mg and naratriptan 2.5 mg. This study continues the systematic series of active comparator trials in the eletriptan clinical development programme. In a multicentre double-blind, double-dummy, parallel-groups trial, 1587 outpatients with migraine by IHS criteria were randomised in a 3: 3 : 3: 1 ratio to eletriptan 80 mg, eletriptan 40 mg, zolmitriptan 2.5 mg or placebo. Of these, 1312 treated a single migraine attack and recorded baseline and outcome data to be included in the intention-to-treat population. The primary analysis was between eletriptan 80 mg and zolmitriptan. For the primary efficacy end-point of 2-h headache response, rates were 74% on eletriptan 80 mg, 64% on eletriptan 40 mg, 60% on zolmitriptan (P < 0.0001 vs. eletriptan 80 mg) and 22% on placebo (P < 0.0001 vs. all active treatments). Eletriptan 80 mg was superior to zolmitriptan on all secondary end-points at 1, 2 and 24 h, in most cases with statistical significance. Eletriptan 40 mg had similar efficacy to zolmitriptan 2.5 mg in earlier end-points, and significantly (P < 0.05) lower recurrence rate and need for rescue medication over 24 h. All treatments were well tolerated; 30-42% of patients on active treatments and 40% on placebo reported all-causality adverse events that were mostly mild and transient. On patients' global ratings of treatment, both eletriptan doses scored significantly better than zolmitriptan.

Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway.

Metastases from prostatic adenocarcinoma (prostate cancer) are characterized by their predilection for bone and typical osteoblastic features. An in vitro model of bone metastases from prostate cancer was developed using a bicompartment coculture system of mouse osteoblasts and human prostate cancer cells. In this model, the bone-derived prostate cancer cell lines MDA PCa 2a and MDA PCa 2b induced a specific and reproducible increase in osteoblast proliferation. Moreover, these cells were able to induce osteoblast differentiation, as assessed by increased alkaline phosphatase activity, Osteocalcin expression, and calcified matrix formation. This osteoblastic reaction was confirmed in vivo by intrafemoral injection of MDA PCa 2b cells into severe combined immunodeficiency disease mice. In contrast, the highly undifferentiated, bone-derived human prostate cancer cell line PC3 did not produce an osteoblastic reaction in vitro and induced osteolytic lesions in vivo. The osteoblast differentiation induced by MDA PCa 2b cells was associated with up-regulation of the osteoblast-specific transcriptor factor Cbfa1. Moreover, treatment of osteoblasts with conditioned medium obtained from MDA PCa 2b cells resulted in up-regulation of Cbfa1 and Osteocalcin expression. In support of the differentiation studies, a microarray analysis showed that primary mouse osteoblasts grown in the presence of MDA PCa 2b cells showed a shift in the pattern of gene expression with an increase in mRNA-encoding Procollagen type I and Osteopontin and a decrease in mRNA-encoding proteins associated with myoblast differentiation, namely myoglobin and myosin light-chain 2. Taken together, these findings suggest that the bone-derived prostate cancer cells MDA PCa 2a and MDA PCa 2b promote differentiation of osteoblast precursors to an osteoblastic phenotype through a Cbfa1-dependent pathway. These results also established that soluble factors produced by prostate cancer cells can induce expression of osteoblast-specific genes. This in vitro model provides a valuable system to isolate molecules secreted by prostate cancer cells that favor osteoblast differentiation. Moreover, it allows to screen for therapeutic agents blocking the osteoblast response to prostate cancer.

Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a common illness associated with significant disability. Few large, placebo-controlled trials have been reported. METHODS: Outpatients with a DSM-III-R diagnosis of moderate-to-severe PTSD were randomized to 12 weeks of double-blind treatment with either sertraline (N = 100) in flexible daily doses in the range of 50 to 200 mg or placebo (N = 108). Primary outcome measures consisted of the Clinician-Administered PTSD Scale (CAPS-2) total severity score, the patient-rated Impact of Event Scale (IES), and the Clinical Global Impression-Severity (CGI-S) and -Improvement (CGI-I) ratings. RESULTS: Mixed-effects analyses found significantly steeper improvement slopes for sertraline compared with placebo on the CAPS-2 (t = 2.96, P =.003), the IES (t = 2.26, P =.02), the CGI-I score (t = 3.62, P<.001), and the CGI-S score (t = 4.40, P<.001). An intent-to-treat end-point analysis found a 60% responder rate for sertraline and a 38% responder rate for placebo (chi(2)(1) = 8.48, P =.004). Sertraline treatment was well tolerated, with a 9% discontinuation rate because of adverse events, compared with 5% for placebo. Adverse events that were significantly more common in subjects given sertraline compared with placebo consisted of insomnia (35% vs 22%), diarrhea (28% vs 11%), nausea (23% vs 11%), fatigue (13% vs 5%), and decreased appetite (12% vs 1%). CONCLUSION: The results of the current study suggest that sertraline is a safe, well-tolerated, and significantly effective treatment for PTSD.

Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial.

CONTEXT: Despite the high prevalence, chronicity, and associated comorbidity of posttraumatic stress disorder (PTSD) in the community, few placebo-controlled studies have evaluated the efficacy of pharmacotherapy for this disorder. OBJECTIVE: To determine if treatment with sertraline hydrochloride effectively diminishes symptoms of PTSD of moderate to marked severity. DESIGN: Twelve-week, double-blind, placebo-controlled trial preceded by a 2-week, single-blind placebo lead-in period, conducted between May 1996 and June 1997. SETTING: Outpatient psychiatric clinics in 8 academic medical centers and 6 clinical research centers. PATIENTS: A total of 187 outpatients with a Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition diagnosis of PTSD and a Clinician Administered PTSD Scale Part 2 (CAPS-2) minimum total severity score of at least 50 at baseline (mean age, 40 years; mean duration of illness, 12 years; 73% were women; and 61.5% experienced physical or sexual assault). INTERVENTION: Patients were randomized to acute treatment with sertraline hydrochloride in flexible daily dosages of 50 to 200 mg/d, following 1 week at 25 mg/d (n=94); or placebo (n=93). MAIN OUTCOME MEASURES: Baseline-to-end-point changes in CAPS-2 total severity score, Impact of Event Scale total score (IES), and Clinical Global Impression-Severity (CGI-S), and CGI-Improvement (CGI-I) ratings, compared by treatment vs placebo groups. Results Sertraline treatment yielded significantly greater improvement than placebo on 3 of the 4 primary outcome measures (mean change from baseline to end point for CAPS-2 total score, -33.0 vs -23.2 [P =.02], and for CGI-S, -1.2 vs -0.8 [P=.01]; mean CGI-I score at end point, 2.5 vs 3.0 [P=.02]), with the fourth measure, the IES total score, showing a trend toward significance (mean change from baseline to end point, -16.2 vs -12.1; P=.07). Using a conservative last-observation-carried-forward analysis, treatment with sertraline resulted in a responder rate of 53% at study end point compared with 32% for placebo (P=.008, with responder defined as >30% reduction from baseline in CAPS-2 total severity score and a CGI-I score of 1 [very much improved], or 2 [much improved]). Significant (P<.05) efficacy was evident for sertraline from week 2 on the CAPS-2 total severity score. Sertraline had significant efficacy vs placebo on the CAPS-2 PTSD symptom clusters of avoidance/numbing (P=.02) and increased arousal (P=.03) but not on reexperiencing/intrusion (P=.14). Sertraline was well tolerated, with insomnia the only adverse effect reported significantly more often than placebo (16.0% vs 4.3%; P=.01). CONCLUSIONS: Our data suggest that sertraline is a safe, well-tolerated, and effective treatment for PTSD.

Prognostic biomarker study in pathologically staged N1 non-small cell lung cancer.

PURPOSE: The prognostic influence of 6 biomarkers correlated to histologic subtypes of non-small cell lung cancer (NSCLC) on loco-regional control, overall survival, disease-free survival (DFS), and distant disease control (DDC) rates, all measured at 5 years, were examined. MATERIALS & METHODS: Cell blocks from the primary tumors of 137 patients with pathologically staged N1 NSCLC at MDACC were analyzed by 6-biomarker status correlated to histological subtypes and their outcomes. RESULTS: The ranges of biomarker values were as follows: apoptotic index, 0.2-2.8%; mitotic index, 0-1.8%; the proportion of cells in S+G2M, 3-36%; p53 status, 0-100%; Ki-67, 0-9.3%; DNA index, 1.0-2.74. Subtypes of 137 cases from the postoperative pathology specimen showed that 74 patients had squamous carcinoma and 63 patients had adenocarcinoma. Mean and median lengths of follow-up were 4.21 years and 2.43 years, respectively. Patients with squamous cell carcinoma (SCC) had a better 5-year survival (p = 0.006), DFS (p = 0.002), and distant metastasis control (p = 0.002) than patients with adenocarcinoma (AC). Among patients with AC, the DNA index was a significant predictor of 5-year DFS (p = 0.02), DDC rate (p = 0.04), and local-regional control (p < 0.05). Higher apoptosis (p = 0.03) and mitosis indices (p = 0.03) were also univariate predictors of increased distant disease among patients with AC. Multivariate analysis of patients with AC revealed that the DNA index and Ki-67 were the only significant independent predictors of distant metastasis (p < 0.04 and p < 0.02, respectively) and DFS (p < 0.04 for both). Among patients with SCC, univariate analysis showed that S+G2M proportion (p < 0.05) and Ki-67 levels (p < 0.02) were significant predictors for local-regional control; for SC, multivariate analysis showed that only mitosis was a significant predictor in this case for overall survival (p < 0.04). CONCLUSION: Spontaneous apoptotic index and Ki-67 were significantly higher in SC than in AC. Patients with SC had less distant metastasis better DFS and overall survival than those with AC. Multivariate analysis revealed that DNA index and Ki-67 status were significant predictors for DDC and DFS in patients with AC, but only mitotic index was a significant predictor of overall survival for patients with SCC.

