Efficacy and safety of tadalafil in men with erectile dysfunction with a high prevalence of comorbid conditions: results from MOMENTUS: multiple observations in men with erectile dysfunction in National Tadalafil Study in the US.

PubMed

Goldstein, Irwin; Kim, Edward; Steers, William D; Pryor, Jon L; Wilde, Dixon W; Natanegara, Fanni; Wong, David G; Ahuja, Sanjeev

2007-01-01

Limited efficacy and safety data exist from open-label clinical trials of phosphodiesterase 5 inhibitors in men with erectile dysfunction (ED) and multiple comorbid (MCM) conditions, historically a difficult group to treat. A multicenter study (Multiple Observations in Men with Erectile Dysfunction in National Tadalafil Study in the US) assessed efficacy and safety of tadalafil in men with ED and MCM conditions. The primary end point was change from baseline in the erectile function (EF) domain of the International Index of Erectile Function. Secondary end points included the Sexual Encounter Profile, Global Assessment Questions, and Sexual Self-Confidence and Spontaneity Domains of the Psychological and Interpersonal Relationship Scales. This was an open-label, multicenter study in men with ED. Tadalafil 20 mg was administered as needed prior to sexual activity, up to once/day, for 12 weeks following a 4-week ED-treatment-free period. The MCM group was 155 of 1,911 men enrolled in this study. Men in the MCM group met eligibility criteria but could not be included in other predefined groups: (i) Caucasian; (ii) Black American; (iii) Hispanic (groups 1-3, < or =65 years, no diabetes or depression); (iv) depression, < or =65 years, no diabetes; (v) diabetes, < or =65 years, no depression; (vi) >65 years, no diabetes or depression; and (vii) ED subsequent to traumatic spinal cord injury. Mean baseline EF domain score in MCM (mean age 65 +/- 9 years) was 12.2 +/- 6.5; 52% of subjects had severe ED; 72% diabetes mellitus; 67% cardiovascular disease (including hypertension); 49% hyperlipidemia; 38% depression; 84% had two or more comorbidities. At end point, there was a significant (P < 0.001) mean change of 7.6 from baseline in mean EF domain score. Among men with severe ED, 22% achieved an EF domain score > or =26. Most common adverse events were headache 5.2%; flushing 3.9% and nasal congestion 3.2%; 3% discontinued use because of an adverse event. In this open

Effect of tadalafil administration on insulin secretion and insulin sensitivity in obese men.

PubMed

González-Ortiz, Manuel; Martínez-Abundis, Esperanza; Hernández-Corona, Diana M; Ramírez-Rodríguez, Alejandra M

2017-10-01

To evaluate the effect of tadalafil administration on insulin secretion and insulin sensitivity in obese men without diabetes. A randomized, double-blind, placebo-controlled clinical trial was carried out in obese male patients between 30 and 50 years of age. Eighteen subjects were randomly assigned to two groups of nine patients each. During a 28-day period, subjects received 5 mg orally of tadalafil or placebo each night. Patients were evaluated before and after the intervention. Total insulin secretion and first phase of insulin secretion were calculated by insulinogenic index and Stumvoll index, respectively, and insulin sensitivity was calculated using the Matsuda index. Tolerability and compliance were evaluated permanently throughout the study. There were no significant differences after administration of tadalafil in total insulin secretion (0.82 ± 0.45 vs. 0.61 ± 0.27, p = 0.594), first phase of insulin secretion (1332 ± 487 vs. 1602 ± 800, p = 0.779) and insulin sensitivity (4.6 ± 1.2 vs. 4.9 ± 2.5, p = 0.779). No significant differences were shown in other measurements. Tadalafil administration for 28 days did not modify insulin secretion or insulin sensitivity in obese men.

Erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) combined responders to tadalafil after 12 weeks of treatment.

PubMed

Roehrborn, Claus G; Egan, Kathryn B; Miner, Martin M; Ni, Xiao; Wong, David G; Rosen, Raymond C

2016-07-01

To analyse the proportion of men taking tadalafil 5 mg once daily who experience a combined improvement in symptoms of both erectile dysfunction (ED) and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). The data from men aged ≥45 years randomized to tadalafil 5 mg once daily or placebo enrolled in one of four randomized, placebo-controlled LUTS/BPH clinical trials were analysed (N = 927). A novel classification of 'combined responders' to ED and LUTS/BPH treatment was defined, based on published criteria for men who showed improvement in both International Index of Erectile Function - Erectile Function domain (IIEF-EF) score and total International Prostate Symptom Score (IPSS). Descriptive analyses assessed the covariate distribution by responder status. Unadjusted and adjusted logistic regressions provided odds ratios with 95% confidence intervals comparing combined responders with all others (partial and non-responders). Among men randomized to tadalafil 5 mg, 40.5% were combined responders (n = 189). Among placebo randomized men, 18.3% were combined responders (n = 84). Combined responders, in the total population, had the highest baseline IPSS and lowest baseline IIEF-EF scores, corresponding to the highest level of dysfunction. The majority of men were aged ≤65 years, white, non-obese, non-smokers, and regular alcohol consumers. Only treatment, baseline IPSS, baseline IIEF-EF, obesity and psychoactive medication use were significantly associated with responder status (P ≤ 0.05). Tadalafil-treated men had 2.8 times significantly increased adjusted odds of being combined responders vs non-responders (P < 0.001). For each unit decrease in baseline IIEF-EF or alcoholic drink consumption per week there was a 4% significant increase in the adjusted odds of being a combined responder to tadalafil therapy. This novel measure of combined response is useful in differentiating patients with clinically relevant symptom

A randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of tadalafil (Cialis[reg]) in the treatment of erectile dysfunction following three-dimensional conformal external-beam radiotherapy for prostatic carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Incrocci, Luca; Slagter, Cleo; Slob, A. Koos

2006-10-01

Purpose: Erectile dysfunction after three-dimensional conformal external-beam radiotherapy (3DCRT) for prostatic carcinoma is reported in as many as 64% of those patients. The purpose of this study was to determine the efficacy of the oral drug tadalafil (Cialis (registered) ) in patients with erectile dysfunction after radiotherapy for prostatic carcinoma. Methods and Materials: Patients (N = 358) who completed radiotherapy at least 12 months before the study were approached by mail. All patients had been treated by 3DCRT; 60 patients were included and entered a double-blind, placebo-controlled, cross-over study lasting 12 weeks. They received 20 mg of tadalafil or placebomore » for 6 weeks. Drug or placebo was taken on demand at patient's discretion, with no restrictions regarding the consumption of alcohol or food, at least once a week and no more than once daily. At 6 weeks patients crossed over to the alternative treatment. Data were collected using the Sexual Encounter Profile (SEP) and the International Index of Erectile Function (IIEF) questionnaires. Side effects were also recorded. Results: Mean age at study entry was 69 years. All patients completed the study. For almost all questions of the IIEF questionnaire there was a significant increase in mean scores from baseline with tadalafil, but not with placebo. Sixty-seven percent of the patients reported an improvement of erectile function with tadalafil (placebo: 20%), and 48% reported successful intercourse with tadalafil (placebo: 9%) (p < 0.0001). Side effects were mild or moderate. Conclusions: Tadalafil is an effective treatment for erectile dysfunction after 3DCRT for prostatic carcinoma with successful intercourse reported in almost 50% of the patients, and it is well tolerated.« less

[Tadalafil combined with behavior therapy for semen collection from infertile males in whom masturbation fails].

PubMed

Tang, Wen-Hao; Jiang, Hui; Ma, Lu-Lin; Hong, Kai; Zhao, Lian-Ming; Liu, De-Feng; Mao, Jia-Ming; Yang, Yi; Zhang, Ju; Gao, Ling; Qiao, Jie

2013-05-01

To study the effect of Tadalafil combined with behavior therapy in helping obtain semen from infertile men in whom masturbation has failed. Sixty male infertile patients from whom masturbation had failed to obtain semen were equally assigned to receive Tadalafil combined with behavior therapy (combination group) or Tadalafil only (control group). All the patients took Tadalafil 20 mg orally the night before the day of semen collection by masturbation. Before this procedure, the patients of the combination group practiced masturbation 16 - 24 times at home. The average ages of the patients were (37.0 +/- 5.1) yr and (37.5 +/- 5.2) yr and their IIEF-5 scores were 16.50 +/- 1.25 and 16.90 +/- 1.09 in the combination and the control group, respectively, neither with statistically significant difference between the two groups. Semen was successfully obtained from 9 patients (30.0%) of the combination group and 1 patient (3.33%) of the control group, with statistically significant difference between the two groups (chi2 = 7.680, P < 0.01). By training the patients and establishing a conditioned response to masturbation, Tadalafil combined with behavior therapy can significantly increase the success rate of semen collection from the male infertile patients in whom masturbation fails.

Effect of tadalafil 5mg daily treatment on the ejaculatory times, lower urinary tract symptoms and erectile function in patients with erectile dysfunction

PubMed Central

Karabakan, Mehmet; Keskin, Ercument; Akdemir, Serkan; Bozkurt, Aliseydi

2017-01-01

ABSTRACT Objective To investigate the effect of a 5mg daily tadalafil treatment on the ejaculation time, erectile function and lower urinary tract symptoms (LUTS) in patients with erectile dysfunction. Materials and Methods A total of 60 patients diagnosed with erectile dysfunction were retrospectively evaluated using the international index of erectile function questionnaire-5 (IIEF-5), intravaginal ejaculatory latency time (IELT) and international prostate symptoms scores (IPSS). After the patients were treated with 5mg tadalafil once a day for three months, their erection, ejaculation and LUTS were assessed again. The fasting levels of blood glucose, total testosterone, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol were measured. The independent-samples t-test was used to compare the pre- and post-treatment scores of the patients. Results The mean age of the 60 participants was 50.4±7.9 and the mean baseline serum total testosterone, total cholesterol, and fasting blood sugar were 444.6±178.6ng dL-1, 188.7±29.6mg/dL-1,104 (80-360) mg dL-1, respectively. The mean baseline scores were 2.2±1.4 min for IELT, 9.5±3.7 for IIEF-5 and 14.1±4.5 for IPSS. Following the three-month daily 5mg tadalafil treatment, the scores were found to be 3.4±1.9 min, 16.1±4.7, and 10.4±3.8 for IELT, IIEF and IPSS, respectively. When the baseline and post-treatment scores were compared, a statistically significant increase was observed in the IELTs and IIEF-5 values whereas there was a significant decrease in IPSS (p<0.01). Conclusion A daily dose of 5mg tadalafil can be safely used in the treatment of erectile dysfunction and LUTS, that prolongs the ejaculatory latency time. PMID:27819758

Effect of tadalafil 5mg daily treatment on the ejaculatory times, lower urinary tract symptoms and erectile function in patients with erectile dysfunction.

PubMed

Karabakan, Mehmet; Keskin, Ercument; Akdemir, Serkan; Bozkurt, Aliseydi

2017-01-01

To investigate the effect of a 5mg daily tadalafil treatment on the ejaculation time, erectile function and lower urinary tract symptoms (LUTS) in patients with erectile dysfunction. A total of 60 patients diagnosed with erectile dysfunction were retrospectively evaluated using the international index of erectile function questionnaire-5 (IIEF-5), intravaginal ejaculatory latency time (IELT) and international prostate symptoms scores (IPSS). After the patients were treated with 5mg tadalafil once a day for three months, their erection, ejaculation and LUTS were assessed again. The fasting levels of blood glucose, total testosterone, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol and total cholesterol were measured. The independentsamples t-test was used to compare the pre- and post-treatment scores of the patients. The mean age of the 60 participants was 50.4±7.9 and the mean baseline serum total testosterone, total cholesterol, and fasting blood sugar were 444.6±178.6ng dL-1, 188.7±29.6mg/dL-1,104 (80-360) mg dL-1, respectively. The mean baseline scores were 2.2±1.4 min for IELT, 9.5±3.7 for IIEF-5 and 14.1±4.5 for IPSS. Following the three-month daily 5mg tadalafil treatment, the scores were found to be 3.4±1.9 min, 16.1±4.7, and 10.4±3.8 for IELT, IIEF and IPSS, respectively. When the baseline and post-treatment scores were compared, a statistically significant increase was observed in the IELTs and IIEF-5 values whereas there was a significant decrease in IPSS (p<0.01). A daily dose of 5mg tadalafil can be safely used in the treatment of erectile dysfunction and LUTS, that prolongs the ejaculatory latency time. Copyright® by the International Brazilian Journal of Urology.

Dissolution enhancement of tadalafil by liquisolid technique.

PubMed

Lu, Mei; Xing, Haonan; Yang, Tianzhi; Yu, Jiankun; Yang, Zhen; Sun, Yanping; Ding, Pingtian

2017-02-01

This study aimed to enhance the dissolution of tadalafil, a poorly water-soluble drug by applying liquisolid technique. The effects of two critical formulation variables, namely drug concentration (17.5% and 35%, w/w) and excipients ratio (10, 15 and 20) on dissolution rates were investigated. Pre-compression tests, including particle size distribution, flowability determination, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and scanning electron microscopy (SEM), were carried out to investigate the mechanism of dissolution enhancement. Tadalafil liquisolid tablets were prepared and their quality control tests, dissolution study, contact angle measurement, Raman mapping, and storage stability test were performed. The results suggested that all the liquisolid tablets exhibited significantly higher dissolution rates than the conventional tablets and pure tadalafil. FT-IR spectrum reflected no drug-excipient interactions. DSC and XRD studies indicated reduction in crystallinity of tadalafil, which was further confirmed by SEM and Raman mapping outcomes. The contact angle measurement demonstrated obvious increase in wetting property. Taken together, the reduction of particle size and crystallinity, and the improvement of wettability were the main mechanisms for the enhanced dissolution rate. No significant changes were observed in drug crystallinity and dissolution behavior after storage based on XRD, SEM and dissolution results.

A randomized clinical trial investigating treatment choice in Chinese men receiving sildenafil citrate and tadalafil for treating erectile dysfunction

PubMed Central

Bai, Wen-Jun; Li, Hong-Jun; Jin, Jian-Jun; Xu, Wen-Ping; Sebastian, Sorsaburu; Wang, Xiao-Feng

2017-01-01

Sildenafil and tadalafil are efficacious and well tolerated in Chinese men with erectile dysfunction (ED). Recent study results indicate that men with ED in China who were naïve to phosphodiesterase inhibitor type 5 (PDE5) therapy prefer tadalafil 20-mg (on-demand) versus sildenafil 100-mg (on-demand). Differences in psychosocial outcomes may help to explain treatment preference in favor of tadalafil. This open-label, randomized, crossover study compared psychosocial outcomes and drug attribute choices between tadalafil and sildenafil in Chinese men with ED naïve to PDE5 inhibitor therapy. Eligible patients were randomized to sequential 20-mg tadalafil/100-mg sildenafil (n = 190) or 100-mg sildenafil/20-mg tadalafil (n = 193) for 8 weeks each and were asked which treatment they preferred to take for the 8-week extension phase. Psychosocial outcomes were assessed using the Psychological and Interpersonal Relationship Scale (PAIRS), Drug Attributes Questionnaire (DRAQ), and Sexual Life Quality Questionnaire (SLQQ). When taking tadalafil versus sildenafil, men had a higher mean endpoint score on the PAIRS Spontaneity Domain (tadalafil = 2.86 vs sildenafil = 2.72; P < 0.001), and a lower mean endpoint score on the Time Concerns Domain (tadalafil = 2.41 vs sildenafil = 2.55; P < 0.001). A numerical increase in the Sexual Self-Confidence Domain was observed when taking tadalafil versus sildenafil (tadalafil = 2.76 vs sildenafil = 2.72; P = 0.102). The most frequently chosen drug attributes explaining treatment preference were able to get an erection long after having drug, and ability to get an erection every time. SLQQ results were comparable between treatment groups. These psychosocial outcomes may explain why more Chinese men preferred tadalafil versus sildenafil for the treatment of ED in this clinical trial. PMID:27101805

A randomized clinical trial investigating treatment choice in Chinese men receiving sildenafil citrate and tadalafil for treating erectile dysfunction.

PubMed

Bai, Wen-Jun; Li, Hong-Jun; Jin, Jian-Jun; Xu, Wen-Ping; Sebastian, Sorsaburu; Wang, Xiao-Feng

2017-01-01

Sildenafil and tadalafil are efficacious and well tolerated in Chinese men with erectile dysfunction (ED). Recent study results indicate that men with ED in China who were naïve to phosphodiesterase inhibitor type 5 (PDE5) therapy prefer tadalafil 20-mg (on-demand) versus sildenafil 100-mg (on-demand). Differences in psychosocial outcomes may help to explain treatment preference in favor of tadalafil. This open-label, randomized, crossover study compared psychosocial outcomes and drug attribute choices between tadalafil and sildenafil in Chinese men with ED naïve to PDE5 inhibitor therapy. Eligible patients were randomized to sequential 20-mg tadalafil/100-mg sildenafil (n = 190) or 100-mg sildenafil/20-mg tadalafil (n = 193) for 8 weeks each and were asked which treatment they preferred to take for the 8-week extension phase. Psychosocial outcomes were assessed using the Psychological and Interpersonal Relationship Scale (PAIRS), Drug Attributes Questionnaire (DRAQ), and Sexual Life Quality Questionnaire (SLQQ). When taking tadalafil versus sildenafil, men had a higher mean endpoint score on the PAIRS Spontaneity Domain (tadalafil = 2.86 vs sildenafil = 2.72; P < 0.001), and a lower mean endpoint score on the Time Concerns Domain (tadalafil = 2.41 vs sildenafil = 2.55; P < 0.001). A numerical increase in the Sexual Self-Confidence Domain was observed when taking tadalafil versus sildenafil (tadalafil = 2.76 vs sildenafil = 2.72; P = 0.102). The most frequently chosen drug attributes explaining treatment preference were able to get an erection long after having drug, and ability to get an erection every time. SLQQ results were comparable between treatment groups. These psychosocial outcomes may explain why more Chinese men preferred tadalafil versus sildenafil for the treatment of ED in this clinical trial.

76 FR 6794 - 30-Day Submission Period for Requests for ONC-Approved Accreditor (ONC-AA) Status

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-08

... Accreditor (ONC-AA) Status AGENCY: Office of the National Coordinator for Health Information Technology... submission of requests for ONC-Approved Accreditor (ONC-AA) status. Authority: 42 U.S.C. 300jj-11. DATES: The... for ONC-AA status may be submitted. The 30-day period for submission of requests for ONC-AA status...

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia.

PubMed

Zarifpour, Mona; Nomiya, Masanori; Sawada, Norifumi; Andersson, Karl-Erik

2015-02-15

The etiology of Benign Prostatic Hyperplasia (BPH), a common among aged men, is not fully understood, however, in addition to androgens and aging, chronic ischemia has been proposed to contribute. Using an established rat model, we investigated whether chronic ischemia alters the structural and functional properties of the ventral rat prostate, and whether phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) may have a protective action. Adult male Sprague-Dawley rats were divided into control, arterial endothelial injury (AI), and AI with tadalafil treatment (AI-tadalafil) groups. AI and AI-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-tadalafil rats were treated with tadalafil (2 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, animals were sacrificed, and pharmacological and morphological studies on prostate tissues were performed. Iliac arteries from AI rats displayed neo-intimal formation and luminal occlusion, an effect that was not prevented by tadalafil treatment. In the AI group, there was an obvious epithelial atrophy and a statistically significant increase in collagen fibers compared with the controls. Immunohistochemically, there was an up-regulation of smooth muscle α-actin (SMA). Contractile responses of prostate strips to KCl, electrical field stimulation (EFS), and phenylephrine (PE) were significantly higher after AI than in controls. Chronic treatment with tadalafil prevented the increase in contractile responses in ischemic tissue, and decreased the collagen deposition compared with the AI group. In this rat model, chronic pelvic ischemia caused distinct functional and morphological changes in the prostate. Prostatic tissue from ischemic animals showed an increased contractile response to electrical and pharmacological stimulation, an increase in SMA, and an increased deposition of collagen. All these changes could be

The use of a single daily dose of tadalafil to treat signs and symptoms of benign prostatic hyperplasia and erectile dysfunction

PubMed Central

Gacci, Mauro; Salvi, Matteo; Sebastianelli, Arcangelo; Vignozzi, Linda; Corona, Giovanni; McVary, Kevin T; Kaplan, Steven A; Maggi, Mario; Carini, Marco; Oelke, Matthias

2013-01-01

A strong and independent association between lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED) has been widely evidenced in several clinical epidemiologic studies. Preclinical animal models have provided a great deal of information on potential common pathogenic mechanisms underlying these two clinical identities. Although the efficacy of the most commonly used treatments for LUTS/BPH is well defined, the negative impact of these treatments on sexual function – in particular, on ED – has triggered the search for new treatment options. In this regard, a new role for phosphodiesterase type 5 inhibitors in the treatment of LUTS/BPH and ED has been claimed. Tadalafil is one of the most extensively investigated phosphodiesterase type 5 inhibitors for this new indication. All evidence reported to date suggests that tadalafil 5 mg once daily is a safe and effective treatment option for both LUTS/BPH and ED. PMID:24400241

Cardiac function and tadalafil used for treating fetal growth restriction in pregnant women without cardiovascular disease.

PubMed

Tanaka, Kayo; Tanaka, Hiroaki; Maki, Shintaro; Kubo, Michiko; Nii, Masafumi; Magawa, Shoichi; Hatano, Fumi; Tsuji, Makoto; Osato, Kazuhiro; Kamimoto, Yuki; Umekawa, Takashi; Ikeda, Tomoaki

2018-02-20

The aim of the present study was to evaluate tadalafil for the treatment of fetal growth restriction (FGR) and the cardiac function in pregnant women without cardiovascular disease who used tadalafil for this reason. We examined nine pregnant women without cardiovascular disease who were using tadalafil to treat FGR. Maternal heart rate, systolic blood pressure (BP), and echocardiographic findings were assessed before and after tadalafil use. Diastolic BP was lower after compared to that before using tadalafil, but the difference was not significant. Echocardiographic findings were not significantly different before and after tadalafil use. Tadalafil did not adversely affect pregnant women without cardiovascular disease and was considered acceptable for use since it did not affect the mother's cardiac function.

Design and in vivo evaluation of oxycodone once-a-day controlled-release tablets

PubMed Central

Kim, Ju-Young; Lee, Sung-Hoon; Park, Chun-Woong; Rhee, Yun-Seok; Kim, Dong-Wook; Park, Junsang; Lee, Moonseok; Seo, Jeong-Woong; Park, Eun-Seok

2015-01-01

The aim of present study was to design oxycodone once-a-day controlled-release (CR) tablets and to perform in vitro/in vivo characterizations. Release profiles to achieve desired plasma concentration versus time curves were established by using simulation software and reported pharmacokinetic parameters of the drug. Hydroxypropyl methylcellulose (HPMC) 100,000 mPa·s was used as a release modifier because the polymer was found to be resistant to changes in conditions of the release study, including rotation speed of paddle and ion strength. The burst release of the drug from the CR tablets could be suppressed by applying an additional HPMC layer as a physical barrier. Finally, the oxycodone once-a-day tablet was comprised of two layers, an inert HPMC layer and a CR layer containing drug and HPMC. Commercial products, either 10 mg bis in die (bid [twice a day]) or once-a-day CR tablets (20 mg) were administered to healthy volunteers, and calculated pharmacokinetic parameters indicated bioequivalence of the two different treatments. The findings of the present study emphasize the potential of oxycodone once-a-day CR tablets for improved patient compliance, safety, and efficacy, which could help researchers to develop new CR dosage forms of oxycodone. PMID:25678774

Effects of tadalafil administration on plasma markers of exercise-induced muscle damage, IL6 and antioxidant status capacity.

PubMed

Ceci, Roberta; Duranti, Guglielmo; Sgrò, Paolo; Sansone, Massimiliano; Guidetti, Laura; Baldari, Carlo; Sabatini, Stefania; Di Luigi, Luigi

2015-03-01

Physical exercise is associated with enhanced production of reactive oxygen species, which if uncontrolled can result in tissue injury. Phosphodiesterase type 5 inhibitors (PDE5i) exhibit protective effect against oxidative stress, both in animals and healthy/unhealthy humans. However, the effect of a chronic administration of PDE5i, particularly combined with physical exercise, has never been investigated. The present study was designed to evaluate the effect of the long-acting PDE5i tadalafil on oxidative status and muscle damage after exhaustive exercise in healthy males included in a double-blind crossover trial. Tadalafil, having a putative antioxidant activity, may reduce oxidative damage after strenuous exercise. Each volunteer randomly received two tablets of placebo or tadalafil (20 mg/day) with 36 h of interval before performing exhaustive exercise. After 2 weeks of washout, the volunteers were crossed over. Blood samples were collected immediately before exercise, immediately after, and during recovery (15, 30, 60 min). Plasma total antioxidant status, glutathione homeostasis (GSH/GSSG), malondialdehyde (MDA), protein carbonyls, creatine kinase (CK), lactate dehydrogenase (LDH) and the inflammatory cytokine interleukin 6 were assessed. Tadalafil administration per se affected redox homeostasis (GSH/GSSG -36%; p < 0.05), cellular (CK +75% and LDH +36%; p < 0.05) and oxidative damage (MDA +41% and protein carbonyls +50%; p < 0.05) markers. The exhaustive exercise increased all the above-reported biochemical parameters, with subjects from the tadalafil group showing significantly higher values with respect to the placebo group. A prolonged exposure to tadalafil decreases antioxidant capacity at resting condition, therefore making subjects more susceptible to the oxidative stress induced by an exhaustive bout of exercise.

Scheduling reinforcement about once a day.

PubMed

Eckerman, D A

1999-04-01

A pigeon earned its daily food by pecking a key according to reinforcement schedules that produced food about once per day. Fixed-interval (FI), Fixed-time (FT), and various complex schedules were arranged to demonstrate the degree to which a scalloped pattern of responding remained. Pausing continued until about an hour before the reinforcer could be earned for FIs of 12, 24, and 48 h. Pausing was not as long for FIs of 18, 19, and 23 h. Pausing of about 24 h was seen for FI 36 h. FT 24 h produced continued responding but at a diminished frequency. The pattern of responding was strongly controlled by the schedule of reinforcement and seemed relatively independent of the cycle of human activity in the surrounding laboratory. Effects of added ratio contingencies and of signaling the availability of reinforcement in FT were also examined. Signaled FTs of 5 min-3 h produced more responding during the signal (autoshaping) than did FTs of 19 or 24 h.

Sexual asthenia: Tradamixina versus Tadalafil 5 mg daily

PubMed Central

2012-01-01

Background Reduced libido is widely considered the most prominent symptomatic reflection of low testosterone (T) levels in men. Testosterone deficiency (TD) afflicts approximately 30% of men aged 40-79 years. This study seeks to evaluate the effect of a new natural compound “tradamixina “in order to improve male sexual function in elderly men, particularly libido and possible erectile dysfunction, versus administration of tadalafil 5 mg daily. Methods Seventy patients (67.3± 3.7 years) with stable marital relations and affected by reduced libido, with or without erectile dysfunction were recruited. They were randomly separated in 2 groups A-B of 35. Group A was administered twice a day a new compound “Tradamixina” (150 mg of Alga Ecklonia Bicyclis, 396 mg of Tribulus Terrestris and 144 mg of D-Glucosamine and N-Acetyl-D-Glucosamine) for two months, while Group B was administered tadalafil 5 mg daily, for two months. At visit and after 60 days of treatment patients were evaluated by means of detailed medical and sexual history, clinical examination, laboratory investigations (Total and Free T), instrumental examination (NPTR- nocturnal penile tumescence and rigidity test- with Rigiscan). Patients completed a self-administered IIEF questionnaire (The international index of erectile function) and SQoLM questionnaire (Sexual quality of life Questionnarie-Male). The results pre and post treatment were compared by Student t test (p<0.005). Results After 2 months of treatment in group A serum TT levels (230±18 ng/dl vs 671±14 ng/dl ) and FT levels(56± 2.4 pg/ml vs 120± 3.9pg/ml) increased, while in group B serum TT levels (245±12 ng/dl vs 247±15 ng/dl ) and FT levels(53± 0.3 pg/ml vs 55± 0.5pg/ml) increased not statistically significant. The patient’s numbers with negative NPTR improved after treatment in group A and B (15 vs 18 and 13 vs 25 respectively). The IIEF total score in group A increased after treatment with tradamixina (15±1.5 vs 29.77±1

Tadalafil Reduces Myeloid-Derived Suppressor Cells and Regulatory T Cells and Promotes Tumor Immunity in Patients with Head and Neck Squamous Cell Carcinoma

PubMed Central

Vella, Jennifer L.; Reis, Isildinha M.; De la fuente, Adriana C.; Gomez, Carmen; Sargi, Zoukaa; Nazarian, Ronen; Califano, Joseph; Borrello, Ivan

2015-01-01

Purpose Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC. Experimental Design First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 μg/day, 20 μg/day, or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8+ T-cell reactivity to tumor antigens were evaluated before and after treatment. Results MDSCs were characterized in HNSCC and their intratumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (P < 0.05). In addition, the concentration of blood CD8+ T cells reactive to autologous tumor antigens significantly increased after treatment (P < 0.05). Tadalafil immunomodulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect antitumor immunity. Conclusions Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8+ T cells in a dose-dependent fashion. PMID:25320361

Tadalafil in the management of lower urinary tract symptoms: a review of the literature and current practices in Russia

PubMed Central

Govorov, Alexander; Kasyan, George; Priymak, Diana; Pushkar, Dmitry

2014-01-01

Introduction Strong epidemiologic evidence supports correlation between lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED). The link has biologic plausibility given phosphodiesterase type 5 (PDE5) expression in pelvic structures. PDE5 inhibitors target pathophysiologic processes implicated in LUTS/BPH. Material and methods This review highlights the efficacy and safety of the daily use of a PDE5 inhibitor tadalafil in LUTS/BPH, with a focus on LUTS/BPH medical management in Russia. Results Alpha–blockers and phytotherapy are major components of the current LUTS/BPH therapy in Russia. Russian regulatory authorities granted approval for once–daily tadalafil for treatment of LUTS/BPH in January 2012. In a pivotal study, tadalafil 5 mg once–daily significantly improved International Prostate Symptom Score (IPSS) over 12 weeks vs. placebo (P = .004) regardless of baseline ED severity. IPSS improvement was maintained at 12 weeks. Integrated analysis of randomized studies showed that tadalafil 5 mg once–daily resulted in significant symptom improvements across a range of men with LUTS/BPH. Relief of LUTS due to tadalafil was independent of improvement in ED; improvements in IPSS and erectile function were only weakly correlated (r = –0.229). Another pooled analysis found similar improvement in LUTS/BPH between men with or without ED, with non–significant P values for treatment–by–ED–status interactions for total IPSS ( P = .73). Non–registration studies of tadalafil and alpha–blocker co–therapy in LUTS/BPH suggest an additive effect, but co–therapy is not recommended in current tadalafil prescribing instructions. Conclusions Tadalafil results in symptom improvements across a range of men with LUTS/BPH and represents a new treatment option for patients in Russia with LUTS/BPH. PMID:25140232

Tadalafil reversal of sexual dysfunction caused by serotonin enhancing medications in women.

PubMed

Ashton, Adam Keller; Weinstein, Wendy

2006-01-01

Sexual dysfunction is a common side effect of many antidepressants, especially those that increase serotonin. Many strategies have been reported to assist patients in minimizing impairment, with variable degrees of success. One of the newer approaches is to augment with phosphodiesterase type-5 inhibitors. Our report using the most recently released agent in this class, tadalafil is the first demonstrating potential benefit in women. We report here of three women who derived benefit from using 20 mg of tadalafil before anticipated sexual activity to reverse medication-induced sexual dysfunction. Tadalafil utility was maintained over time and was well tolerated.

Treatment satisfaction with tadalafil or tamsulosin vs placebo in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH): results from a randomised, placebo-controlled study.

