Perinatal Administration of a Selective Serotonin Reuptake Inhibitor Induces Impairments in Reproductive Function and Follicular Dynamics in Female Rat Offspring.

INTRODUCTION: Up to 10% of pregnant women take antidepressants, of which selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed. Using a rodent model, we investigated the reproductive impacts of perinatal SSRI treatment on reproductive cyclicity and function in female offspring. METHODS: Virgin Wistar rats were given oral vehicle (n = 10) or fluoxetine hydrochloride (FLX, 10 mg/kg/d; n = 11) from 2 weeks prior to mating until weaning. Pubertal onset and reproductive cyclicity in offspring were assessed. Blood and ovarian tissues were collected for measures of reproductive function. RESULTS: Perinatal FLX tends to induce irregular reproductive cycles in adult offspring, which most commonly manifest as a prolonged estrus phase (FLX 34% vs control [CON] 10%) relative to CON offspring. The FLX offspring tended to have longer cycles (P = .052), had more secondary follicles (P = .0067), more total follicles (P = .0310), and increased apoptotic ovarian cells (P < .001). Prenatally exposed FLX offspring demonstrated elevated ovarian messenger RNA (mRNA) levels of ERß (P = .008), Cry1 (P = .043), and tryptophan hydroxylase 2 (P = .024), independent of stage of cycle. Ovarian mRNA levels of brain and muscle Arnt-like protein 1 (P = .046) and Pet-1 (P = .021) were increased in FLX offspring a manner that was reproductive cycle stage dependent. CONCLUSIONS: This is the first study to investigate the postnatal effects of maternal perinatal exposure to FLX on adult offspring reproduction. We show that genes that regulate serotonin signaling and action in the ovary are altered in prenatally FLX-exposed offspring, which when coupled with increased expression of components of the core Circadian Locomotor Output Cycles Kaput (CLOCK) gene regulatory loop may suggest an interaction between serotonergic signaling and clock gene signaling pathways leading to the altered reproductive phenotype.

Early-life nutritional effects on the female reproductive system.

There is now considerable epidemiological and experimental evidence indicating that early-life environmental conditions, including nutrition, affect subsequent development in later life. These conditions induce highly integrated responses in endocrine-related homeostasis, resulting in persistent changes in the developmental trajectory producing an altered adult phenotype. Early-life events trigger processes that prepare the individual for particular circumstances that are anticipated in the postnatal environment. However, where the intrauterine and postnatal environments differ markedly, such modifications to the developmental trajectory may prove maladaptive in later life. Reproductive maturation and function are similarly influenced by early-life events. This should not be surprising, because the primordial follicle pool is established early in life and is thus vulnerable to early-life events. Results of clinical and experimental studies have indicated that early-life adversity is associated with a decline in ovarian follicular reserve, changes in ovulation rates, and altered age at onset of puberty. However, the underlying mechanisms regulating the relationship between the early-life developmental environment and postnatal reproductive development and function are unclear. This review examines the evidence linking early-life nutrition and effects on the female reproductive system, bringing together clinical observations in humans and experimental data from targeted animal models.

A prospective, claims-based assessment of the risk of pancreatitis and pancreatic cancer with liraglutide compared to other antidiabetic drugs.

AIM: We evaluated the relationship between liraglutide and acute pancreatitis or pancreatic cancer in an ongoing post-marketing safety assessment programme. METHODS: Initiators of liraglutide, exenatide, metformin, pioglitazone or groups containing initiators of dipeptidyl peptidase-4 inhibitors or sulfonylureas were identified in a US commercial health insurance claims database (1 February 2010 to 31 March 2013) and followed for a median of 15 months. We estimated incidence rates (IR/100 000 person-years), rate ratio (RR) and 95% confidence intervals (CI) of new insurance claims with diagnoses of primary inpatient acute pancreatitis or pancreatic cancer from Poisson regression models. RESULTS: The IR for acute pancreatitis for liraglutide was 187.5 compared with 154.4 for all non-glucagon-like peptide-1 (GLP-1)-based therapies (adjusted RR 1.10; CI 0.81-1.49). The IR for pancreatic cancer was 19.9 for liraglutide compared with 33.0 for all non-GLP-1-based therapies (adjusted RR 0.65; 95% CI 0.26-1.60). CONCLUSION: We did not observe excess risk of either outcome associated with liraglutide relative to individual or pooled comparator drugs.

Sex differences in gout epidemiology: evaluation and treatment.

