Pharmacokinetics and pharmacodynamics of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione in patients with postmenopausal breast cancer

Summary The pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3–4 days, oestradiol levels fell to 31.1%±6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2 g/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates forC _o (21.7±1.82 g/ml),K _m (2.66±0.68 g/ml) and V_max (0.86±0.06 g ml^–1 h^–1). On subsequent repeated dosing with PyG, both theK _m (4.31±0.48 g/ml) and the V_max (1.83±0.13 g ml^–1 h^–1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.Abbreviations PyG 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione - AG aminoglutethimide - CSCC cholesterol side-chain cleavage - HPLC high-performance liquid chromatography - AUC area under the concentration versus time curve This study was supported in part by grants to the Institute of Cancer Research (Royal Cancer Hospital) from the Cancer Research Campaign and Medical Research Council     

Liver transplant recipient sera derived soluble HLA mediates allele specific CTL apoptosis

BACKGROUND: Significant levels of donor soluble human leukocyte antigen (HLA) class I (sHLA) are present in patients after transplants. We investigated the possibility that sHLA may inhibit cytolytic T lymphocyte (CTL) activity by inducing apoptosis of the CTL, thereby serving as a mechanism for specific tolerance. METHODS: sHLA-A2 and A3 were isolated from the sera of liver transplant recipients by affinity chromatography. T cell bulk lines directed against HLA-A2 and HLA-A3 were generated by stimulation with HLA-A2, A3+ peripheral blood leukocytes and B-lymphoblastoid cells. Induction of T cell apoptosis by sHLA was analyzed by adding sHLA to allospecific CTL 4 or for 24 hr before flow cytometric analysis of propidium iodide and fluorescein isothiocyanate-conjugated annexin V stained cells. T cell receptor (TCR) engagement by sHLA was demonstrated using a monoclonal antibody specific for the TCR. RESULTS: sHLA-A3 inhibited CTL activity of a HLA-A3 T cell line by 53%, whereas sHLA-A2 had no effect. sHLA-A3 also increased T cell death by 77% over the control, whereas sHLA-A2 had no significant effect. However, sHLA-A2 induced 21% apoptosis of an anti-HLA-A2 T cell line, whereas sHLA-A3 caused only 3% apoptosis. The antibody complexed form of sHLA was ineffective in the induction of apoptosis. Preincubation of the T cells with anti-T cell receptor monoclonal antibody protected the T cells from sHLA-induced apoptosis, indicating that sHLA-TCR engagement is necessary for this process to occur. CONCLUSION: TCR-mediated apoptosis of alloreactive CTL may serve as a mechanism by which sHLA can modulate the immune response.     

Continuous infusion cisplatin and etoposide chemotherapy for cancer of unknown primary site (CUPS) in Taiwan, a region with a high prevalence of endemic viral infections

BACKGROUND: To evaluate the efficacy and toxicity of cisplatin/etoposide continuous infusion chemotherapy for cancer of unknown primary site in Taiwan, a region with a high prevalence of endemic viral infections. METHOD: Between April 1994 and February 1996, 20 patients with a diagnosis of CUPS were treated, including 15 males and five females, of average age 63.3 years (range 41-83 years). Continuous intravenous infusion of etoposide 80 mg/m2 and cisplatin 25 mg/m2 was given for 3 days every 3 weeks. Pretreatment tumor marker and viral serology studies were performed for baseline evaluation. Nearly two-thirds of the patients had poorly differentiated carcinoma. The average number of metastatic sites was 2.65 (range 1-4), with liver and lymph node involvement predominating. RESULTS: The overall response rate was 25% (95% CI 17.7-32.3%); 30.7% for poorly differentiated cancers and 25% for well differentiated cancers. Median survival was 4 months (range 1-12 months), 4.8 months for patients attaining partial response. Toxicity was moderate, grade 3 and 4 neutropenia occurred in 55% and grade 3 and 4 thrombocytopenia in 40%; other toxicities were mild. CA125 and CA199 were elevated in more than 50% of patients. Viral serology studies were not significantly different from those of the indigenous population. CONCLUSION: Etoposide and cisplatin combination chemotherapy has modest activity in patients with extensive CUPS and, at the schedule and dosage given, it is associated with moderate toxicity.      