PubMed

Oelke, Matthias; Giuliano, François; Baygani, Simin K; Melby, Thomas; Sontag, Angelina

2014-10-01

To assess treatment satisfaction with tadalafil or tamsulosin vs placebo in a 12-week, randomised, double-blind study of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). After a 4-week placebo lead-in period, men aged ≥45 years with an International Prostate Symptom Score (IPSS) of ≥13 and a maximum urinary flow rate of ≥4 to ≤15 mL/s received placebo (172 men), tadalafil 5 mg (171), or tamsulosin 0.4 mg (168) once daily for 12 weeks. Treatment Satisfaction Scale-BPH (TSS-BPH) responses were assessed based on median treatment differences using the van Elteren test. Overall treatment satisfaction was greater for tadalafil vs placebo (P = 0.005), based on greater satisfaction with efficacy (P = 0.003); neither overall treatment satisfaction nor satisfaction with efficacy was greater for tamsulosin vs placebo (P ≥ 0.409). For individual questions, 66.5% of men rated tadalafil treatment as 'effective/very effective' (Question 1, Q1) vs placebo (P = 0.011), 72.6% would 'definitely/probably recommend their treatment' (Q3; P = 0.043), 71.8% were generally 'very satisfied/satisfied with their medication' (Q8; P < 0.003), and 65.0% would 'definitely/probably continue therapy' (Q10; P = 0.035). With tamsulosin, differences vs placebo were not statistically significant. Subgroup analyses of overall TSS-BPH by baseline age (≤65/>65 years), history of erectile dysfunction (yes/no), LUTS/BPH severity (IPSStadalafil vs placebo, with only borderline difference for men without prior therapy. Treatment satisfaction was greater with tadalafil vs placebo, with no significant difference between tamsulosin and placebo. © 2014 The Authors. BJU International

Efficacy and treatment satisfaction with on-demand tadalafil (Cialis) in men with erectile dysfunction.

PubMed

Skoumal, René; Chen, Juza; Kula, Krzysztof; Breza, Jan; Calomfirescu, Nicolae; Basson, Bruce R; Kopernicky, Vladimir

2004-09-01

Tadalafil (Cialis) is an inhibitor of phosphodiesterase type 5, which mediates relaxation of vascular smooth muscle in the corpus cavernosum thus facilitating erection. The purpose of this multicentre, randomized, double-blind, parallel group, placebo-controlled study was to evaluate efficacy and treatment satisfaction of on-demand Cialis in men with mild-to-severe erectile dysfunction (ED). Following a 4-week treatment-free run in period, patients stratified into three severity groups by the International Index of Erectile Function (IIEF) Erectile Function (EF) domain score were randomized to receive either placebo or Cialis 20 mg taken on demand over a 12-week period. Efficacy endpoints were change from baseline in IIEF EF domain scores, responses to Sexual Encounter Profile diary (SEP) questions, and responses to the Global Assessment Questions (GAQ). Treatment satisfaction was evaluated using the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire in two of seven participating countries where validated translations were available. Of the 443 men who entered the trial, 409 (mean age, 52 years) formed the intent-to-treat population. Mean baseline demographics and ED severity measures were balanced between treatment groups except for a higher percentage of patients naïve to sildenafil in the tadalafil group compared to placebo (50% versus 36%). The percentage of patients in each IIEF EF severity class (mild, moderate and severe) was 47%, 30% and 23% for placebo patients and 48%, 29% and 23% for tadalafil patients, respectively. Tadalafil was significantly superior to placebo on all primary efficacy measures (IIEF EF domain scores, SEP15, GAQ1; p < 0.001); notably 64% of tadalafil patients achieved a normal IIEF EF domain score at endpoint compared to 16% of placebo patients (p < 0.001). Of the 185 patients completing the EDITS questionnaire (137 receiving Cialis and 48 receiving placebo), tadalafil-treated patients had a median EDITS

Effect of Tadalafil on Seizure Threshold and Activity of Antiepileptic Drugs in Three Acute Seizure Tests in Mice.

PubMed

Socała, Katarzyna; Nieoczym, Dorota; Pieróg, Mateusz; Wyska, Elżbieta; Szafarz, Małgorzata; Doboszewska, Urszula; Wlaź, Piotr

2018-02-09

Tadalafil, a selective phosphodiesterase type 5 inhibitor, is a long-acting oral agent for the treatment of erectile dysfunction of multiple etiologies. Although generalized tonic-clonic seizures were reported in a healthy man after taking tadalafil, the influence of tadalafil on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of tadalafil on seizure threshold as well as on the activity of some first- and second-generation antiepileptic drugs in three acute seizure tests in mice. The obtained results showed that tadalafil, at the highest dose tested (20 mg/kg), significantly decreased the threshold for the first myoclonic twitch in the intravenous pentylenetetrazole (i.v. PTZ) seizure test. It did not affect the threshold for generalized clonic seizure and forelimb tonus in the i.v. PTZ, for tonic hindlimb extension in the maximal electroshock seizure threshold test, and for psychomotor seizure in the 6-Hz-induced seizure threshold test. Tadalafil did not alter the anticonvulsant activity of any of the studied antiepileptic drugs in electrically induced seizure tests. Interestingly, tadalafil potentiated the anticonvulsant activity of clonazepam and decreased the anticonvulsant activity of oxcarbazepine in the i.v. PTZ test. These interactions were pharmacodynamic in nature, as tadalafil did not alter clonazepam and oxcarbazepine concentrations both in serum and brain tissue. Furthermore, neither tadalafil alone nor its combinations with the studied antiepileptic drugs produced any significant impairment of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test), and long-term memory (assessed in the passive avoidance task). In conclusion, tadalafil may increase the risk of myoclonic seizure and decrease the anticonvulsant efficacy of oxcarbazepine. Further studies are warranted to evaluate the safety of tadalafil usage in patients with

Tadalafil inclusion in microporous silica as effective dissolution enhancer: optimization of loading procedure and molecular state characterization.

PubMed

Mehanna, Mohammed M; Motawaa, Adel M; Samaha, Magda W

2011-05-01

Tadalafil is an efficient drug used to treat erectile dysfunction characterized by poor water solubility, which has a negative influence on its bioavailability. Utilization of microporous silica represents an effective and facile technology to increase the dissolution rate of poorly soluble drugs. Our strategy involved directly introducing tadalafil as guest molecule into microporous silica as host material by incipient wetness impregnation method. To optimize tadalafil inclusion, response surface methodology (RSM) using 3(3) factorial design was utilized. Furthermore, to investigate the molecular state of tadalafil, Fourier-transform infrared spectroscopy, differential scanning calorimetery, thermal gravimetrical analysis, nitrogen adsorption, and powder X-ray diffraction (PXRD) were carried out. The results obtained pointed out that the quantity of microporous silica was the predominant factor that increased the loading efficiency. For the optimized formula, the loading efficiency was 42.50 wt %. Adsorption-desorption experiments indicated that tadalafil has been introduced into the micropores. Powder XRD and differential scanning calorimetry analyses revealed that tadalafil is arranged in amorphous form. In addition, the dissolution rate of tadalafil from the microporous silica was faster than that of free drug. Amorphous tadalafil occluded in microporous silica did not crystallize over 3 months. These findings contributed in opening a new strategy concerning the utilization of porous silica for the dissolution rate enhancement. Copyright © 2010 Wiley-Liss, Inc.

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.

PubMed

Coghlan, John Gerry; Galiè, Nazzareno; Barberà, Joan Albert; Frost, Adaani E; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M; Kuwana, Masataka; McLaughlin, Vallerie V; Peacock, Andrew J; Simonneau, Gérald; Vachiéry, Jean-Luc; Blair, Christiana; Gillies, Hunter; Miller, Karen L; Harris, Julia H N; Langley, Jonathan; Rubin, Lewis J

2017-07-01

Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. NCT01178073, post results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial

PubMed Central

Coghlan, John Gerry; Galiè, Nazzareno; Barberà, Joan Albert; Frost, Adaani E; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M; Kuwana, Masataka; McLaughlin, Vallerie V; Peacock, Andrew J; Simonneau, Gérald; Vachiéry, Jean-Luc; Blair, Christiana; Gillies, Hunter; Miller, Karen L; Harris, Julia H N; Langley, Jonathan; Rubin, Lewis J

2017-01-01

Background Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. Objective To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. Methods This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). Results In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. Conclusions This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. Trial registration number NCT01178073, post results. PMID:28039187

Switching patients with erectile dysfunction from sildenafil citrate to tadalafil: results of a European multicenter, open-label study of patient preference.

PubMed

Ströberg, Peter; Murphy, Aileen; Costigan, Tim

2003-11-01

Three inhibitors of phosphodiesterase 5 (PDE5) are now available for the treatment of erectile dysfunction (ED): sildenafil citrate, vardenafil, and tadalafil. Pharmacologic differences between these compounds may result in patient preferences for one over another and may influence treatment decisions made by the physician and patient. Therefore, clinical research is needed to investigate whether individual properties of the PDE5 inhibitors play a role in shaping patient preference. The goal of this study was to determine what proportion of ED patients currently taking sildenafil would, after a period of treatment with tadalafil, elect to resume treatment with sildenafil at the customary dose and what proportion would elect a switch to tadalafil 20 mg for a longer period. The tolerability of both treatments was also investigated. This was a short-term, multicenter, open-label, 1-way crossover trial conducted in Sweden and Italy. Eligible patients included men aged >or=18 years with a minimum 3-month history of ED who had been taking sildenafil at stable fixed doses of 25, 50, or 100 mg as needed for at least 6 weeks and up to 24 weeks. The study consisted of 6 phases: a 1-week screening phase, a 3-week sildenafil assessment phase, a 1-week washout phase, a 6-week tadalafil initiation phase, a 3-week tadalafil assessment phase, and a 6-month extension phase, during which patients received their treatment of choice free of charge. The primary outcome measure was the proportion of patients electing to take sildenafil or tadalafil during the extension phase. Of 155 men enrolled, 147 (97.8%) completed the assessment phases of the trial. Of these 147 men, 133 (90.5%) elected to receive tadalafil in the 6-month extension phase and 14 (9.5%) elected to receive sildenafil (P < 0.001). The proportions preferring tadalafil to sildenafil were similar irrespective of age group (>or=50 years, 92%; <50 years, 90%), severity of ED (mild, 95%; moderate, 88%; severe, 96%), etiology

"ONCE UPON A DAY," A SERIES OF VIDEOTAPED TELEVISION PROGRAMS FOR CHILDREN.

ERIC Educational Resources Information Center

NATHANSON, NORBERT H.

THIS BOOKLET DESCRIBES "ONCE UPON A DAY," AN EDUCATIONAL TELEVISION SERIES FOR CHILDREN AGED 4 TO 7. THE PROGRAM IS AVAILABLE AT NO COST TO ALL NEW YORK STATE EDUCATIONAL TELEVISION STATIONS, CLOSED CIRCUIT AND 2500 MEGACYCLES AND COMMUNITY ANTENNA SYSTEMS SERVING NEW YORK SCHOOLS. THE PROGRAM PRESENTS USEFUL CONCEPTS AND INFORMATION IN…

Understanding Motivations to Adopt Once-a-Day Milking amongst New Zealand Dairy Farmers

ERIC Educational Resources Information Center

Bewsell, D.; Clark, D. A.; Dalley, D. E.

2008-01-01

This paper reports the results of a study to understand why some New Zealand dairy farmers are changing from twice-a-day (TAD) to once-a-day (OAD) milking. Increasing herd size, unavailability of suitable labour and changing lifestyle expectations from farmers and their staff have led some to explore OAD milking as a means of alleviating these…

Tadalafil enhances the neuroprotective effects of ischemic postconditioning in mice, probably in a nitric oxide associated manner.

PubMed

Gulati, Puja; Singh, Nirmal

2014-05-01

This study investigates the modulatory effect of tadalafil, a selective phosphodiesterase (PDE-5) inhibitor, on the neuroprotective effects of ischemic postconditioning (iPoCo) in mice. Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion induced cerebral injury. Cerebral infarct size was measured using TTC staining. Memory was assessed using the Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walking, rota-rod, and lateral push tests. Brain nitrite/nitrate, acetylcholinesterase activity, TBARS, and glutathione levels were also estimated. BCAO followed by reperfusion produced a significant increase in cerebral infarct size, brain nitrite/nitrate and TBARS levels, and acetylcholinesterase activity along with a reduction in glutathione. Marked impairment of memory and motor coordination was also noted. iPoCo consisting of 3 episodes of 10 s carotid artery occlusion and reperfusion instituted immediately after BCAO significantly decreased infarct size, memory impairment, motor incoordination, and altered biochemistry. Pretreatment with tadalafil mimicked the neuroprotective effects of iPoCo. The tadalafil-induced neuroprotective effects were significantly attenuated by l-NAME, a nonselective NOS inhibitor. We concluded that tadalafil mimics the neuroprotective effects of iPoCo, probably through a nitric oxide dependent pathway, and PDE-5 could be a target of interest with respect to the neuroprotective mechanism of iPoCo.

Tadalafil attenuates hypotonicity-induced Ca2+ influx via TRPV2 and TRPV4 in primary rat bladder urothelial cell cultures.

PubMed

Dong, Xiao; Nakagomi, Hiroshi; Miyamoto, Tatsuya; Ihara, Tatsuya; Kira, Satoru; Sawada, Norifumi; Mitsui, Takahiko; Takeda, Masayuki

2018-03-22

To investigate the localization of phosphodiesterase 5 (PDE5) and the molecular mechanism underlying the effect of the PDE5 inhibitor tadalafil in signal transduction in the bladder urothelium. PDE5 expression in rat bladder tissues and cultured primary rat bladder urothelial cells was evaluated using immunochemistry and western blot assays. Ca 2+ influx in cells exposed to isotonic solution, hypotonic solution, a selective transient receptor potential vanilloid 2 (TRPV2) channel agonist (cannabidiol), a selective TRPV4 channel agonist (GSK1016790A), a TRP cation channel melastatin 7 (TRPM7) channel agonist (PIP2), or a purinergic receptor agonist (ATP) in the presence or absence of 10 µM tadalafil was evaluated using calcium imaging techniques. We also evaluated stretch-induced changes in ATP concentration in the mouse bladder in the presence or absence of 100 µM tadalafil. Immunochemistry and western blot analyses demonstrated that PDE5 is abundantly expressed in the bladder urothelium and in primary rat urothelial cells. Ca 2+ influx induced by hypotonic stimulation, GSK1016790A, or cannabidiol was significantly inhibited by tadalafil, whereas ATP-induced Ca 2+ influx was unaffected by tadalafil. PIP2 did not induce Ca2+ influx. ATP release in tadalafil-pretreated bladders significantly decreased compared to control bladders. Tadalafil attenuates Ca 2+ influx via TRPV4 and TRPV2, and inhibits ATP release in the bladder urothelium. These findings indicate that tadalafil functions as an inhibitor of urothelial signal transduction. © 2018 Wiley Periodicals, Inc.

Urinary Tract Symptoms (LUTS) Secondary to Benign Prostatic Hyperplasia (BPH) and LUTS/BPH with Erectile Dysfunction in Asian Men: A Systematic Review Focusing on Tadalafil.

PubMed

Park, Hyun Jun; Won, Ji Eon Joanne; Sorsaburu, Sebastian; Rivera, Paul David; Lee, Seung Wook

2013-12-01

This review assesses lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) with or without erectile dysfunction (ED) and related therapies focusing on tadalafil. A literature search was obtained and reviewed for the epidemiology, treatment therapies, pathophysiology, and efficacy and safety of phosphodiesterase type 5 inhibitor (PDE5i) tadalafil in patients with LUTS/BPH. Approximately 42% of men aged 51 to 60 years have BPH. Approximately 90% of men aged 45 to 80 years have LUTS. Occurrence of LUTS increases with age for almost all racial/ethnic groups (range, 32% to 56%) with prevalence of LUTS highest among Hispanic men, then Blacks, Caucasians, and Asians. There is an independent relationship with LUTS/BPH and ED, with approximately 70% of men with LUTS/BPH having ED with severity of one disease often correlating with the other. The European Urological Association guidelines include the use of the PDE5i tadalafil. Tadalafil is the only therapy recommended for treatment of co-existing BPH and ED, while other therapies have unwanted ED side effects. The mode of action of tadalafil may involve different areas of the lower urinary tract such as smooth muscle cell relaxation in the bladder neck, prostate, and urethra, but there may also be resulting modulation of the afferent nerve activity. Tadalafil (5 mg) in Asian men with LUTS/BPH, similar to global studies, is efficacious and safe. Tadalafil (5 mg) improves co-existing LUTS/BPH and ED, independently. Men with LUTS/BPH likely also have ED. Asian men with LUTS/BPH have similar incidence rates, co-existing ED, comorbid diseases, and risks as non-Asian men. Tadalafil can improve co-existing LUTS/BPH and ED.

Central serous chorioretinopathy due to tadalafil use.

PubMed

Türkcü, Fatih Mehmet; Yüksel, Harun; Şahin, Alparslan; Murat, Mehmet; Bozkurt, Yaşar; Çaça, Ihsan

2013-04-01

Phosphodiesterase-5 (PDE5) inhibitors are commonly used in the treatment of erectile dysfunction. There are a small number of case reports that associate this agent with central serous chorioretinopathy (CSCR). Our report presents the treatment approach to a 42-year-old patient who described blurred vision and metamorphopsia and was diagnosed with CSCR following the use of tadalafil, a PDE5 inhibitor.

Urinary Tract Symptoms (LUTS) Secondary to Benign Prostatic Hyperplasia (BPH) and LUTS/BPH with Erectile Dysfunction in Asian Men: A Systematic Review Focusing on Tadalafil

PubMed Central

Park, Hyun Jun; Won, Ji Eon Joanne; Sorsaburu, Sebastian; Rivera, Paul David

2013-01-01

This review assesses lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) with or without erectile dysfunction (ED) and related therapies focusing on tadalafil. A literature search was obtained and reviewed for the epidemiology, treatment therapies, pathophysiology, and efficacy and safety of phosphodiesterase type 5 inhibitor (PDE5i) tadalafil in patients with LUTS/BPH. Approximately 42% of men aged 51 to 60 years have BPH. Approximately 90% of men aged 45 to 80 years have LUTS. Occurrence of LUTS increases with age for almost all racial/ethnic groups (range, 32% to 56%) with prevalence of LUTS highest among Hispanic men, then Blacks, Caucasians, and Asians. There is an independent relationship with LUTS/BPH and ED, with approximately 70% of men with LUTS/BPH having ED with severity of one disease often correlating with the other. The European Urological Association guidelines include the use of the PDE5i tadalafil. Tadalafil is the only therapy recommended for treatment of co-existing BPH and ED, while other therapies have unwanted ED side effects. The mode of action of tadalafil may involve different areas of the lower urinary tract such as smooth muscle cell relaxation in the bladder neck, prostate, and urethra, but there may also be resulting modulation of the afferent nerve activity. Tadalafil (5 mg) in Asian men with LUTS/BPH, similar to global studies, is efficacious and safe. Tadalafil (5 mg) improves co-existing LUTS/BPH and ED, independently. Men with LUTS/BPH likely also have ED. Asian men with LUTS/BPH have similar incidence rates, co-existing ED, comorbid diseases, and risks as non-Asian men. Tadalafil can improve co-existing LUTS/BPH and ED. PMID:24459652

Effect of sprint training: training once daily versus twice every second day.

PubMed

Ijichi, Toshiaki; Hasegawa, Yuta; Morishima, Takuma; Kurihara, Toshiyuki; Hamaoka, Takafumi; Goto, Kazushige

2015-01-01

This study compared training adaptations between once daily (SINGLE) and twice every second day (REPEATED) sprint training, with same number of training sessions. Twenty physically active males (20.9 ± 1.3 yr) were assigned randomly to the SINGLE (n = 10) or REPEATED (n = 10) group. The SINGLE group trained once per day (5 days per week) for 4 weeks (20 sessions in total). The REPEATED group conducted two consecutive training sessions on the same day, separated by a rest period of 1 h (2-3 days per week) for 4 weeks (20 sessions in total). Each training session consisted of three consecutive 30-s maximal pedalling sets with a 10-min rest between sets. Before and after the training period, the power output during two bouts of 30-s maximal pedalling, exercise duration during submaximal pedalling and resting muscle phosphocreatine (PCr) levels were evaluated. Both groups showed significant increases in peak and mean power output during the two 30-s bouts of maximal pedalling after the training period (P < 0.05). The groups showed similar increases in VO2max after the training period (P < 0.05). The REPEATED group showed a significant increase in the onset of blood lactate accumulation (OBLA) after the training period (P < 0.05), whereas no change was observed in the SINGLE group. The time to exhaustion at 90% of VO2max and muscle PCr concentration at baseline did not change significantly in either group. Sprint training twice every second day improved OBLA during endurance exercise more than the same training once daily.

Effectiveness of sildenafil citrate (Viagra) and tadalafil (Cialis) on sexual responses in Saudi men with erectile dysfunction in routine clinical practice.

PubMed

Ali, Syed Tabrez

2008-07-01

Satisfaction with the sexual experience is considered important when evaluating the impact of treatments for erectile dysfunction, yet enhanced satisfaction has been infrequently assessed in the sexual trials. We evaluated the efficacy of sildenafil vs. tadalafil, in Saudi men with erectile dysfunction and determined the self-based rating of medicinal preference. Sildenafil citrate (Viagra) is a potent inhibitor of the electrolytic enzyme type V phosphodiesterase (PDE5), in the corpus cavernosum and therefore increases the penile response to sexual stimulation. Tadalafil (Cialis) is also a PDE5 inhibitor that increases the level of cyclic guanosine monophosphate (cGMP) in cavernous smooth muscle cells. Whereas cGMP is a second messenger for the vasodilator effects of nitric oxide causing smooth muscle relaxation, which in turn leads to penile erection; however the mechanism by which cGMP stimulates relaxation of the smooth muscles remains to be elucidated. Both sildenafil and tadalafil have a rapid onset with the effectiveness up to 4 hours and 36 hours respectively. In this study subjects treated with 100 mg oral dose of sildenafil / 20 mg tadalafil were found to be associated with higher mean scores for the questions of the International Index of Erectile Function (IIEF). Frequency of penetration and maintenance of erection after sexual penetration and/or during masturbation were found to be enhanced significantly (p<0.001) in both sildenafil/tadalafil treated men. Similarly mean domain of erectile function, orgasmic function, and intercourse satisfaction also showed a significantly positive improvement (p/0.001) in both the treated groups in comparison with their age matched untreated controls. Interestingly in all the cases, tadalafil group showed considerably greater positive responses than the sildenafil group but within the same significant levels. Strikingly the sexual-desire domain in sildenafil treated men with respect to their aged matched controls

A Two-Impulse Plan for Performing Rendezvous on a Once-A-Day Basis

NASA Technical Reports Server (NTRS)

Bird, John D.; Thomas, David F., Jr.

1960-01-01

An investigation of a two-impulse plan for performing rendezvous on a once-a-day basis with a near-earth satellite station indicates that launch into rendezvous from slightly less than maximum satellite latitude is an unusually favorable circumstance in that no appreciable expense in mass ratio is incurred. In addition, it was found for the two-impulse maneuver employed in this study that the optimum angular travel of the ferry vehicle to rendezvous was considerably less than the 1800 transfer which is optimum for the two-impulse in-plane launch.

Efficacy and safety of rosuvastatin every other day compared with once daily in patients with hypercholesterolemia.

PubMed

Wongwiwatthananukit, Supakit; Sansanayudh, Nakarin; Dhummauppakorn, Rawadee; Kitiyadisai, Chutiporn

2006-11-01

Although most patients with hypercholesterolemia require life-long therapy with statins, these drugs are underused due to high costs. Every-other-day therapy could be one strategy to resolve this problem. To compare the efficacy and safety of rosuvastatin 10 mg administered every other day versus once daily. An 8 week, randomized, open-label, parallel trial was conducted at the outpatient department of Phramongkutklao Hospital in Bangkok, Thailand. Eighty patients with primary hypercholesterolemia were equally randomized to receive rosuvastatin 10 mg once daily or every other day; 76 patients completed the study. Laboratory data were assessed at baseline and at the end of the study. Low-density lipoprotein cholesterol (LDL-C) levels were reduced by 48% and 39% in the once-daily and every-other-day groups, respectively (p = 0.011). The percentage of patients who achieved LDL-C goals according to National Cholesterol Education Program-Adult Treatment Panel III guidelines was not significantly different between the once-daily (85%) and every-other-day (70%) groups (p = 0.180). In addition, both regimens were well tolerated, with no patient developing an elevation of more than 3 times baseline levels of aspartate aminotransferase or alanine aminotransferase or 10 times that of creatine kinase. As expected, the monthly cost per percent LDL-C reduction of the once-daily (0.72 dollars) regimen was about 38% higher than that of the every-other-day (0.44 dollars) regimen. Every-other-day dosing of rosuvastatin may be an alternative regimen for cost savings, without a major decrease in therapeutic benefit or increase in adverse events, in patients with hypercholesterolemia. The number of patients achieving their LDL-C goal using the every-other-day regimen is comparable with the number using the once-daily regimen, especially in the low-risk patient category.

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic-Banded Mini-Swine.

PubMed

Hiemstra, Jessica A; Lee, Dong I; Chakir, Khalid; Gutiérrez-Aguilar, Manuel; Marshall, Kurt D; Zgoda, Pamela J; Cruz Rivera, Noelany; Dozier, Daniel G; Ferguson, Brian S; Heublein, Denise M; Burnett, John C; Scherf, Carolin; Ivey, Jan R; Minervini, Gianmaria; McDonald, Kerry S; Baines, Christopher P; Krenz, Maike; Domeier, Timothy L; Emter, Craig A

2016-04-20

Cyclic guanosine monophosphate-protein kinase G-phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl-peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function. We assessed LV hypertrophy and function at the organ and cellular level in aortic-banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end-systolic pressure-volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil-treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening-frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium-retention capacity and Complex II-dependent respiratory control, was present in both HF and tadalafil-treated animals. Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin

Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies.

PubMed

Brock, Gerald B; McVary, Kevin T; Roehrborn, Claus G; Watts, Steven; Ni, Xiao; Viktrup, Lars; Wong, David G; Donatucci, Craig

2014-02-01

Tadalafil has regulatory approval for the treatment of men with signs/symptoms of benign prostatic hyperplasia with and without erectile dysfunction. We assessed whether the effects of treatment with tadalafil for lower urinary tract symptoms/benign prostatic hyperplasia are independent of improvements in erectile dysfunction. Four separate analyses used integrated data from 4 randomized, double-blind, placebo controlled studies in men with lower urinary tract symptoms/benign prostatic hyperplasia with and without erectile dysfunction to test whether total I-PSS (International Prostate Symptom Score) improvement was due to improvement in IIEF-EF (International Index of Erectile Function-Erectile Function domain score). Unidirectional and bidirectional path analysis models determined direct and indirect treatment effects mediated by improvements in lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction symptoms. A total of 1,496 men, of whom 77% had erectile dysfunction, received at least 1 dose of tadalafil 5 mg once daily or placebo. The placebo adjusted treatment effect for men with erectile dysfunction was represented by a mean decrease of -2.3 (p <0.0001) in total I-PSS vs -2.2 (p = 0.0007) for men without erectile dysfunction. The correlation between change from baseline in total I-PSS and IIEF-EF was weak (r(2) = 0.08, p <0.0001). The unidirectional path analysis model suggested that the total treatment effect on total I-PSS score improvement (2.25) was derived from a direct treatment effect of 1.57 (70%, p <0.001) and an indirect treatment effect of 0.67 (30% via IIEF-EF improvement, p <0.001). Bidirectional path analysis showed that total I-PSS improvement was largely attributed to direct (92.5%, p <0.001) vs indirect (7.5%, p = 0.32) treatment effects via IIEF-EF improvement. Regardless of the analytical approach, self-reported erectile dysfunction status did not appreciably influence tadalafil treatment response in men with

An open-label, multicenter, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in Chinese men naïve to phosphodiesterase 5 inhibitor therapy.

PubMed

Bai, Wen-Jun; Li, Hong-Jun; Dai, Yu-Tian; He, Xue-You; Huang, Yi-Ran; Liu, Ji-Hong; Sorsaburu, Sebastian; Ji, Chen; Jin, Jian-Jun; Wang, Xiao-Feng

2015-01-01

The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in Chinese men naοve to phosphodiesterase 5 (PDE5) inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire (PITPQ). Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function (IIEF) erectile function (EF) domain, sexual encounter profile (SEP) Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men (91%) completed the randomized treatment phase. Two hundred and forty-two per 350 (69.1%) patients preferred 20-mg tadalafil, and 108/350 (30.9%) preferred 100-mg sildenafil (P < 0.001) as their treatment in the 8 weeks extension. Ninety-two per 242 (38%) patients strongly preferred tadalafil and 37/108 (34.3%) strongly the preferred sildenafil. The SEP2 (penetration), SEP3 (successful intercourse), and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by > 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED naοve to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe.

An open-label, multicenter, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in Chinese men naïve to phosphodiesterase 5 inhibitor therapy

PubMed Central

Bai, Wen-Jun; Li, Hong-Jun; Dai, Yu-Tian; He, Xue-You; Huang, Yi-Ran; Liu, Ji-Hong; Sorsaburu, Sebastian; Ji, Chen; Jin, Jian-Jun; Wang, Xiao-Feng

2015-01-01

The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in Chinese men naïve to phosphodiesterase 5 (PDE5) inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire (PITPQ). Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function (IIEF) erectile function (EF) domain, sexual encounter profile (SEP) Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men (91%) completed the randomized treatment phase. Two hundred and forty-two per 350 (69.1%) patients preferred 20-mg tadalafil, and 108/350 (30.9%) preferred 100-mg sildenafil (P < 0.001) as their treatment in the 8 weeks extension. Ninety-two per 242 (38%) patients strongly preferred tadalafil and 37/108 (34.3%) strongly the preferred sildenafil. The SEP2 (penetration), SEP3 (successful intercourse), and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by > 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED naïve to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe. PMID:25370206

Do vardenafil and tadalafil have advantages over sildenafil in the treatment of erectile dysfunction?

PubMed

Doggrell, S

2007-01-01

Erectile dysfunction (ED) affects up to 50% of men between the ages of 40 and 70 years of age. Sildenafil, vardenafil and tadalafil have all been shown to be similarly effective in the treatment of men with ED of vary etiologies, to have similar adverse effects profiles, and to improve quality-of-life by similar amounts. As these phosphodiesterase 5 (PDE5) inhibitors all increase the hypotensive effects of nitrates, they are not suitable for use in patients taking nitrates for the treatment of ischaemic heart disease. All three inhibitors must be used with caution in patients taking alpha(1)-adrenoceptors antagonists for benign prostatic hyperplasia. Although nonarteritic anterior ischaemic neuropathy has been reported in some users of the PDE5 inhibitors, there is no conclusive evidence that PDE5 inhibitors cause this rare effect. Tadalafil has a longer half-life than sildenafil or vardenafil, and a longer duration of action than sildenafil and vardenafil. Most preference studies have shown tadalafil to be preferred, but there are serious limitations to some of these studies. One approach to treatment is to give each patient a short- and long-acting agent, and for individuals to decide their preference.

Effects of Sildenafil and Tadalafil on Edema and Reactive Oxygen Species Production in an Experimental Model of Lung Ischemia-Reperfusion Injury.

PubMed

Guerra-Mora, J R; Perales-Caldera, E; Aguilar-León, D; Nava-Sanchez, C; Díaz-Cruz, A; Díaz-Martínez, N E; Santillán-Doherty, P; Torres-Villalobos, G; Bravo-Reyna, C C

Lung ischemia-reperfusion injury is characterized by formation of reactive oxygen species and cellular swelling leading to pulmonary edema and primary graft dysfunction. Phosphodiesterase 5 inhibitors could ameliorate lung ischemia-reperfusion injury by interfering in many molecular pathways. The aim of this work was to evaluate and compare the effects of sildenafil and tadalafil on edema and reactive oxygen species formation in an ex vivo nonhuman animal model of lung ischemia-reperfusion injury. Thirty-two Wistar rats were distributed, treated, perfused and the cardiopulmonary blocks were managed as follows: control group: immediate excision and reperfusion without pretreatment; ischemia reperfusion group: treatment with dimethylsulfoxide 0.9% and excision 1 hour later; sildenafil group: treatment with sildenafil (0.7 mg/kg) and excision 1 hour later; and tadalafil group: treatment with tadalafil (0.15 mg/kg) and excision 2 hours later. All cardiopulmonary blocks except control group were preserved for 8 hours and then reperfused. Pulmonary arterial pressure, pulmonary venous pressure, and capillary filtration coefficient were measured. Reactive oxygen species were measured. Edema was similar between control and sildenafil groups, but significantly greater in the ischemia-reperfusion (P ≤ .04) and tadalafil (P ≤ .003) groups compared with the sildenafil group. The malondialdehyde levels were significantly lower in the sildenafil (P ≤ .001) and tadalafil (P ≤ .001) groups than the ischemia-reperfusion group. Administration of sildenafil, but not tadalafil, decreased edema in lung ischemia-reperfusion injury. Both drugs decreased reactive oxygen species formation in a lung ischemia-reperfusion injury model. Copyright © 2017 Elsevier Inc. All rights reserved.

