Time course of the interaction between tadalafil and nitrates

AbstractObjectivesThis study was designed to determine the time course of nitrate interaction with tadalafil, a phosphodiesterase 5 (PDE5) inhibitor with a half-life (t1/2) of 17.5 h.BackgroundThe PDE5 inhibitors augment the blood pressure (BP)-lowering effects of nitrates, yet the time course of this interaction is unclear. Recent guidelines from the American College of Cardiology/American Heart Association recommend that nitrates be withheld for 24 h after taking sildenafil (t1/2= 4 h).MethodsMale subjects (n = 150) received seven consecutive daily doses of placebo or tadalafil (20 mg). On day 7 and beyond, subjects received repeated doses of sublingual nitroglycerin (0.4 mg) after the last dose of placebo or tadalafil. After a 10- to 21-day washout period, subjects crossed over to either placebo or tadalafil, and nitrate dosing was repeated.ResultsIn response to nitroglycerin at 4, 8, and 24 h, standing systolic BP fell below 85 mm Hg in more subjects on tadalafil compared with placebo (p < 0.05), with no difference in the response to nitroglycerin at 48, 72, and 96 h (p > 0.2). Similar observations were made for standing diastolic BP <45 mm Hg, decrease in systolic BP >30 mm Hg, and decrease in diastolic BP >20 mm Hg. Nitroglycerin also evoked greater mean maximal decreases in standing systolic BP at 8 and 24 h after taking tadalafil versus placebo (p < 0.02), with no significant difference at 48, 72, or 96 h (p > 0.49).ConclusionsThe hemodynamic interaction between tadalafil and sublingual nitroglycerin lasted 24 h, but was not seen at 48 h and beyond. Similar to other PDE5 inhibitors, tadalafil should not be administered in combination with organic nitrates

The holistic phase model of early adult crisis

The objective of the current study was to explore the structural, temporal and experiential manifestations of crisis episodes in early adulthood, using a holistic-systemic theoretical framework. Based on an analysis of 50 interviews with individuals about a crisis episode between the ages of 25 and 35, a holistic model was developed. The model comprises four phases: (1) Locked-in, (2) Separation/Time-out, (3) Exploration and (4) Rebuilding, which in turn have characteristic features at four levels—person-in-environment, identity, motivation and affect-cognition. A crisis starts out with a commitment at work or home that has been made but is no longer desired, and this is followed by an emotionally volatile period of change as that commitment is terminated. The positive trajectory of crisis involves movement through an exploratory period towards active rebuilding of a new commitment, but ‘fast-forward’ and ‘relapse’ loops can interrupt Phases 3 and 4 and make a positive resolution of the episode less likely. The model shows conceptual links with life stage theories of emerging adulthood and early adulthood, and it extends current understandings of the transitional developmental challenges that young adults encounter

Recommendations for the design of therapeutic trials for neonatal seizures

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from welldesigned clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population

Exploring the responsiveness of goal attainment scaling in relation to number of goals set in a sample of hemophilia-A patients

Abstract Purpose Guidelines for the use of goal attainment scaling (GAS) recommend that the patient specify at least three goals. Even so, this may not always be feasible or align with patient preferences. Investigations into the psychometric properties of GAS using three or more goals largely support its reliability, validity, and responsiveness compared with standard measures. As evaluations of responsiveness rely on variability estimates, this metric may be impacted when GAS is based on fewer than three goals. For this reason, we investigated the responsiveness of one- and two-goal GAS. Methods Secondary analyses were conducted on data from a mixed sample of pediatric, adolescent and adult subjects with hemophilia A. The standardized response mean (SRM) and its 95% confidence intervals (CI) were used to assess responsiveness of one- and two-goal GAS at six and twelve weeks. Results Both one-goal and two-goal GAS demonstrated similar responsiveness to change at 6-week (Patient-Rated GAS: one-goal SRM [95% CI] = 0.70 [0.45–1.08], two-goal = 0.96 [0.68–1.30]; Clinician-Rated GAS: one-goal = 1.26 [0.81–1.77], two-goal = 1.01 [0.73–1.32]) and 12-week follow-up (Patient-Rated GAS: one-goal SRM [95% CI] = 1.14 [0.53–1.71], two-goal = 1.35 [0.92–1.82]; Clinician-Rated GAS: one-goal = 1.71 [1.12–2.30], two-goal = 1.48 [1.02–2.02]). Larger SRMs were observed for clinician-rated GAS, but all were within the rubric of a large effect size. Conclusions One-goal GAS is responsive to change in a clinical population. Further research is recommended in a larger sample where responsiveness of one- and multiple-goal GAS can be compare

Faunal turnover at Mille-Logya (Plio-Pleistocene, Ethiopia) reflects in situ environmental change: implications for the origins of Homo

The lower Awash Valley of Ethiopia preserves a significant record of Australopithecus afarensis at Hadar and Dikika in addition to the earliest fossil yet attributed to Homo from Ledi-Geraru at 2.8 Ma. However, understanding the context of the extinction of A. afarensis and the origin of Homo is hampered by the limited preservation of sediments between 2.9 – 2.3 Ma in the region. The Mille-Logya Project (MLP) preserves fossiliferous sediments post-dating 2.9 Ma. Here we present a quantitative analysis of the MLP mammalian fauna and explore implications of MLP faunal change for the origin of Homo.info:eu-repo/semantics/publishedVersio

Physical and Functional Interactions of Human Endogenous Retrovirus Proteins Np9 and Rec with the Promyelocytic Leukemia Zinc Finger Protein▿

Only few of the human endogenous retrovirus (HERV) sequences in the human genome can produce proteins. We have previously reported that (i) patients with germ cell tumors often make antibodies against proteins encoded by HERV-K elements, (ii) expression of the HERV-K rec gene in transgenic mice can interfere with germ cell development and induce carcinoma in situ, and (iii) HERV-K np9 transcript is overproduced in many tumors including breast cancers. Here we document that both Np9 and Rec physically and functionally interact with the promyelocytic leukemia zinc finger (PLZF) tumor suppressor, a transcriptional repressor and chromatin remodeler implicated in cancer and the self-renewal of spermatogonial stem cells. Interaction is mediated via two different central and C-terminal domains of Np9 and Rec and the C-terminal zinc fingers of PLZF. One major target of PLZF is the c-myc proto-oncogene. Coexpression of Np9 and Rec with PLZF abrogates the transcriptional repression of the c-myc gene promoter by PLZF and results in c-Myc overproduction, altered expression of c-Myc-regulated genes, and corresponding effects on cell proliferation and survival. Thus, the human endogenous retrovirus proteins Np9 and Rec may act oncogenically by derepressing c-myc through the inhibition of PLZF