The Influence of Dirithromycin on the Pharmacokinetics of Cyclosporine in Healthy Subjects and in Renal Transplant Patients

The effect of a standard regimen of the investigational macrolide antibiotic, dirithromycin, on the single-dose kinetics of orally administered cyclosporine (CSA) was investigated in healthy young males and on the steady-state disposition kinetics of cyclosporine in a panel of renal transplant patients. Eight male volunteers participated after giving informed consent. CSA was administered in three single doses (15 mg kg(minus sign1) p.o. each) in each of three phases: (1) prior to a 14-day regimen of dirithromycin; (2) at the end of a 14-day regimen of dirithromycin (500 mg p.o. qAM); and (3) 2 weeks after the last dose of a 14-day regimen of dirithromycin. Pharmacokinetic parameters of CSA were estimated, and the differences among treatments were assessed by analysis of variation. No significant differences among treatment (phase) means were detected (p < 0.05). We conclude that a typical 14-day regimen of dirithromycin failed to alter the disposition kinetics of CSA when taken orally healthy young adult males. The effect of a standard regimen of dirithromycin on the steady-state disposition kinetics of orally administered CSA was investigated in a panel of 15 stable renal transplant patients. Pharmacokinetic parameters for CSA were evaluated prior to, during, and 2 weeks after discontinuing a 14-day (500 mg day(minus sign1)) oral regimen of dirithromycin. Dirithromycin elicited small but significant changes in the following parameters: C(av) was increased by 16% during dirithromycin treatment, and the changes in normalized C(av) were comparable. Likewise, C(SS,min) and normalized C(SS,min) were increased by 19% and 20%, respectively, during dirithromycin treatment. CSA oral clearance, CL/F(SS), decreased by 17% during dirithromycin treatment. C(SS,max) and normalized C(SS,max) were increased by 13% and 17%, respectively, during dirithromycin treatment but were not significantly different from those either before or after dirithromycin. The magnitude of the pharmacokinetic changes for CSA during dirithromycin treatment (<15% in normal subjects and 15--20% in renal transplant patients) when considered in the context of the therapeutic range of cyclosporine concentrations was relatively small, and not likely to warrant special attention to the dosing of CSA in such patients beyond routine whole-blood CSA and serum creatinine monitoring.     

Thoughts about encounters between nondisabled and disabled peers: Situational constraints,states-of-mind,valenced thought categories

This study explores three issues: thoughts and feelings of individuals with and without physical disabilities concerning encounters in different situations, ways of grouping self-statements into valenced categories, and use of states-of-mind (SOM) ratios as an alternative to positive and negative thought frequencies. Data from 127 able-bodied and 46 physically disabled college students indicate that, in everyday social encounters, nondisabled individuals' thoughts and feelings were more negative, while those of disabled individuals were more negative when helping was involved and when encounters centered on the impairment. Thus, problematic encounters between people with and without disabilities may be due to the reactions of individuals with disabilities in situations which involve help, and to reactions of able-bodied persons in everyday contexts. The data also confirm the utility of SOM ratios as an alternative to valenced frequencies in cognitive assessment: SOM scores discriminated groups when situational demands were manipulated and scores were linearly related to criterion measures. However, SOM ratios differed dramatically, depending on the attentional focus of thoughts. The findings illustrate types of thoughts which occur during interaction between people with and without disabilities, demonstrate a simple technique for grouping thoughts into valenced categories on an empirical basis, and highlight the relative contribution of cognitive and affective elements to overall valenced scores. Implications for research on assessment of self-statements are discussed and recommendations are made concerning programming to facilitate the social integration of people with disabilities.This research was supported by grants to the first author from the Social Sciences and Humanities Research Council of Canada and from Fonds F.C.A.R. pour l'aide et le soutien à la recherche. Thanks are due to Meribah Aikens, Maria Barile, Leo Bissonette, Bosco Daude, Jim Dubois, Lillian Fox, Evelyn Gold, Naomi Goodz, Darlene Judd, André Leblanc, John Martos, Sue McKenzie, Irwin Slopak, and Joan Wolforth for their assistance with various stages of this investigation.     

Differential response of human ovarian cancer cells to induction of apoptosis by vitamin E Succinate and vitamin E analogue, alpha-TEA.

A vitamin E derivative, vitamin E succinate (VES; RRR-alpha-tocopheryl succinate), and a vitamin E analogue, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid (alpha-TEA), induce human breast, prostate, colon, lung, cervical, and endometrial tumor cells in culture to undergo apoptosis but not normal human mammary epithelial cells, immortalized, nontumorigenic breast cells, or normal human prostate epithelial cells. Human ovarian and cervical cancer cell lines are exceptions, with alpha-TEA exhibiting greater proapoptotic effects. Although both VES and alpha-TEA can induce A2780 and subline A2780/cp70 ovarian cancer cells to undergo DNA synthesis arrest within 24 h of treatment, only alpha-TEA is an effective inducer of apoptosis. VES or alpha-TEA treatment of cp70 cells with 5, 10, or 20 microg/ml for 3 days induced 5, 6, and 19% versus 9, 36, and 71% apoptosis, respectively. Colony formation data provide additional evidence that cp70 cells are more sensitive to growth inhibition by alpha-TEA than VES. Differences in stability of the ester-linked succinate moiety of VES versus the ether-linked acetic acid moiety of alpha-TEA were demonstrated by high-performance liquid chromatography analyses that showed alpha-TEA to remain intact, whereas VES was hydrolyzed to the free phenol, RRR-alpha-tocopherol. Pretreatment of cp70 cells with bis-(p-nitrophenyl) phosphate, an esterase inhibitor, before VES treatment, resulted in increased levels of intact VES and apoptosis. Taken together, these data show alpha-TEA to be a potent and stable proapoptotic agent for human ovarian tumor cells and suggest that endogenous ovarian esterases can hydrolyze the succinate moiety of VES, yielding RRR-alpha-tocopherol, an ineffective apoptotic-inducing agent.     

Comparing Medications in a Therapeutic Area Using an NNT Model

OBJECTIVES: Clinicians are told to use the number needed to treat (NNT) to compare the benefits of therapeutic strategies, and researchers are asked to report results this way, generally without considering differences among the studies from which these were derived. METHODS: The crude NNT currently advocated is compared to the NNT standardized for a common outcome, follow-up time, study population and comparator. An NNT model for cardiovascular disease is described as an example that addresses differences among studies of secondary prevention of cardiovascular disease. Crude NNTs are compared to those obtained from the model. RESULTS: Follow-up in the 18 trials identified varied from 1.0 to 6.2 years; rates of cardiovascular events in the untreated subgroups ranged from 4.8% to 45.9%. The crude NNTs were more variable (9.1-163.7) than those obtained from the model (9.1-75.2). The effect of standardization was substantial in some cases, with proportional changes ranging from a 91% decrease to a 223% increase. CONCLUSION: Using an NNT model to account for differences in study design allows for more meaningful comparisons.     

Contribution of Cardiorespiratory Fitness to the Obesity Paradox

Until recently, cardiorespiratory fitness (CRF) has been overlooked as a potential modifier of the inverse association between obesity and mortality (the so-called obesity paradox), observed in patients with known or suspected cardiovascular (CV) disease. Evidence from five observational cohort studies of 30,104 patients (87% male) with CV disease indicates that CRF significantly alters the obesity paradox. There is general agreement across studies that the obesity paradox persists among patients with low CRF, regardless of whether adiposity is assessed by body mass index, waist circumference, or percentage body fat. However, among patients with high CRF, risk of all-cause mortality is lowest for the overweight category in some, but not all, studies, suggesting that higher levels of fitness may modify the relationship between body fatness and survival in patients manifesting an obesity paradox. Further study is needed to better characterize the joint contribution of CRF and obesity on mortality in diverse populations.     

Use of the Location-Based Social Networking Application GRINDR as a Recruitment Tool in Rectal Microbicide Development Research

Mobile phone social networking applications such as GRINDR are potential tools for recruitment of men who have sex with men (MSM) for HIV prevention research. Demographics and sexual risk behaviors of men recruited through GRINDR and through traditional media were compared. GRINDR participants were younger (mean age 31 vs. 42, p?<?0.0001), more White identified (44 vs. 30?%, p?<?0.01), and had more sex partners in the previous 14 days (1.88 vs. 1.10, p?<?0.05) than other recruits. Email responses were less successful for enrollment than phone calls (5 vs. 50?%). This approach resulted in successful recruitment of younger and more educated, White identified MSM.     

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.     

Transmetatarsal Amputation in the Setting of Antiphospholipid Antibody Syndrome

Antiphospholipid syndrome is a hypercoagulable disease that can present foot and ankle surgeons with a unique challenge in treating patients who present with thrombosis and ischemia despite having normal pedal pulses. Appropriate perioperative management is imperative in these patients, because limb- and life-threatening complications can occur postoperatively, despite aggressive anticoagulation. We present the case of a 46-year-old male who underwent a transmetatarsal amputation and, despite aggressive therapy, developed a myriad of complications postoperatively. At 10 months postoperatively, the patient was doing well in an accommodative orthotic with minimal pain while receiving continued aggressive therapy and follow-up examinations by a number of specialists to treat his antiphospholipid syndrome.