Hypothalamic-pituitary-adrenal axis in psychiatric disorders.

Hypothalamic-pituitary-adrenocortical (HPA) physiology is complex, and dysregulation of this neuroendocrine axis cannot be characterized adequately by isolated or unintegrated measures. Repeated assessments over time, involving multiple measures of axis activity (basal and dynamic tests), have furthered our understanding of the character of the HPA abnormalities reported in various psychiatric disorders. We review the nature and clinical significance of these HPA disturbances in the affective disorders and other psychiatric illnesses.

The influence of blood chemistry on T4 and FT4I in major depression.

The pathophysiology underlying thyroid dysfunction in some depressed patients has not yet been determined. In order to clarify possible biochemical influences on thyroid regulation in these patients, we retrospectively examined several thyroid indices in charts from 81 depressed inpatients and 82 psychiatric controls. The depressed group had significantly higher T4 levels and free T4 index (FT4I), as well as lower chloride (CL) levels than controls. Albumin (ALB) also tended to be higher in the depressives. After adjustment for previously reported effects of ALB and CL on thyroid hormone binding in plasma, the initial differences in thyroid indices became non-significant. We suggest from these findings that plasma biochemical factors contribute significantly to the transient changes in thyroid function observed in some acutely depressed patients. Potential explanations for these biochemical alterations are discussed.

The hypothalamic-pituitary-adrenocortical axis in major depression.

The clinical utility of the tests of hypothalamic-pituitary-adrenocortical function discussed in this article are still to be ascertained. As with the dexamethasone suppression test, reviewed elsewhere in this issue, the application of other basal and challenge tests have furthered our understanding of the character of observed hypothalamic-pituitary-adrenocortical function in psychiatric patients. Hypothalamic-pituitary-adrenocortical physiology is complex and plastic and cannot be understood in terms of oversimplified explanations or concepts. Repeated measures over time, involving multiple assessments of axis activity, are essential in understanding the modulating effects of prior activity of the system (induced by endogenous regulatory systems or by superimposed environmental stressors) on the current function of the various levels in this closed-loop axis, where all parts influence the function of the remainder. From such an appreciation and understanding of this system can come more simplified assessments of its function, which would allow application to clinical psychiatry.

The hypothalamic-pituitary-adrenocortical axis in major depression.

The clinical utility of the tests of hypothalamic-pituitary-adrenocortical function discussed in this article are still to be ascertained. As with the dexamethasone suppression test, reviewed elsewhere in this issue, the application of other basal and challenge tests have furthered our understanding of the character of observed hypothalamic-pituitary-adrenocortical function in psychiatric patients. Hypothalamic-pituitary-adrenocortical physiology is complex and plastic and cannot be understood in terms of oversimplified explanations or concepts. Repeated measures over time, involving multiple assessments of axis activity, are essential in understanding the modulating effects of prior activity of the system (induced by endogenous regulatory systems or by superimposed environmental stressors) on the current function of the various levels in this closed-loop axis, where all parts influence the function of the remainder. From such an appreciation and understanding of this system can come more simplified assessments of its function, which would allow application to clinical psychiatry.

Control of ingestion in 6-day-old rat pups: termination of intake by gastric fill alone?

Six-day-old rat pups, tested away from the dam, vigorously ingested orally infused milk for up to 90 min when the ingested milk was allowed to drain through a gastric fistula. Total intake in pups with unplugged fistulas was more than double that consumed by littermates with plugged fistulas. This persistent feeding could not be due to the absence of postgastric cues because blocking movement of the milk into the intestine with a closed pyloric noose resulted in less intake than when the noose was open. Furthermore, a 5% body weight gastric preload of milk or nonnutritive saline suppressed intake in pups with either open or closed pyloric nooses by an amount equal to the preload. Regardless of noose or preload condition, ingestion stopped when stomach content reached approximately 6.5% of body weight. Thus level of gastric fill appeared critical for intake control. When gastric fistulas were unplugged after pups had ingested milk until they stopped, vigorous ingestion followed, with total intakes of up to 20% body weight. Intake termination in young rat pups thus appears to be controlled exclusively by gastric fill level; pregastric signals alone appear insufficient, and postgastric signals appear unnecessary for termination of intake.