The role of initial success rates and other factors in determining reliability of outcomes of phosphodiesterase inhibitor therapy for erectile dysfunction: a pooled analysis of 17 placebo-controlled trials of tadalafil for use as needed.

PubMed

Sontag, Angelina; Rosen, Raymond C; Litman, Heather J; Ni, Xiao; Araujo, Andre B

2013-02-01

Reliability of successful outcomes in men with erectile dysfunction (ED) on phosphodiesterase type 5 inhibitors is an important aspect of patient management. We examined reliability of successful outcomes in a large integrated dataset of randomized tadalafil trials. Success rates, time to success, subsequent success after first success, and probability of success were analyzed based on Sexual Encounter Profile questions 2 and 3. Data from 3,254 ED patients treated with tadalafil 10 mg (N = 510), 20 mg (N = 1,772), or placebo (N = 972) were pooled from 17 placebo-controlled studies. Tadalafil patients had significantly higher first-attempt success rates vs. placebo. This effect was consistent across most subgroups; however, patients with severe ED experienced a greater response to tadalafil than patients with mild-moderate ED. Approximately 80% of patients achieved successful penile insertion within two attempts with either tadalafil dose and successful intercourse within eight attempts for tadalafil 10 mg and four attempts for tadalafil 20 mg. However, approximately 70% of tadalafil-treated patients achieved successful intercourse even by the second attempt. Subsequent success rates were higher for patients with first-attempt success (81.5% for 10 mg and 86.1% for 20 mg vs. 66.2% for placebo, P < 0.001) vs. patients with later initial success (53.2% for 10 mg and 56.4% for 20 mg vs. 39.9% for placebo, P < 0.001). Among patients treated with tadalafil, intercourse success rates at early attempts were similar to rates at later attempts (i.e., attempts 5 and 10 vs. 25), although insertion success rates were significantly lower earlier in treatment. The findings affirm the reliability of successful outcomes with tadalafil treatment and that first-attempt success is a critical factor affecting subsequent outcomes. The results further show that even among men who did not succeed on first attempt, a substantial proportion will have successful outcomes if treatment is

Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy.

PubMed

Montorsi, Francesco; Oelke, Matthias; Henneges, Carsten; Brock, Gerald; Salonia, Andrea; d'Anzeo, Gianluca; Rossi, Andrea; Mulhall, John P; Büttner, Hartwig

2016-09-01

Understanding predictors for the recovery of erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) might help clinicians and patients in preoperative counseling and expectation management of EF rehabilitation strategies. To describe the effect of potential predictors on EF recovery after nsRP by post hoc decision-tree modeling of data from A Study of Tadalafil After Radical Prostatectomy (REACTT). Randomized double-blind double-dummy placebo-controlled trial in 423 men aged <68 yr with adenocarcinoma of the prostate (Gleason ≤7, normal preoperative EF) who underwent nsRP at 50 centers from nine European countries and Canada. Postsurgery 1:1:1 randomization to 9-mo double-blind treatment with tadalafil 5mg once a day (OaD), tadalafil 20mg on demand, or placebo, followed by a 6-wk drug-free-washout, and a 3-mo open-label tadalafil OaD treatment. Three decision-tree models, using the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score at the end of double-blind treatment, washout, and open-label treatment as response variable. Each model evaluated the association between potential predictors: presurgery IIEF domain and IIEF single-item scores, surgical approach, nerve-sparing score (NSS), and postsurgery randomized treatment group. The first decision-tree model (n=422, intention-to-treat population) identified high presurgery sexual desire (IIEF item 12: ≥3.5 and <3.5) as the key predictor for IIEF-EF at the end of double-blind treatment (mean IIEF-EF: 14.9 and 11.1), followed by high confidence to get and maintain an erection (IIEF item 15: ≥3.5 and <3.5; IIEF-EF: 15.4 and 7.1). For patients meeting these criteria, additional non-IIEF-related predictors included robot-assisted laparoscopic surgery (yes or no; IIEF-EF: 19.3 and 12.6), quality of nerve sparing (NSS: <2.5 and ≥2.5; IIEF-EF: 14.3 and 10.5), and treatment with tadalafil OaD (yes and no; IIEF-EF: 17.6 and 14.3). Additional analyses after washout and

Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy

PubMed Central

Montorsi, Francesco; Oelke, Matthias; Henneges, Carsten; Brock, Gerald; Salonia, Andrea; d’Anzeo, Gianluca; Rossi, Andrea; Mulhall, John P.; Büttner, Hartwig

2017-01-01

Background Understanding predictors for the recovery of erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) might help clinicians and patients in preoperative counseling and expectation management of EF rehabilitation strategies. Objective To describe the effect of potential predictors on EF recovery after nsRP by post hoc decision-tree modeling of data from A Study of Tadalafil After Radical Prostatectomy (REACTT). Design, setting, and participants Randomized double-blind double-dummy placebo-controlled trial in 423 men aged <68 yr with adenocarcinoma of the prostate (Gleason ≤7, normal preoperative EF) who underwent nsRP at 50 centers from nine European countries and Canada. Intervention Postsurgery 1:1:1 randomization to 9-mo double-blind treatment with tadalafil 5 mg once a day (OaD), tadalafil 20 mg on demand, or placebo, followed by a 6-wk drug-free-washout, and a 3-mo open-label tadalafil OaD treatment. Outcome measurements and statistical analysis Three decision-tree models, using the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score at the end of double-blind treatment, washout, and open-label treatment as response variable. Each model evaluated the association between potential predictors: presurgery IIEF domain and IIEF single-item scores, surgical approach, nerve-sparing score (NSS), and postsurgery randomized treatment group. Results and limitations The first decision-tree model (n = 422, intention-to-treat population) identified high presurgery sexual desire (IIEF item 12: ≥3.5 and <3.5) as the key predictor for IIEF-EF at the end of double-blind treatment (mean IIEF-EF: 14.9 and 11.1), followed by high confidence to get and maintain an erection (IIEF item 15: ≥3.5 and <3.5; IIEF-EF: 15.4 and 7.1). For patients meeting these criteria, additional non-IIEF–related predictors included robot-assisted laparoscopic surgery (yes or no; IIEF-EF: 19.3 and 12.6), quality of nerve sparing (NSS: <2.5 and

Development of a Video-Microscopic Tool To Evaluate the Precipitation Kinetics of Poorly Water Soluble Drugs: A Case Study with Tadalafil and HPMC.

PubMed

Christfort, Juliane Fjelrad; Plum, Jakob; Madsen, Cecilie Maria; Nielsen, Line Hagner; Sandau, Martin; Andersen, Klaus; Müllertz, Anette; Rades, Thomas

2017-12-04

Many drug candidates today have a low aqueous solubility and, hence, may show a low oral bioavailability, presenting a major formulation and drug delivery challenge. One way to increase the bioavailability of these drugs is to use a supersaturating drug delivery strategy. The aim of this study was to develop a video-microscopic method, to evaluate the effect of a precipitation inhibitor on supersaturated solutions of the poorly soluble drug tadalafil, using a novel video-microscopic small scale setup. Based on preliminary studies, a degree of supersaturation of 29 was chosen for the supersaturation studies with tadalafil in FaSSIF. Different amounts of hydroxypropyl methyl cellulose (HPMC) were predissolved in FaSSIF to give four different concentrations, and the supersaturated system was then created using a solvent shift method. Precipitation of tadalafil from the supersaturated solutions was monitored by video-microscopy as a function of time. Single-particle analysis was possible using commercially available software; however, to investigate the entire population of precipitating particles (i.e., their number and area covered in the field of view), an image analysis algorithm was developed (multiparticle analysis). The induction time for precipitation of tadalafil in FaSSIF was significantly prolonged by adding 0.01% (w/v) HPMC to FaSSIF, and the maximum inhibition was reached at 0.1% (w/v) HPMC, after which additional HPMC did not further increase the induction time. The single-particle and multiparticle analyses yielded the same ranking of the HPMC concentrations, regarding the inhibitory effect on precipitation. The developed small scale method to assess the effect of precipitation inhibitors can speed up the process of choosing the right precipitation inhibitor and the concentration to be used.

Identification of a new tadalafil analogue, N-3-hydroxypropylnortadalafil, in a supplement product.

PubMed

Lee, Hui-Chun; Lin, Yun-Lian; Huang, Yen-Chun; Tsai, Chia-Fen; Wang, Der-Yuan

2018-06-01

A novel tadalafil analogue, which exhibits similarity to 2-hydroxypropylnortadalafil, was found in dietary supplements using adulterants screening and isolated using column chromatography. By using extensive 1D- and 2D-NMR and MS spectral analyses, the structure was determined as 6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-(3-hydroxypropyl)pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione, and the analogue was named N-3-hydroxypropylnortadalafil. Copyright © 2018 Elsevier B.V. All rights reserved.

Influence of the PDE5 inhibitor tadalafil on redox status and antioxidant defense system in C2C12 skeletal muscle cells.

PubMed

Duranti, Guglielmo; Ceci, Roberta; Sgrò, Paolo; Sabatini, Stefania; Di Luigi, Luigi

2017-05-01

Phosphodiesterase type 5 inhibitors (PDE5Is), widely known for their beneficial effects onto male erectile dysfunction, seem to exert favorable effects onto metabolism as well. Tadalafil exposure increases oxidative metabolism of C2C12 skeletal muscle cells. A rise in fatty acid (FA) metabolism, requiring more oxygen, could induce a larger reactive oxygen species (ROS) release as a byproduct thus leading to a redox imbalance. The aim of this study was to determine how PDE5I tadalafil influences redox status in skeletal muscle cells to match the increasing oxidative metabolism. To this purpose, differentiated C2C12 skeletal muscle cells were treated with tadalafil and analyzed for total antioxidant capacity (TAC) and glutathione levels as marker of redox status; enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) engaged in antioxidant defense; and lipid peroxidation (TBARS) and protein carbonyls (PrCar) as markers of oxidative damage. Tadalafil increased total intracellular glutathione (tGSH), CAT, SOD, and GPx enzymatic activities while no changes were found in TAC. A perturbation of redox status, as showed by the decrease in the ratio between reduced/oxidized glutathione (GSH/GSSG), was observed. Nevertheless, it did not cause any change in TBARS and PrCar levels probably due to the enhancement in the antioxidant enzymatic network. Taken together, these data indicate that tadalafil, besides improving oxidative metabolism, may be beneficial to skeletal muscle cells by enhancing the enzymatic antioxidant system capacity.

Validated spectrofluorimetric method for determination of two phosphodiesterase inhibitors tadalafil and vardenafil in pharmaceutical preparations and spiked human plasma.

PubMed

Abu El-Enin, Mohammed Abu Bakr; Al-Ghaffar Hammouda, Mohammed El-Sayed Abd; El-Sherbiny, Dina Tawfik; El-Wasseef, Dalia Rashad; El-Ashry, Saadia Mahmoud

2016-02-01

A valid, sensitive and rapid spectrofluorimetric method has been developed and validated for determination of both tadalafil (TAD) and vardenafil (VAR) either in their pure form, in their tablet dosage forms or spiked in human plasma. This method is based on measurement of the native fluorescence of both drugs in acetonitrile at λem 330 and 470 nm after excitation at 280 and 275 nm for tadalafil and vardenafil, respectively. Linear relationships were obtained over the concentration range 4-40 and 10-250 ng/mL with a minimum detection of 1 and 3 ng/mL for tadalafil and vardenafil, respectively. Various experimental parameters affecting the fluorescence intensity were carefully studied and optimized. The developed method was applied successfully for the determination of tadalafil and vardenafil in bulk drugs and tablet dosage forms. Moreover, the high sensitivity of the proposed method permitted their determination in spiked human plasma. The developed method was validated in terms of specificity, linearity, lower limit of quantification (LOQ), lower limit of detection (LOD), precision and accuracy. The mean recoveries of the analytes in pharmaceutical preparations were in agreement with those obtained from the comparison methods, as revealed by statistical analysis of the obtained results using Student's t-test and the variance ratio F-test. Copyright © 2015 John Wiley & Sons, Ltd.

Safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension: a sub-group analysis based on Japan post-marketing surveillance.

PubMed

Yamazaki, Hiroyoshi; Kobayashi, Noriko; Taketsuna, Masanori; Tajima, Koyuki; Suzuki, Nahoko; Murakami, Masahiro

2017-12-01

To evaluate the long-term safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension (PAH) in real-world clinical practice. This is an observational surveillance of PAH patients receiving tadalafil in the contracted sites. A sub-group analysis was performed of 391 pediatric PAH patients (<18 years) who were included from 1,704 total patients in this surveillance. Safety was assessed from the frequency of adverse drug reactions (ADRs), discontinuations due to adverse events (AEs), and serious adverse drug reactions (SADRs). Effectiveness measurements included change in World Health Organization (WHO) functional classification of PAH, cardiac catheterization (pulmonary arterial pressure: PAP), and echocardiography (tricuspid regurgitation pressure gradient: TRPG). Survival rate was also measured. The mean patient age was 5.7 ± 5.34 years. Associated PAH (APAH) and idiopathic PAH (IPAH) accounted for 76.0% and 17.6%, respectively, of the PAH patients. Patients were followed for up to 2 years. Among 391 patients analyzed for safety, the overall incidence rate of ADRs was 16.6%. The common ADRs (≥ 1%) were headache (2.8%), hepatic function abnormal, platelet count decreased (1.3% each), and epistaxis, (1.0%). Eleven patients (2.8%) reported 16 SADRs. Three patients died secondary to SADRs. For the effectiveness analysis, the incidence of WHO functional class improvement at 3 months, 1 year, and 2 years after the initiation of tadalafil and last observation in pediatric patients were 16.5%, 19.7%, and 16.3%, respectively. Both PAP and TRPG showed a statistically significant reduction at last observation. This manuscript reveals the use of tadalafil in the real-world pediatric population with an acceptable safety profile in Japan.

Safety and effectiveness of tadalafil in patients with pulmonary arterial hypertension: Japanese post-marketing surveillance data.

PubMed

Yamazaki, Hiroyoshi; Kobayashi, Noriko; Taketsuna, Masanori; Tajima, Koyuki; Murakami, Masahiro

2017-05-01

To evaluate the long-term safety and effectiveness of tadalafil in patients with pulmonary arterial hypertension (PAH) in real-world clinical practice. This prospective, multicenter, noninterventional, post-marketing surveillance included patients with PAH who were observed for up to 2 years after initiation of tadalafil. Safety was assessed by analyzing the frequency of adverse drug reactions (ADRs), discontinuations due to adverse events (AEs), and serious adverse drug reactions (SADRs). Effectiveness measurements included the assessment of the change in World Health Organization (WHO) functional classification of PAH, 6-minute walk test, cardiac catheterization, and echocardiography. Among 1676 patients analyzed for safety, the overall incidence of ADRs was 31.2%. The common ADRs (≥1.0%) were headache (7.0%), diarrhea (1.9%), platelet count decreased (1.8%), anemia, epistaxis, and nausea (1.6% each), flushing (1.3%), hepatic function abnormal (1.1%), hot flush, and myalgia (1.0% each). The common SADRs (≥0.3%) were cardiac failure (0.7%), interstitial lung disease, worsening of PAH, and platelet count decreased (0.3% each). Among 1556 patients analyzed for effectiveness, the percentages of patients with improvement of WHO functional class at 3 months, 1 year, and 2 years after the initiation of tadalafil, and last observation were 17.1%, 24.8%, 28.9%, and 22.5%, respectively. At all observation points (except pulmonary regurgitation pressure gradient at end diastole at 3 months), the mean 6-minute walk distance, cardiac catheterization, and echocardiogram measurements showed statistically significant improvement. This surveillance demonstrated that tadalafil has favorable safety and effectiveness profiles for long-term use in patients with PAH in Japan.

Comparing the Efficacy of Tadalafil Versus Placebo on Pulmonary Artery Systolic Pressure and Right Ventricular Function in Patients with Beta-Thalassaemia Intermedia.

PubMed

Jalalian, Rozita; Moghadamnia, Ali Akbar; Tamaddoni, Ahmad; Khafri, Soraya; Iranian, Mohammadreza

2017-07-01

Conventional oral therapies in the management of pulmonary hypertension in people without haemoglobinopathies are of limited value in thalassaemia patients because of toxicity and poor effectiveness. This study was conducted to assess the effect of tadalafil on pulmonary artery pressure and right ventricular systolic function in patients with beta-thalassaemia intermedia. Forty-four patients with beta-thalassaemia intermedia with pulmonary hypertension based on transthoracic echocardiography (TTE) were entered in the study. Patients with hepatic or renal insufficiency and also patients who were treated with organic nitrates or alpha-blockers were excluded. The patients were randomly divided into two groups (n=22) and they were treated for six weeks with tadalafil (40mg daily) or placebo. The pulmonary artery systolic pressure (PASP), tricuspid regurgitation velocity (TRV) and parameters related to systolic function of the right ventricle were measured by the TTE before and after treatment. Significant improvement in TRV (3.02±0.02 m/s-2.52±0.06 m/s), PASP (45.31±0.66 mmHg-34.26±1.15mmHg) and parameters related to systolic function of the right ventricle were observed in the group who received tadalafil compared to placebo (p< 0.05). Tadalafil significantly decreased PASP and TRV in patients with beta-thalassaemia intermedia. Likewise, tadalafil improved right ventricular systolic function in the patients. Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Skeletal muscle adaptation and performance responses to once a day versus twice every second day endurance training regimens.

PubMed

Yeo, Wee Kian; Paton, Carl D; Garnham, Andrew P; Burke, Louise M; Carey, Andrew L; Hawley, John A

2008-11-01

, the performance of a 1-h time trial undertaken after a 60-min steady-state ride was similar after once daily or twice every second day training programs.

Effect of sprint training on resting serum irisin concentration - Sprint training once daily vs. twice every other day.

PubMed

Tsuchiya, Yoshifumi; Ijichi, Toshiaki; Goto, Kazushige

2016-04-01

Exercise twice every other day has been shown to lead to increasing peroxisome proliferator receptor γ coactivator-1α (PGC-1α) expression (up-stream factor of irisin) via lowered muscle glycogen level during second of exercise compared with exercise once daily. This study determined the influence of 4weeks of sprint training (training once daily vs. twice every other day) on the serum irisin concentration. Twenty healthy males (20.9±1.3years) were assigned randomly to either the SINGLE or REPEATED group (n=10 per group). The subjects in the SINGLE group participated in a sprint training session once daily (5days per week), whereas those in the REPEATED group performed two consecutive training sessions on the same day with a 1-h rest between sessions (2-3days per week). Both groups completed 20 training sessions over 4weeks. Each training session consisted of three consecutive 30-s maximal pedaling exercises with a 10-min rest between sets. Blood samples were collected before and after training period (48h after completing the last training session). The serum irisin concentration decreased significantly after training in each group (SINGLE, 338.5±77.8 to 207.6±64.6ng/mL; REPEATED, 329.5±83.9 to 234.2±72.8ng/mL, p<0.05). The plasma interleukin-6 (IL-6) concentration tended to be lower after training in both groups (main effect for period, p=0.054). However, there was no significant difference in the serum irisin or plasma IL-6 concentration between groups after training. The serum high-molecular-weight adiponectin concentration did not change significantly after training in either group. Sprint training for 4weeks significantly decreased the resting serum irisin concentration, despite different training programs (training once daily vs. twice every other day). Copyright © 2016 Elsevier Inc. All rights reserved.

Comparison of once a day rifaximin to twice a day dosage in the prevention of recurrence of hepatic encephalopathy in patients with chronic liver disease.

PubMed

Khokhar, Nasir; Qureshi, Muhammad Omar; Ahmad, Shafiq; Ahmad, Aiza; Khan, Hamza Hassan; Shafqat, Farzana; Salih, Muhammad

2015-09-01

Rifaximin has been used for prevention of recurrence of hepatic encephalopathy in twice a day dosage. The drug is expensive and lower dising may be possible. To determine the efficacy of rifaximin once a day dose in the prevention of hepatic encephalopathy (HE) in patients with liver cirrhosis as compared with twice daily dose of rifaximin. This Randomized control trial was carried out at the Department of Gastroenterology and Hepatology, Shifa International Hospital, Islamabad, Pakistan from November 2012 to February 2014. Patients with known chronic liver disease with at least one episode of HE in the past were randomized to group A (rifaximin 550 mg OD) and group B (rifaximin 550 mg BD), after fulfilling the inclusion criteria. Each patient was followed for 6 months for any episode of HE. Patients in each group were identified for any breakthrough episode of encephalopathy during this period. Data were analyzed using SPSS version 16. Chi-squared test and t-test were applied where required to determine the significant difference between the two groups. There were a total of 306 patients: 128 patients in Group A while 178 in group B. Majority of patients (75.81%) had hepatitis C virus with mean age of 52.30 ± 9.92, MELD score 13.58 ± 8.3, and 55.22% were in Child-Pugh B. Eighty-one patients had an episode of HE during the study period. There were 27 patients in group A and 54 patients in group B with breakthrough episode of HE (P = 0.088). This study suggests that there is no significant difference in rifaximin once a day or twice daily dose in preventing HE. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Daily tadalafil for the chronic phase of stuttering priapism: a case report.

PubMed

Massenio, Paolo; D'Altilia, Nicola; Sanguedolce, Francesca; Carrieri, Giuseppe; Cormio, Luigi

2018-05-31

Recurrent (stuttering) ischemic priapism is a challenging clinical condition. Frequent recurrences result in frequent hospital admissions whereas treatment with a shunting procedure often results in erectile dysfunction. A 22-year-old man with stuttering idiopathic priapism developed erectile dysfunction (IIEF-5 score 12) following a Winter's shunt; he was given tadalafil, 5 mg/daily, for 6 months. This treatment resulted in progressive restoration of erectile function in the 6 months following the shunt as well as in preventing recurrence of priapic episodes over a 24-month follow-up. This is the first report in literature of chronic treatment of stuttering priapism with a phosphodiesterase-5 inhibitor being able not only to prevent recurrent priapic episodes but also to restore erectile function following a Winter's shunt.

[Therapy of organic brain syndrome with nicergoline given once a day].

PubMed

Ladurner, G; Erhart, P; Erhart, C; Scheiber, V

1991-01-01

In a double-blind, active-controlled study 30 patients with mild to moderate multiinfarct dementia diagnosed according to DSM III definition were treated by either 20 mg nicergoline or 4.5 mg co-dergocrine mesilate once daily during eight weeks. Therapeutic effects on symptoms of the organic brain syndrome were quantitatively measured by standardized psychological and psychometric methods evaluating cognitive and thymopsychic functions. Main criteria, which were tested by inferential analysis, were SCAG total score (Sandoz Clinical Assessment Geriatric Scale), SCAG overall impression and the AD Test (alphabetischer Durchstreichtest). Other results were assessed by descriptive statistics. Both treatments resulted in a statistically significant improvement in most of the tested functions. The effects of 4.5 mg co-dergocrine mesilate s.i.d. were in accordance with published results. Although differing slightly with respect to individual results 20 mg of nicergoline once daily showed the same efficacy on the whole.

Safety and efficacy of silodosin and tadalafil in ease of negotiation of large ureteroscope in the management of ureteral stone: A prosective randomized trial.

PubMed

Bhattar, Rohit; Jain, Vipin; Tomar, Vinay; Yadav, Sher Singh

2017-12-01

To evaluate the safety and efficacy of silodosin and tadalafil in ease of negotiation of large size ureteroscope (8/9.8 Fr) in the management of ureteral stone. Between June 2015 and May 2016, 86 patients presented with ureteral stone of size 6-15 mm were on consent randomly assigned to 1 of 3 outpatient treatment arms: silodosin (Group A), tadalafil (Group B), and placebo (Group C). After two weeks of therapy 67 patients underwent ureteroscopy, and ureteral orifice configuration, ureteroscopic negotiation, ureteral dilatation, operating time, procedural complication and drug related side effects were noted in each group. Ureteral negotiation was significantly better in Groups A (73.9%) and B (69.6%) as compared to Group C (38.1%) (p<0.01). Statistically significant difference was noted in the requirement for dilatation in Group C (71.4%) as compared to Groups A (26.1%) and B (39.1%) (p<0.01). Ureteral orifice was found to be more dilated in Groups A (69.6%) and B (60.9%) as compared to Group C (28.6%). Mean operating time was statistically lower in Groups A (35.2 min) and B (34.91 min) as compared to Group C (41.14 min) (p<0.01). Both silodosin and tadalafil not only relax ureteral smooth muscle but also help in forward propagation of large size ureteroscope (8/9.8 Fr) without any significant risk of adverse events.

Safety and efficacy of silodosin and tadalafil in ease of negotiation of large ureteroscope in the management of ureteral stone: A prosective randomized trial

PubMed Central

Bhattar, Rohit; Jain, Vipin; Tomar, Vinay; Yadav, Sher Singh

2017-01-01

Objective To evaluate the safety and efficacy of silodosin and tadalafil in ease of negotiation of large size ureteroscope (8/9.8 Fr) in the management of ureteral stone. Material and methods Between June 2015 and May 2016, 86 patients presented with ureteral stone of size 6–15 mm were on consent randomly assigned to 1 of 3 outpatient treatment arms: silodosin (Group A), tadalafil (Group B), and placebo (Group C). After two weeks of therapy 67 patients underwent ureteroscopy, and ureteral orifice configuration, ureteroscopic negotiation, ureteral dilatation, operating time, procedural complication and drug related side effects were noted in each group. Results Ureteral negotiation was significantly better in Groups A (73.9%) and B (69.6%) as compared to Group C (38.1%) (p<0.01). Statistically significant difference was noted in the requirement for dilatation in Group C (71.4%) as compared to Groups A (26.1%) and B (39.1%) (p<0.01). Ureteral orifice was found to be more dilated in Groups A (69.6%) and B (60.9%) as compared to Group C (28.6%). Mean operating time was statistically lower in Groups A (35.2 min) and B (34.91 min) as compared to Group C (41.14 min) (p<0.01). Conclusion Both silodosin and tadalafil not only relax ureteral smooth muscle but also help in forward propagation of large size ureteroscope (8/9.8 Fr) without any significant risk of adverse events. PMID:29201512

Effects of tadalafil on ischemia/reperfusion injury in rat brain.

PubMed

Altaş, Murat; Aras, M; Meydan, S; Nacar, E; Ulutaş, K T; Serarslan, Y; Yılmaz, N

2014-03-01

Cerebral ischemia-reperfusion (I/R) injury is caused by lack of blood supply to the brain. The accumulation of toxic products such as reactive oxygen species (ROS) occurs on reperfusion, when the occlusion is removed. The resulting oxidative stress results in the initiation of pathways leading to necrotic and apoptotic cell death. Tadalafil (TAD) prevents the accumulation of ROS and increases antioxidant cellular protective mechanisms. The aim of this study was to investigate the effect of TAD treatment against short-term global brain I/R injury in rats. The study was carried out on 30 Wistar-albino rats, which were divided into three groups including a control group (n = 10), an I/R group (n = 10) and an I/R + TAD group (n = 10) (2 mg/kg/day for 4 days before ischemia). At the end of the experiment, tissue samples were collected for both biochemical and histopathological analyses. Malondialdehyde was significantly lower in the TAD-administered group (9.06 ± 0.15) than in the I/R group (p < 0.05). However, no significant difference was observed in nitric oxide levels in the TAD-administered group compared to the I/R group. The mean superoxide dismutase level was significantly higher in the I/R-TAD group than the I/R group. There was no statistically significant difference in glutathione peroxidase levels in I/R + TAD group compared to I/R group. Histopathologically, TAD-administered group provided significant morphological improvement compared to the I/R group. We concluded that TAD prevented I/R-induced neurotoxicity as shown by obtained biochemical and histopathological findings.

A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis.

PubMed

Peterson, Janet; Kaul, Simrati; Khashab, Mohammed; Fisher, Alan C; Kahn, James B

2008-01-01

A clinical study was conducted to compare the efficacy and safety of levofloxacin 750 mg once daily for 5 days to ciprofloxacin twice daily for 10 days for the treatment of complicated urinary tract infections (cUTI) or acute pyelonephritis (AP). A multicenter, double-blind, randomized, noninferiority study enrolled subjects with AP or cUTI. Subjects received either levofloxacin 750 mg intravenously or orally once daily for 5 days or ciprofloxacin 400 mg intravenously and/or ciprofloxacin 500 mg orally twice daily for 10 days and were evaluated at end of therapy, posttherapy, and poststudy for microbiologic eradication and clinical outcome. A total of 1109 subjects were enrolled; 619 with confirmed diagnosis of AP or cUTI and a study entry uropathogen with a colony count 10(5) CFU/mL or greater and were included in the modified intent-to-treat population. Five hundred six subjects met all criteria for inclusion and were included in the microbiologically evaluable population. At end of therapy, eradication rates in the modified intent-to-treat population were 79.8% for levofloxacin and 77.5% for ciprofloxacin-treated subjects (95% CI, -8.8% to 4.1%). In the microbiologically evaluable population, eradication rates were 88.3% for levofloxacin and 86.7% for ciprofloxacin-treated subjects (95% CI, -7.4% to 4.2%). Outcomes were comparable for the 2 treatments at posttherapy and poststudy. This study demonstrates that both drug regimens are safe and effective and that a 5-day course of therapy with levofloxacin, administered at a dose of 750 mg once daily, is noninferior to a 10-day course of therapy with ciprofloxacin for the treatment of AP and cUTI.

Tadalafil in idiopathic or heritable pulmonary arterial hypertension (PAH) compared to PAH associated with connective tissue disease.

PubMed

Galiè, Nazzareno; Denton, Christopher P; Dardi, Fabio; Manes, Alessandra; Mazzanti, Gaia; Li, Baohui; Varanese, Lucio; Esler, Anne; Harmon, Cathi; Palazzini, Massimiliano

2017-05-15

The primary objective of this post hoc analysis was to evaluate clinical outcomes of tadalafil in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD-PAH) compared with patients with idiopathic/heritable PAH (I/H-PAH) for primary and key secondary efficacy endpoints, and safety. This analysis included adult patients with CTD-PAH or I/H-PAH who participated in the PHIRST and PHIRST-2 studies. Patients were randomized 1:1:1:1:1 to tadalafil (2.5, 10, 20, or 40mg) or placebo in the PHIRST study and the majority of these patients were subsequently assigned 40mg in PHIRST-2. Patients taking 20mg in PHIRST without demonstrating clinical worsening continued on 20mg in PHIRST-2. Outcomes analyzed included 6MWD, WHO-FC, and incidence and time to first occurrence of clinical worsening. Safety was assessed through evaluation of adverse events (AEs), clinical laboratory data, electrocardiograms, and physical examinations. Increased 6MWD in PHIRST was maintained in both CTD-PAH and I/H-PAH subgroups for 52weeks. Patients with CTD-PAH tended to be older, were more likely female, had lower exercise capacity, were more likely to have clinical worsening, and experienced AEs more frequently than patients with I/H-PAH. The effect of tadalafil treatment in patients enrolled in both PHIRST studies was detectable for both I/H-PAH and CTD-PAH subgroups. In general, subgroup differences were modest. Patients with CTD-PAH may perform less well than patients with I/H-PAH in safety and efficacy measures in all treatment groups, which is similar to other studies demonstrating a worse prognosis for patients with CTD-PAH. Copyright © 2017. Published by Elsevier B.V.

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

PubMed

Aversa, A; Fittipaldi, S; Bimonte, V M; Wannenes, F; Papa, V; Francomano, D; Greco, E A; Lenzi, A; Migliaccio, S

2016-02-01

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

A trial of levofloxacin 750 mg once daily for 5 days versus ciprofloxacin 400 mg and/or 500 mg twice daily for 10 days in the treatment of acute pyelonephritis.