Toxic cardiogenic shock in a patient receiving weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin

A 54-year-old man was treated with weekly 24-h infusion of high-dose 5-fluorouracil (2600 mg/m2) and leucovorin (100 mg/m2) for metastatic colon cancer. At first, he tolerated the treatment well and no significant toxicity was identified. After a total of eight courses of treatment, a stable disease was observed, but mild shortness of breath was found on occasion. The patient had no previous history of cardiac disease and the heart performance assessed by left ventricular ejection fraction before treatment was normal. Unfortunately, acute pulmonary edema with lethal cardiogenic shock occurred during the ninth course of treatment, in spite of intensive medical treatment. The chest X-ray showed extreme cardiomegaly. Repeated assessment of his heart function by echocardiogram and ventricular ejection fraction revealed a very poor cardiac performance. Toxic cardiogenic shock during weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin is extremely rare. To the best of our knowledge, no case has been reported in the English literature. We report a case and the relevant literature about the incidence, clinical picture and possible pathophysiology on 5-fluorouracil-related cardioxicity is reviewed.      

Assessing the risk of stroke from neck manipulation: a systematic review

Background: Strokes, typically involving vertebral artery dissection, can follow cervical spinal manipulative therapy, and these types of stroke occur rarely. There is disagreement about whether a strong association between neck manipulation and stroke exists. An earlier systematic review found two relevant studies of association that used controls, which also discussed the limitations of the two papers. Our systematic review updates the earlier review, and aims to determine whether conclusive evidence of a strong association exists. Methods: PRISMA guidelines for systematic reviews were followed, and the literature was searched using a strategy that included the terms ‘neck manipulation’ and ‘stroke’ from the PubMed, Embase, CINAHL Plus and AMED databases. Citations were included if they met criteria such as being case–control studies, and dealt with neck manipulation and/or neck movement/positioning. Papers were scored for their quality, using similar criteria to the earlier review. For individual criteria, each study was assigned a full positive score if the criterion was satisfied completely. Results: Four case–control studies and one case–control study, which included a case‐ crossover design, met the selection criteria, but all of them had at least three items in the quality assessment that failed to be completely positive. Two studies were assessed to be the most robustly designed, one indicating a strong association between stroke and various intensities of neck movement, including manipulation, and the other suggesting a much reduced relative association when using primary care practitioners’ visits as controls. However, potential biases and confounders render the results inconclusive. Conclusion: Conclusive evidence is lacking for a strong association between neck manipulation and stroke, but is also absent for no association. Future studies of association will need to minimise potential biases and confounders, and ideally have sufficient numbers of cases to allow subgroup analysis for different types of neck manipulation and neck movement.     

Evaluation of the Heart Truth Professional Education Campaign on Provider Knowledge of Women and Heart Disease

BackgroundThe Heart Truth Professional Education Campaign was developed to facilitate education of health care providers in evidence-based strategies to prevent cardiovascular disease (CVD) in women.MethodsAs part of the 3-year campaign, lectures based on the American Heart Association's evidence-based guidelines for CVD prevention in women were presented by local speakers to healthcare providers and students in three high-risk states: Delaware, Ohio, and New York. Participants' responses to pretest and posttest questions about CVD in women are presented. We performed t-test and multivariable linear regression to assess the influence of provider characteristics on baseline knowledge and knowledge change after the lecture.ResultsBetween 2008 and 2011, 2,995 healthcare providers, students, and other participants completed the baseline assessment. Knowledge scores at baseline were highest for physicians, with obstetrician/gynecologists scoring lowest (63%) and cardiologists highest (76%). Nurses had intermediate total knowledge (56%) and students had the lowest total knowledge (49%) at baseline. Pre- and post-lecture assessments were completed by 1,893 (63%) of attendees. Scores were significantly higher after the educational lecture (p ≤ .001), with greater increase for those with lower baseline scores. Baseline knowledge of the use of statins, hormone therapy, and antioxidants, as well as approaches to smoking cessation and treatment of hypertension, differed by provider type.ConclusionTailoring of lectures for non-physician audiences may be beneficial given differences in baseline knowledge. More emphasis is needed on statin use for all providers and on smoking cessation and treatment of hypertension for nurses, students, and other healthcare professionals.