Neuropsychiatric events with varenicline: a modified prescription-event monitoring study in general practice in England.

BACKGROUND: Varenicline (Champix(®)), launched in the UK in December 2006, is indicated for the treatment of smoking cessation in adults (≥18 years of age). In 2008, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK issued a warning suggesting that varenicline was associated with disparate neuropsychiatric symptoms, including depression, suicidal thoughts and behaviour. In response to this regulatory warning, the Drug Safety Research Unit conducted a modified prescription-event monitoring (M-PEM) study to monitor the safety of varenicline. OBJECTIVE: The aim of this study was to estimate the incidence and examine the pattern of neuropsychiatric events reported to general practitioners (GPs) in England during the immediate postmarketing period for varenicline. METHODS: A postmarketing surveillance study was conducted using the observational cohort technique of M-PEM. Patients were identified from dispensed prescriptions issued by primary care physicians between December 2006 and March 2007. Data on exposure, previous history of psychiatric illness and events reported during and after treatment were collected from questionnaires. In order to determine whether hazards for neuropsychiatric events of interest (depression, anxiety, aggression, suicidal ideation, non-fatal self-harm) were non-constant over time (which could indicate a possible association with the drug), the pattern of events was examined by plotting the smoothed hazard function estimate and then fitting a Weibull model. The Weibull model shape parameter (ß) and 95 % confidence interval were used as a test for a non-constant hazard function (where a value of 1 indicates a constant hazard over time). In addition to this analysis, the difference in incidence densities (IDs) between month 1 and months 2-3 were calculated and compared. RESULTS: The cohort comprised of 12,159 patients (median age 47 years [interquartile range 19]; 56.9 % [n = 6924 female]). The number of events reported during treatment, reason for stopping, adverse drug reactions (ADRs), and the p-value for the Weibull shape parameter were as follows: depression (n = 94; 42; 19; p = 0.144); anxiety (n = 94; 49; 9; p = 0.009); aggression (n = 7; 4; 2; p = 0.465); suicidal ideation (n = 8; 4; 1; p = 0.989) and non-fatal self-harm (n = 5; 1; 0; p = 0.771). No differences in the IDs between months 1 and months 2-3 were found for any of the events. CONCLUSION: Whilst between 7 and 17 % of neuropsychiatric events were attributed to the drug by GPs and approximately 20-50 % were given as reasons for stopping, no signal was raised using the ID differences approach, and only anxiety was flagged as a potential signal for an ADR using the Weibull model. The signal for anxiety requires further evaluation to determine whether the drug plays a part in the development of anxiety or whether it is a withdrawal symptom caused by smoking cessation. Analysis methods will lack power when the numbers of events are low even when a large number of participants are included in the study.

Reasons for and time to discontinuation of rimonabant therapy: a modified prescription-event monitoring study.

BACKGROUND: Early treatment discontinuation will have a negative effect on a drug's benefit-risk profile if discontinuation occurs earlier in time than the positive effects of treatment. This non-persistence of therapy has been associated with an increased risk of adverse health outcomes. OBJECTIVE: The aim of this study was to explore relationships between patient characteristics and reasons for and time to discontinuation of rimonabant therapy, focusing on psychiatric events, because these were the main safety concerns for rimonabant. METHODS: A modified prescription-event monitoring (M-PEM) study was conducted for rimonabant. Descriptive statistics were used to describe the patient population. Rate ratios with 95% confidence intervals (CIs) were calculated to explore associations between patient characteristics and selected categories of reasons for stopping (RfS). Median times to discontinuation were compared using the Mann-Whitney U test. RESULTS: The cohort comprised 10,011 users of rimonabant, three of which were excluded from this analysis because of missing age or sex. A total of 7204 patients (72.0%) stopped using rimonabant (median observation time 323 days, interquartile range: 279-371 days). In addition, patients with a history of psychiatric illness were more likely to discontinue rimonabant therapy early for all reasons, but most pronounced due to psychiatric events (rate ratio 1.79; 95% CI 1.54, 2.09) than those without a history of psychiatric illness. In contrast, the rates of discontinuation due to lack of effectiveness, any clinical events and psychiatric events in patients with cardiovascular disease, type 2 diabetes mellitus, dyslipidaemia or hypertension tended to be lower (not all being significant) than those without. For patients who discontinued treatment due to lack of effectiveness, the median time to discontinuation was significantly shorter for patients with a history of psychiatric illness, compared with patients without a history of psychiatric illness (86 vs 97 days, p = 0.03). For patients discontinuing treatment due to psychiatric events, the difference in median time to discontinuation was also 11 days (64 vs 75 days, p = 0.38), although not statistically significant. For patients stopping due to any clinical event, median time to discontinuation was comparable for patients with and without a history of psychiatric illness (61 vs 63 days, p = 0.90). CONCLUSIONS: In this study, reasons for and time to discontinuation were associated with patient characteristics such as medical history. Patients discontinued treatment because of psychiatric events early after starting. In general, identification and characterization of early discontinuers, and increasing the understanding of reasons for stopping, may help healthcare professionals to develop targeted interventions to further improve treatment compliance, thereby optimizing treatment benefits and drug safety.