PubMed

Klausner, Howard A; Brown, Patricia; Peterson, Janet; Kaul, Simrati; Khashab, Mohammed; Fisher, Alan C; Kahn, James B

2007-11-01

A double-blind, noninferiority trial was conducted to establish the safety and efficacy of a once-daily, 5-day course of levofloxacin 750 mg compared to a twice-daily, 10-day course of ciprofloxacin in complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). This report focuses on subjects with AP. Adult male and female subjects with clinical signs and symptoms of AP and laboratory confirmation of their diagnosis were randomized to receive one dose of levofloxacin 750 mg once daily intravenously (i.v.) or orally and one dose of placebo for 5 days, followed by placebo; or ciprofloxacin 400 mg i.v. and/or 500 mg orally twice daily for 10 days. The primary, prospectively defined end point was microbiologic eradication at post-therapy (study days 15-22). Secondary outcomes included clinical response and safety and tolerability. In the modified intent-to-treat (mITT) population (levofloxacin 94, ciprofloxacin 98), 83% of levofloxacin-treated and 79.6% of ciprofloxacin-treated subjects achieved microbiological eradication (difference -3.4, 95% CI -14.4%, 7.6%). In the microbiologically evaluable (ME) population (levofloxacin 80, ciprofloxacin 76), 92.5% of levofloxacin-treated vs. 93.4% of ciprofloxacin-treated subjects (difference -0.9, 95% CI -7.1%, 8.9%) achieved microbiologic eradication. Clinical success was achieved in 86.2% vs. 80.6% (mITT) and in 92.5% vs. 89.5% (ME) of levofloxacin-treated and ciprofloxacin-treated subjects, respectively. Escherichia coli was the most commonly isolated uropathogen. Few (2.1%) of the pathogens were fluoroquinolone-resistant. Adverse events (AEs) were similar to those seen previously with both agents. Potential limitations are that this analysis is based on a subset of subjects from a larger study and, because of different durations of therapy, the results may be biased against levofloxacin. High-dose, short-course therapy with levofloxacin in subjects with AP is at least as effective as standard 10-day therapy

Once-Yearly Zoledronic Acid and Days of Disability, Bed Rest, and Back Pain: Randomized, Controlled HORIZON Pivotal Fracture Trial

PubMed Central

Cauley, Jane A.; Black, Dennis; Boonen, Steven; Cummings, Steven R.; Mesenbrink, Peter; Palermo, Lisa; Man, Zulema; Hadji, Peyman; Reid, Ian R.

2016-01-01

The objective of this study was to determine the effect of once-yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double-blind, placebo-controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15-minute intravenous infusion of zoledronic acid (5 mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were self-reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3-year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p = .0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p = .0017). In Cox proportional-hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR) = 0.94, 95% confidence interval (CI) 0.90–0.99] or limited activity owing to back pain (RR = 0.94, 95% CI 0.87–1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed-rest days owing to a fracture (RR = 0.58, 95% CI 0.47–0.72) and 7 or more limited-activity days owing to a fracture (RR = 0.67, 95% CI 0.58–0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once-yearly infusion with zoledronic acid over a 3-year period significantly reduced the number of days that

Comparison of efficacy of once daily multimatrix mesalazine 2.4 g/day and 4.8 g/day with other 5-aminosalicylic acid preparation in active ulcerative colitis: a randomized, double-blind study.

PubMed

Ogata, Haruhiko; Yokoyama, Tadashi; Mizushima, Seiichi; Hagino, Atsushi; Hibi, Toshifumi

2018-04-01

This study compared the efficacy of multimatrix mesalazine 2.4 g/day and 4.8 g/day with controlled-release mesalazine 2.25 g/day. In this multicenter, randomized, double-blind study, 251 patients with mildly to moderately active ulcerative colitis received multimatrix mesalazine 2.4 g/day once daily (Multimatrix-2.4), 4.8 g/day once daily (Multimatrix-4.8), or controlled-release (time-dependent) mesalazine 2.25 g/day 3 times daily (Time-2.25) for 8 weeks. The primary efficacy endpoint was the change in the ulcerative colitis-disease activity index (UC-DAI) score. The mean change in the UC-DAI score and standard deviation in the per protocol set was -1.9±2.5 for Multimatrix-2.4 and -2.4±2.8 for Time-2.25. The difference between Multimatrix-2.4 and Time-2.25 was 0.3 (two-sided 95% confidence interval [CI], -0.5 to 1.1), thus non-inferiority was not demonstrated based on the pre-defined non-inferiority margin (1.0). In the full analysis set, the difference between Multimatrix-4.8 and Time-2.25 was -1.2 (two-sided 95% CI, -2.0 to -0.5), and the mean change in UC-DAI score in the FAS was -3.3 (two-sided 95% CI, -3.9 to -2.8) for Multimatrix-4.8 and -1.9 (two-sided 95% CI, -2.5 to -1.3) for Multimatrix-2.4, indicating that Multimatrix-4.8 was more effective than Time-2.25 and Multimatrix-2.4. There was no difference among the treatment groups in terms of safety. This study showed that the efficacy of multimatrix mesalazine 2.4 g/day was comparable to controlled release mesalazine 2.25 g/day, although non-inferiority was not demonstrated. Importantly, this was the first study to indicate that multimatrix mesalazine 4.8 g/day was more effective than 2.4g/day with no associated safety concerns.

Chronic Administration of Tadalafil Improves the Symptoms of Patients with Amicrobic MAGI: An Open Study

PubMed Central

Condorelli, Rosita A.

2017-01-01

Aim of this study was to evaluate the effects of pharmacological treatment with Tadalafil 5 mg daily on symptoms and quality of sperm parameters in selected patients with amicrobic MAGI (male accessory gland inflammation). 120 patients with amicrobic MAGI (mean age 27.0 ± 6.0 years) with mild-moderate ED (erectile dysfunction) according to IIEF-5 (International Index of Erectile Function 5 Items) scores underwent pharmacological treatment with Tadalafil 5 mg daily for six months. Before and after treatment these patients were evaluated through IIEF-5, semen analysis (according to WHO Criteria, 2010), SI-MAGI (Structured Interview about Male Accessory Gland Inflammation), and ultrasound evaluation. Patients with PVE (prostate-vesciculo-epididymitis) showed a significant increase in the percentage of spermatozoa with total (16.0 ± 8.0 versus 30.0 ± 6.0%) and progressive motility (8.00 ± 10.0 versus 25.0 ± 6.00%). It was a significant reduction of the number of patients with complicated ultrasound forms (30.0 versus 52.0) and a significant increase of the number of patients with uncomplicated ultrasound form (90.0 versus 68.0). Finally, there was a significant reduction in the percentage of patients with alterations of sexual function different from DE, such as premature ejaculation (4.00 versus 8.00%), painful ejaculation (4.00 versus 10.0%), delayed ejaculation (12.50 versus 8.00%), and decreased libido (10.0 versus 25.0%). PMID:28465683

Comparison of efficacy of once daily multimatrix mesalazine 2.4 g/day and 4.8 g/day with other 5-aminosalicylic acid preparation in active ulcerative colitis: a randomized, double-blind study

PubMed Central

Yokoyama, Tadashi; Mizushima, Seiichi; Hagino, Atsushi; Hibi, Toshifumi

2018-01-01

Background/Aims This study compared the efficacy of multimatrix mesalazine 2.4 g/day and 4.8 g/day with controlled-release mesalazine 2.25 g/day. Methods In this multicenter, randomized, double-blind study, 251 patients with mildly to moderately active ulcerative colitis received multimatrix mesalazine 2.4 g/day once daily (Multimatrix-2.4), 4.8 g/day once daily (Multimatrix-4.8), or controlled-release (time-dependent) mesalazine 2.25 g/day 3 times daily (Time-2.25) for 8 weeks. The primary efficacy endpoint was the change in the ulcerative colitis-disease activity index (UC-DAI) score. Results The mean change in the UC-DAI score and standard deviation in the per protocol set was −1.9±2.5 for Multimatrix-2.4 and −2.4±2.8 for Time-2.25. The difference between Multimatrix-2.4 and Time-2.25 was 0.3 (two-sided 95% confidence interval [CI], −0.5 to 1.1), thus non-inferiority was not demonstrated based on the pre-defined non-inferiority margin (1.0). In the full analysis set, the difference between Multimatrix-4.8 and Time-2.25 was −1.2 (two-sided 95% CI, −2.0 to −0.5), and the mean change in UC-DAI score in the FAS was −3.3 (two-sided 95% CI, −3.9 to −2.8) for Multimatrix-4.8 and −1.9 (two-sided 95% CI, −2.5 to −1.3) for Multimatrix-2.4, indicating that Multimatrix-4.8 was more effective than Time-2.25 and Multimatrix-2.4. There was no difference among the treatment groups in terms of safety. Conclusions This study showed that the efficacy of multimatrix mesalazine 2.4 g/day was comparable to controlled release mesalazine 2.25 g/day, although non-inferiority was not demonstrated. Importantly, this was the first study to indicate that multimatrix mesalazine 4.8 g/day was more effective than 2.4g/day with no associated safety concerns. PMID:29743838

ATR-FTIR characterization of generic brand-named and counterfeit sildenafil- and tadalafil-based tablets found on the Brazilian market.

PubMed

Coelho Neto, José; Lisboa, Fernanda L C

2017-07-01

Viagra and Cialis are among the most counterfeited medicines in many parts of the world, including Brazil. Despite the many studies that have been made regarding discrimination between genuine and counterfeit samples, most published works do not contemplate generic and similar versions of these medicines and also do not explore excipients/adjuvants contributions when characterizing genuine and suspected samples. In this study, we present our findings in exploring ATR-FTIR spectral profiles for characterizing both genuine and questioned samples of several generic and brand-name sildenafil- and tadalafil-based tablets available on the Brazilian market, including Viagra and Cialis. Multi-component spectral matching (deconvolution), objective visual comparison and correlation tests were used during analysis. Besides from allowing simple and quick identification of counterfeits, results obtained evidenced the strong spectral similarities between generic and brand-named tablets employing the same active ingredient and the indistinguishability between samples produced by the same manufacturer, generic or not. For all sildenafil-based and some tadalafil-based tablets tested, differentiation between samples from different manufacturers, attributed to slight variations in excipients/adjuvants proportions, was achieved, thus allowing the possibility of tracing an unknown/unidentified tablet back to a specific manufacturer. Copyright © 2017 The Chartered Society of Forensic Sciences. Published by Elsevier B.V. All rights reserved.

Toilet training in healthy children: results of a questionnaire study involving parents who make use of day-care at least once a week.

PubMed

Kaerts, Nore; Vermandel, Alexandra; Van Hal, Guido; Wyndaele, Jean-Jacques

2014-03-01

To investigate how toilet training (TT) is dealt with and what the associated feelings are in Flemish families using day-care at least once a week. A questionnaire was provided to 256 parents of healthy children between 15 and 35 months old, using day-care every week. Data were analyzed using SPSS18.0. Two hundred twenty-two questionnaires were completed (response rate: 87%), of which 221 were valid. The overall results show that the start of TT and method used are mainly in line with current recommendations, and that the cooperation between parents and day-care is seen as positive, providing support for the parents in guiding their child in the TT-process. Most parents (74%) stated that day-care and parents should play an equal role in the TT-process. However, 17% of the parents experienced uncertainty, stress, and/or frustration related to TT. This percentage increased to 30% when asked about the right moment to start TT. Moreover, 18% of the parents reported a lack of time to guide their child in the TT-process. Eighteen percent of the parents agreed that responsibility for TT is increasingly passed on to day-care, while 46% remained undecided. In addition, 40% of the parents had no idea whether they used the same TT method as the day-care center. The results, in general, reflect a positive image of how TT is dealt with. However, several concerns were raised about the shared TT between parents and day-care, implying that further research on this topic is needed. © 2013 Wiley Periodicals, Inc.

Lansoprazole 15 mg once daily for 14 days is effective for treatment of frequent heartburn: results of 2 randomized, placebo-controlled, double-blind studies.

PubMed

Kushner, Pamela R; Snoddy, Andrew M; Gilderman, Larry; Peura, David A

2009-07-01

To investigate the efficacy and safety of a 14-day treatment period with lansoprazole 15 mg for frequent heartburn in patients who are likely to select a nonprescription medication before consulting a prescriber. Adults with untreated frequent heartburn > or = 2 days a week over the past month were recruited for 2 identical multicenter, double-blind studies conducted with a 1-week screening and heartburn medication washout, a 1-week placebo run-in, a 2-week placebo-controlled treatment, and a 1-week placebo follow-up. After the washout and placebo run-in, subjects were randomly assigned to receive lansoprazole 15 mg or placebo once daily for 14 days in a double-blind fashion. Antacid tablets were permitted as rescue medication. Endpoints included percentage of 24-hour days without heartburn (primary), percentage of night-times without heartburn, and percentage of subjects without heartburn during day 1 of treatment (secondary endpoints). Data were collected daily via an interactive voice response system. In studies 1 and 2, 282 and 288 subjects, respectively, were randomly assigned to lansoprazole, and 282 in each study received placebo. The mean percentage of days without heartburn was greater among lansoprazole recipients compared with placebo recipients (P < 0.0001). Significantly more subjects treated with lansoprazole also reported no night-time heartburn and no heartburn during day 1 of the 14-day treatment. Adverse events were infrequent and were similar for lansoprazole and placebo groups. During the 14-day treatment period in a population with frequent heartburn who were likely to select a medication without consulting a prescriber, lansoprazole 15 mg once daily showed rapid and sustained effectiveness throughout a 24-hour period and was well tolerated.

A randomized, multicenter, double-blind, vehicle-controlled study evaluating the efficacy and safety of luliconazole cream 1% once daily for 7 days in patients aged ≥ 12 years with tinea cruris.

PubMed

Jones, Terry M; Jarratt, Michael T; Mendez-Moguel, Ines; Paz, Nelly; Grekin, Steven K; Cognata Smith, Christina; Kaur, Mandeep

2014-01-01

Tinea cruris, a pruritic superficial fungal infection of the groin, is the second most common clinical presentation for dermatophytosis. This phase 3 study evaluated the safety and efficacy of topical luliconazole cream 1% in patients with tinea cruris. 483 patients were enrolled and 256 male and female patients aged ≥12 years with clinically evident tinea cruris and eligible for modified intent-to-treat analysis were randomized 2:1 to receive luliconazole cream 1% (n=165) or vehicle (n=91) once daily for 7 days. Efficacy was evaluated at baseline and at days 7, 14, 21, and 28 based on mycology (potassium hydroxide, fungal culture) and clinical signs (erythema, scaling, pruritus). The primary outcome was complete clearance at day 28 (21 days posttreatment). Safety evaluations included adverse events and laboratory assessments. Complete clearance was obtained in 21.2% (35/165) of patients treated with luliconazole cream 1% compared with 4.4% (4/91) treated with vehicle (P<0.001). The safety profile of luliconazole cream 1% was similar to vehicle. The study was conducted under controlled conditions in a relatively small population. Luliconazole cream 1% applied once daily for 7 days is more effective than vehicle and well tolerated in patients with tinea cruris.

Effect of chronic low-dose tadalafil on penile cavernous tissues in diabetic rats.

PubMed

Mostafa, Mohamed E; Senbel, Amira M; Mostafa, Taymour

2013-06-01

To assess the effect of chronic low-dose administration of tadalafil (Td) on penile cavernous tissue in induced diabetic rats. The study investigaged 48 adult male albino rats, comprising a control group, sham controls, streptozotocin-induced diabetic rats, and induced diabetic rats that received Td low-dose daily (0.09 mg/200 g weight) for 2 months. The rats were euthanized 1 day after the last dose. Cavernous tissues were subjected to histologic, immunohistochemical, morphometric studies, and measurement of intracavernosal pressure and mean arterial pressure in anesthetized rats. Diabetic rats demonstrated dilated cavernous spaces, smooth muscles with heterochromatic nuclei, degenerated mitochondria, vacuolated cytoplasm, and negative smooth muscle immunoreactivity. Nerve fibers demonstrated a thick myelin sheath and intra-axonal edema, where blood capillaries exhibited thick basement membrane. Diabetic rats on Td showed improved cavernous organization with significant morphometric increases in the area percentage of smooth muscles and elastic tissue and a significant decrease of fibrous tissue. The Td-treated group showed enhanced erectile function (intracavernosal pressure/mean arterial pressure) at 0.3, 0.5, 1, 3, and 5 Hz compared with diabetic group values at the respective frequencies (P <.05) that approached control values. Chronic low-dose administration of Td in diabetic rats is associated with substantial improvement of the structure of penile cavernous tissue, with increased smooth muscles and elastic tissue, decreased fibrous tissue, and functional enhancement of the erectile function. This raises the idea that the change in penile architecture with Td treatment improves erectile function beyond its half-life and its direct pharmacologic action on phosphodiesterase type 5. Copyright © 2013 Elsevier Inc. All rights reserved.

Evidence for the efficacy and safety of tadalafil and finasteride in combination for the treatment of lower urinary tract symptoms and erectile dysfunction in men with benign prostatic hyperplasia

PubMed Central

Olesovsky, Chris; Kapoor, Anil

2016-01-01

Benign prostatic hyperplasia (BPH) is an age-related phenomenon associated with prostatic enlargement and bladder outlet obstruction that can cause significant lower urinary tract symptoms (LUTS). These LUTS have a negative impact on an individual’s quality of life, which is why treatment of symptomatic BPH has become a major priority. Although surgical interventions exist for treating BPH, pharmacological therapies are often preferred due to their minimal invasiveness and high degree of effectiveness. The three classes of drugs approved for treating BPH include α-blockers, 5-α-reductase inhibitors (5-ARIs) and phosphodiesterase 5 (PDE-5) inhibitors. Individually, each class of drug has been studied and shown to improve symptom relief through a variety of different mechanisms. A more recent focus has been on the development of combinatorial therapies that combine classes of drugs in order to provide maximal benefit. The mTOPS and CombAT studies were the first of their kind to examine whether the combination of 5-ARIs and α-blockers was more effective than monotherapy alone. Both studies found similar results in that the combinatorial therapy was superior to monotherapy. Over the last decade other combinatorial therapies have been at the forefront of investigation. One in particular is the combination of tadalafil, a PDE-5 inhibitor, with finasteride, a 5-ARI. Studies have shown that the combination of tadalafil and finasteride is a safe, effective, and well tolerated treatment for BPH. Evidence suggests that this combination may be particularly effective in reducing treatment-related sexual adverse events associated with 5-ARI treatments. The following review will explore in detail the current evidence surrounding treatment of BPH LUTS using tadalafil and finasteride. PMID:27928428

Oncocin derivative Onc72 is highly active against Escherichia coli in a systemic septicaemia infection mouse model.

PubMed

Knappe, Daniel; Fritsche, Stefanie; Alber, Gottfried; Köhler, Gabriele; Hoffmann, Ralf; Müller, Uwe

2012-10-01

The antimicrobial oncocin derivative Onc72 is highly active against a number of Gram-negative bacteria, including resistant strains. Here we study its toxicity and efficacy in a lethal mouse infection model. In an acute toxicity study, purified Onc72 was administered to NMRI mice in four consecutive injections within a period of 24 h as an intraperitoneal bolus. The animals' behaviour was monitored for 5 days, before several organs were examined by histopathology. A lethal Escherichia coli infection model was established and the efficacy of Onc72 was evaluated for different peptide doses considering the survival rates of each dose group and the bacterial counts in blood, lavage and organs. Intraperitoneal bolus injections with single doses of 20 or 40 mg of Onc72 per kg of body weight did not result in any abnormal animal behaviour. No mouse became moribund or died within the studied period. Histopathological examinations revealed no toxic effects. When infected with E. coli at a lethal dose, none of the untreated animals survived the next 24 h, whereas all animals treated three times with Onc72 at doses of ≥5 mg/kg survived the observation period of 5 days. No bacteria were detected in the blood of treated animals after day 5 post-infection. The effective dose (ED(50)) was ∼2 mg/kg. No toxic effects were observed for Onc72 within the studied dose range up to 40 mg/kg, indicating a safety margin of >20.

Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk.

PubMed

Rosano, Giuseppe M C; Aversa, Antonio; Vitale, Cristiana; Fabbri, Andrea; Fini, Massimo; Spera, Giovanni

2005-02-01

Erectile dysfunction (ED) is often associated with a cluster of risk factors for coronary artery disease and reduced endothelial function. Acute and chronic administration of oral sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, improves endothelial function in patients with ED. Tadalafil (TAD) is a new PDE5 inhibitor with a long half life that allows alternate day administration. Aim of the study was to evaluate whether chronic therapy (4 weeks) with TAD improves endothelial function in patients with increased cardiovascular risk and whether this effect is sustained after discontinuation of therapy. We randomized 32 patients with increased cardiovascular risk to receive either TAD 20 mg on alternate days or matching placebo (PLB) for 4 weeks. Patients underwent evaluation of brachial artery flow-mediated dilation (FMD), nitrite/nitrate and endothelin-1 plasma levels at baseline, at the end of treatment period and after two-weeks follow-up. At 4 weeks, FMD was significantly improved by TAD (from 4.2+/-3.2 to 9.3+/-3.7%, p<0.01 vs. baseline), but was not modified by PLB (from 4.1+/-2.8 to 4.0+/-3.4%, p=NS). At 6 weeks the benefit in FMD was sustained in patients that received TAD (9.1+/-3.9% vs. 4.2+/-3.2%, p=0.01 vs. baseline; 9.1+/-3.9% vs. 9.3+/-3.7%, vs. 4 weeks, p=NS) while no changes in FMD were observed in patients randomized to PLB. Also, compared to baseline, a net increase in nitrite/nitrate levels (38.2+/-12.3 vs. 52.6+/-11.7 and 51.1+/-3.1, p<0.05) and a decrease in endothelin-1 levels (3.3+/-0.9 vs. 2.9.+/-0.7 and 2.9+/-0.9, p<0.05) was found both at four and six-weeks after TAD; these changes were inversely correlated as shown by regression analysis (adjusted R2=0.81, p<0.0001). Chronic therapy with TAD improves endothelial function in patients with increased cardiovascular risk regardless their degree of ED. The benefit of this therapy is sustained for at least two weeks after the discontinuation of therapy. Larger studies are needed in order

Productive, economic and risk assessment of grazing dairy systems with supplemented cows milked once a day.

PubMed

Lazzarini, B; Lopez-Villalobos, N; Lyons, N; Hendrikse, L; Baudracco, J

2018-05-01

Milking cows once a day (OAD) is a herd management practice that may help to reduce working effort and labour demand in dairy farms. However, a decrease in milk yield per cow occurs in OAD systems compared with twice a day (TAD) systems and this may affect profitability of dairy systems. The objective of this study was to assess productive and economic impact and risk of reducing milking frequency from TAD to OAD for grazing dairy systems, using a whole-farm model. Five scenarios were evaluated by deterministic and stochastic simulations: one scenario under TAD milking (TADAR) and four scenarios under OAD milking. The OAD scenarios assumed that milk yield per cow decreased by 30% (OAD30), 24% (OAD24), 19% (OAD19) and 10% (OAD10), compared with TADAR scenario, based on experimental and commercial farms data. Stocking rate (SR) was increased in all OAD scenarios compared to TADAR and two levels of reduction in labour cost were tested, namely 15% and 30%. Milk and concentrate feeds prices, and pasture and crop yields, were allowed to behave stochastically to account for market and climate variations, respectively, to perform risk analyses. Scenario OAD10 showed similar milk yield per ha compared with TADAR, as the increased SR compensated for the reduction in milk yield per cow. For scenarios OAD30, OAD24 and OAD19 the greater number of cows per ha partially compensated for the reduction of milk yield per cow and milk yield per ha decreased 21%, 15% and 10%, respectively, compared with TADAR. Farm operating profit per ha per year also decreased in all OAD scenarios compared with TADAR, and were US$684, US$161, US$ 303, US$424 and US$598 for TADAR, OAD30, OAD24, OAD19, OAD10, respectively, when labour cost was reduced 15% in OAD scenarios. When labour cost was reduced 30% in OAD scenarios, only OAD10 showed higher profit (US$706) than TADAR. Stochastic simulations showed that exposure to risk would be higher in OAD scenarios compared with TADAR. Results showed that OAD

Once-daily mesalamine granules for ulcerative colitis.

PubMed

Lawlor, Garrett; Ahmed, Awais; Moss, Alan C

2010-07-01

Mesalamine extended-release capsules (Apriso [Salix Pharmaceuticals, Raleigh, NC, USA]) are the first once-daily mesalamine preparation approved by the US FDA for the maintenance of remission of ulcerative colitis (UC). Each mesalamine extended-release capsule contains granules of a mesalamine-polymer matrix that are coated with a pH-sensitive resin. This design begins releasing mesalamine (0.375 g) once the pH is more than 6 in the ileum and colon. Two clinical trials have reported that mesalamine extended-release capsules (1.5 g/day) maintained remission in 79% of patients with UC who were in clinical remission. Reported adherence with mesalamine extended-release capsules once daily was high (>90%) in these studies. This article examines the efficacy and safety of mesalamine extended-release capsules in the maintenance of remission in patients with UC.

Efficacy and safety of once-daily insulin degludec/insulin aspart compared with once-daily insulin glargine in participants with Type 2 diabetes: a randomized, treat-to-target study.

PubMed

Kumar, S; Jang, H C; Demirağ, N G; Skjøth, T V; Endahl, L; Bode, B

2017-02-01

To investigate, in a 26-week, open-label, randomized, treat-to-target trial, the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily vs insulin glargine (IGlar) once daily in adults with Type 2 diabetes, inadequately controlled on basal insulin. Participants were randomized (1:1) to IDegAsp once daily or IGlar once daily in combination with existing oral antidiabetic drugs. IDegAsp once daily was administered with the main evening meal or the largest meal of the day (agreed at baseline); dosing time was maintained throughout the trial. Participants titrated their insulin dose weekly to a mean pre-breakfast self-measured plasma glucose target [3.9-4.9 mmol/l (70-89 mg/dl)]. IDegAsp once daily was non-inferior to IGlar once daily in reducing HbA 1c after 26 weeks [mean estimated treatment difference IDegAsp once daily - IGlar once daily: -0.03% (95% CI -0.20, 0.14)]. The evening meal glucose increment was significantly lower with IDegAsp once daily vs IGlar once daily [estimated treatment difference IDegAsp once daily - IGlar once daily: -1.32 mmol/l (95% CI -1.93, -0.72); P < 0.05]. The overall confirmed hypoglycaemia rate was higher with IDegAsp once daily (estimated rate ratio 1.43; 95% CI 1.07, 1.92; P < 0.05). The rate of nocturnal hypoglycaemia did not significantly differ between the IDegAsp and IGlar groups [estimated rate ratio 0.80 (95% CI 0.49, 1.30); not significant]. In participants with Type 2 diabetes inadequately controlled on basal insulin, IDegAsp once daily improved glycaemic control and was non-inferior to IGlar once daily. IDegAsp led to higher rates of overall hypoglycaemia than IGlar, with no significant difference in rates of nocturnal hypoglycaemia. © 2016 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Treatment of streptococcal pharyngitis with once-daily compared with twice-daily amoxicillin: a noninferiority trial.

PubMed

Clegg, Herbert W; Ryan, Amy G; Dallas, Steven D; Kaplan, Edward L; Johnson, Dwight R; Norton, H James; Roddey, Oliver F; Martin, Edward S; Swetenburg, Raymond L; Koonce, Elizabeth W; Felkner, Mary M; Giftos, P Michael

2006-09-01

Two relatively small previous studies comparing once-daily amoxicillin with conventional therapy for group A streptococcal (GAS) pharyngitis reported similar rates of bacteriologic success for each treatment group. The purpose of this study was to further evaluate once-daily amoxicillin for GAS pharyngitis in a larger study. In a single pediatric practice, from October through May for 2 consecutive years (2001-2003), we recruited children 3 to 18 years of age who had symptoms and signs suggestive of GAS pharyngitis. Patients with a positive rapid test for GAS were stratified by weight (<40 kg or >or=40 kg) and then randomly assigned to receive once-daily (750 mg or 1000 mg) or twice-daily (2 doses of 375 mg or 500 mg) amoxicillin for 10 days. We determined bacteriologic failure rates for GAS in the pharynx from subsequent swabs taken at 14 to 21 (visit 2) and 28 to 35 (visit 3) days after treatment initiation. We conducted a randomized, controlled, investigator-blinded, noninferiority trial to evaluate whether amoxicillin given once daily would have a bacteriologic failure rate no worse than that of amoxicillin given twice daily within a prespecified margin of 10%. GAS isolates were characterized to distinguish bacteriologic failures from new acquisitions. Adverse events were described and adherence was evaluated by review of returned daily logs and dosage bottles. Of 2139 potential study patients during the 2-year period, we enrolled 652 patients, 326 into each treatment group. Children in the 2 groups were comparable with respect to all demographic and clinical characteristics except that children <40 kg more often presented with rash in each treatment group. At visit 2, failure rates were 20.1% (59 of 294) for the once-daily group and 15.5% (46 of 296) for the twice-daily group (difference, 4.53%; 90% confidence interval [CI], -0.6 to 9.7). At visit 3, failure rates were 2.8% (6 of 216) for the once-daily group and 7.1% (16 of 225) for the twice-daily group

Real-world glycemic outcomes in patients with type 2 diabetes initiating exenatide once weekly and liraglutide once daily: a retrospective cohort study.

PubMed

Saunders, William B; Nguyen, Hiep; Kalsekar, Iftekhar

2016-01-01

The glucagon-like peptide-1 receptor agonists exenatide once weekly (QW) and liraglutide once daily (QD) have demonstrated improvements in glycemic outcomes in patients with type 2 diabetes mellitus in randomized clinical trials. However, little is known about their real-world comparative effectiveness. This retrospective cohort study used the Quintiles Electronic Medical Record database to evaluate the 6-month change in glycated hemoglobin (A1C) for patients initiating exenatide QW or liraglutide QD. Patients with type 2 diabetes mellitus prescribed exenatide QW (n=664) or liraglutide QD (n=3,283) between February 1, 2012 and May 31, 2013 were identified. Baseline A1C measures were from 75 days before to 15 days after initiating exenatide QW or liraglutide QD, with follow-up measures documented at 6 months (±45 days). Adjusted linear regression models compared the difference in mean A1C change. A priori defined sensitivity analysis was performed in the subgroup of patients with baseline A1C ≥7.0% and no prescription for insulin during the 12-month pre-index period. For exenatide QW and liraglutide QD, respectively, mean (SD) age of the main study cohort was 58.01 (10.97) and 58.12 (11.05) years, mean (SD) baseline A1C was 8.4% (1.6) and 8.4% (1.6), and 48.2% and 54.2% of patients were women. In adjusted models, change in A1C did not differ between exenatide QW and liraglutide QD during 6 months of follow-up. Results were consistent in the subgroup analyses. In a real-world setting, A1C similarly improves in patients initiating exenatide QW or liraglutide QD.

Clinical trial: a novel high-dose 1 g mesalamine suppository (Salofalk) once daily is as efficacious as a 500-mg suppository thrice daily in active ulcerative proctitis.

PubMed

Andus, Tilo; Kocjan, Andreas; Müser, Moritz; Baranovsky, Andrey; Mikhailova, Tatyana L; Zvyagintseva, Tatyana D; Dorofeyev, Andrey E; Lozynskyy, Yurii S; Cascorbi, Ingolf; Stolte, Manfred; Vieth, Michael; Dilger, Karin; Mohrbacher, Ralf; Greinwald, Roland

2010-11-01

Mesalamine suppositories are first-line therapy in active ulcerative proctitis; the standard regime still recommends multiple doses per day. The primary objective of this study was to show the noninferiority of once-daily administration of a novel 1 g mesalamine suppository versus thrice-daily administration of the 0.5 g mesalamine suppository. This was a single-blind (investigator-blinded), randomized, multicenter, comparative, Phase III clinical trial. Patients with mild to moderately active ulcerative proctitis inserted either one mesalamine 1 g suppository at bedtime or one mesalamine 0.5 g suppository thrice daily over a 6-week period. The primary endpoint was rate of remission (Disease Activity Index below 4). In all, 354 patients were evaluable for safety and per-protocol analysis. The new regimen demonstrated noninferiority: The percentage of patients with remission was 87.9% for the once-daily 1 g mesalamine suppository and 90.7% for the thrice-daily 0.5 g mesalamine suppository. Each regimen resulted in prompt cessation of clinical symptoms (e.g., median time to ≤3 stools per day (all without blood): 5 days in the 1 g mesalamine once-daily and 7 days in the 0.5 g mesalamine thrice-daily group). Patients preferred applying suppositories once a day. In active ulcerative proctitis the once-daily administration of a 1 g mesalamine suppository is as effective and safe, yet considerably more convenient, than the standard thrice-daily administration of a 0.5 g mesalamine suppository.

