Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam

BACKGROUND: Pregabalin inhibits release of excess excitatory neurotransmitters, presumably by binding to the alpha2-delta subunit protein of widely distributed voltage-dependent calcium channels in the brain and spinal cord. OBJECTIVE: To assess the anxiolytic efficacy of pregabalin in patients with generalized anxiety disorder. DESIGN: Double-blind, placebo-controlled, active-comparator trial. Patients were randomized to 4 weeks of treatment with pregabalin, 300 mg/d (n = 91), 450 mg/d (n = 90), or 600 mg/d (n = 89); alprazolam, 1.5 mg/d (n = 93); or placebo (n = 91). SETTING: Psychiatry research and clinic settings. PATIENTS: Outpatients meeting the DSM-IV criteria for generalized anxiety disorder, with a baseline Hamilton Anxiety Rating Scale (HAM-A) total score of 20 or greater. MAIN OUTCOME MEASURES: Change from baseline to end point in total HAM-A score in the pregabalin and alprazolam groups compared with the placebo group. The end point response criterion was 50% or greater reduction in the HAM-A total score. RESULTS: Pregabalin and alprazolam produced a significantly greater reduction in mean +/- SE HAM-A total score at last-observation-carried-forward end point compared with placebo (-8.4 +/- 0.8): pregabalin, 300 mg (-12.2 +/- 0.8, P<.001), 450 mg (-11.0 +/- 0.8, P = .02), and 600 mg (-11.8 +/- 0.8, P = .002), and alprazolam (-10.9 +/- 0.8, P = .02). By week 1 and at last-observation-carried-forward end point, the 3 pregabalin groups and the alprazolam group had significantly (P<.01) improved HAM-A psychic anxiety symptoms compared with the placebo group. Compared with the placebo group, HAM-A somatic anxiety symptoms were also significantly (P<.02) improved by the 300- and 600-mg pregabalin groups, but not by the 450-mg pregabalin (week 1, P = .06; week 4, P = .32) and the alprazolam groups (week 1, P = .21; week 4, P = .15). Of the 5 treatment groups, the 300-mg pregabalin group was the only medication group that differed statistically in global improvement at treatment end point not only from the placebo group but also from the alprazolam group. CONCLUSION: Pregabalin was significantly more efficacious than placebo for the treatment of psychic and somatic symptoms of generalized anxiety disorder and was well tolerated by most study patients.     

Justice and welfare: two ethical paradigms in forensic psychiatry

Forensic psychiatry, as a medical specialty, perhaps understandably leans toward beneficence or welfare as its main ethical underpinning. However, the special nature of the art or science of forensic psychiatry makes it imperative that beneficence is not the only ethical principle that guides the 'good' forensic psychiatrist. Indeed, the commonest ethical dilemmas in forensic psychiatry arise from a conflict between two ethical principles: beneficence, or promotion of welfare, and respect for justice. These two paradigms dominate discussions about the moral role and ethical duties of forensic psychiatrists and, in effect, give rise to two different practices in forensic psychiatry, each of which can also be said to have acquired a national identity. We discuss these competing principles and offer some thoughts about what this means for the ethics and values of forensic psychiatry.     

Re-organization of P2X3 receptor localization on epidermal nerve fibers in a murine model of cancer pain

To determine whether ATP and P2X3 receptors contribute to bone-cancer pain in a mouse model, immunohistochemical techniques were used to identify whether changes in the labeling of P2X3 receptors on epidermal nerve fibers (ENFs) occurred during tumor development. C3H mice were injected with osteolytic fibrosarcoma cells in and around the calcaneus bone. These mice exhibited mechanical hyperalgesia by day 10 post-implantation as assessed using von Frey monofilaments. Biopsies of the plantar skin overlying the tumor were obtained at days 10, 14, and 18 post-implantation. Confocal images were analyzed for the number of PGP 9.5, P2X3, and CGRP immunoreactive (ir) ENFs. The overall ENF population (PGP-ir) decreased progressively over time, whereas the subsets of P2X3-ir fibers demonstrated a modest increase and CGRP-ir nerve fibers remained fairly constant. Importantly, the proportion of CGRP-ir fibers that labeled for P2X3 increased from approximately 6% in control animals to nearly 30% at day 14 following tumor cell implantation. These studies demonstrate increased expression of P2X3 receptors on CGRP-ir ENFs during tumor growth and suggest a role for ATP in cancer-related pain.     

Emergency contraceptive pills in Sweden: evaluation of an information campaign

OBJECTIVE: To evaluate a community-based intervention regarding emergency contraceptive pills, including a mass media campaign and information to women visiting family planning clinics. DESIGN: Quasi-experimental. SETTING: Two counties in Sweden. POPULATION: Eight hundred randomly selected women aged 16-30 years, 400 women in the intervention group and 400 in a comparison group. METHODS: Postal questionnaires before (2002) and after (2003) the intervention. MAIN OUTCOME MEASURES: Exposure to the intervention, knowledge, attitudes, practices and intention to use emergency contraceptive pills. RESULTS: Before the intervention, the response rate was 71% (n= 564); after the intervention, the corresponding figure was 83% (n= 467); overall response rate 58%. Two-thirds (64%) of the targeted women had noticed the information campaign. One out of six who had visited a family planning clinic during the intervention year recalled being given information about emergency contraceptive pills. Specific knowledge and attitudes improved over time in both groups, but there was no difference in change between the groups. The proportion of women who had used emergency contraceptive pills increased from 27% to 31% over time. Intention to use emergency contraceptive pills in case of need was reported by 74% of the women and remained stable over time, but logistic regression showed that information during the previous year contributed to willingness to use the method in the intervention group. CONCLUSIONS: Knowledge, attitudes and practices about emergency contraceptive pills increased in both groups. Emergency contraceptive pills is gradually becoming a more widely known, accepted and used contraceptive method in Sweden, a trend that may have limited the impact of the intervention.     

Opportunistic screening for genital Chlamydia trachomatis infection and partner follow-up in family planning clinics in three Scottish cities

Three large urban family planning clinics (FPCs) in Scotland participated in a study to examine the implications of opportunistically offering urine testing for genital Chlamydia trachomatis infection and FPC follow-up of positive women and of their male partners. Ninety-eight percent (3029) of women accepted the test. The prevalence of infection was 5.2% and this decreased significantly with age. There was no significant difference in prevalence between centres. Ninety-one percent of positive women intended to inform at least one partner about their infection status. Pretest counselling took about 10 minutes per woman while management (excluding full screening for sexually transmitted infections) of positive women took an additional 10 minutes. Screening in the FPC is acceptable to many women and to some of their male partners. Training and resources for administration and staffing are required if opportunistic screening is to be implemented.     

Phase I and pharmacokinetic study of the farnesyltransferase inhibitor R115777 in combination with irinotecan in patients with advanced cancer

Purpose R115777 is a selective, nonpeptidomimetic inhibitor of farnesyltransferase (FTase), an enzyme responsible for the post-translational modification of several proteins, including Ras. Given the high frequency of K-Ras mutations in malignancies commonly treated with irinotecan, the broad preclinical antiproliferative activity of R115777 and its largely non-overlapping toxicity profile with irinotecan, this phase I study of the combination of R115777 and irinotecan in patients with advanced cancer was undertaken.Patients and methods Enrolled onto the study were 14 patients (eight male, six female; median age 63 years, range 48–72 years). Five patients had an ECOG performance status (PS) of 0, eight patients PS 1, and one patient PS 2. The patients were treated with R115777 orally twice daily for 28 days and irinotecan 100 mg/m² as an intravenous infusion on days 1, 8, 15, and 22 of each 42-day cycle. Seven patients received R115777 100 mg twice daily and seven received R115777 200 mg twice daily.Results Dose-limiting toxicity (DLT) was experienced by one of seven patients treated with R115777 100 mg (grade 3 fatigue), and two of seven patients treated with R115777 200 mg (grade 3 diarrhea, grade 4 neutropenia lasting >5 days). The maximum tolerated dose (MTD) was R115777 100 mg twice daily and irinotecan 100 mg/m² weekly. Non-DLTs were primarily rash, fatigue, diarrhea, and neutropenia. R115777 demonstrated linear pharmacokinetics without interaction with irinotecan and achieved serum levels required for antitumor activity in vitro.Conclusions Serum levels of R115777 exceeded those necessary for FTase inhibition in vitro without evidence of interaction with irinotecan. However, the MTD of R115777 in this study was lower than that obtained with an alternate schedule. Thus, further development of this schedule is not recommended.This work was supported by a grant from Johnson and Johnson Pharmaceutical Research and Development and NCI K12 CA01728.     

Adjuvant therapy in pancreatic cancer: Phase I trial of radiation dose escalation with concurrent full-dose gemcitabine

PURPOSE: To evaluate the clinical significance of the interval between surgery and postoperative radiotherapy (RT) for patients with soft tissue sarcoma. METHODS AND MATERIALS: The records of 799 patients who underwent postoperative RT for soft tissue sarcoma between 1960 and 2000 were retrospectively reviewed. Univariate and multivariate analyses were used to evaluate the potential impact of the timing of postoperative RT on the rate of local control (LC). RESULTS: The actuarial overall LC rate was 79% at 10 years and 78% at 15 years. Univariate analysis indicated that the factors associated with an inferior 10-year LC rate were positive resection margins (p <0.0001); treatment for recurrent disease (p <0.0001); primary location in the head and neck or deep trunk (p <0.0001); age >64 years (p <0.0001); histopathologic subtype of malignant fibrous histiocytoma, neurogenic sarcoma, or epithelioid sarcoma (p = 0.01); tumor size >10 cm (p = 0.02); postoperative radiation dose <64 Gy (p = 0.03); and high histologic grade (p = 0.05). On multivariate analysis, all these factors remained statistically significant, except for high histologic grade and large size. A delay between surgery and the start of RT of >30 days was associated with a decreased 10-year LC rate, but this association was not statistically significant (76% vs. 83%, p = 0.07). The potential association between RT delay and inferior LC could be explained by an imbalance in the distribution of other prognostic factors. CONCLUSION: The interval between surgery and RT did not significantly impact the 10-year LC rate. These findings indicate that an RT delay should not be viewed as an independent adverse factor for LC and that treatment intensification may not be necessary for patients in whom a treatment delay has already occurred.