Risk of depressive episodes with rimonabant: a before and after modified prescription event monitoring study conducted in England.

BACKGROUND: Marketing authorization for rimonabant was withdrawn in October 2008, mainly because the psychiatric adverse effects could not be addressed by further risk minimization. OBJECTIVE: The aim of the study was to compare the risk of major and minor depressive episodes in the 6 months prior to and the 6 months after starting treatment with rimonabant. METHODS: We conducted a before and after study using the observational cohort technique of Modified Prescription Event Monitoring to compare the risk of major and minor depressive episodes in new users of rimonabant reported in the 6 months before to the 6 months after starting treatment with rimonabant. Patients were identified from dispensed prescriptions issued by primary care physicians from June 2006 to October 2008. Patient demographics and information on depressive episodes were requested 6 months after the date of the first prescription for each patient. Risk ratios (RR) were calculated by comparing before and after events using a matched analysis. RESULTS: The cohort comprised 10,011 patients. The number of patients who had major depressive episodes before and after starting treatment were 147 and 168, respectively (RR 1.14; 95% CI 0.94, 1.39) and the number of patients who had minor depressive episodes were 825 and 829, respectively (RR 1.00; 95% CI 0.93, 1.10). For patients who had a previous history of psychiatric illness (n = 1132), 91 and 73, respectively, experienced major depressive episodes (RR 0.80; 95% CI 0.62, 1.03), and 367 and 220, respectively, experienced minor depressive episodes (RR 0.59; 95% CI 0.53, 0.68). For patients without a previous history of psychiatric illness (n = 8879), 56 and 95, respectively, experienced major depressive episodes (RR 1.7; 95% CI 1.2, 2.3), and 458 and 609, respectively, experienced minor depressive episodes (RR 1.33; 95% CI 1.20, 1.48). CONCLUSIONS: When comparing all patients in the cohort, there was no increased risk of developing a depressive episode whilst taking rimonabant. However, when considering subsets of patients with and without a previous history of psychiatric illness, the risk profiles were different. In patients without a previous history of psychiatric illness, there were more depressive episodes in the 6 months after starting treatment compared with the 6 months before starting treatment with rimonabant.

Safety profile of oxcarbazepine: results from a prescription-event monitoring study.

PURPOSE: To monitor safety of oxcarbazepine, prescribed in primary care in England, using prescription-event monitoring (PEM). METHODS: Postmarketing surveillance using observational cohort technique of PEM. Exposure data were obtained from dispensed British National Health Service prescriptions issued by general practitioners (GPs) March 2000-July 2003. Demographic, drug utilization, and clinical event data were collected from questionnaires posted to GPs at least 6 months after first prescription date for each patient. Incidence densities (IDs) (number of first reports per 1,000 patient-months of treatment) were calculated and differences for events reported in month 1 (ID(1)) and months 2-6 (ID(2-6)) (99% confidence intervals) were examined for changes in event rates. Follow-up and causality assessment of medically significant events were undertaken. RESULTS: The cohort comprised 2,243 patients [mean age 40.4 years; range 2-99 years; standard deviation (SD) 18.8; 46.3% (n = 1,038) male]. Most frequently reported primary indications were epilepsy, convulsion (n = 1,111; 49.5%, n = 209; 9.3%, respectively). GPs recorded 932 reasons for stopping medication in 698 (31.1%) patients; most frequent clinical reason "drowsiness/sedation" (n = 57; 2.5% of cohort). Clinical events (excluding indication) associated with starting treatment (lower 99% CI > 0) included: "drowsiness/sedation" (ID(1)-ID(2-6) = 14.2), "nausea/vomiting" (ID(1)-ID(2-6) = 13.0), and dizziness (ID(1)-ID(2-6) = 11.6). Events followed up and assessed as probably related to oxcarbazepine use included rash (7 of 11) and hyponatremia (15 of 38). DISCUSSION: There were no serious adverse drug reactions reported during this study. Results of the study should be taken in context with other epidemiologic studies.

Tamoxifen-induced ER-alpha-SRC-3 interaction in HER2 positive human breast cancer; a possible mechanism for ER isoform specific recurrence.

Differential signalling between the two oestrogen receptor (ER) isoforms in the presence of tamoxifen has been described. We hypothesise that differential recruitment of the steroid receptor co-activator, SRC-3 to ER-alpha and ER-beta may in part explain associations between ER isoforms and response to endocrine treatment. SRC-3 was localised within epithelial cells of breast tumour tissue and was co-localised with ER-alpha and ER-beta, (n=112). Expression of SRC-3 was found to be positively associated with ER-alpha (P=0.0021) and inversely with ER-beta (P<0.0001). Uniquely, this study utilises primary cell cultures derived from patient tumours, thus providing samples not readily available in most molecular model systems. These samples have enabled us to investigate the influence of growth factor pathways on steroid receptor-co-activator interactions. In HER2 (human epidermal growth factor receptor 2) positive primary tumour cell cultures 17beta-estradiol induced a decrease in SRC-3, whereas upregulated SRC-3 expression. Furthermore, treatment with tamoxifen-induced SRC-3 recruitment to the ER-oestrogen response element and enhanced interaction between SRC-3 and ER-alpha, but not ER-beta. Knockdown of SRC-3 results in a concomitant loss of expression of the oestrogen target gene pS2. Furthermore, silencing of SRC-3 resensitizes endocrine resistant, HER2 positive cells to the anti-proliferative effects of tamoxifen. The ability of ER-alpha, but not ER-beta to recruit SRC-3 in the presence of tamoxifen may in part explain the differential ER isoform associations with recurrence in human breast cancer.

Expression of the breast cancer metastasis suppressor gene, BRMS1, in human breast carcinoma: lack of correlation with metastasis to axillary lymph nodes.

The BRMS1 (breast cancer metastasis suppressor 1) gene has been found to suppress metastasis in animal models without inhibiting primary tumor growth. The aim of this study was to measure expression of BRMS1 mRNA in a panel of human breast carcinomas and compare its expression with parameters of local dissemination such as tumor size and lymph node metastasis. We also compared expression of BRMS1 mRNA in normal breast tissue, fibroadenomas, primary breast cancers and axillary nodal metastases from primary breast cancers. BRMS1 mRNA was detected in 10/11 (90%) specimens of normal breast tissue, 12/16 (75%) fibroadenomas, 64/82 (78%) primary breast cancer and 11/15 (64%) lymph node metastases (p, NS). In the primary cancer, expression was independent of tumor size, tumor grade, metastasis to axillary nodes and hormone receptor status. Furthermore, similar levels of BRMS1 were found in normal breast tissue, primary breast carcinomas and lymph node metastases from primary breast cancer. Our results do not suggest a role for BRMS1 in suppressing metastasis to local lymph nodes in patients with breast cancer.

Associations and interactions between Ets-1 and Ets-2 and coregulatory proteins, SRC-1, AIB1, and NCoR in breast cancer.

PURPOSE: Associations between p160 coactivator proteins and the development of resistance to endocrine treatment have been described. We hypothesized that nuclear receptor coregulatory proteins may interact with nonsteroid receptors. We investigated the mitogen-activated protein kinase-activated transcription factors, Ets, as possible interaction proteins for the coactivators SRC-1 and AIB1 and the corepressor NCoR in human breast cancer. EXPERIMENTAL DESIGN: Expression and coexpression of Ets and the coregulatory proteins was investigated using immunohistochemistry and immunofluorescence in a cohort of breast tumor patients (N = 134). Protein expression, protein-DNA interactions and protein-protein interactions were assessed using Western blot, electromobility shift, and coimmunoprecipitation analysis, respectively. RESULTS: Ets-1 and Ets-2 associated with reduced disease-free survival (P < 0.0292, P < 0.0001, respectively), whereas NCoR was a positive prognostic indicator (P < 0.0297). Up-regulation of Ets-1 protein expression in cell cultures derived from patient tumors in the presence of growth factors associated with tumor grade (P < 0.0013; n = 28). In primary breast tumor cell cultures and in the SKBR3 breast cell line, growth factors induced interaction between Ets and their DNA response element, induced recruitment of coactivators to the transcription factor-DNA complex, and up-regulated protein expression of HER2. Ets-1 and Ets-2 interacted with the coregulators under basal conditions, and growth factors up-regulated Ets-2 interaction with SRC-1 and AIB1. Coexpression of Ets-2 and SRC-1 significantly associated with the rate of recurrence and HER expression, compared with patients who expressed Ets-2 but not SRC-1 (P < 0.0001 and P < 0.0001, respectively). CONCLUSIONS: These data describe associations and interactions between nonsteroid transcription factors and coregulatory proteins in human breast cancer.

Expression of ADAM-9 mRNA and protein in human breast cancer.

The ADAMs (a disintegrin and metalloprotease) are membrane proteins containing both protease and adhesion domains and thus may be potentially important in cancer invasion and metastasis. The aim of our study was to investigate the distribution and potential clinical significance of ADAM-9 in breast cancer. ADAM-9 expression was measured using both reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. ADAM-9 mRNA was expressed more frequently in both breast carcinomas (72/110, 66%) and fibroadenomas (21/38, 55%) compared to normal breast tissue (6/25, 24%) (p = 0.0004, p = 0.028, respectively). Multiple forms of ADAM-9 protein were detected by Western blotting, i.e., at 124, 84 and 48 kDa under reducing conditions and at 115, 76, 55, 52 and 46 kDa under nonreducing conditions. The 84 and 55 kDa forms were detected more frequently in the primary cancers compared to normal breast tissue (p < 0.0001, p = 0.0002, respectively). In addition, relative levels of the 84 kDa mature form were significantly higher in the primary cancers than in the fibroadenomas (p = 0.003), while the reverse was found for the 124 kDa precursor form (p = 0.026). In the carcinomas, the 84 kDa form of ADAM-9 protein was expressed at higher levels in node-positive than node-negative cancers (p = 0.05) and correlated positively with HER-2/neu protein levels (r = 0.313, p = 0.016). This is the first report to describe expression of any ADAM in a large number of human carcinomas.