BACKGROUND: Little is known about the characteristics, evaluation and treatment of women with gout. OBJECTIVE: To examine the epidemiological differences and differences in treatment between men and women in a large patient population. METHODS: The data from approximately 1.4 million people who were members of seven managed care plans in the USA for at least 1 year between 1 January 1999 and 31 December 2003 were examined. Adult members who had pharmacy benefits and at least two ambulatory claims specifying a diagnosis of gout were identified. In addition, men and women who were new users of urate-lowering drugs (ULDs) were identified to assess adherence with recommended surveillance of serum urate levels within 6 months of initiating urate-lowering treatment. RESULTS: A total of 6133 people (4975 men and 1158 women) with two or more International Classification of Disease-9 codes for gout were identified. As compared with men with gout, women were older (mean age 70 (SD 13) v 58 (SD 14), p<0.001) and had comorbidities and received diuretics more often (77% v 40%; p<0.001). Only 37% of new users of urate-lowering treatment had appropriate surveillance of serum urate levels post-initiation of urate-lowering treatment. After controlling for age, comorbidities, gout treatments, number of ULD dispensings and health plan, women were more likely (odds ratio 1.36, 95% confidence interval 1.11 to 1.67) to receive the recommended serum urate level testing. CONCLUSIONS: Women with gout were older, had greater comorbidities and more often used diuretics and received appropriate surveillance of serum urate levels, suggesting that the factors leading to gout as well as monitoring of treatment are very different in women and men.

Meta-analysis: ribavirin-induced haemolytic anaemia in patients with chronic hepatitis C.

AIM: To use meta-analysis to study the risk of anaemiarelated to ribavirin therapy for chronic hepatitisC. METHODS: The MEDLINE database up to January 2001 was searched for randomized controlled trials of ribavirin (monotherapy or combined with interferon) for chronic hepatitis C. The outcomes evaluated were withdrawal from the study due to anaemia, ribavirin dosage reduction due to a decrease in haemoglobin and haemoglobin levels below 10 g/dL. RESULTS: Based on 17 studies, the overall risk difference (ribavirin vs. no ribavirin) for anaemia was 0.09 [95% confidence interval (CI), 0.04-0.13]. Two Asian studies reported risk differences of 0.29 and 0.22, greater than the pooled risk difference of 0.07 (95% CI, 0.03-0.12) for 15 non-Asian studies. The risk associated with 1 g or more of ribavirin per day was higher (risk difference, 0.09; 95% CI, 0.04-0.14) than that for 0.8 g of ribavirin per day (risk difference, 0.01; 95% CI, - 0.04-0.06). CONCLUSIONS: Chronic hepatitis C patients treated with 1 g or more of ribavirin per day were at a higher risk of developing anaemia. Reported risks were higher among Asian studies, which may be due to differences in study entrance criteria, dosage titration strategy or ethnic vulnerability.

Preoperative drug dispensing as predictor of surgical site infection.

The system used by the National Nosocomial Infection Surveillance (NNIS) program to measure risk of surgical site infection uses a score of 3 on the American Society of Anesthesiologists (ASA)-physical status scale as a measure of underlying illness. The chronic disease score measures health status as a function of age, sex, and 29 chronic diseases, inferred from dispensing of prescription drugs. We studied the relationship between the chronic disease score and surgical site infection and whether the score can supplement the NNIS risk index. In a retrospective comparison of 191 patients with surgical site infection and 378 uninfected controls, the chronic disease score and ASA score were highly correlated. The chronic disease score improved prediction of infection by the NNIS risk index and augmented the ASA score for risk adjustment.

Multicenter epidemiologic and health services research on therapeutics in the HMO Research Network Center for Education and Research on Therapeutics.

Research and education programs in therapeutics that combine the data, organizational capabilities, and expertise of several managed care organizations working in concert can serve an important role when a single organization is not large enough to address a question of interest, when diversity in populations or delivery systems is required, and when it is necessary to establish consistency of results in different settings. Nine members of the HMO Research Network, a consortium of health maintenance organizations (HMOs) that perform public domain research, have formed a Center for Education and Research on Therapeutics (CERT), sponsored by the Agency for Healthcare Research and Quality, to conduct multicenter research in therapeutics. The CERT uses a distributed organizational model with shared leadership, in which data reside at the originating organization until they are needed to support a specific study. Extraction of data from the host computer systems, and some manipulation of data, is typically accomplished through computer programs that are developed centrally, then modified for use at each site. For complex studies, pooled analysis files are created by a coordinating center, and then analysed by investigators throughout the HMOs. It is also possible to contact HMO members when necessary. This multicenter environment has several benefits, addressing: (1) a wide array of questions about the safety and effectiveness of therapeutics, (2) the impact of efforts to change clinicians' and patients' behavior, and (3) pharmacoeconomic and pharmacogenetic questions.

Contraindicated use of cisapride: impact of food and drug administration regulatory action.

CONTEXT: Cisapride, a gastrointestinal tract promotility agent, can cause life-threatening cardiac arrhythmias in patients susceptible either because of concurrent use of medications that interfere with cisapride metabolism or prolong the QT interval or because of the presence of other diseases that predispose to such arrhythmias. In June 1998, the US Food and Drug Administration (FDA) determined that use of cisapride was contraindicated in such patients and informed practitioners through additions to the boxed warning in the label and a "Dear Health Care Professional" letter sent by the drug's manufacturer. OBJECTIVE: To evaluate the impact of the FDA's 1998 regulatory action regarding contraindicated use of cisapride. DESIGN AND SETTING: Analysis of data for the 1-year periods before (July 1997-June 1998) and after (July 1998-June 1999) the regulatory action from the population-based, pharmacoepidemiology research databases of 2 managed care organizations (sites A and B) and a state Medicaid program (site C). PARTICIPANTS: Patients with at least 180 days of prior enrollment in 1 of the 3 sites who were prescribed cisapride at least once in the period before (n = 24 840) or after (n = 22 459) regulatory action. Patients could be included in both cohorts. MAIN OUTCOME MEASURES: Proportion of cisapride users in each period for whom cisapride use was contraindicated by the product label, based on computerized patient medical encounter records. RESULTS: In the year prior to regulatory action, cisapride use was contraindicated for 26%, 30%, and 60% of users in study sites A, B, and C, respectively. In the year after regulatory action, use was contraindicated for 24%, 28%, and 58% of users, a reduction in contraindicated use of approximately 2 per 100 cisapride users at each site. When the analysis was restricted to new users of cisapride after regulatory action, only minor reductions in contraindicated use were found. CONCLUSION: The FDA's 1998 regulatory action regarding cisapride use had no material effect on contraindicated cisapride use. More effective ways to communicate new information about drug safety are needed.

Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women.

BACKGROUND: Inhibitors of hydroxymethylglutaryl-coenzyme A reductase (statins) increase new bone formation in rodents and in human cells in vitro. Statin use is associated with increased bone mineral density of the femoral neck. We undertook a population-based case-control study at six health-maintenance organisations in the USA to investigate further the relation between statin use and fracture risk among older women. METHODS: We investigated women aged 60 years or older. Exposure, outcome, and confounder information was obtained from automated claims and pharmacy data from October, 1994, to September, 1997. Cases had an incident diagnosis of non-pathological fracture of the hip, humerus, distal tibia, wrist, or vertebrae between October, 1996, and September, 1997. Controls had no fracture during this period. We excluded women with records of dispensing of drugs to treat osteoporosis. FINDINGS: There were 928 cases and 2747 controls. Compared with women who had no record of statin dispensing during the previous 2 years, women with 13 or more statin dispensings during this period had a decreased risk of non-pathological fracture (odds ratio 0.48 [95% CI 0.27-0.83]) after adjustment for age, number of hospital admissions during the previous year, chronic disease score, and use of non-statin lipid-lowering drugs. No association was found between fracture risk and fewer than 13 dispensings of statins or between fracture risk and use of non-statin lipid-lowering drugs. INTERPRETATION: Statins seem to be protective against non-pathological fracture among older women. These findings are compatible with the hypothesis that statins increase bone mineral density in human beings and thereby decrease the risk of osteoporotic fractures.

High prevalence of voiding symptoms in Taiwanese women.

OBJECTIVE: To describe the voiding symptoms of Taiwanese women using the International Prostate Symptom Score (IPSS). SUBJECTS AND METHODS: A self-administered questionnaire was used to collect information on demographic characteristics and the IPSS used to determine the voiding symptoms of 583 consecutive women undergoing a health examination. The symptom scores of different age groups were compared using a one-way analysis of variance with a posteriori comparisons made using Scheffe's test. RESULTS: The seven symptom scores could be separated by factor analysis into two factors which corresponded with obstructive (incomplete emptying, intermittency, weak stream, and hesitancy) and irritative (frequency, urgency, and nocturia) symptoms. Various degrees of frequency and nocturia were commonly reported by the respondents, whereas obstructive symptoms were infrequently reported, except in the elderly (age > or = 65 years). The irritative scores, obstructive scores and total scores increased significantly with age (all P<0.001). The total symptom scores correlated significantly with the quality-of-life score (Pearson's r = 0.70, P < 0.001). Overall, 124 (21%) of the respondents reported an IPSS of > 7, and 98 (17%) of the respondents reported being 'mostly dissatisfied' with their urination. However, only nine (1.5%) of the respondents had ever consulted a urologist about their voiding problems. CONCLUSIONS: There was an age-dependent change in voiding symptoms in these Taiwanese women. The prevalence of voiding symptoms in women is much higher than encountered in clinical practice.

Personality disorder and suicide. A case-control study.

BACKGROUND: The relationships between personality disorders and suicide were investigated among two aboriginal groups and the Han Chinese in East Taiwan. METHOD: Biographical reconstructive interviews were conducted for consecutive suicides from each of the three ethnic groups (116 suicides in total), 113 of whom were matched with two controls for age, gender, and area of residence. RESULTS: In all three groups, a high proportion of suicides suffered from ICD-10 personality disorder before suicide (46.7-76.7%), and the most prevalent category was emotionally unstable personality disorder (F60.3) (26.7-56.7%). The risk for suicide was mainly significantly associated with F60.3, comorbidity among personality disorders, and comorbidity of personality disorder with other psychiatric disorders, particularly severe depression. CONCLUSION: The main category of personality disorder significantly associated with the risk of suicide is F60.3 in ICD-10. The risk is highest for a comorbidity of this category and severe depression.