Once-a-Week Versus Once-Every-3-Weeks Cisplatin Chemoradiation for Locally Advanced Head and Neck Cancer: A Phase III Randomized Noninferiority Trial.

PubMed

Noronha, Vanita; Joshi, Amit; Patil, Vijay Maruti; Agarwal, Jaiprakash; Ghosh-Laskar, Sarbani; Budrukkar, Ashwini; Murthy, Vedang; Gupta, Tejpal; D'Cruz, Anil K; Banavali, Shripad; Pai, Prathamesh S; Chaturvedi, Pankaj; Chaukar, Devendra; Pande, Nikhil; Chandrasekharan, Arun; Talreja, Vikas; Vallathol, Dilip Harindran; Mathrudev, Vijayalakshmi; Manjrekar, Aparna; Maske, Kamesh; Bhelekar, Arati Sanjay; Nawale, Kavita; Kannan, Sadhana; Gota, Vikram; Bhattacharjee, Atanu; Kane, Shubhada; Juvekar, Shashikant L; Prabhash, Kumar

2018-04-10

Purpose Chemoradiation with cisplatin 100 mg/m 2 given once every 3 weeks is the standard of care in locally advanced head and neck squamous cell cancer (LAHNSCC). Increasingly, low-dose once-a-week cisplatin is substituted because of perceived lower toxicity and convenience. However, there is no level 1 evidence of comparable efficacy to cisplatin once every 3 weeks. Patients and Methods In this phase III randomized trial, we assessed the noninferiority of cisplatin 30 mg/m 2 given once a week compared with cisplatin 100 mg/m 2 given once every 3 weeks, both administered concurrently with curative intent radiotherapy in patients with LAHNSCC. The primary end point was locoregional control (LRC); secondary end points included toxicity, compliance, response, progression-free survival, and overall survival. Results Between 2013 and 2017, we randomly assigned 300 patients, 150 to each arm. Two hundred seventy-nine patients (93%) received chemoradiotherapy in the adjuvant setting. At a median follow-up of 22 months, the estimated cumulative 2-year LRC rate was 58.5% in the once-a-week arm and 73.1% in the once-every-3-weeks arm, leading to an absolute difference of 14.6% (95% CI, 5.7% to 23.5%); P = .014; hazard ratio (HR), 1.76 (95% CI, 1.11 to 2.79). Acute toxicities of grade 3 or higher occurred in 71.6% of patients in the once-a-week arm and in 84.6% of patients in the once-every-3-weeks arm ( P = .006). Estimated median progression-free survival in the once-a-week arm was 17.7 months (95% CI, 0.42 to 35.05 months) and in the once-every-3-weeks arm, 28.6 months (95% CI, 15.90 to 41.30 months); HR, 1.24 (95% CI, 0.89 to 1.73); P = .21. Estimated median overall survival in the once-a-week arm was 39.5 months and was not reached in the once-every-3-weeks arm (HR, 1.14 [95% CI, 0.79 to 1.65]; P = .48). Conclusion Once-every-3-weeks cisplatin at 100 mg/m 2 resulted in superior LRC, albeit with more toxicity, than did once-a-week cisplatin at 30 mg/m 2 , and should

Current medical treatment of lower urinary tract symptoms/BPH: do we have a standard?

PubMed

Silva, João; Silva, Carlos Martins; Cruz, Francisco

2014-01-01

The pharmacological treatment of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH) is based on alpha-blockers and 5α-reductase inhibitors isolated or in combination. Silodosin, an alpha-1A specific alpha-blocker is the only innovation in these groups of agents. This classical paradigm is being challenged by antimuscarinics, 5-phosphodiesterase inhibitors (PDE5i) and β3-adrenoreceptor agonists. Silodosin is effective in reducing BPH/LUTS, including nocturia and shows little cardiovascular adverse events. Antimuscarinic drugs isolated or in combination with alpha-blockers improve storage symptoms without any harmful effect to the voiding function. PDE5i alone improve BPH/LUTS. Combination of PDE5i with alpha-blockers provides better symptomatic control than alpha-blockers alone. A recent head-to-head comparison of tadalafil 5 mg/day with tamsulosin 0.4 mg/day showed that these agents provided the same improvement in BPH/LUTS and, surprisingly, the same improvement in the urinary flow. In fact, previous studies with tadalafil had not shown any effect of tadalafil on flow. In addition, tadalafil but not tamsulosin improved sexual function. Mirabegron, the first β3-adrenoreceptor agonist, while improving BPH/LUTS in men with bladder outlet obstruction, do not decrease urinary flow or detrusor pressure. The standard medical treatment for BPH/LUTS is still based on alpha-blockers, 5ARIs or its combination. In the future, it is expected that BPH/LUTS treatment will become individualized, according to the type of symptoms, presence of sexual dysfunction and risk of BPH progression. This will challenge our concept of standard treatment for BPH/LUTS.

Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy.

PubMed

Martin, Elizabeth A; Barresi, Rita; Byrne, Barry J; Tsimerinov, Evgeny I; Scott, Bryan L; Walker, Ashley E; Gurudevan, Swaminatha V; Anene, Francine; Elashoff, Robert M; Thomas, Gail D; Victor, Ronald G

2012-11-28

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective-causing functional muscle ischemia-in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3',5'-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.

Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy

PubMed Central

Martin, Elizabeth A.; Barresi, Rita; Byrne, Barry J.; Tsimerinov, Evgeny I.; Scott, Bryan L.; Walker, Ashley E.; Gurudevan, Swaminatha V.; Anene, Francine; Elashoff, Robert M.; Thomas, Gail D.; Victor, Ronald G.

2013-01-01

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin’s rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived nitric oxide (NO) attenuates local α-adrenergic vasoconstriction thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective—causing functional muscle ischemia—in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. Here, we report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled cross-over trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation fully restored in the muscles of men with BMD by boosting NO-cGMP signaling with a single dose of the drug tadalafil, a phosphodiesterase (PDE5A) inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD. PMID:23197572

The influence of amorphization methods on the apparent solubility and dissolution rate of tadalafil.

PubMed

Wlodarski, K; Sawicki, W; Paluch, K J; Tajber, L; Grembecka, M; Hawelek, L; Wojnarowska, Z; Grzybowska, K; Talik, E; Paluch, M

2014-10-01

This study for the first time investigates the solubility and dissolution rate of amorphous tadalafil (Td)--a poorly water soluble chemical compound which is commonly used for treating the erectile dysfunction. To convert the crystalline form of Td drug to its amorphous counterpart we have employed most of the commercially available amorphization techniques i.e. vitrification, cryogenic grinding, ball milling, spray drying, freeze drying and antisolvent precipitation. Among the mentioned methods only quenched cooling of the molten sample was found to be an inappropriate method of Td amorphization. This is due to the thermal decomposition of Td above 200°C, as proved by the thermogravimetric analysis (TGA). Disordered character of all examined samples was confirmed using differential scanning calorimetry (DSC) and X-ray powder diffraction (PXRD). In the case of most amorphous powders, the largest 3-fold increase of apparent solubility was observed after 5 min, indicating their fast recrystallization in water. On the other hand, the partially amorphous precipitate of Td and hypromellose enhanced the solubility of Td approximately 14 times, as compared with a crystalline substance, which remained constant for half an hour. Finally, disk intrinsic dissolution rate (DIDR) of amorphous forms of Td was also examined. Copyright © 2014 Elsevier B.V. All rights reserved.

Once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (PATRIOT): A phase 2 randomized trial.

PubMed

Quon, Harvey C; Ong, Aldrich; Cheung, Patrick; Chu, William; Chung, Hans T; Vesprini, Danny; Chowdhury, Amit; Panjwani, Dilip; Pang, Geordi; Korol, Renee; Davidson, Melanie; Ravi, Ananth; McCurdy, Boyd; Zhang, Liying; Mamedov, Alexandre; Deabreu, Andrea; Loblaw, Andrew

2018-05-01

Prostate stereotactic body radiotherapy (SBRT) regimens differ in time, dose, and fractionation. We completed a multicentre, randomized phase II study to investigate the impact of overall treatment time on quality of life (QOL). Men with low and intermediate-risk prostate cancer were randomly assigned to 40 Gy in 5 fractions delivered once per week (QW) vs. every other day (EOD). QOL was assessed using the Expanded Prostate Cancer Index Composite. The primary endpoint was the proportion with a minimum clinically important change (MCIC) in bowel QOL during the acute (≤12 week) period, and analysis was by intention-to-treat. ClinicalTrials.gov NCT01423474. 152 men from 3 centres were randomized with median follow-up of 47 months. Patients treated QW had superior acute bowel QOL with 47/69 (68%) reporting a MCIC compared to 63/70 (90%) treated EOD (p = 0.002). Fewer patients treated QW reported moderate-severe problems with bowel QOL during the acute period compared with EOD (14/70 [20%] vs. 40/70 [57%], p < 0.001). Acute urinary QOL was also better in the QW arm, with 52/67 (78%) vs 65/69 (94%) experiencing a MCIC (p = 0.006). There were no significant differences in late urinary or bowel QOL at 2 years or last follow-up. Prostate SBRT delivered QW improved acute bowel and urinary QOL compared to EOD. Patients should be counselled regarding the potential for reduced short-term toxicity and improved QOL with QW prostate SBRT. Copyright © 2018 Elsevier B.V. All rights reserved.

Cardioprotective role of tadalafil against cisplatin-induced cardiovascular damage in rats.

PubMed

Saleh, Rasha M; Awadin, Walaa F; El-Shafei, Reham A; Elseady, Yousef Y; Wehaish, Faheim E; Elshal, Mohamed F

2015-10-15

The present study investigated the possible cardioprotective effect of tadalafil (Tad) on cisplatin (CDDP)-induced cardiac and vascular damages in rats. A total number of seventy two healthy male albino rats initially weighting between 200 and 220 g were used and randomly divided into four groups,18 rats in each. The control group received no treatment; CDDP group received a single dose of CDDP (4 mg/kg) intraperitoneal (i.p.) per week for 4 weeks the duration of the experiment; Tad group received 0.4 mg/kg BW Tad i.p. daily and Tad +CDDP group received 0.4 mg/kg BW Tad i.p. +4 mg/kg BW CDDP i.p. The results showed that Tad was able to decrease blood pressure, heart rate, levels of serum cardiac troponin (cTn-I), malondialdehyde (MDA) and increased levels of reduced glutathione (GSH) and nitric oxide (NO) in the heart homogenate sample from CDDP treated rats. Semi-quantitative analysis showed that Tad was able to decrease the histopathological scores of cardiac muscular hyalinzation and fibrosis in three sacrifices in CDDP treated rats. CDDP treated rats showed significantly increased thickening in wall of aorta with an irregular luminal layer of endothelial cell linings in three sacrifices when it was compared to other groups. Moreover, immunohistochemical labeling of α- smooth muscle actin (α-SMA) in aorta revealed significant lower scores in Tad +CDDP group when they were compared to CDDP group. In conclusion, Tad alone did not induce any harmful effects on blood pressure, selective antioxidant, peroxidation markers or cardiac histology, in addition, Tad has a cardio-protective role against CDDP. Copyright © 2015 Elsevier B.V. All rights reserved.

Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial.

PubMed

Dungan, Kathleen M; Povedano, Santiago Tofé; Forst, Thomas; González, José G González; Atisso, Charles; Sealls, Whitney; Fahrbach, Jessie L

2014-10-11

Dulaglutide and liraglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists, improve glycaemic control and reduce weight in patients with type 2 diabetes. In a head-to-head trial, we compared the safety and efficacy of once-weekly dulaglutide with that of once-daily liraglutide in metformin-treated patients with uncontrolled type 2 diabetes. We did a phase 3, randomised, open-label, parallel-group study at 62 sites in nine countries between June 20, 2012, and Nov 25, 2013. Patients with inadequately controlled type 2 diabetes receiving metformin (≥1500 mg/day), aged 18 years or older, with glycated haemoglobin (HbA1c) 7·0% or greater (≥53 mmol/mol) and 10·0% or lower (≤86 mmol/mol), and body-mass index 45 kg/m(2) or lower were randomly assigned to receive once-weekly dulaglutide (1·5 mg) or once-daily liraglutide (1·8 mg). Randomisation was done according to a computer-generated random sequence with an interactive voice response system. Participants and investigators were not masked to treatment allocation. The primary outcome was non-inferiority (margin 0·4%) of dulaglutide compared with liraglutide for change in HbA1c (least-squares mean change from baseline) at 26 weeks. Safety data were collected for a further 4 weeks' follow-up. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01624259. We randomly assigned 599 patients to receive once-weekly dulaglutide (299 patients) or once-daily liraglutide (300 patients). 269 participants in each group completed treatment at week 26. Least-squares mean reduction in HbA1c was -1·42% (SE 0·05) in the dulaglutide group and -1·36% (0·05) in the liraglutide group. Mean treatment difference in HbA1c was -0·06% (95% CI -0·19 to 0·07, pnon-inferiority<0·0001) between the two groups. The most common gastrointestinal adverse events were nausea (61 [20%] in dulaglutide group vs 54 [18%] in liraglutide group), diarrhoea (36 [12%] vs 36 [12%]), dyspepsia (24 [8

Concentrations of dapivirine in the rhesus macaque and rabbit following once daily intravaginal administration of a gel formulation of [14C]dapivirine for 7 days.

PubMed

Nuttall, Jeremy P; Thake, Daryl C; Lewis, Mark G; Ferkany, John W; Romano, Joseph W; Mitchnick, Mark A

2008-03-01

Dapivirine is a nonnucleoside reverse transcriptase inhibitor being developed as a topical microbicide for the prevention of human immunodeficiency virus infection. The distribution of radioactivity and drug in plasma and in vaginal, cervical, and draining lymph node tissues was investigated after daily application of a vaginal gel formulation of [14C]dapivirine to rhesus macaques. This was preceded by a preliminary study with rabbits. Following the intravaginal administration of [14C]dapivirine ( approximately 0.1 mg/ml [15 microCi/ml]) to rabbits (0.5 ml/day) and macaques (1 ml/day) for 7 days, the dapivirine levels associated with vaginal and cervical tissue samples 1 h after the final dose were high (quantities of microg/g of tissue) and remained detectable at 24 h (mean, >or=2.5 ng/g in rabbits) and 48 h (mean, >80 ng/g in macaques). Radioactivity levels were low in the plasma and very low or unquantifiable in the draining lymph nodes of the macaques. Microautoradiography identified drug-related material (DRM) on the surfaces of the vaginal and cervical tissues of the rabbits and macaques. Although DRM was primarily associated with the outermost layer of shedding cells in rabbits, two animals showed some evidence of small quantities in the mucosal epithelium of the cervix. In macaques, DRM was seen within the keratinized layer of the vaginal epithelium and and was found to extend into the superficial cellular layers, and in at least one animal it appeared to be present in the deepest (germinal) layer of the epithelium and in submucosal tissues. The persistence of biologically significant concentrations of dapivirine in vaginal and cervical tissues for >24 h supports the development of dapivirine as a microbicide for once daily application.

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

PubMed

Rao, Shripada C; Srinivasjois, Ravisha; Moon, Kwi

2016-12-06

Animal studies and trials in older children and adults suggest that a 'one dose per day' regimen of gentamicin is superior to a 'multiple doses per day' regimen. To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3) in the Cochrane Library (searched 8 April 2016), MEDLINE (1966 to 8 April 2016), Embase (1980 to 8 April 2016), and CINAHL (December 1982 to 8 April 2016). All randomised or quasi-randomised controlled trials comparing one dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin to newborn infants. Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI -0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD -0.13, 95% CI -0.19 to -0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD -0.22, 95% CI -0.29 to -0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD -0.57, 95% CI -0.69 to -0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups

Once-daily MMX(®) mesalamine for endoscopic maintenance of remission of ulcerative colitis.

PubMed

D'Haens, Geert; Sandborn, William J; Barrett, Karen; Hodgson, Ian; Streck, Paul

2012-07-01

Treatment with mesalamine to maintain endoscopic remission (mucosal healing) of ulcerative colitis (UC) has been shown to reduce the risk of relapse and is the recommended first-line maintenance therapy. To improve treatment adherence, a mesalamine formulation that can be administered once-daily, MMX(®) mesalamine (Lialda; Shire Pharmaceuticals LLC, Wayne, PA), was developed. This study was conducted to determine the efficacy and safety of once-daily MMX mesalamine compared with twice-daily delayed-release mesalamine (Asacol; Warner Chilcott, Dublin, Ireland) for maintaining endoscopic remission in patients with UC. A multicenter, randomized, double-blind, 6-month, active-control trial was conducted to assess the non-inferiority of once-daily MMX mesalamine 2.4 g/day compared with twice-daily delayed-release mesalamine at a total daily dose of 1.6 g/day in patients with UC in endoscopic remission. The primary end point was maintenance of endoscopic remission at month 6 in the per-protocol (PP) population. Overall, 826 patients were randomized and dosed. The primary objective (non-inferiority) was met. At month 6, 83.7 and 77.8% of patients receiving MMX mesalamine in the PP and intent-to-treat (ITT) populations, respectively, had maintained endoscopic remission compared with 81.5% (PP) and 76.9% (ITT) of patients receiving delayed-release mesalamine (95% confidence interval for difference: -3.9%, 8.1% (PP); -5.0%, 6.9% (ITT)). Time to relapse was not significantly different between the two treatment groups (log-rank test, P=0.5116 (PP); P=0.5455 (ITT)). The proportion of patients with adverse events was 37.1 and 36.0% in patients receiving MMX mesalamine and delayed-release mesalamine, respectively. Once-daily dosing of MMX mesalamine 2.4 g/day was shown to be well tolerated and non-inferior to twice-daily dosing with delayed-release mesalamine 1.6 g/day for maintenance of endoscopic remission in patients with UC.

Comparison of once-daily versus twice-weekly terbinafine administration for the treatment of canine Malassezia dermatitis - a pilot study.

PubMed

Berger, Darren J; Lewis, Thomas P; Schick, Anthea E; Stone, Richard T

2012-10-01

Terbinafine, an allylamine antifungal, is used in pulsatile dose regimens for superficial mycoses in human medicine. To compare the clinical efficacy of twice-weekly versus once-daily terbinafine administration to determine whether preliminary proof-of-concept evidence exists for pulsatile administration of terbinafine in the treatment of canine Malassezia dermatitis and to determine whether twice-weekly treatment results in fewer clinical and owner-perceived adverse events. Twenty client-owned dogs with Malassezia dermatitis. In this randomized, single-blinded clinical trial, dogs were randomly assigned to receive terbinafine (30 mg/kg) either once daily for 21 days (n = 10) or once daily on two consecutive days per week for six doses (n = 10). On day 0 and day 21, a mean yeast count was calculated from eight anatomical locations via adhesive tape-strip cytology, clinical lesion scores were assigned to the same locations, and owners assessed pruritus using a visual analog scale. There was no significant difference between treatment groups with respect to the reduction in mean yeast count (P = 0.343) and clinical lesion scores (P = 0.887). Pruritus measured by visual analog scale was significantly decreased in the twice-weekly treatment group compared with the daily treatment group (P = 0.047). Seven of 20 dogs had a clinically measurable or owner-reported adverse event during treatment that included gastrointestinal disturbances, excessive panting and elevated hepatic enzymes, with no significant difference noted between treatment groups. This pilot study indicates that twice-weekly terbinafine administration may be an effective alternative treatment for canine Malassezia dermatitis and merits further investigation. © 2012 The Authors. Veterinary Dermatology © 2012 ESVD and ACVD.

Fluticasone furoate/Vilanterol 92/22 μg once-a-day vs Beclomethasone dipropionate/Formoterol 100/6 μg b.I.D.: a 12-month comparison of outcomes in mild-to-moderate asthma.

PubMed

Dal Negro, Roberto W; Bonadiman, Luca; Turco, Paola

2018-01-01

Bronchial asthma is an inflammatory disease of the airways. Beclomethasone dipropionate/Formoterol (BDP/F) and Fluticasone furoate/Vilanterol (FF/V) are two of the most effective LABA/ICS combinations for managing persistent bronchial asthma. Aim of the study was to compare the outcomes achieved in mild-to-moderate asthma patients assuming BDP/F 100/6 μg b.i.d. (Group A) or FF/V 92/22 μg once-daily (Group B) for 12-months. No head-to-head long-term comparison is available at present. Data were automatically and anonymously obtained from the institutional database: FEV 1 % predicted values; the exacerbation and hospitalization rates; days of hospitalization; GP and/or specialist visits; days of inactivity; courses of systemic steroids and/or antibiotics were recorded at baseline and after 3, 6 and 12 months of both treatments. The overall adherence to treatments was also calculated. The propensity score method was used for matching and comparing the two cohorts of patients; Anova and Wilcoxon tests were used for checking the trends and time-to-time comparisons over the period; statistical significance was accepted for p  < 0.05. The PS-matching process returned a cohort of 40 group A patients matched with 40 patients of group B, fully comparable for demographics, clinical characteristics, and comorbidities. The improvement in lung function was significant in both groups ( p  < 0.001), even if it was significantly higher and time-dependent in group B. The mean (±SE) exacerbation rate/patient changed from 0.63 (±0.13) at baseline to 0.53 (±0.12) after three; to 0.58 (±0.13) after six, and to 0.60 (±0.18) after twelve months in group A (p = ns), while from of 1.05 (±0.16) at baseline, to 0.28 (±0.07) after three; to 0.33 (±0.08) after six, and to 0.18 (±0.08) after twelve months in group B ( p  < 0.001), respectively. The mean hospitalization rate/patient changed from 0.25 ± 0.07 at baseline to 0.15 (±0.06) after three; to 0.08 (±0

Losartan improves erectile dysfunction in diabetic patients: a clinical trial.

PubMed

Chen, Y; Cui, S; Lin, H; Xu, Z; Zhu, W; Shi, L; Yang, R; Wang, R; Dai, Y

2012-01-01

The activation of cavernous local renin-angiotensin system has an important role in pathogenesis of diabetic erectile dysfunction (ED). In our primary study, we found that angiotensin Type 1 receptor blocker improved the erectile function of diabetic rats. Therefore we explored the losartan in clinical treatment for diabetic patients suffering with ED. A total of 124 diabetic patients with ED were included in this study and treated with losartan or tadalafil or losartan plus tadalafil or watch for waiting as control for 12 weeks. Erectile function was assessed by International Index of Erectile Function (IIEF-5) questionnaire, the percentage of positive responses to sexual encounter profile questions 2 (SEP2), 3 (SEP3) and the global assessment question (GAQ). Losartan or tadalafil or losartan plus tadalafil significantly improved the mean IIEF-5 scores, the percentage of successful penetrations (SEP2), the successful intercourse completions (SEP3) and GAQ (P<0.05). The combination of losartan and tadalafil is more effective than the single-use of losartan or tadalafil (P<0.05). The patients with moderate and mild ED had better response rates to losartan than patients with severe ED. This is the first clinical trial in losartan therapy on diabetic patients suffering from ED. Losartan seems to be effective and well-tolerated in diabetic ED patients, especially for mild to moderate ones. The combination therapy of losartan and tadalafil appeared to be more effective than monotherapy.

Co-possession of phosphodiesterase type-5 inhibitors (PDE5-I) with nitrates.

PubMed

Chang, Li-Ling; Ma, Mark; Allmen, Heather von; Henderson, Scott C; Harper, Kristine; Hornbuckle, Kenneth

2010-06-01

Estimate the proportion of phosphodiesterase type-5 inhibitor (PDE5-I) patients who co-possess nitrates and compare the proportion of tadalafil patients dispensed nitrates to a matched control group. Secondarily, examine the percentage of co-possession of PDE5-Is and nitrates where the products were dispensed on the same day or written by the same prescriber. Male patients aged 18+ years filling PDE5-I prescriptions between December 2003 and March 2006 were identified using a U.S. longitudinal prescription database (IMS Health LRx). Similar patients not dispensed a PDE5-I during this period were matched to the tadalafil-dispensed cohort using a propensity score approach. Co-possession, as a proxy for concurrent use, was defined as an overlap in time on therapy for a PDE5-I and nitrate and was compared for the three PDE5-Is and for tadalafil to the matched control group. Among 601,063 tadalafil patients, 3.31% were dispensed a nitrate during the study period, compared to 6.18% in control patients (n = 601,063). When co-possessed prescriptions were defined by overlapping exposure periods, the proportion of PDE5-I patients with co-possessed nitrates ranged from 1.44% (tadalafil) to 1.72% (vardenafil) and 2.13% (sildenafil). Co-possession percentages of PDE5-I prescriptions were 0.83% for tadalafil and 1.07% for sildenafil and vardenafil. The majority (54.29%) of co-possessed PDE5-I and nitrate prescriptions had the nitrate dispensed prior to the PDE5-I prescription identified in the study cohort. Keeping in mind the limitations of observational studies, these results suggest that co-dispensing of nitrates and PDE5-Is is low. Compared to control patients, the proportion of nitrate co-possession was lowest for patients filling tadalafil. Tadalafil patients also had the lowest co-possessed proportion among the three PDE5-I cohorts. While the majority of co-possessed drug pairs were prescribed by different providers, the highest percentage of co-prescribing from the same

Day-to-Day Variability of Postural Sway and Its Association With Cognitive Function in Older Adults: A Pilot Study

PubMed Central

Leach, Julia M.; Mancini, Martina; Kaye, Jeffrey A.; Hayes, Tamara L.; Horak, Fay B.

2018-01-01

Introduction: Increased variability in motor function has been observed during the initial stages of cognitive decline. However, the natural variability of postural control, as well as its association with cognitive status and decline, remains unknown. The objective of this pilot study was to characterize the day-to-day variability in postural sway in non-demented older adults. We hypothesized that older adults with a lower cognitive status would have higher day-to-day variability in postural sway. Materials and Methods: A Nintendo Wii balance board (WBB) was used to quantify postural sway in the home twice daily for 30 days in 20 non-demented, community-dwelling older adults: once under a single-task condition and once under a dual-task condition (using a daily word search task administered via a Nook tablet). Mean sway distance, velocity, area, centroidal frequency and frequency dispersion were derived from the center of pressure data acquired from the WBB. Results: Linear relationships were observed between the day-to-day variability in postural sway and cognitive status (indexed by cognitive global z-scores). More variability in time-domain postural sway (sway distance and area) and less variability in frequency-domain postural sway (centroidal sway frequency) were associated with a lower cognitive status under both the single- and dual-task conditions. Additionally, lower cognitive performance rates on the daily word search task were related to a lower cognitive status. Discussion: This small pilot study conducted on a short time scale motivates large-scale implementations over more extended time periods. Tracking longitudinal changes in postural sway may further our understanding of early-stage postural decline and its association with cognitive decline and, in turn, may aid in the early detection of dementia during preclinical stages when the utility of disease-modifying therapies would be greatest. PMID:29780319

Day-to-Day Variability of Postural Sway and Its Association With Cognitive Function in Older Adults: A Pilot Study.

PubMed

Leach, Julia M; Mancini, Martina; Kaye, Jeffrey A; Hayes, Tamara L; Horak, Fay B

2018-01-01

Introduction : Increased variability in motor function has been observed during the initial stages of cognitive decline. However, the natural variability of postural control, as well as its association with cognitive status and decline, remains unknown. The objective of this pilot study was to characterize the day-to-day variability in postural sway in non-demented older adults. We hypothesized that older adults with a lower cognitive status would have higher day-to-day variability in postural sway. Materials and Methods : A Nintendo Wii balance board (WBB) was used to quantify postural sway in the home twice daily for 30 days in 20 non-demented, community-dwelling older adults: once under a single-task condition and once under a dual-task condition (using a daily word search task administered via a Nook tablet). Mean sway distance, velocity, area, centroidal frequency and frequency dispersion were derived from the center of pressure data acquired from the WBB. Results : Linear relationships were observed between the day-to-day variability in postural sway and cognitive status (indexed by cognitive global z-scores). More variability in time-domain postural sway (sway distance and area) and less variability in frequency-domain postural sway (centroidal sway frequency) were associated with a lower cognitive status under both the single- and dual-task conditions. Additionally, lower cognitive performance rates on the daily word search task were related to a lower cognitive status. Discussion : This small pilot study conducted on a short time scale motivates large-scale implementations over more extended time periods. Tracking longitudinal changes in postural sway may further our understanding of early-stage postural decline and its association with cognitive decline and, in turn, may aid in the early detection of dementia during preclinical stages when the utility of disease-modifying therapies would be greatest.

Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects.

PubMed

Dooley, Kelly E; Sayre, Patrick; Borland, Julie; Purdy, Elizabeth; Chen, Shuguang; Song, Ivy; Peppercorn, Amanda; Everts, Stephanie; Piscitelli, Stephen; Flexner, Charles

2013-01-01

Cotreatment of tuberculosis (TB) and HIV among coinfected patients is now the standard of care. Rifampin (RIF) is a standard part of TB treatment but is a potent inducer of drug metabolizing enzymes. This study evaluated the effect of RIF or rifabutin (RBT) on the pharmacokinetics of the investigational HIV integrase inhibitor, dolutegravir (DTG). Phase I pharmacokinetic drug interaction study. In arm 1, healthy subjects received 50 mg of DTG once daily for 7 days (period 1), then 50 mg of DTG twice daily for 7 days (period 2), then 50 mg of DTG twice daily together with 600 mg of RIF once daily for 14 days (period 3). In arm 2, subjects received 50 mg of DTG once daily for 7 days (period 1) then 50 mg of DTG once daily together with 300 mg of RBT once daily for 14 days (period 2). PK sampling was performed at the end of each period. In arm 1, comparing period 3 to period 1, the geometric mean ratio (GMR) for the 24-hour area under the time-concentration curve (AUC0-24) was 1.33 [90% confidence interval (CI): 1.14 to 1.53], and the GMR for the trough (Cτ) was 1.22 (90% CI: 1.01 to 1.48). Comparing period 2 to period 1 in arm 2, the GMR for the AUC0-24 was 0.95 (90% CI: 0.82 to 1.10), and the GMR for the Cτ was 0.70 (90% CI: 0.57 to 0.87). Regimens including twice-daily DTG and RIF or once-daily DTG and RBT may represent a new treatment option for patients who require concomitant treatment of HIV and TB.

20 CFR 404.1807 - Monthly payment day.

Code of Federal Regulations, 2010 CFR

2010-04-01

... in writing if your monthly payment day is being changed to the 3rd of the month due to this provision... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Monthly payment day. 404.1807 Section 404... INSURANCE (1950- ) Payment Procedures § 404.1807 Monthly payment day. (a) General. Once we have made a...

Blue laser inorganic write-once media

NASA Astrophysics Data System (ADS)

Chen, Bing-Mau; Yeh, Ru-Lin

2004-09-01

With the advantages of low cost, portability and compliance with ROM disc, write once disk has become the most popular storage media for computer and audio/video application. In addition, write once media, like CD-R and DVD-/+ R, are used to store permanent or nonalterable information, such as financial data transitions, legal documentation, and medical data. Several write once recording materials, such as TeO[1], TeOPd[2] and Si/Cu [3] have been proposed to realize inorganic write once media. Moreover, we propose AlSi alloy [4] to be used for recording layer of write once media. It had good recording properties in DVD system although the reflectivity is too low to be used for DVD-R disk. In this paper, we report the further results in blue laser system, such as the static and dynamic characteristics of write once media.

Conversion From Twice-Daily Tacrolimus Capsules to Once-Daily Extended-Release Tacrolimus (LCPT): A Phase 2 Trial of Stable Renal Transplant Recipients

PubMed Central

Gaber, A. Osama; Alloway, Rita R.; Bodziak, Kenneth; Kaplan, Bruce; Bunnapradist, Suphamai

2013-01-01

Background LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Phase 1 studies demonstrated greater bioavailability to twice-daily tacrolimus capsules and no new safety concerns. Methods In this phase 2 study, adult stable kidney transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCP-Tacro) once-daily; patients continued on LCP-Tacro once-daily for days 8 to 21; trough levels were to be maintained between 5 and 15 ng/mL; 24-hr pharmacokinetic assessments were done on days 7 (baseline pre-switch), 14, and 21. Results Forty-seven patients completed LCP-Tacro dosing per protocol. The mean conversion ratio was 0.71. Pharmacokinetic data demonstrated consistent exposure (AUC) at the lower conversion dose. Cmax (P=0.0001), Cmax/Cmin ratio (P<0.001), percent fluctuation (P<0.0001), and swing (P=0.0004) were significantly lower and Tmax significantly (P<0.001) longer for LCP-Tacro versus Prograf. AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy were 0.86 or more, demonstrating a robust correlation between LCP-Tacro tacrolimus exposure and trough levels. There were three serious adverse events; none were related to study drug and all were resolved. Conclusions Stable kidney transplant patients can be safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allows for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displays flatter kinetics characterized by significantly lower peak-trough fluctuations. PMID:23715050

High-Energy Ball Milling as Green Process To Vitrify Tadalafil and Improve Bioavailability.

PubMed

Krupa, Anna; Descamps, Marc; Willart, Jean-François; Strach, Beata; Wyska, Elżbieta; Jachowicz, Renata; Danède, Florence

2016-11-07

In this study, the suitability of high-energy ball milling was investigated with the aim to vitrify tadalafil (TD) and improve its bioavailability. To achieve this goal, pure TD as well as binary mixtures composed of the drug and Soluplus (SL) were coprocessed by high-energy ball milling. Modulated differential scanning calorimetry (MDSC) and X-ray powder diffraction (XRD) demonstrated that after such coprocessing, the crystalline form of TD was transformed into an amorphous form. The presence of a single glass transition (T g ) for all the comilled formulations indicated that TD was dispersed into SL at the molecular level, forming amorphous molecular alloys, regardless of the drug concentration. The high values of T g determined for amorphous formulations, ranging from 70 to 147 °C, foreshow their high stability during storage at room temperature, which was verified by XRD and MDSC studies. The stabilizing effect of SL on the amorphous form of TD in comilled formulations was confirmed. Dissolution tests showed immediate drug release with sustained supersaturation in either simulated gastric fluid of pH 1.2 or in phosphate buffer of pH 7.2. The beneficial effect of both amorphization and coamorphization on the bioavailability of TD was found. In comparison to aqueous suspension, the relative bioavailability of TD was only 11% for its crystalline form and 53% for the crystalline physical mixture, whereas the bioavailability of milled amorphous TD and the comilled solid dispersion was 128% and 289%, respectively. Thus, the results provide evidence that not only the presence of polymeric surfactant but also the vitrification of TD is necessary to improve bioavailability.

Once a physicist: David Florence

NASA Astrophysics Data System (ADS)

Florence, David

2009-03-01

I did mathematical physics because it was just what I was best at. I enjoyed it at school, so I applied to do it at Nottingham University. I fell into it, to be quite honest. Once at university, I struggled at first, partly because I found it quite difficult to combine studying with competing and training in sport, which is pretty much full time as well. But by the end of my university career, I had learned to be organized, and to manage my time pretty effectively, so I enjoyed it a lot more.

PDE5 Inhibitor Tadalafil and Hydroxychloroquine Cotreatment Provides Synergistic Protection against Type 2 Diabetes and Myocardial Infarction in Mice.

PubMed

Wang, Rui; Xi, Lei; Kukreja, Rakesh C

2017-04-01

Diabetes is associated with a high risk for ischemic heart disease. We have previously shown that phosphodiesterase 5 inhibitor tadalafil (TAD) induces cardioprotection against ischemia/ reperfusion (I/R) injury in diabetic mice. Hydroxychloroquine (HCQ) is a widely used antimalarial and anti-inflammatory drug that has been reported to reduce hyperglycemia in diabetic patients. Therefore, we hypothesized that a combination of TAD and HCQ may induce synergistic cardioprotection in diabetes. We also investigated the role of insulin-Akt-mammalian target of rapamycin (mTOR) signaling, which regulates protein synthesis and cell survival. Adult male db/db mice were randomized to receive vehicle, TAD (6 mg/kg), HCQ (50 mg/kg), or TAD + HCQ daily by gastric gavage for 7 days. Hearts were isolated and subjected to 30-minute global ischemia, followed by 1-hour reperfusion in Langendorff mode. Cardiac function and myocardial infarct size were determined. Plasma glucose, insulin and lipid levels, and relevant pancreatic and cardiac protein markers were measured. Treatment with TAD + HCQ reduced myocardial infarct size (17.4% ± 4.3% vs. 37.8% ± 4.9% in control group, P < 0.05) and enhanced the production of ATP. The TAD + HCQ combination treatment also reduced fasting blood glucose, plasma free fatty acids, and triglyceride levels. Furthermore, TAD + HCQ increased plasma insulin levels (513 ± 73 vs. 232 ± 30 mU/liter, P < 0.05) with improved insulin sensitivity, larger pancreatic β -cell area, and pancreas mass. Insulin-like growth factor-1 (IGF-1) levels were also elevated by TAD + HCQ (343 ± 14 vs. 262 ± 22 ng/ml, P < 0.05). The increased insulin/IGF-1 resulted in activation of downstream Akt/mTOR cellular survival pathway. These results suggest that combination treatment with TAD and HCQ could be a novel and readily translational pharmacotherapy for reducing cardiovascular risk factors and protecting against myocardial I/R injury in type 2 diabetes. Copyright © 2017

PDE5 Inhibitor Tadalafil and Hydroxychloroquine Cotreatment Provides Synergistic Protection against Type 2 Diabetes and Myocardial Infarction in Mice

PubMed Central

Wang, Rui; Xi, Lei

2017-01-01

Diabetes is associated with a high risk for ischemic heart disease. We have previously shown that phosphodiesterase 5 inhibitor tadalafil (TAD) induces cardioprotection against ischemia/ reperfusion (I/R) injury in diabetic mice. Hydroxychloroquine (HCQ) is a widely used antimalarial and anti-inflammatory drug that has been reported to reduce hyperglycemia in diabetic patients. Therefore, we hypothesized that a combination of TAD and HCQ may induce synergistic cardioprotection in diabetes. We also investigated the role of insulin-Akt-mammalian target of rapamycin (mTOR) signaling, which regulates protein synthesis and cell survival. Adult male db/db mice were randomized to receive vehicle, TAD (6 mg/kg), HCQ (50 mg/kg), or TAD + HCQ daily by gastric gavage for 7 days. Hearts were isolated and subjected to 30-minute global ischemia, followed by 1-hour reperfusion in Langendorff mode. Cardiac function and myocardial infarct size were determined. Plasma glucose, insulin and lipid levels, and relevant pancreatic and cardiac protein markers were measured. Treatment with TAD + HCQ reduced myocardial infarct size (17.4% ± 4.3% vs. 37.8% ± 4.9% in control group, P < 0.05) and enhanced the production of ATP. The TAD + HCQ combination treatment also reduced fasting blood glucose, plasma free fatty acids, and triglyceride levels. Furthermore, TAD + HCQ increased plasma insulin levels (513 ± 73 vs. 232 ± 30 mU/liter, P < 0.05) with improved insulin sensitivity, larger pancreatic β-cell area, and pancreas mass. Insulin-like growth factor-1 (IGF-1) levels were also elevated by TAD + HCQ (343 ± 14 vs. 262 ± 22 ng/ml, P < 0.05). The increased insulin/IGF-1 resulted in activation of downstream Akt/mTOR cellular survival pathway. These results suggest that combination treatment with TAD and HCQ could be a novel and readily translational pharmacotherapy for reducing cardiovascular risk factors and protecting against myocardial I/R injury in type 2 diabetes. PMID:28123046

Trials for development of once-a-month injectable, hormonal male contraceptive using dienogest plus testosterone undecanoate: dose standardization, efficacy and reversibility studies in rats.

PubMed

Misro, Man M; Chaki, Shankar P; Kaushik, Mahesh C; Nandan, Deoki

2009-06-01

The study was conducted to test the potential of using dienogest (DNG) plus testosterone undecanoate (TU) in rats for development of a once-a-month injectable male hormonal contraceptive. Dose selection studies were initiated with administration of DNG in three different doses of 20, 30 and 40 mg/kg body weight (bw) per week plus TU 25 mg/kg bw once in every 6 weeks. Status of spermatogenesis and sperm count in epididymis was evaluated. The frequency of DNG intervention was later extended to every 2- and 4-week intervals. Mating studies, toxicity and reversibility of spermatogenesis following stoppage of treatment were carried out with DNG 40 mg/kg bw at 4-week intervals. Complete arrest of spermatogenesis was observed after 60 days of treatment at all doses of DNG (20, 30 and 40 mg/kg bw per week)+TU. However, weights of testis and accessory sex organs (epididymis, prostate and seminal vesicle) declined significantly 60 days post treatment compared to vehicle-treated controls. Epididymis in the treated animals was completely devoid of sperm. When the frequency of DNG injection (20 mg/kg bw) was extended to once every 15 days, a few immotile and decapitated sperm were observed in the epididymis. With TU treatment unchanged, animals receiving DNG (40 mg/kg bw) once either every 2- or 4-week intervals demonstrated good and uniform arrest of spermatogenesis. DNG 40 mg/kg per 4 weeks+TU also demonstrated a significant rise in germ cell apoptosis in the seminiferous epithelium. There was no significant increase in the serum high-density lipoprotein and low-density lipoprotein levels at the end of 120 days of treatment. Following withdrawal of treatment after 60 or 120 days, qualitative restoration of spermatogenesis was rapid in the former compared to the latter. Dienogest plus TU has the potential for development as a monthly injectable showing reversible hormonal male contraception with good efficacy.

WPC Medium-Range Forecasts (Days 3-7)

Science.gov Websites

Pressures Day 7 [b/w] [full color] *The Northern Hemispheric view is updated once daily at 1900Z. EXTENDED Level Pressures and Fronts CONUS View* Final Day 3 Fronts and Pressures for the CONUS Day 3 [b/w] [full color] Final Day 4 Fronts and Pressures for the CONUS Day 4 [b/w] [full color] Final Day 5 Fronts and

A 14-day regimen of esomeprazole 20 mg/day for frequent heartburn: durability of effects, symptomatic rebound, and treatment satisfaction.

PubMed

Peura, David; Le Moigne, Anne; Pollack, Charles; Nagy, Peter; Lind, Tore

2016-08-01

Esomeprazole 20 mg once daily has been shown to be effective for treating frequent heartburn over 14 days in subjects who are likely to self-treat with over-the-counter medications. These analyses were conducted to assess durability of effects and symptomatic rebound after cessation of treatment, treatment satisfaction, and rescue antacid use with esomeprazole 20 mg once daily for 14 days. Adults with frequent heartburn (≥ two days/week in the past four weeks) were randomly assigned to 14 days of double-blind treatment with esomeprazole 20 mg or placebo in two identical multicenter studies. All subjects entered a 1-week single-blind placebo follow-up period after treatment. The results of the primary efficacy endpoints were reported previously. The percentage of heartburn-free days during the 1-week follow-up, use of rescue antacids, and treatment satisfaction, measured with the Global Assessment Questions instrument, are described. The percentage of heartburn-free days was maintained during the 1-week follow-up period; the proportion was 43% among esomeprazole subjects in these studies, suggesting no evidence of symptomatic rebound. Rescue antacid use generally decreased compared with the run-in period in the 14-day treatment and 1-week follow-up periods. Significantly more subjects taking esomeprazole were "very satisfied" or "satisfied" with treatment versus placebo (Study 1: 78% vs. 63%, respectively, P = 0.0038; Study 2: 81% vs. 60%, respectively, P = 0.0002). Subjects who are likely to self-treat their frequent heartburn with over-the-counter medications reported satisfaction with esomeprazole 20 mg. Esomeprazole's treatment effect was maintained for ≥ one week after treatment ended, with no sign of symptomatic rebound. These trials were registered at ClinicalTrials.gov: NCT01370525; NCT01370538.

Efficacy of phosphodiesterase type 5 inhibitors for the treatment of distal ureteral calculi: A systematic review and meta-analysis

PubMed Central

García-Perdomo, Herney Andrés

2017-01-01

Purpose To determine the efficacy of phosphodiesterase type 5 inhibitors (PDE5i) as medical expulsive therapy (MET) for the treatment of distal ureteral calculi. Materials and Methods A search strategy was conducted in the MEDLINE, CENTRAL, and Embase databases. Searches were also conducted in other databases and unpublished literature. Clinical trials were included without language restrictions. The risk of bias was evaluated with the Cochrane Collaboration's tool. An analysis of random effects due to statistical heterogeneity was conducted. The primary outcome was the expulsion rate of the distal ureteral calculus in 28 days. The secondary outcomes were the time to expulsion, side effects of treatment, and amount (mg) of nonopioid analgesia. The measure of the effect was the risk difference (RD) with a 95% confidence interval (CI). The planned interventions were PDE5i vs. placebo, tadalafil vs. placebo, and tadalafil vs. tamsulosin. Results Four articles were included in the qualitative and quantitative analysis. Records of 580 patients were found among the four studies. A low risk of bias was shown for the majority of the study items. The calculi expulsion rate had an RD of 0.26 (95% CI, 0.15–0.37) and a less prolonged expulsion as a secondary outcome with a mean difference of -4.39 days (95% CI, -6.69 to -2.09) in favor of PDE5i compared with the placebo. No significant difference was found for these outcomes when comparing tadalafil with tamsulosin. Conclusions Compared with a placebo, PDE5i could be effective as MET for the treatment of distal ureter calculi. PMID:28261676

Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212

PubMed Central

Olson, Gary L.; Nallaganchu, Bhaskara Rao; Benes, Cyril H.; Allen, Joshua E.; Prabhu, Varun V.; Stogniew, Martin; Oster, Wolfgang; El-Deiry, Wafik S.

2017-01-01

ABSTRACT Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitro potencies were identified in an exploration of chemical derivatives. Based on in vitro potency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones. PMID:28489985

Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212.

PubMed

Wagner, Jessica; Kline, Christina Leah; Ralff, Marie D; Lev, Avital; Lulla, Amriti; Zhou, Lanlan; Olson, Gary L; Nallaganchu, Bhaskara Rao; Benes, Cyril H; Allen, Joshua E; Prabhu, Varun V; Stogniew, Martin; Oster, Wolfgang; El-Deiry, Wafik S

2017-10-02

Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitro potencies were identified in an exploration of chemical derivatives. Based on in vitro potency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.

Once daily, extended release ciprofloxacin for complicated urinary tract infections and acute uncomplicated pyelonephritis.

PubMed

Talan, David A; Klimberg, Ira W; Nicolle, Lindsay E; Song, James; Kowalsky, Steven F; Church, Deborah A

2004-02-01

We assessed the efficacy and safety of 1,000 mg extended release ciprofloxacin orally once daily vs conventional 500 mg ciprofloxacin orally twice daily, each for 7 to 14 days, in patients with a complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP). In this prospective, randomized, double-blind, North American multicenter clinical trial adults were stratified based on clinical presentation of cUTI or AUP and randomized to extended release ciprofloxacin or ciprofloxacin twice daily. Efficacy valid patients had positive pretherapy urine cultures (105 or greater cFU/ml) and pyuria within 48 hours of study entry. Bacteriological and clinical outcomes were assessed at the test of cure visit (5 to 11 days after therapy) and the late followup visit (28 to 42 days after therapy). The intent to treat population comprised 1,035 patients (extended release ciprofloxacin in 517 and twice daily in 518), of whom 435 were efficacy valid (cUTI in 343 and AUP in 92). For efficacy valid patients (cUTI and AUP combined) bacteriological eradication rates at test of cure were 89% (183 of 206) vs 85% (195 of 229) (95% CI -2.4%, 10.3%) and clinical cure rates were 97% (198 of 205) vs 94% (211 of 225) (95% CI -1.2%, 6.9%) for extended release vs twice daily ciprofloxacin. Late followup outcomes were consistent with test of cure findings. Eradication rates for Escherichia coli, which accounted for 58% of pathogens, were 97% or greater per group. Drug related adverse event rates were similar for extended release and twice daily ciprofloxacin (13% and 14%, respectively). Extended release ciprofloxacin at a dose of 1,000 mg once daily was as safe and effective as conventional treatment with 500 mg ciprofloxacin twice daily, each given orally for 7 to 14 days in adults with cUTI or AUP. It provides a convenient, once daily, empirical treatment option.

Diurnal and day-to-day variation of isometric muscle strength in myasthenia gravis.

PubMed

Vinge, Lotte; Jakobsen, Johannes; Pedersen, Asger Roer; Andersen, Henning

2016-01-01

In patients with myasthenia gravis (MG), muscle strength is expected to decrease gradually during the day due to physical activities. Isometric muscle strength at the shoulder, knee, and ankle was determined in 10 MG patients (MGFA class II-IV) who were receiving usual medical treatment and in 10 control subjects. To determine diurnal and day-to-day variation, muscle strength was measured 4 times during day 1 and once at day 2. Knee extension strength decreased during the day in both patients and controls. Neither diurnal nor day-to-day variation of muscle strength was higher in patients compared with controls. Patients with mild to moderate MG did not have increased variation of isometric muscle strength during the day or from day-to-day compared with controls. This suggests that isometric muscle performance can be determined with high reproducibility in similar groups of MG patients without regard to time of day. © 2015 Wiley Periodicals, Inc.

On evaluating compliance with air pollution levels 'not to be exceeded more than once per year'

NASA Technical Reports Server (NTRS)

Neustadter, H. E.; Sidik, S. M.

1974-01-01

The point of view taken is that the Environmental Protection Agency (EPA) Air Quality Standards (AQS) represent conditions which must be made to exist in the ambient environment. The statistical techniques developed should serve as tools for measuring the closeness to achieving the desired quality of air. It is shown that the sampling frequency recommended by EPA is inadequate to meet these objectives when the standard is expressed as a level not to be exceeded more than once per year and sampling frequency is once every three days or less frequent.

Once-daily administration of intranasal corticosteroids for allergic rhinitis: a comparative review of efficacy, safety, patient preference, and cost.

PubMed

Herman, Howard

2007-01-01

The aim of this review was to compare the efficacy, safety, patient preference, and cost-effectiveness of once-daily budesonide aqueous nasal spray (BANS), fluticasone propionate nasal spray (FPNS), mometasone furoate nasal spray (MFNS), and triamcinolone aqueous nasal spray (TANS) for treatment of allergic rhinitis (AR) in adult patients. A MEDLINE search (1966 to January 2004) was conducted to identify potentially relevant English language articles. Pertinent abstracts from recent allergy society meetings were identified also. The medical subject heading search terms included were intranasal corticosteroid (INS), nasal steroid, BANS, MFNS, FPNS, or TANS and AR. Selected studies were randomized, controlled, comparison trials of patients with AR treated with once-daily BANS, MFNS, FPNS, or TANS. All four INSs administered once daily were effective and well tolerated in the treatment of AR in adult patients, with similar efficacy and adverse event profiles. No differences were seen between INSs in systemic effects, except for significantly lower overnight urinary cortisol levels in healthy volunteers treated with FPNS compared with placebo. Based on sensory attributes, patients preferred BANS and TANS versus MFNS and FPNS. BANS was associated with more days of treatment per prescription at a lower cost per day for adults compared with the other INSs and is the only INS with a pregnancy category B rating. BANS, FPNS, MFNS, and TANS have similar efficacy and safety profiles. Differences in sensory attributes, documented safety during pregnancy, and cost may contribute to better patient acceptance of one INS versus another and promote better adherence to therapy.

Sex differences in the response of children with ADHD to once-daily formulations of methylphenidate.

PubMed

Sonuga-Barke, Edmund J S; Coghill, David; Markowitz, John S; Swanson, James M; Vandenberghe, Mieke; Hatch, Simon J

2007-06-01

Studies of sex differences in methylphenidate response by children with attention-deficit/hyperactivity disorder have lacked methodological rigor and statistical power. This paper reports an examination of sex differences based on further analysis of data from a comparison of two once-daily methylphenidate formulations (the COMACS study), which addresses these shortcomings. Children (184: 48 females; mean [SD] age, 9.58 [1.83] years) entered a double-blind, crossover trial of Concerta, MetadateCD/Equasym XL, or placebo. Attention-deficit/hyperactivity disorder symptoms were recorded at seven time points across the school day on the seventh day of treatment, using a laboratory classroom setting. More females had comorbid anxiety disorder. Males and females did not differ with regard to other characteristics. Observed sex differences in pharmacodynamic symptom profiles persisted after controlling for placebo and time 0 hours attention-deficit/hyperactivity disorder scores and the presence of an anxiety disorder. Females had a statistically superior response at 1.5 hours post-dosing and an inferior response at the 12-hour time point relative to their male counterparts, no matter which methylphenidate formulation was being assessed. Dose titration of once-daily formulations of methylphenidate should ideally be based on systematic evidence of response at different periods across the day. The responses of female patients may require additional assessments later in the day to determine the optimal dose.

Efficacy, tolerance, and pharmacokinetics of once daily tobramycin for pseudomonas exacerbations in cystic fibrosis.

PubMed

Vic, P; Ategbo, S; Turck, D; Husson, M O; Launay, V; Loeuille, G A; Sardet, A; Deschildre, A; Druon, D; Arrouet-Lagande, C

1998-06-01

To compare once daily with thrice daily tobramycin for treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis. 22 patients with cystic fibrosis, mean (SD) age 11 (3.4) years (range 5.6-19.3), with pulmonary pseudomonas exacerbations were randomly assigned to receive a 14 day course of tobramycin (15 mg/kg/day) either in three infusions (group A) (n = 10) or a single daily infusion (group B) (n = 12), combined with ceftazidime (200 mg/kg/day as three intravenous injections). Efficacy was assessed by comparison of pulmonary, nutritional, and inflammatory indices on days 1 and 14. Cochlear and renal tolerance were assessed on days 1 and 14. Tobramycin concentration was measured in serum and sputum 1, 2, 3, 4, 8, and 24 hours after the start of the infusion. Analysis was by non-parametric Wilcoxon test. Variables improving (p < 0.05) in both groups A and B were, respectively: weight/height (+4% and +3.1%), plasma prealbumin (+66 and +63 mg/l), forced vital capacity (FVC) (+14% and +11%), forced expiratory volume in one second (+15% and +14%), and forced expiratory flow between 25% and 75% of FVC (+13% and +21%). Improvement was not significantly different between groups. Renal and cochlear indices remained within the normal range. Serum peak concentration of tobramycin on day 1 was 13.2 (7.1) mg/l in group A and 42.5 (11.2) mg/l in group B (p < 0.001); serum trough was 1.1 (0.8) mg/l in group A and 0.3 (0.2) mg/l in group B (p < 0.01). Tobramycin concentrations in sputum were two to three times higher in group B than group A. Once daily tobramycin combined with three injections of ceftazidime is safe and effective for the treatment of pseudomonas exacerbations in cystic fibrosis patients.

ONC201: Stressing tumors to death.

PubMed

Endo Greer, Yoshimi; Lipkowitz, Stanley

2016-02-16

The small molecule ONC201 was identified in a screen for compounds that would induce expression of the gene encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in tumors and thus cause an autocrine- or paracrine-induced death in tumor cells. Two Research Articles in this issue of Science Signaling by Ishizawa et al. and Kline et al. describe how ONC201 can also trigger cytotoxicity by inducing a stress response. The mechanisms of the stress response induced differ between hematological malignancies and solid tumors, highlighting the complexity of ONC201-induced toxicity and raising intriguing issues of tissue-specific pathways activated by the drug. Copyright © 2016, American Association for the Advancement of Science.

Healthcare resource utilization for anemia management: current practice with erythropoiesis-stimulating agents and the impact of converting to once-monthly C.E.R.A.

PubMed

Saueressig, Ulrich; Kwan, Jonathan T C; De Cock, Erwin; Sapède, Claudine

2008-01-01

Background andMethods: A prospective, observational study in 12 German and UK dialysis centers which quantified personnel time for anemia treatment using erythropoiesis-stimulating agents (ESAs). Tasks directly observable were measured through the time-and-motion method; time for non-observable tasks was estimated by healthcare staff. Using activity-based costing methods, time was converted into monetary units. Modeling was used to estimate potential time and cost savings using once-monthly C.E.R.A., a continuous erythropoietin receptor activator. For current ESAs in Germany and the UK, respectively: mean observed time was 1.67 and 2.67 min/patient/administration, corresponding to 31 and 42 days/year/center/100 patients; mean total time/center/100 patients/year was estimated at 79 and 95 days, equivalent to EUR 17,031 and GBP 18,739. Assuming 100% once-monthly C.E.R.A. uptake, the observed time/patient/year may decrease by 79 and 84% in Germany and the UK, respectively, compared with traditional ESAs. Conversion to once-monthly C.E.R.A. may offer the potential to reduce time spent on ESA administration in hemodialysis centers. Copyright 2008 S. Karger AG, Basel.

ONCE DAILY RISPERIDONE IN TREATMENT OF SCHIZOPHRENIA

PubMed Central

Agarwal, Vivek; Chadda, Rakesh K.

2001-01-01

Forty four schizophrenic patients were randomly assigned to receive risperidone in 4-8 mg doses either once daily or twice daily for 8 weeks. An open trial was conducted to determine the efficacy of once daily administration of risperidone as compared to twice daily administration. Assessment were done on Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) scale Eighty two percent of the once daily patients and 79% of the twice daily patients showed a significant treatment response. No significant differences were observed between the two groups in response pattern and adverse effects at the end point. Risperidone given once daily was as effective as twice daily administration. PMID:21407835

Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase

PubMed Central

Rajfer, R. A.; Kilic, A.; Neviaser, A. S.; Schulte, L. M.; Hlaing, S. M.; Landeros, J.; Ferrini, M. G.; Ebramzadeh, E.

2017-01-01

Objectives We investigated the effects on fracture healing of two up-regulators of inducible nitric oxide synthase (iNOS) in a rat model of an open femoral osteotomy: tadalafil, a phosphodiesterase inhibitor, and the recently reported nutraceutical, COMB-4 (consisting of L-citrulline, Paullinia cupana, ginger and muira puama), given orally for either 14 or 42 days. Materials and Methods Unilateral femoral osteotomies were created in 58 male rats and fixed with an intramedullary compression nail. Rats were treated daily either with vehicle, tadalafil or COMB-4. Biomechanical testing of the healed fracture was performed on day 42. The volume, mineral content and bone density of the callus were measured by quantitative CT on days 14 and 42. Expression of iNOS was measured by immunohistochemistry. Results When compared with the control group, the COMB-4 group exhibited 46% higher maximum strength (t-test, p = 0.029) and 92% higher stiffness (t-test, p = 0.023), but no significant changes were observed in the tadalafil group. At days 14 and 42, there was no significant difference between the three groups with respect to callus volume, mineral content and bone density. Expression of iNOS at day 14 was significantly higher in the COMB-4 group which, as expected, had returned to baseline levels at day 42. Conclusion This study demonstrates an enhancement in fracture healing by an oral natural product known to augment iNOS expression. Cite this article: R. A. Rajfer, A. Kilic, A. S. Neviaser, L. M. Schulte, S. M. Hlaing, J. Landeros, M. G. Ferrini, E. Ebramzadeh, S-H. Park. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase. Bone Joint Res 2017:6:–97. DOI: 10.1302/2046-3758.62.BJR-2016-0164.R2. PMID:28188129

Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase.

PubMed

Rajfer, R A; Kilic, A; Neviaser, A S; Schulte, L M; Hlaing, S M; Landeros, J; Ferrini, M G; Ebramzadeh, E; Park, S-H

2017-02-01

We investigated the effects on fracture healing of two up-regulators of inducible nitric oxide synthase (iNOS) in a rat model of an open femoral osteotomy: tadalafil, a phosphodiesterase inhibitor, and the recently reported nutraceutical, COMB-4 (consisting of L-citrulline, Paullinia cupana, ginger and muira puama), given orally for either 14 or 42 days. Unilateral femoral osteotomies were created in 58 male rats and fixed with an intramedullary compression nail. Rats were treated daily either with vehicle, tadalafil or COMB-4. Biomechanical testing of the healed fracture was performed on day 42. The volume, mineral content and bone density of the callus were measured by quantitative CT on days 14 and 42. Expression of iNOS was measured by immunohistochemistry. When compared with the control group, the COMB-4 group exhibited 46% higher maximum strength ( t -test, p = 0.029) and 92% higher stiffness ( t -test, p = 0.023), but no significant changes were observed in the tadalafil group. At days 14 and 42, there was no significant difference between the three groups with respect to callus volume, mineral content and bone density. Expression of iNOS at day 14 was significantly higher in the COMB-4 group which, as expected, had returned to baseline levels at day 42. This study demonstrates an enhancement in fracture healing by an oral natural product known to augment iNOS expression. Cite this article: R. A. Rajfer, A. Kilic, A. S. Neviaser, L. M. Schulte, S. M. Hlaing, J. Landeros, M. G. Ferrini, E. Ebramzadeh, S-H. Park. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase. Bone Joint Res 2017:6:-97. DOI: 10.1302/2046-3758.62.BJR-2016-0164.R2. © 2017 Park et al.

Effects of changing milk replacer feedings from twice to once daily on Holstein calf innate immune responses before and after weaning

USDA-ARS?s Scientific Manuscript database

The objectives of this study were to determine the effects of switching Holstein calves to once-a-day feeding during the 4th week of life (24 ± 2.3 d of age; once-fed n = 22; twice-fed n = 22) on innate immune responses, and also evaluate whether there were any carry-over effects when the calves wer...

Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial.

PubMed

Battelino, Tadej; Rasmussen, Michael Højby; De Schepper, Jean; Zuckerman-Levin, Nehama; Gucev, Zoran; Sävendahl, Lars

2017-10-01

To evaluate the safety, local tolerability, pharmacodynamics and pharmacokinetics of escalating single doses of once-weekly somapacitan, a reversible, albumin-binding GH derivative, vs once-daily GH in children with GH deficiency (GHD). Phase 1, randomized, open-label, active-controlled, dose-escalation trial (NCT01973244). Thirty-two prepubertal GH-treated children with GHD were sequentially randomized 3:1 within each of four cohorts to a single dose of somapacitan (0.02, 0.04, 0.08 and 0.16 mg/kg; n=6 each), or once-daily Norditropin ® SimpleXx ® (0.03 mg/kg; n=2 each) for 7 days. Pharmacokinetic and pharmacodynamic profiles were assessed. Adverse events were all mild, and there were no apparent treatment-dependent patterns in type or frequency. Four mild transient injection site reactions were reported in three of 24 children treated with somapacitan. No antisomapacitan/anti-human growth hormone (hGH) antibodies were detected. Mean serum concentrations of somapacitan increased in a dose-dependent but nonlinear manner: maximum concentration ranged from 21.8 ng/mL (0.02 mg/kg dose) to 458.4 ng/mL (0.16 mg/kg dose). IGF-I and IGFBP-3, and change from baseline in IGF-I standard deviation score (SDS) and IGFBP-3 SDS, increased dose dependently; greatest changes in SDS values were seen for 0.16 mg/kg. IGF-I SDS values were between -2 and +2 SDS, except for peak IGF-I SDS with 0.08 mg/kg somapacitan. Postdosing, IGF-I SDS remained above baseline levels for at least 1 week. Single doses of once-weekly somapacitan (0.02-0.16 mg/kg) were well tolerated in children with GHD, with IGF-I profiles supporting a once-weekly treatment profile. No clinically significant safety/tolerability signals or immunogenicity concerns were identified. © 2017 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.

Comparing a single-day swabbing regimen with an established 3-day protocol for MRSA decolonization control.

PubMed

Frickmann, H; Schwarz, N G; Hahn, A; Ludyga, A; Warnke, P; Podbielski, A

2018-05-01

Success of methicillin-resistant Staphylococcus aureus (MRSA) decolonization procedures is usually verified by control swabs of the colonized body region. This prospective controlled study compared a single-day regimen with a well-established 3-day scheme for noninferiority and adherence to the testing scheme. Two sampling schemes for screening MRSA patients of a single study cohort at a German tertiary-care hospital 2 days after decolonization were compared regarding their ability to identify MRSA colonization in throat or nose. In each patient, three nose and three throat swabs were taken at 3- to 4-hour intervals during screening day 1, and in the same patients once daily on days 1, 2 and 3. Swabs were analysed using chromogenic agar and broth enrichment. The study aimed to investigate whether the single-day swabbing scheme is not inferior to the 3-day scheme with a 15% noninferiority margin. One hundred sixty patients were included, comprising 105 and 101 patients with results on all three swabs for decolonization screening of the nose and throat, respectively. Noninferiority of the single-day swabbing scheme was confirmed for both pharyngeal and nasal swabs, with 91.8% and 89% agreement, respectively. The absolute difference of positivity rates between the swabbing regimens was 0.025 (-0.082, 0.131) for the nose and 0.006 (-0.102, 0.114) (95% confidence interval) for the pharynx as calculated with McNemar's test for matched or paired data. Compliance with the single-day scheme was better, with 12% lacking second-day swabs and 27% lacking third-day swabs from the nostrils. The better adherence to the single-day screening scheme with noninferiority suggests its implementation as the new gold standard. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

45 CFR 170.540 - ONC-ACB status.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.540 ONC-ACB status. (a...

45 CFR 170.540 - ONC-ACB status.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Welfare Department of Health and Human Services HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.540 ONC-ACB status. (a...

Effect of once daily and twice daily sustained release theophylline formulations on daytime variation of bronchial hyperresponsiveness in asthmatic patients

PubMed Central

Ferrari, M.; Olivieri, M.; Lampronti, G.; Bonazza, L.; Biasin, C.; Nacci, P.; Talamini, G.; Lo, C

1997-01-01

BACKGROUND: Previous studies evaluating spirometric values and symptoms have shown that once daily theophylline administered in the evening produces greater stabilisation of the airway function in asthmatic patients than the prototype theophylline given twice a day. The aim of this study was to compare the effects on bronchial responsiveness to methacholine of an ultrasustained release theophylline formulation (Diffumal-24, Malesci, Florence, Italy) administered once a day, a sustained release theophylline formulation (Theo-Dur, Recordati, Milan, Italy) administered twice a day, and placebo. METHODS: The study was performed in 12 adult patients with asthma using a randomised, double blind, three phase, cross-over design. Each phase lasted seven days and was followed or preceded by at least three days of theophylline washout. Diffumal-24 was administered once a day at 20.00 hours whereas Theo-Dur was given twice a day at 08.00 hours and 20.00 hours. In each patient the total daily dose of theophylline was the same during both phases. The dose of the two active preparations was titrated to individual needs before the beginning of the study and then given in divided or once daily doses. At 08.00, 14.00, and 20.00 hours on day 7 of each phase serum theophylline concentrations were measured and spirometric tests (FEV1) and bronchial challenge with methacholine were also performed. RESULTS: When the administration of Diffumal-24 was compared with that of Theo-Dur, a higher serum theophylline concentration of the former was seen in the morning whereas at 20.00 hours the reverse was true. Compared with placebo, at 08.00 hours Diffumal-24 improved FEV1 whereas Theo-Dur did not (difference between treatments 0.29 1, 95% CI 0.12 to 0.45). At 08.00 hours Diffumal-24 decreased bronchial sensitivity to methacholine, expressed as a natural logarithm of PD20, to a greater extent than Theo-Dur (difference between treatments 0.54 log units, 95% CI 0.016 to 1.08). The morning

Short communication: Pharmacokinetics of intramammary hetacillin in dairy cattle milked 3 times per day.

PubMed

Lindquist, Danielle A; Baynes, Ronald E; Smith, Geof W

2015-03-01

Mastitis remains a critical disease in the dairy industry and the use of intramammary antibiotics plays a critical role in mastitis treatment. Hetacillin is currently approved as an intramammary antibiotic that is used to treat mastitis in dairy cows. It is approved for once a day administration and can be used for a total of 3 d. An increasing number of dairy farms are milking 3 times per day (instead of the traditional 2 times per day) and very little pharmacokinetic data exists on the use of intramammary drugs in a 3×system. The primary purpose of this study was to determine if once a day intramammary infusion of hetacillin is sufficient to maintain therapeutic drug concentrations in cattle milked 3 times per day. Eight Holstein cattle milked 3 times per day were used in this study. After collecting a baseline milk sample, each cow received intramammary infusions of hetacillin in the left front and right rear quarters once a day for 3 d. Milk samples from each of the treated quarters were collected at each milking and frozen until analysis. Milk samples were analyzed for ampicillin concentrations using an ultra-performance liquid chromatography method. All treated quarters had antibiotic concentrations well above the minimum inhibitory concentration (MIC) for gram-positive mastitis pathogens at 8 and 16 h postinfusion. Milk concentrations had fallen well below the MIC by the 24-h period (before the next infusion). All 8 cows in this study consistently had individual quarter milk ampicillin concentrations below the FDA tolerance of 0.01 μg/mL (10 ppb) within 48 h of the last infusion. Based on this study, milk ampicillin concentrations exceed the minimum inhibitory concentration required to inhibit the growth of 90% of organisms (MIC90) for at least 65% of the dosing interval, which is sufficient for once-daily dosing with most cases of gram-positive mastitis. Therefore, intramammary hetacillin should be an effective treatment for the vast majority of gram

Efficacy and safety of once-daily luliconazole 1% cream in patients ≥12 years of age with interdigital tinea pedis: a phase 3, randomized, double-blind,vehicle-controlled study.

PubMed

Jarratt, Michael; Jones, Terry; Adelglass, Jeffrey; Bucko, Alicia; Pollak, Richard; Roman-Miranda, Amaury; Olin, Jason T; Swinyer, Leonard

2014-07-01

Interdigital tinea pedis is one of the most common clinical presentations of dermatophytosis. This phase 3 study evaluated the safety and efficacy of luliconazole cream 1% in patients with tinea pedis. A total of 321 male and female patients aged ≥12 years with tinea pedis and eligible for modified intent-to-treat analysis were randomized 1:1 to receive luliconazole cream 1% (n=159) or vehicle (n=162) once daily for 14 days. Efficacy was evaluated at days 28 and 42 (i.e., days 14 and 28 posttreatment) based on clinical signs (erythema, scaling, pruritus) and mycology (KOH, fungal culture). The primary outcome was complete clearance at day 42. Safety evaluations included adverse events and laboratory assessments. Complete clearance at day 42 was achieved in 26.4% (28/106) of patients treated with luliconazole cream 1% compared with 1.9% (2/103) of patients treated with vehicle (P< 0.001). Similar safety profiles were obtained for luliconazole cream 1% and vehicle. This study was conducted in a relatively small population under controlled clinical trial conditions. Luliconazole cream 1% applied once daily for 14 days is well tolerated and more effective than vehicle in patients with tinea pedis.

ONC201 kills breast cancer cells in vitro by targeting mitochondria.

PubMed

Greer, Yoshimi Endo; Porat-Shliom, Natalie; Nagashima, Kunio; Stuelten, Christina; Crooks, Dan; Koparde, Vishal N; Gilbert, Samuel F; Islam, Celia; Ubaldini, Ashley; Ji, Yun; Gattinoni, Luca; Soheilian, Ferri; Wang, Xiantao; Hafner, Markus; Shetty, Jyoti; Tran, Bao; Jailwala, Parthav; Cam, Maggie; Lang, Martin; Voeller, Donna; Reinhold, William C; Rajapakse, Vinodh; Pommier, Yves; Weigert, Roberto; Linehan, W Marston; Lipkowitz, Stanley

2018-04-06

We report a novel mechanism of action of ONC201 as a mitochondria-targeting drug in cancer cells. ONC201 was originally identified as a small molecule that induces transcription of TNF-related apoptosis-inducing ligand (TRAIL) and subsequently kills cancer cells by activating TRAIL death receptors. In this study, we examined ONC201 toxicity on multiple human breast and endometrial cancer cell lines. ONC201 attenuated cell viability in all cancer cell lines tested. Unexpectedly, ONC201 toxicity was not dependent on either TRAIL receptors nor caspases. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. Further investigation found that ONC201 induces phosphorylation of AMP-dependent kinase and ATP loss. Cytotoxicity and ATP depletion were significantly enhanced in the absence of glucose, suggesting that ONC201 targets mitochondrial respiration. Further analysis indicated that ONC201 indirectly inhibits mitochondrial respiration. Confocal and electron microscopic analysis demonstrated that ONC201 triggers mitochondrial structural damage and functional impairment. Moreover, ONC201 decreased mitochondrial DNA (mtDNA). RNAseq analysis revealed that ONC201 suppresses expression of multiple mtDNA-encoded genes and nuclear-encoded mitochondrial genes involved in oxidative phosphorylation and other mitochondrial functions. Importantly, fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mtDNA were resistant to ONC201. These results indicate that cells not dependent on mitochondrial respiration are ONC201-resistant. Our data demonstrate that ONC201 kills cancer cells by disrupting mitochondrial function and further suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201.

ONC201 kills breast cancer cells in vitro by targeting mitochondria

PubMed Central

Greer, Yoshimi Endo; Porat-Shliom, Natalie; Nagashima, Kunio; Stuelten, Christina; Crooks, Dan; Koparde, Vishal N.; Gilbert, Samuel F.; Islam, Celia; Ubaldini, Ashley; Ji, Yun; Gattinoni, Luca; Soheilian, Ferri; Wang, Xiantao; Hafner, Markus; Shetty, Jyoti; Tran, Bao; Jailwala, Parthav; Cam, Maggie; Lang, Martin; Voeller, Donna; Reinhold, William C.; Rajapakse, Vinodh; Pommier, Yves; Weigert, Roberto; Linehan, W. Marston; Lipkowitz, Stanley

2018-01-01

We report a novel mechanism of action of ONC201 as a mitochondria-targeting drug in cancer cells. ONC201 was originally identified as a small molecule that induces transcription of TNF-related apoptosis-inducing ligand (TRAIL) and subsequently kills cancer cells by activating TRAIL death receptors. In this study, we examined ONC201 toxicity on multiple human breast and endometrial cancer cell lines. ONC201 attenuated cell viability in all cancer cell lines tested. Unexpectedly, ONC201 toxicity was not dependent on either TRAIL receptors nor caspases. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. Further investigation found that ONC201 induces phosphorylation of AMP-dependent kinase and ATP loss. Cytotoxicity and ATP depletion were significantly enhanced in the absence of glucose, suggesting that ONC201 targets mitochondrial respiration. Further analysis indicated that ONC201 indirectly inhibits mitochondrial respiration. Confocal and electron microscopic analysis demonstrated that ONC201 triggers mitochondrial structural damage and functional impairment. Moreover, ONC201 decreased mitochondrial DNA (mtDNA). RNAseq analysis revealed that ONC201 suppresses expression of multiple mtDNA-encoded genes and nuclear-encoded mitochondrial genes involved in oxidative phosphorylation and other mitochondrial functions. Importantly, fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mtDNA were resistant to ONC201. These results indicate that cells not dependent on mitochondrial respiration are ONC201-resistant. Our data demonstrate that ONC201 kills cancer cells by disrupting mitochondrial function and further suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201. PMID:29719618

Single-use autoinjector for once-weekly intramuscular injection of IFNβ-1a.

PubMed

Limmroth, Volker; Gerbershagen, Kathrin

2014-12-01

IFNβ products and glatiramer acetate are established treatment first-line options in long-term disease-modifying therapy of multiple sclerosis (MS). These self-injectable medications are used once weekly to once daily. Injection-related issues are common patient-cited reasons for nonadherence. Autoinjectors have been shown to support long-term adherence to injectable medications. The ability to self-inject in MS patients has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patient independence. The recently introduced easy-to-use prefilled once-weekly pen is a safe and effective device for intramuscular (IM) IFNβ-1a application and provides a convenient method for self-injection. We reviewed the available published evidence on the characteristics of this device. The once-weekly pen facilitates self-injection and was preferred over prefilled syringes by patients in a prospective open-label, multicenter Phase IIIb trial in MS patients who had been using IM IFNβ-1a in prefilled syringes. The simple and safe handling, shielded short needle, single-use disposable design and virtually painless injection by the device may contribute to adherence, quality of life and independence in patients using IM IFNβ-1a.

Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study

PubMed Central

Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

2016-01-01

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201’s cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201. PMID:27626799

Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study.

PubMed

Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

2016-01-01

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201's cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the in vivo studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201.

Once-daily luliconazole cream 1% for the treatment of interdigital tinea pedis.

PubMed

Gold, Michael H; Olin, Jason T

2015-01-01

Luliconazole is an imidazole antifungal agent with a unique chemical structure. In this article, we summarize the in vitro data, animal studies and clinical trial data relating to the use of topical luliconazole cream 1% in the treatment of tinea pedis. Preclinical studies have demonstrated potent activity against dermatophytes. Luliconazole has strong fungicidal activity against Trichophyton spp., similar to that seen with terbinafine. Evidence from clinical trials in tinea pedis have shown once-daily application of luliconazole cream 1% for 14 days to be effective and well tolerated.

Efficacy of two once-daily methylphenidate formulations compared across dose levels at different times of the day: preliminary indications from a secondary analysis of the COMACS study data.

PubMed

Sonuga-Barke, Edmund J S; Swanson, James M; Coghill, David; DeCory, Heleen H; Hatch, Simon J

2004-09-30

Methylphenidate (MPH) is commonly prescribed in the treatment of Attention-Deficit/Hyperactivity Disorder or ADHD. Concerta and Metadate CD are once-daily formulations of MPH using different delivery mechanisms resulting in different pharmacokinetic profiles. A recent study (COMACS) showed that for near-milligram (mg) equivalent daily doses, Metadate CD provides greater symptom control in the morning (1.5 through 4.5 hours post-dose), while Concerta provides greater control in the early evening (12 hours post-dose). Non-inferential comparison of effects for different dose levels of the two formulations suggested that equivalent levels of morning symptom control could be obtained with lower daily doses of Metadate CD than Concerta; the situation being reversed in the evening. The current paper presents a secondary analysis that provides a statistical test of these observations. The COMACS study was a multi-center, double-blind crossover study of Metadate CD, Concerta and placebo with each treatment administered for 1 week. Children were assigned on the basis of their pre-trial dosage to either high (Metadate CD 60 mg; Concerta 54 mg), medium (Metadate CD 40 mg; Concerta 36 mg) or low doses (Metadate CD 20 mg; Concerta 18 mg) of MPH, and attended a laboratory school on the 7th day for assessment at 7 sessions across the day. For the post-hoc comparisons across dose levels presented here, total SKAMP scores with the active treatments (adjusted for placebo response) were analyzed using an analysis of covariance, with a combined measure modeling placebo response across all time period as the covariate. Symptom control from 1.5 through 6.0 hours post-dose was as good with lower doses of Metadate CD (20 and 40 mg) as with higher doses of Concerta (36 and 54 mg, respectively). Lower daily doses of Concerta (18 and 36 mg) and higher doses of Metadate CD (40 and 60 mg, respectively) gave equivalent control at 7.5 and 12 hours with Metadate CD giving better control from1

Dry matter intake, body condition score, and grazing behavior of nonlactating, pregnant dairy cows fed kale or grass once versus twice daily during winter.

PubMed

Rugoho, I; Edwards, G R

2018-01-01

The objective of this study was to examine the effect of wintering pregnant, nonlactating dairy cows outdoors on either kale or grass, fed in 1 [11 kg dry matter (DM) of kale or grass + 3 kg DM of baled barley straw offered in the morning] or 2 allocations (5.5 kg DM of kale or grass grazed + 1.5 kg DM of barley straw offered morning and afternoon) per day. The body condition score (BCS) gain over the 47-d winter feeding period was higher for grass-fed (0.5 BCS units) than kale-fed cows (0.3 BCS units), but was unaffected by feeding frequency. Forage DM utilization was higher for kale-fed (97%) than grass-fed cows (76%), leading to higher estimated dry matter intake (DMI) in kale-fed (10.7 kg of DM/cow per day) than grass-fed cows (7.7 kg of DM/cow per day). Forage DM utilization and estimated DMI were not affected by feeding frequency. Prehension bite rate was greater for grass-fed (37.3 bites/min) than kale-fed cows (7.6 bites/min), but more mastication bites were required for kale-fed cows. Cumulative DMI after 2, 3, and 6 h was greater in cows allocated forage once than twice a day and for kale than grass after 3 and 6 h. Mean eating time was greater for cows offered forage once (477 min) than twice (414 min) per day. In conclusion, increasing feeding frequency from once to twice per day decreased the intake rate within the first 6 h after allocation, but did not affect total daily DMI, DM utilization or BCS gain. Thus, moving cows more frequently would not have any significant advantage. It may increase labor requirements, thereby creating a more challenging wintering management than feeding once per day. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Update on ONC's Substellar IMF: A Second Peak in the Brown Dwarf Regime

NASA Astrophysics Data System (ADS)

Drass, Holger; Bayo, A.; Chini, R.; Haas, M.

2017-06-01

The Orion Nebular Cluster (ONC) has become the prototype cluster for studying the Initial Mass Function (IMF). In a deep JHK survey of the ONC with HAWK-I we detected a large population of 900 Brown Dwarfs and Planetary Mass Object candidates presenting a pronounced second peak in the substellar IMF. One of the most obvious issues of this result is the verification of cluster membership. The analysis so far was mainly based on statistical consideration. In this presentation I will show the results from using different high-resolution extinction map to determine the ONC membership.

Emtricitabine: a once-daily nucleoside reverse transcriptase inhibitor.

PubMed

Modrzejewski, Krysten A; Herman, Ronald A

2004-06-01

To review the pharmacology, virology, pharmacokinetics, safety, and efficacy of the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine. English-language reports were accessed using MEDLINE (1966-June 2003) and the Iowa Drug Information Service database (1966-June 2003) using emtricitabine and Coviracil as key words. (Coviracil was the proposed trade name for the product prior to approval.) The Internet was also searched using the terms HIV/AIDS conferences, then emtricitabine within the conference proceedings. Abstracts, posters, and oral presentations from scientific conferences, both published and unpublished, were included. Preference was given to published controlled trials. Studies providing a description of the pharmacology, virology, effectiveness, safety, or pharmacokinetics of emtricitabine were used in this review. Emtricitabine is an NRTI used to treat HIV-1 infection. Once-daily administration can decrease pill burden and potentially increase adherence to multidrug HIV therapy. Further, emtricitabine has shown equivalent or improved outcomes compared with lamivudine and stavudine. Emtricitabine is a safe and effective option for HIV-1 infection in adults as part of a multidrug regimen. It may be a better alternative than lamivudine for once-daily therapy because of its extended intracellular half-life and better than lamivudine and stavudine because of a possibly decreased potential for drug resistance.

1. WEIDER'S CROSSING STONE HOUSE. WEIDER'S CROSSING WAS ONCE A ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. WEIDER'S CROSSING STONE HOUSE. WEIDER'S CROSSING WAS ONCE A SIZABLE COMMUNITY. THIS IS ONE OF ONLY TWO HOUSES REMAINING MARKING WEIDER'S CROSSING. - Weider's Crossing Stone House, Weissport, Carbon County, PA

The dynamic response of visual accommodation over a seven-day period

NASA Technical Reports Server (NTRS)

Randle, R. J.; Murphy, M. R.

1974-01-01

Four college students, ranging in age from 18 to 21 years, were tested on their dynamic, monocular accommodation responses to a square wave stimulus and sine waves of two frequencies. The tests were conducted over a period of seven days in a controlled environment, each subject being tested once every three hours. Latency, magnitude, velocity, gain and phase lag of the responses were measured, and means and standard deviations were computed. The latency of response was stable throughout and agreed fairly well with previous studies. The response magnitude was relatively stable. Three of the subjects had higher velocities on receding targets; one was faster on approaching targets. The group mean velocity increased over the seven days of the study. In keeping with the trend to faster dynamics over the seven days, both gain and phase lag improved.

Involvement of NO-cGMP pathway in anti-hyperalgesic effect of PDE5 inhibitor tadalafil in experimental hyperalgesia.

PubMed

Otari, K V; Upasani, C D

2015-08-01

The association of elevated level of cyclic guanosine monophosphate (cGMP) with inhibition of hyperalgesia and involvement of nitric oxide (NO)-cGMP pathway in the modulation of pain perception was previously reported. Phosphodiesterases 5 (PDE5) inhibitors, sildenafil and tadalafil (TAD) used in erectile dysfunction, are known to act via the NO-cGMP pathway. TAD exerts its action by increasing the levels of intracellular cGMP. Hence, the present study investigated the effect of TAD 5, 10, or 20 mg/kg, per os (p.o.) or L-NAME 20 mg/kg, intraperitoneally (i.p.) and TAD (20 mg/kg, p.o.) in carrageenan- and diabetes-induced hyperalgesia in rats using hot plate test at 55 ± 2 °C. In carrageenan- and diabetes-induced hyperalgesia, TAD (10 and 20 mg/kg, p.o.) significantly increased paw withdrawal latencies (PWLs) as compared to the control group. L-NAME significantly decreased PWLs as compared to the normal group and aggravated the hyperalgesia. Moreover, significant difference in PWLs of L-NAME and TAD 20 was evident. Co-administration of L-NAME (20 mg/kg) with TAD (20 mg/kg) showed significant difference in PWLs as compared to the TAD (20 mg/kg), indicating L-NAME reversed and antagonized TAD-induced anti-hyperalgesia. This suggested an important role of NO-cGMP pathway in TAD-induced anti-hyperalgesic effect.

Once upon a Tale. 1995 Florida Library Youth Program.

ERIC Educational Resources Information Center

Abramoff, Carolann Palm, Comp.; And Others

The Florida Library Youth Program is an extension of the Florida Summer Library Program. Many libraries have wanted to provide programs for school-age children at times other than the traditional summer vacation, and this guide responds to their needs. The theme, "Once Upon a Tale," focuses on folklore, stories, and storytelling. The…

The experience of a good day: a phenomenological study to explain a good day as experienced by a newly qualified RN.

PubMed

Jackson, Carole

2005-04-01

The main aim of this study was to provide an explanation of the newly qualified nurse's experience and description of a good day. Secondly, it sought to provide an explanation of how a good day made them feel about nursing. By identifying the main components of a good day and what positively effects the experience of a working day for a newly qualified nurse, it may be possible to move towards an increase in the occurrence of the components and emulation of a good day. While there is evidence to suggest that positive experiences within nursing increase job satisfaction and aid retention to the profession, the experience of a good day and what constitutes a good day for a newly qualified nurse has not been explored. The main components of a good day have not been identified and no work has been carried out to ascertain how these days make nurses feel about their chosen career. The aims of the study lent themselves to a phenomenological descriptive approach to research, the objective of which is identification of the essence of behaviour. Eight newly qualified nurses agreed to take part in the research. Each participant was interviewed twice, and in addition one group interview was arranged to clarify themes. The interviews, which were audio taped, were informal allowing the participants to answer in an open and unstructured manner. Once completed, all the tapes were transcribed and immersion and analysis of the data led to 5 themes naturally emerging as the components of a good day. The identified themes were, doing something well, good relationships with patients, feeling that you've achieved something, getting the work done and you need team work. In addition, although not a theme of a good day but of great importance was the description of 'that wonderful feeling at the end of a good day'. These themes contributed to feelings of job satisfaction and the pleasure of nursing. More specifically the concept of knowing the patient both from a personal level and

Zaleplon-induced Anemsic Somnambulism with Eating Behaviors Under Once Dose.

PubMed

Chen, Yen-Wen; Tseng, Ping-Tao; Wu, Ching-Kuan; Chen, Chien-Chih

2014-12-01

Zaleplon is a newly-developed rapid-acting non-benzodiazepine hypnotic. Few reports discuss zaleplon-induced somnambulism. This report describes a patient without history of somnambulism, who developed amnesic somnambulism after taking low-dose of zaleplon. A 43-year-old schizophrenic male without history of physical illness, seizure, or somnambulism developed amnesic somnambulism after taking once low-dose of zaleplon from the outpatient-department. Somnambulism did not reoccur after discontinuing zaleplon. However, similar behaviors recurred after accidentally prescribing zaleplon on the first-day of hospitalization. This patient is the first case without history of somnambulism, who developed zaleploninduced somnambulism after taking low-dose of zaleplon. This study underscores the importance of monitoring for zaleplon-induced somnambulism, even when administering low-dosage to those without risk factors or history of somnambulism.

The efficacy of bromfenac ophthalmic solution 0.07% dosed once daily in achieving zero-to-trace anterior chamber cell severity following cataract surgery

PubMed Central

Silverstein, Steven M; Jackson, Mitchell A; Goldberg, Damien F; Muñoz, Mauricio

2014-01-01

Purpose To evaluate the efficacy of bromfenac ophthalmic solution 0.07% dosed once daily in achieving zero-to-trace (0–5 cells) anterior chamber cells, following cataract surgery with posterior chamber intraocular lens implantation. Methods The study designed employed two Phase III, double-masked, placebo-controlled, multicenter clinical trials of 440 subjects, randomized to either bromfenac ophthalmic solution 0.07% (n=222) or placebo (n=218). Subjects self-dosed once daily, beginning 1 day before undergoing cataract surgery with intraocular lens implantation (day –1) and again on the day of surgery (day 0) and for 14 days postoperatively. Follow-up was on days 1, 3, 8, and 15. The outcome measures included the percentage of subjects with zero-to-trace anterior chamber cells at each visit, as determined by the percentage of subjects with ≤5 anterior chamber cells, overall anterior chamber cell grades, and summed ocular inflammation score (SOIS) (combined anterior chamber cell and flare scores). Results The proportion of subjects with zero-to-trace anterior chamber cells was significantly higher in the bromfenac 0.07% group compared with the placebo group as early as day 3 (P=0.0007), continued at day 8 (P<0.0001), and through day 15 (P<0.0001). At day 15, 80.2% of subjects in the bromfenac 0.07% group achieved zero-to-trace anterior chamber cells compared with 47.2% of subjects who did so in the placebo group. The overall anterior chamber cell scores were significantly lower in the bromfenac 0.07% group compared with the placebo group at days 3, 8, and 15 (P<0.0001 at each visit). The SOIS were also significantly lower in the bromfenac group compared with the placebo group at days 3, 8, and 15 (P<0.0001 at each visit). Conclusion Bromfenac ophthalmic solution 0.07%, dosed once daily was clinically effective in achieving zero-to-trace anterior chamber cell severity after cataract surgery and was superior to placebo in all anterior chamber cell severity and

Dissociation between the pharmacokinetics and pharmacodynamics of once-daily rivaroxaban and twice-daily apixaban: a randomized crossover study.

PubMed

Kreutz, R; Persson, P B; Kubitza, D; Thelen, K; Heitmeier, S; Schwers, S; Becka, M; Hemmrich, M

2017-10-01

Essentials In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time. Background The anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. Objectives To compare directly the steady-state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non-valvular atrial fibrillation. Methods Twenty-four healthy Caucasian male volunteers were included in this open-label, two-period crossover, phase 1 study (EudraCT number: 2015-002612-32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. Results Overall exposure was similar for both drugs: the geometric mean area under the plasma concentration-time curve for the 0-24-h interval was 1830 μg h L -1 for rivaroxaban and 1860 μg h L -1 for apixaban. Rivaroxaban was associated with greater inhibition of endogenous thrombin potential (geometric mean area under the curve relative to baseline during the 0-24-h interval: 15.5 h versus 17.5 h) and a more pronounced maximal prolongation relative to baseline of prothrombin time (PT) (1.66-fold versus 1.14-fold) and activated partial thromboplastin time (APTT) (1.43-fold versus 1.16-fold) at steady state than apixaban. Conclusions Despite similar exposure to both drugs, rivaroxaban 20 mg once daily was associated with greater and more

45 CFR 170.503 - Requests for ONC-AA status and ONC-AA ongoing responsibilities.

Code of Federal Regulations, 2014 CFR

2014-10-01

... responsibilities. 170.503 Section 170.503 Public Welfare Department of Health and Human Services HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.503...

45 CFR 170.503 - Requests for ONC-AA status and ONC-AA ongoing responsibilities.

Code of Federal Regulations, 2013 CFR

2013-10-01

... responsibilities. 170.503 Section 170.503 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.503...

45 CFR 170.535 - ONC-ACB application reconsideration.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Section 170.535 Public Welfare Department of Health and Human Services HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.535 ONC-ACB...

45 CFR 170.535 - ONC-ACB application reconsideration.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Section 170.535 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.535 ONC-ACB...

Abort-once-around entry corridor analysis program document

NASA Technical Reports Server (NTRS)

Kyle, H. C.

1975-01-01

The abort once around entry target corridor analysis program (ABECAP) was studied. The allowable range of flight path angles at entry interface for acceptable entry trajectories from a shuttle abort once around (AOA) situation was established. The solutions thus determined may be shown as corridor plots of entry interface flight path angle versus range from entry interface (EI) to the target.

45 CFR 170.575 - Removal of the ONC-AA.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.575 Removal of the ONC-AA. (a...

45 CFR 170.575 - Removal of the ONC-AA.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Public Welfare Department of Health and Human Services HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.575 Removal of the ONC-AA. (a...

Discovery and clinical introduction of first-in-class imipridone ONC201.

PubMed

Allen, Joshua E; Kline, C Leah B; Prabhu, Varun V; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L; Pottorf, Richard S; Nallaganchu, B Rao; Olson, Gary L; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T; Talekar, Mala K; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S

2016-11-08

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

Discovery and clinical introduction of first-in-class imipridone ONC201

PubMed Central

Allen, Joshua E.; Kline, C. Leah B.; Prabhu, Varun V.; Wagner, Jessica; Ishizawa, Jo; Madhukar, Neel; Lev, Avital; Baumeister, Marie; Zhou, Lanlan; Lulla, Amriti; Stogniew, Martin; Schalop, Lee; Benes, Cyril; Kaufman, Howard L.; Pottorf, Richard S.; Nallaganchu, B. Rao; Olson, Gary L.; Al-Mulla, Fahd; Duvic, Madeleine; Wu, Gen Sheng; Dicker, David T.; Talekar, Mala K.; Lim, Bora; Elemento, Olivier; Oster, Wolfgang; Bertino, Joseph; Flaherty, Keith; Wang, Michael L.; Borthakur, Gautam; Andreeff, Michael; Stein, Mark; El-Deiry, Wafik S.

2016-01-01

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials. PMID:27602582

Memantine extended release (28 mg once daily): a review of its use in Alzheimer's disease.

PubMed

Plosker, Greg L

2015-05-01

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that is a well-established treatment option for moderate to severe dementia of the Alzheimer's type, either alone or in combination with cholinesterase inhibitors. The immediate-release (IR) formulations of memantine (tablets and oral solution) have been available in numerous countries, including the USA, for more than a decade and are administered orally twice daily at a maximum recommended total daily dosage of 20 mg/day. The memantine extended-release (ER) (Namenda XR(®)) 28 mg once-daily capsule formulation was approved in the USA in 2010 and became available more recently. The potential advantages of memantine ER over the IR formulation include a more convenient dosage regimen and lower pill burden that may improve adherence to therapy; also, memantine ER capsules may be opened and the contents sprinkled on applesauce for patients who have difficulty swallowing. Memantine ER provides a higher total daily dosage than the recommended memantine IR regimen and pharmacokinetic data indicate greater exposure with the ER formulation, but the clinical implications of this are unclear, as the two formulations have not been assessed in a comparative clinical trial. The efficacy of memantine ER 28 mg once daily was demonstrated in a large, multinational, phase III trial, which showed that the addition of memantine ER to ongoing oral cholinesterase inhibitors improved key outcomes compared with cholinesterase inhibitor monotherapy, including measures of cognition and global status, which were the co-primary endpoints of the study. The most common adverse events were headache, diarrhoea and dizziness.

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

PubMed Central

Talekar, Mala K; Allen, Joshua E; Dicker, David T; El-Deiry, Wafik S

2015-01-01

ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin's lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin's lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL. PMID:26030065

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells.

PubMed

Talekar, Mala K; Allen, Joshua E; Dicker, David T; El-Deiry, Wafik S

2015-08-03

ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin's lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin's lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL.

Double oral esomeprazole after a 3-day intravenous esomeprazole infusion reduces recurrent peptic ulcer bleeding in high-risk patients: a randomised controlled study.

PubMed

Cheng, Hsiu-Chi; Wu, Chung-Tai; Chang, Wei-Lun; Cheng, Wei-Chun; Chen, Wei-Ying; Sheu, Bor-Shyang

2014-12-01

Patients with high Rockall scores have increased risk of ulcer rebleeding after 3-day esomeprazole infusions. To investigate whether double oral esomeprazole given after a 3-day esomeprazole infusion decreases ulcer rebleeding for patients with high Rockall scores. We prospectively enrolled 293 patients with peptic ulcer bleeding who had achieved endoscopic haemostasis. After a 3-day esomeprazole infusion, patients with Rockall scores ≥6 were randomised into the oral double-dose group (n=93) or the oral standard-dose group (n=94) to receive 11 days of oral esomeprazole 40 mg twice daily or once daily, respectively. The patients with Rockall scores <6 served as controls (n=89); they received 11 days of oral esomeprazole 40 mg once daily. Thereafter, all patients received oral esomeprazole 40 mg once daily for two more weeks until the end of the 28-day study period. The primary end point was peptic ulcer rebleeding. Among patients with Rockall scores ≥6, the oral double-dose group had a higher cumulative rebleeding-free proportion than the oral standard-dose group (p=0.02, log-rank test). The proportion of patients free from recurrent bleeding during the 4th-28th day in the oral double-dose group remained lower than that of the group with Rockall scores <6 (p=0.03, log-rank test). Among patients with Rockall scores ≥6, the rebleeding rate was lower in the oral double-dose group than in the oral standard-dose group (4th-28th day: 10.8% vs 28.7%, p=0.002). Double oral esomeprazole at 40 mg twice daily after esomeprazole infusion reduced recurrent peptic ulcer bleeding in high-risk patients with Rockall scores ≥6. NCT01591083. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Long-term experience with deferasirox (ICL670), a once-daily oral iron chelator, in the treatment of transfusional iron overload.

PubMed

Cappellini, M D; Taher, A

2008-09-01

Chronic iron overload from frequent blood transfusions to treat patients with severe anaemias leads to significant morbidity and mortality. While deferoxamine, the current standard of care, is an effective iron chelator, it requires subcutaneous infusion for 8-12 h/day, 5-7 days/week. This regimen is problematic and impacts significantly on patients' daily life. To evaluate the efficacy and tolerability of deferasirox, a once-daily oral iron chelator. To review the available data reported in peer-reviewed journals (using PubMed) and at medical conferences. Deferasirox is effective in reducing or maintaining iron burden in patients with transfusion-dependent anaemias. As deferasirox is orally administered, the inconvenience of parenteral administration with deferasirox is avoided. Deferasirox improves patient satisfaction and is expected to improve compliance with iron chelation therapy.

mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.

PubMed

Jin, Zhe-Zhu; Wang, Wei; Fang, Di-Long; Jin, Yong-Jun

2016-09-30

We here tested the anti-colorectal cancer (CRC) activity by a first-in-class small molecule TRAIL inducer ONC201. The potential effect of mTOR on ONC201's actions was also examined. ONC201 induced moderate cytotoxicity against CRC cell lines (HT-29, HCT-116 and DLD-1) and primary human CRC cells. Significantly, AZD-8055, a mTOR kinase inhibitor, sensitized ONC201-induced cytotoxicity in CRC cells. Meanwhile, ONC201-induced TRAIL/death receptor-5 (DR-5) expression, caspase-8 activation and CRC cell apoptosis were also potentiated with AZD-8055 co-treatment. Reversely, TRAIL sequestering antibody RIK-2 or the caspase-8 specific inhibitor z-IETD-fmk attenuated AZD-8055 plus ONC201-induced CRC cell death. Further, mTOR kinase-dead mutation (Asp-2338-Ala) or shRNA knockdown significantly sensitized ONC201's activity in CRC cells, leading to profound cell death and apoptosis. On the other hand, expression of a constitutively-active S6K1 (T389E) attenuated ONC201-induced CRC cell apoptosis. For the mechanism study, we showed that ONC201 blocked Akt, but only slightly inhibited mTOR in CRC cells. Co-treatment with AZD-8055 also concurrently blocked mTOR activation. These results suggest that mTOR could be a primary resistance factor of ONC201 in CRC cells. Copyright © 2016 Elsevier Inc. All rights reserved.

Atenolol Is Associated with Lower Day of Surgery Heart Rate as compared to Long and Short-acting Metoprolol

PubMed Central

Schonberger, Robert B.; Brandt, Cynthia; Feinleib, Jessica; Dai, Feng; Burg, Matthew M.

2012-01-01

Objectives We analyzed the association between outpatient beta-blocker type and day-of-surgery heart rate in ambulatory surgical patients. We further investigated whether differences in day of surgery heart rate between atenolol and metoprolol could be explained by once-daily versus twice-daily dosing regimens. Design Retrospective observational study. Setting VA Hospital Participants Ambulatory surgical patients on chronic atenolol or metoprolol. Interventions None. Measurements and Main Results Using a propensity-score matched cohort, we compared day of surgery heart rates of patients prescribed atenolol versus metoprolol. We then differentiated between once-daily and twice-daily metoprolol formulations and compared day of surgery heart rates within a general linear model. Day of surgery heart rates in patients prescribed atenolol vs. any metoprolol formulation were slower by a mean of 5.1 beats/min (66.6 vs. 71.7; 95% CI of difference 1.9 to 8.3, p=0.002), a difference that was not observed in preoperative primary care visits. The general linear model demonstrated that patients prescribed atenolol (typically QD dosing) had a mean day of surgery heart rate 5.6 beats/min lower compared to patients prescribed once-daily metoprolol succinate (68.9 vs. 74.5; 95% CI of difference: −8.6 to −2.6, p<0.001) and 3.8 beats/minute lower compared to patients prescribed twice-daily metoprolol tartrate (68.9 vs. 72.7; 95% CI of difference: −6.1 to −1.6, p<0.001). Day of surgery heart rates were similar between different formulations of metoprolol (95% CI of difference: −1.0 to +4.6, p=0.22). Conclusions Atenolol is associated with lower day of surgery heart rate vs. metoprolol. The heart rate difference is specific to the day of surgery and is not explained by once-daily versus twice-daily dosing regimens. PMID:22889605

Semaglutide, a Once-Weekly Human GLP-1 Analog, Does Not Reduce the Bioavailability of the Combined Oral Contraceptive, Ethinylestradiol/Levonorgestrel

PubMed Central

Kapitza, Christoph; Nosek, Leszek; Jensen, Lene; Hartvig, Helle; Jensen, Christine B; Flint, Anne

2015-01-01

The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80–1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0–24 h) for semaglutide steady-state/semaglutide-free; 1.11 (1.06–1.15). AUC0–24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15–1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (–1.1 ± 0.6%) and weight (–4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel. PMID:25475122

Health status of Seventh-Day Adventists.

PubMed

Webster, I W; Rawson, G K

1979-05-19

A comparison of health status between 779 Seventh-day Adventists, who have a strong commitment to heal-related life styles, and two other groups of people--8363 persons referred by general practitioners and 9825 volunteers--was made. The Seventh-day Adventists showed less impairment of systolic and diastolic blood pressures, of plasma cholesterol and plasma urate concentrations, and of lung ventilatory capacity; and less obesity at most specific ages. With increasing age, the level of breathlessness, reported heart disease, hypertension, and hypertensive and diuretic therapy in this sample approached that of the comparative groups, possibly because of natural attrition of high-risk persons in the latter. Depression, sleeplessness, use of sedatives and tranquillizers were lower in the Seventh-day Adventists; although, once again, a drawing together of the three groups in older age categories was evident. It is concluded that the life style of Seventh-day Adventists is conducive to lessened morbidity, delayed mortality, and decreased call on health services in comparison with the general population.

Pharmacokinetic Comparison of Once-Daily Topical Minocycline Foam 4% vs Oral Minocycline for Moderate-to-Severe Acne.

PubMed

Jones, Terry M; Ellman, Herman; deVries, Tina

2017-10-01

To characterize minocycline pharmacokinetics and relative bioavailability following multiple-dose topical administration of minocycline hydrochloride (HCl) foam 4% (FMX101 4%) as compared with single-dose oral administration of minocycline HCl extended-release tablets (Solodyn®) in subjects with moderate-to-severe acne. A Phase 1, single-center, nonrandomized, open-label, active-controlled, 2-period, 2-treatment crossover clinical study. The study included 30 healthy adults (mean age, 22.6 years; 90% white, and 60% females) who had moderate-to-severe acne. Subjects were assigned to first receive a single oral dose of a minocycline HCl extended-release tablet (approximately 1 mg/kg). At 10 days after the oral minocycline dose, topical minocycline foam 4% was applied, once daily for 21 days. Serial blood samples were obtained before and after administration of oral minocycline and each topical application of minocycline foam 4% on days 1, 12, and 21. Following oral administration of minocycline (approximately 1 mg/kg), plasma minocycline concentration increased until 3 hours, followed by a log-linear decrease over the remainder of the 96-hour sampling period. Following topical application of a 4-g maximal-use dose of minocycline foam 4% for 21 days, plasma minocycline concentration was very low, with geometric mean Cmax values ranging from 1.1 ng/mL to 1.5 ng/mL. Steady state was achieved by day 6. Overall, minocycline exposure with topical minocycline foam 4% was 730 to 765 times lower than that with oral minocycline. There was no evidence of minocycline accumulation over the 21 days of topical application of minocycline foam 4%. Topical minocycline foam 4% appeared to be safe and well tolerated, with no serious treatment-emergent adverse events (TEAEs), treatment-related TEAEs, or TEAEs that led to treatment discontinuation. Once-daily topical application of minocycline foam 4% did not lead to significant systemic exposure to minocycline. It appears to be a well

HemOnc.org: A Collaborative Online Knowledge Platform for Oncology Professionals

PubMed Central

Warner, Jeremy L.; Cowan, Andrew J.; Hall, Aric C.; Yang, Peter C.

2015-01-01

Purpose: Cancer care involves extensive knowledge about numerous chemotherapy drugs and chemotherapy regimens. This information is constantly evolving, and there has been no freely available, comprehensive, centralized repository of chemotherapy information to date. Methods: We created an online, freely accessible, ad-free, collaborative wiki of chemotherapy information entitled HemOnc.org to address the unmet need for a central repository of this information. This Web site was developed with wiki development software and is hosted on a cloud platform. Chemotherapy drug and regimen information (including regimen variants), as well as other information of interest to hematology/oncology professionals, is housed on the site in a fully referenced and standardized format. Accredited users are allowed to freely contribute information to the site. Results: From its inception in November 2011, HemOnc.org has grown rapidly and most recently has detailed information on 383 drugs and 1,298 distinct chemotherapy regimens (not counting variants) in 92 disease subtypes. There are regularly more than 2,000 visitors per week from the United States and international locations. A user evaluation demonstrated that users find the site useful, usable, and recommendable. Conclusion: HemOnc.org is now the largest free source of chemotherapy drug and regimen information and is widely used. Future enhancements, including more metadata about drugs and increasingly detailed efficacy and toxicity information, will continue to improve the value of the resource. PMID:25736385

Plasma pharmacokinetics of once-daily abacavir- and lamivudine-containing regimens and week 96 efficacy in HIV-infected Thai children.

PubMed

Bunupuradah, Torsak; Punyahotra, Passorn; Cressey, Tim R; Srimuan, Amornrat; Thammajaruk, Narukjaporn; Sophonphan, Jiratchaya; Sriheara, Chulalak; Burger, David M; Puthanakit, Thanyawee; Ananworanich, Jintanat

2015-07-01

Abacavir and lamivudine are approved for once-daily use in HIV-infected adults. Limited pharmacokinetic (PK) data for abacavir and lamivudine in children are available. A crossover study to compare PK of once- versus twice-daily abacavir and lamivudine was conducted in virologically suppressed HIV-infected Thai children aged <18years, with bodyweight of at least 14 kg, HIV RNA <50 copies/mL and HLA-B*5701 negative. Abacavir and lamivudine daily doses by bodyweight were 300 and 150 mg for 14-<20 kg, 450 and 300 mg for 20-<25 kg, and 600 and 300 mg for ≥25 kg, respectively. Originator abacavir and lamivudine scored tablets were administered. Intensive PK sampling was performed after 14 days of each dose. PK parameters were determined using non-compartmental analysis. Thirty children (57% male) were enrolled, 10 per weight band. Median (IQR) age was 8.8 (6.6-11.3) years and bodyweight was 21.9 (19.2-30.6) kg. The geometric means (GM) AUC0-24 of once- and twice-daily abacavir were 14.43 and 10.65 mg.h/L, respectively. The geometric mean ratio (GMR) of AUC0-24 for once- versus twice-daily abacavir dosing was 1.36 [90% confidence interval (CI) 1.11-1.66]. The GM AUC0-24 of once- and twice-daily lamivudine were 17.70 and 18.11 mg.h/L, respectively. The GMR of AUC0-24 for once- versus twice-daily lamivudine dosing was 0.98 (90% CI 0.84-1.14). At 96 weeks, 90% had HIV RNA <50 copies/mL and there were no serious adverse events. Abacavir exposure was greater with once-daily dosing, while lamivudine once- and twice-daily exposures were bioequivalent. Once-daily abacavir and lamivudine using weight-band dosing is a treatment option for children.

Role of Dopamine Receptors in the Anticancer Activity of ONC201.

PubMed

Kline, Christina Leah B; Ralff, Marie D; Lulla, Amriti R; Wagner, Jessica M; Abbosh, Phillip H; Dicker, David T; Allen, Joshua E; El-Deiry, Wafik S

2018-01-01

ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response. Its promising safety profile and broad-spectrum efficacy in vitro have been confirmed in Phase I/II trials in several advanced malignancies. Binding and reporter assays have shown that ONC201 is a selective antagonist of the dopamine D2-like receptors, specifically, DRD2 and DRD3. We hypothesized that ONC201's interaction with DRD2 plays a role in ONC201's anticancer effects. Using cBioportal and quantitative reverse-transcription polymerase chain reaction analyses, we confirmed that DRD2 is expressed in different cancer cell types in a cell type-specific manner. On the other hand, DRD3 was generally not detectable. Overexpressing DRD2 in cells with low DRD2 levels increased ONC201-induced PARP cleavage, which was preceded and correlated with an increase in ONC201-induced CHOP mRNA expression. On the other hand, knocking out DRD2 using CRISPR/Cas9 in three cancer cell lines was not sufficient to abrogate ONC201's anticancer effects. Although ONC201's anticancer activity was not dependent on DRD2 expression in the cancer cell types tested, we assessed the cytotoxic potential of DRD2 blockade. Transient DRD2 knockdown in HCT116 cells activated the integrated stress response and reduced cell number. Pharmacological antagonism of DRD2 significantly reduced cell viability. Thus, we demonstrate in this study that disrupting dopamine receptor expression and activity can have cytotoxic effects that may at least be in part due to the activation of the integrated stress response. On the other hand, ONC201's anticancer activity goes beyond its ability to antagonize DRD2, potentially due to ONC201's ability to activate other pathways that are independent of DRD2. Nevertheless, blocking the dopamine D1-like receptor DRD5 via siRNA or the use of a pharmacological antagonist promoted ONC201-induced anticancer activity. Copyright © 2018 The Authors

Once-daily, high-dose levofloxacin versus ticarcillin-clavulanate alone or followed by amoxicillin-clavulanate for complicated skin and skin-structure infections: a randomized, open-label trial.

PubMed

Graham, Donald R; Talan, David A; Nichols, Ronald L; Lucasti, Christopher; Corrado, Michael; Morgan, Nancy; Fowler, Cynthia L

2002-08-15

This study tested whether levofloxacin, at a new high dose of 750 mg, was effective for the treatment of complicated skin and skin-structure infections (SSSIs). Patients with complicated SSSIs (n=399) were randomly assigned in a ratio of 1:1 to 2 treatment arms: levofloxacin (750 mg given once per day intravenously [iv], orally, or iv/orally) or ticarcillin-clavulanate (TC; 3.1 g given iv every 4-6 hours) followed, at the investigator's discretion, by amoxicillin-clavulanate (AC; 875 mg given orally every 12 hours). In the clinically evaluable population, therapeutic equivalence was demonstrated between the levofloxacin and TC/AC regimens (success rates of 84.1% and 80.3%, respectively). In the microbiologically evaluable population, the overall rate of eradication was 83.7% in the levofloxacin treatment group and 71.4% in the TC/AC treatment group (95% confidence interval, -24.3 to -0.2). Both levofloxacin and TC/AC were well tolerated. These data demonstrate that levofloxacin (750 mg once per day) is safe and at least as effective as TC/AC for complicated SSSIs.

Once vs twice-daily abacavir and lamivudine in African children.

PubMed

Musiime, Victor; Kasirye, Philip; Naidoo-James, Bethany; Nahirya-Ntege, Patricia; Mhute, Tawanda; Cook, Adrian; Mugarura, Lincoln; Munjoma, Marshall; Thoofer, Navdeep K; Ndashimye, Emmanuel; Nankya, Immaculate; Spyer, Moira J; Thomason, Margaret J; Snowden, Wendy; Gibb, Diana M; Walker, Ann Sarah

2016-07-17

Antiretroviral therapy (ART) adherence is critical for successful HIV treatment outcomes. Once-daily dosing could improve adherence. Plasma concentrations of once-daily vs twice-daily abacavir + lamivudine are bioequivalent in children, but no randomized trial has compared virological outcomes. Children taking abacavir + lamivudine-containing first-line regimens twice daily for more than 36 weeks in the ARROW trial (NCT02028676, ISRCTN24791884) were randomized to continue twice-daily vs move to once-daily abacavir + lamivudine (open-label). Co-primary outcomes were viral load suppression at week 48 (12% noninferiority margin, measured retrospectively) and lamivudine or abacavir-related grade 3/4 adverse events. Six hundred and sixty-nine children (median 5 years, range 1-16) were randomized to twice daily (n = 333) vs once daily (n = 336) after median 1.8 years on twice-daily abacavir + lamivudine-containing first-line ART. Children were followed for median 114 weeks. At week 48, 242/331 (73%) twice daily vs 236/330 (72%) once daily had viral load less than 80 copies/ml [difference -1.6% (95% confidence interval -8.4,+5.2%) P = 0.65]; 79% twice daily vs 78% once daily had viral load less than 400 copies/ml (P = 0.76) (week 96 results similar). One grade 3/4 adverse event was judged uncertainly related to abacavir + lamivudine (hepatitis; once daily). At week 48, 9% twice daily vs 10% once daily reported missing one or more ART pills in the last 4 weeks (P = 0.74) and 8 vs 8% at week 96 (P = 0.90). Carers strongly preferred once-daily dosing. There was no difference between randomized groups in postbaseline drug-resistance mutations or drug-susceptibility; WHO 3/4 events; ART-modifying, grade 3/4 or serious adverse events; CD4% or weight-for-age/height-for-age (all P > 0.15). Once-daily abacavir + lamivudine was noninferior to twice daily in viral load suppression, with similar resistance, adherence, clinical

A Student Sleuth Haunts the Grounds where a College Once Burned

ERIC Educational Resources Information Center

Biemiller, Lawrence

2009-01-01

On the 224th anniversary of the laying of Cokesbury College's cornerstone, Bonnie J. McCubbin drove to the little church that was once the institution's chapel and told the congregation that she might have solved a two-centuries-old mystery: Who set the fire that destroyed the pioneering Methodist college one December night in 1795? Ms. McCubbin,…

45 CFR 170.423 - Principles of proper conduct for ONC-ATCBs.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Principles of proper conduct for ONC-ATCBs. 170... § 170.423 Principles of proper conduct for ONC-ATCBs. An ONC-ATCB shall: (a) Operate its certification... EHR Module developer conspicuously include the following text on its Web site and in all marketing...

HemOnc.org: A Collaborative Online Knowledge Platform for Oncology Professionals.

PubMed

Warner, Jeremy L; Cowan, Andrew J; Hall, Aric C; Yang, Peter C

2015-05-01

Cancer care involves extensive knowledge about numerous chemotherapy drugs and chemotherapy regimens. This information is constantly evolving, and there has been no freely available, comprehensive, centralized repository of chemotherapy information to date. We created an online, freely accessible, ad-free, collaborative wiki of chemotherapy information entitled HemOnc.org to address the unmet need for a central repository of this information. This Web site was developed with wiki development software and is hosted on a cloud platform. Chemotherapy drug and regimen information (including regimen variants), as well as other information of interest to hematology/oncology professionals, is housed on the site in a fully referenced and standardized format. Accredited users are allowed to freely contribute information to the site. From its inception in November 2011, HemOnc.org has grown rapidly and most recently has detailed information on 383 drugs and 1,298 distinct chemotherapy regimens (not counting variants) in 92 disease subtypes. There are regularly more than 2,000 visitors per week from the United States and international locations. A user evaluation demonstrated that users find the site useful, usable, and recommendable. HemOnc.org is now the largest free source of chemotherapy drug and regimen information and is widely used. Future enhancements, including more metadata about drugs and increasingly detailed efficacy and toxicity information, will continue to improve the value of the resource. Copyright © 2015 by American Society of Clinical Oncology.

Once-daily, oral levofloxacin monotherapy for low-risk neutropenic fever in cancer patients: a pilot study in China

PubMed Central

He, Lixian; Zhao, Su; Weng, Heng; Yang, Guowang

2015-01-01

This pilot study assesses the safety and efficacy of once-daily, oral levofloxacin monotherapy in Chinese patients with low-risk febrile neutropenia. In this prospective, single-arm, open-label, multicenter clinical trial, 46 adult Chinese patients with solid tumors and low-risk febrile neutropenia were included. Patients received oral levofloxacin monotherapy (500 mg orally/day) until day 12, followed by 7 days of follow-up (day 19). Body temperature was measured three times per day. On days 2, 3, 5–7, 9, 12, and 19, disease symptoms and vital signs were recorded, adverse drug reactions were assessed, and blood samples were collected to determine the whole-blood cell count and the absolute neutrophil count. Blood cultures and chest radiographs were performed simultaneously until negative results were found. Oral levofloxacin was effective and well tolerated in 97.6% of patients irrespective of the cancer type and cause of fever. Body temperature began to decline in 24.4, 68.3, and 90.2% of patients, respectively, at 12, 24, and 48 h after initiating levofloxacin therapy. On days 5 and 7, 95.1 and 97.6% of the patients had complete defervescence, respectively. The median time for absolute neutrophil count recovery to at least 1500/mm3 after initiation of treatment was 3 days. Only one patient reported mild diarrhea. This pilot study showed that oral levofloxacin quickly and effectively reduced fever, initiated neutrophil recovery, and was well tolerated in Chinese low-risk febrile neutropenic patients with solid tumors. Further study is needed to compare patient data of levofloxacin with the standard amoxicillin/ciprofloxacin protocol in this population for both safety and efficacy. PMID:25486597

Selective and rapid determination of tadalafil and finasteride using solid phase extraction by high performance liquid chromatography and tandem mass spectrometry.

PubMed

Pappula, Nagaraju; Kodali, Balaji; Datla, Peda Varma

2018-04-15

Highly selective and fast liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for simultaneous determination of tadalafil (TDL) and finasteride (FNS) in human plasma. The method was successfully applied for analysis of TDL and FNS samples in clinical study. The method was validated as per USFDA (United States Food and Drug Administration), EMA (European Medicines Agency), and ANVISA (Agência Nacional de Vigilância Sanitária-Brazil) bio analytical method validation guidelines. Glyburide (GLB) was used as common internal standard (ISTD) for both analytes. The selected multiple reaction monitoring (MRM) transitions for mass spectrometric analysis were m/z 390.2/268.2, m/z 373.3/305.4 and m/z 494.2/369.1 for TDL, FNS and ISTD respectively. The extraction of analytes and ISTD was accomplished by a simple solid phase extraction (SPE) procedure. Rapid analysis time was achieved on Zorbax Eclipse C18 column (50 × 4.6 mm, 5 μm). The calibration ranges for TDL and FNS were 5-800 ng/ml and 0.2-30 ng/ml respectively. The results of precision and accuracy, linearity, recovery and matrix effect of the method are acceptable. The accuracy was in the range of 92.9%-106.4% and method precision was also good; %CV was less than 8.1%. Copyright © 2018 Elsevier B.V. All rights reserved.

Does this case hold the answer to one of the worse types of pain in medicine--that of loin pain haematuria syndrome (LPHS).

PubMed

Russell, Alan; Chatterjee, Suman; Seed, Michael

2015-04-26

A patient with loin pain haematuria syndrome suffering chronic throbbing pulsing pain overlaid with prolonged periods of incapacitating colic and overnight vomiting was presented 10 months following diagnosis. Ultrasound was normal. No renal or ureteral stones, or filling defects were seen on CT. At cytoscopy, bladder and urethra were normal, and bloody urine effluxed from the left ureteric orifice. The ureters were normal at diagnosis, and developed new abutting non-penetrating calcifications by 8 months. Pain episodes of complete incapacitating intensity of 2-4 h duration were reduced to 10 min with 5 mg crushed tadalafil administered at onset. If tadalafil was delayed to after onset, the original course of agony resulted. Daily tadalafil reduced loin pain intensity, but not the exacerbations. Tadalafil efficacy may indicate that the pain exacerbations are due to spasm of ureter smooth muscle. 5 mg tadalafil taken at onset alleviated severe loin pain exacerbations in this case of loin pain haematuria syndrome. 2015 BMJ Publishing Group Ltd.

5-Day versus 10-Day Course of Fluoroquinolones in Outpatient Males with a Urinary Tract Infection (UTI).

PubMed

Mospan, Geoffrey A; Wargo, Kurt A

Current guidelines classify urinary tract infections (UTIs) in males as complicated and recommend longer treatment than for UTIs in females. The objective of this study is to demonstrate that males with UTIs may be successfully treated with an outpatient 5-day course of levofloxacin. Data were obtained from a previously conducted clinical trial (www.clinicaltrials.gov identifier NCT00210886), a multicenter, double-blind, randomized, noninferiority study comparing levofloxacin 750 mg intravenously/by mouth once daily for 5 days and ciprofloxacin 400/500 mg intravenously/by mouth twice daily for 10 days in complicated UTI (cUTI). The current study was a post hoc, subgroup analysis of male and female subjects with cUTI. Subjects were stratified into groups based on sex and antibiotic received. The subjects were analyzed at the end of therapy (EOT) and post therapy (PT) for clinical success rates, defined as no further need for antimicrobial treatment. Totals of 427 patients (224 male, 203 female) and 350 patients (189 male, 161 female) were included in the modified intent-to-treat (mITT) population and microbiologically evaluable (ME) populations, respectively. Clinical success rates between males and females were not statistically different between antibiotic groups in either the mITT or ME populations at EOT or PT. This study demonstrates that males with UTI may be treated with a shorter course of antimicrobial therapy for UTI than previously recommended. © Copyright 2016 by the American Board of Family Medicine.

Comparison of efficacy and satisfaction profile, between penile prosthesis implantation and oral PDE5 inhibitor tadalafil therapy, in men with nerve-sparing radical prostatectomy erectile dysfunction.

PubMed

Megas, Georgios; Papadopoulos, Georgios; Stathouros, Georgios; Moschonas, Dimitrios; Gkialas, Ioannis; Ntoumas, Konstantinos

2013-07-01

-free and subdivided into two arms according to treatment modality, either tadalafil three times/week or penile prosthesis implantation. All patients were evaluated using the International Index of Erectile Function (IIEF) questionnaire preoperatively and at 6, 12 and 24 month postoperatively. Repeated measurements analysis of variance was conducted to evaluate the effect of time and group on IIEF total score. There was a significant reduction in IIEF score from preoperative values to the first measurement after surgery in both treatment groups. The overall degree of change from the first time point immediately after surgery to 2 years was greater in the penile prosthesis group than the tadalafil group (20.4 ± 1.3 vs 8.1 ± 2.4, P < 0.001). The efficacy and satisfaction results of both treatment types are considered acceptable. However, regarding the erection frequency, firmness, penetration ability, maintenance and erection confidence it seems that penile prosthesis implantation is superior to oral treatment. The concept of early penile intervention should be considered and is promising for all patients with post-RRP erectile dysfunction. © 2012 BJU International.

45 CFR 170.565 - Revocation of ONC-ACB status.

Code of Federal Regulations, 2013 CFR

2013-10-01

....565 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.565 Revocation of ONC-ACB...

45 CFR 170.565 - Revocation of ONC-ACB status.

Code of Federal Regulations, 2014 CFR

2014-10-01

....565 Public Welfare Department of Health and Human Services HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.565 Revocation of ONC-ACB...

Time of Day Does Not Modulate Improvements in Motor Performance following a Repetitive Ballistic Motor Training Task

PubMed Central

Sale, Martin V.; Ridding, Michael C.; Nordstrom, Michael A.

2013-01-01

Repetitive performance of a task can result in learning. The neural mechanisms underpinning such use-dependent plasticity are influenced by several neuromodulators. Variations in neuromodulator levels may contribute to the variability in performance outcomes following training. Circulating levels of the neuromodulator cortisol change throughout the day. High cortisol levels inhibit neuroplasticity induced with a transcranial magnetic stimulation (TMS) paradigm that has similarities to use-dependent plasticity. The present study investigated whether performance changes following a motor training task are modulated by time of day and/or changes in endogenous cortisol levels. Motor training involving 30 minutes of repeated maximum left thumb abduction was undertaken by twenty-two participants twice, once in the morning (8 AM) and once in the evening (8 PM) on separate occasions. Saliva was assayed for cortisol concentration. Motor performance, quantified by measuring maximum left thumb abduction acceleration, significantly increased by 28% following training. Neuroplastic changes in corticomotor excitability of abductor pollicis brevis, quantified with TMS, increased significantly by 23% following training. Training-related motor performance improvements and neuroplasticity were unaffected by time of day and salivary cortisol concentration. Although similar neural elements and processes contribute to motor learning, training-induced neuroplasticity, and TMS-induced neuroplasticity, our findings suggest that the influence of time of day and cortisol differs for these three interventions. PMID:23577271

PDE5 inhibitors blunt inflammation in human BPH: a potential mechanism of action for PDE5 inhibitors in LUTS.

PubMed

Vignozzi, Linda; Gacci, Mauro; Cellai, Ilaria; Morelli, Annamaria; Maneschi, Elena; Comeglio, Paolo; Santi, Raffaella; Filippi, Sandra; Sebastianelli, Arcangelo; Nesi, Gabriella; Serni, Sergio; Carini, Marco; Maggi, Mario

2013-09-01

Metabolic syndrome (MetS) and benign prostate hyperplasia (BPH)/low urinary tract symptoms (LUTS) are often comorbid. Chronic inflammation is one of the putative links between these diseases. Phosphodiesterase type 5 inhibitors (PDE5i) are recognized as an effective treatment of BPH-related LUTS. One proposed mechanism of action of PDE5 is the inhibition of intraprostatic inflammation. In this study we investigate whether PDE5i could blunt inflammation in the human prostate. Evaluation of the effect of tadalafil and vardenafil on secretion of interleukin 8 (IL-8, a surrogate marker of prostate inflammation) by human myofibroblast prostatic cells (hBPH) exposed to different inflammatory stimuli. We preliminary evaluate histological features of prostatic inflammatory infiltrates in BPH patients enrolled in a randomized, double bind, placebo controlled study aimed at investigating the efficacy of vardenafil (10 mg/day, for 12 weeks) on BPH/LUTS. In vitro treatment with tadalafil or vardenafil on hBPH reduced IL-8 secretion induced by either TNFα or metabolic factors, including oxidized low-density lipoprotein, oxLDL, to the same extent as a PDE5-insensitive PKG agonist Sp-8-Br-PET-cGMP. These effects were reverted by the PKG inhibitor KT5823, suggesting a cGMP/PKG-dependency. Treatment with tadalafil or vardenafil significantly suppressed oxLDL receptor (LOX-1) expression. Histological evaluation of anti-CD45 staining (CD45 score) in prostatectomy specimens of BPH patients showed a positive association with MetS severity. Reduced HDL-cholesterol and elevated triglycerides were the only MetS factors significantly associated with CD45 score. In the MetS cohort there was a significant lower CD45 score in the vardenafil-arm versus the placebo-one. © 2013 Wiley Periodicals, Inc.

Safety and Efficacy of Once-Daily Intravenous Busulfan in Allogeneic Transplantation: A Matched-Pair Analysis.

PubMed

Kako, Shinichi; Fujiwara, Shinichiro; Sato, Miki; Kimura, Shun-Ichi; Nakasone, Hideki; Ohashi, Kazuteru; Kawakita, Toshiro; Maeda, Tetsuo; Morishita, Takanobu; Suzuki, Ritsuro; Fukuda, Takahiro; Ichinohe, Tatsuo; Kurata, Mio; