Urogenital ageing and its effect on sexual health in older British women

Objective To provide information on the extent of problems of urogenital ageing in older British women.
Design A MORI survey of a representative population sample of older British women.
Setting Home interviews.
Participants Two thousand and forty-five women aged 55–85+.
Results Urogenital symptoms had affected 48.8% of the women at some time, but no more than 11% were currently affected by individual symptoms; however, these were often of long duration. The majority (73%) were not sexually active, with lack of a partner being a factor for many. There was also a decreasing prevalence of sexual activity with increasing age. Those sexually active in the 65–74 year old age group (   n = 148  ) tended to have a similar sexual frequency (at least once per month) compared with the younger women studied. Approximately 12% of those who reported dyspareunia and/or vaginal dryness claimed a severe problem; 33% did not seek professional advice and 36% resorted to an over the counter remedy. Use of hormone replacement therapy was generally of relatively short duration. There was a declining gradient of ever-use with age.
Conclusions The extent of significant urogenital symptoms is relatively low, but some women are seriously affected and use self-help as well as professional assistance. The extent of sexual activity in older women and factors affecting this have been defined, and the effect of urogenital symptoms on sexual activity demonstrated.     

Off-pump coronary artery bypass (OPCAB) in southern Mississippi

Off-Pump Coronary Artery Bypass (OPCAB) allows myocardial revascularization without use of cardiopulmonary bypass and may be associated with fewer postoperative complications. A retrospective review was undertaken to assess the value of this new strategy in our surgical practice. The records of all our patients (n = 259) undergoing isolated coronary artery bypass (CAB) operations from January 1 through December 31, 1999, were reviewed (Table 1). Patient characteristics and comorbidities were similar in both groups with the exception of age and diabetes (Table 2). Mean operating room time, blood products transfused, morbidity, mortality, and length of stay (LOS) were all significantly less in the OPCAB group. We conclude that OPCAB techniques may offer significant benefits to our population of patients undergoing myocardial revascularization.     

Ifosfamide, carboplatin, and etoposide with midcycle vincristine versus standard chemotherapy in patients with small-cell lung cancer and good performance status: clinical and quality-of-life results of the British Medical Research Council multicenter randomized LU21 trial.

PURPOSE: Ifosfamide, carboplatin, etoposide, and vincristine, alone and in combination, are highly active against small-cell lung cancer (SCLC). This trial was designed to investigate whether survival could be improved by a regimen of all four drugs (ICE-V) compared with standard chemotherapy in patients with SCLC and good performance status, and to assess the patients' quality of life (QL). PATIENTS AND METHODS: Patients were randomly assigned to receive six cycles of either ICE-V at 4-week intervals without dose reduction or standard chemotherapy administered according to local practice. The recommended standard control regimens were cyclophosphamide, doxorubicin, and etoposide; and cisplatin and etoposide. RESULTS: A total of 402 patients were randomly assigned, and 350 (87%) patients have died. Overall survival was longer in the ICE-V group (hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P = .0049), median survival was 15.6 months in the ICE-V group and 11.6 months in the control group, and 2-year survival rates were 20% and 11%, respectively. There was no evidence that the relative survival benefit for ICE-V was less in extensive-stage than in limited-stage patients. An increased rate of septicemia was reported in the ICE-V group (15% v 7% in the control group), but this did not result in an increase in reported treatment-related deaths (four patients [2%] in both groups). The findings on QL were broadly similar in both groups, with some benefit in favor of ICE-V. CONCLUSION: Compared with standard chemotherapy, the ICE-V regimen improves overall survival without QL penalties, despite an increased but manageable level of toxicity.     

Generalization testing with atypical and typical antipsychotic drugs in rats trained to discriminate 5.0 mg/kg clozapine from vehicle in a two‐choice drug discrimination task

Clozapine (CLZ) drug discrimination is used as a preclinical model to evaluate compounds for putative atypical antipsychotic properties. In rats, a 1.25 mg/kg CLZ training dose appears to have greater pharmacological specificity for atypical antipsychotic drugs than the traditional 5.0 mg/kg CLZ training dose; however, methodological differences among studies have precluded a direct comparison between these training doses. In the present study, rats were trained to discriminate a 5.0 mg/kg CLZ dose from vehicle in a two‐choice drug discrimination task using methods similar to those in a previous study from our laboratory that used a 1.25 mg/kg CLZ training dose. Clozapine produced full substitution (≥80% CLZ‐lever responding) for itself at the training dose (5.0 mg/kg). The atypical antipsychotics olanzapine, quetiapine, and ziprasidone also produced full substitution for 5.0 mg/kg CLZ, whereas the atypical antipsychotics risperidone and sertindole produced partial substitution (≥60% CLZ‐lever responding). The typical antipsychotic, thioridazine, produced full substitution for the 5.0 mg/kg CLZ training dose, but the typical antipsychotics chlorpromazine, fluphenazine, and haloperidol failed to substitute for clozapine. In a subgroup of 1.25 mg/kg CLZ‐trained rats, ziprasidone produced strong partial substitution (73.0 % CLZ‐lever responding) for the 1.25 mg/kg CLZ training dose. Based on these findings, some atypical antipsychotic drugs (i.e., quetiapine and ziprasidone) produce full substitution only for the 5.0 mg/kg CLZ training dose, whereas other atypical antipsychotic drugs (i.e., sertindole and risperidone) produce full substitution only for the 1.25 mg/kg CLZ training dose. Thus, both of these training doses are important for the screening of putative atypical antipsychotic drugs with the clozapine drug discrimination assay. Drug Dev. Res. 64:55–65, 2005. © 2005 Wiley‐Liss, Inc.     

Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02029443","term_id":"NCT02029443"}}NCT02029443, {"type":"clinical-trial","attrs":{"text":"NCT02475681","term_id":"NCT02475681"}}NCT02475681, {"type":"clinical-trial","attrs":{"text":"NCT02970318","term_id":"NCT02970318"}}NCT02970318 and {"type":"clinical-trial","attrs":{"text":"NCT02337829","term_id":"NCT02337829"}}NCT02337829). Acalabrutinib was given orally at total daily doses of 100–400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32–89]; median follow-up: 25.9 months [range, 0–58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with high-risk CLL (clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02477696","term_id":"NCT02477696"}}NCT02477696) prospectively assess differences in CV toxicity between the two agents.     

Alcohol consumption and casualties; drinking in the event

The data reported are from a 20% probability sample (n = 2516) of all adult patients seeking care in the emergency room at San Francisco General Hospital during a 60-day period. Thirty-five percent (35%) of the injured and 18% of the non-injured reported drinking prior to the event. This paper compares the following variables related to drinking-in-the-event for injured and non-injured: drinking places, drinking companions, amount consumed, time lapsed between drinking and the event, effects of drinking and causality attributed by the patient to drinking and the event. When these variables were entered into a logistic regression to evaluate their predictive value on injury status, only time lapsed since the last drink and drug use prior to the event were predictive of injury with both being negatively associated with admission to the emergency room for an injury. Injuries were more likely than non-injuries to occur in close proximity to drinking (44% of injuries occurred in less than 1 h of the last drink), and close to a third of the injured attributed a causal association of drinking with the event, with 60% of these feeling they were drunk at the time of injury.     

Phase II trial of daily oral etoposide in patients with advanced non-small cell lung cancer

Forty-six previously untreated patients with advanced non-small cell lung cancer (NSCLC) were entered into a Hoosier Oncology Group phase II trial of daily oral etoposide 50 mg/m²/d. The dose limiting toxicity was granulocytopenia. The non-hematologic toxicity was mild, with only 19% of patients developing Grade 3 or 4 leukopenia. Two partial responses of 10 and 16 weeks duration were seen in 43 evaluable patients, for an overall response rate of 4%. We conclude that daily oral etoposide has minimal activity in advanced NSCLC, and does not improve response rates over conventional 1–5 day intravenous etoposide administration.from the Hoosier Oncology Group, the Walther Cancer Institute, Indianapolis, IN; Department of Medicine, Indiana University, Indianapolis, IN, USADr. Einhorn is the Walther American Cancer Society Professor of Clinical Oncology.     

Characterization of the in vitro activity of AZD3409, a novel prenyl transferase inhibitor

Purpose

AZD3409 is a novel DPTI that has potent activity against both FTase and GGTase-1. The in vitro inhibition profile of AZD3409 was characterized using three different cell lines: mouse embryogenic fibroblasts, transfected with H-Ras^V12 (MEF), A549 cells (Ki4B-Ras mutation) and MCF-7 cells (no Ras mutation).

Methods

Both cytotoxicity and levels of inhibition of farnesylation and geranylgeranylation were determined in different assays in relation to the concentration of AZD3409. Results were compared with those obtained with the first-generation FTase inhibitor lonafarnib or the GGTase-1 inhibitor GGTI-2147.

Results

The mean IC₅₀ for cytotoxicity of AZD3409 and lonafarnib was 510 and 15,200?nM in MEF cells, 10,600 and 2,740?nM in A549 cells and 6,170 and 9,490?nM in MCF7 cells, respectively. In these cells, the IC₅₀ for FTase activity of AZD3409 ranged from 3.0 to 14.2?nM and of lonafarnib from 0.26 to 31.3?nM. The inhibiting activity of AZD3409 and lonafarnib on general protein farnesylation was comparable with the specific farnesylation levels of HDJ-2. In vitro geranylgeranylation of Rap1a could be inhibited by GGTI-2147 in all three cell lines, but only in MCF-7 cells by AZD3409. These results are in agreement with the IC₅₀ values for GGTase-1 activity as the lowest IC₅₀ for AZD3409 was found in the MCF-7 cell line.

Conclusions

AZD3409 inhibits farnesylation to a higher extent than geranylgeranylation. Both inhibition of farnesylation and geranylgeranylation could not be correlated to the antiproliferative activity of the drug.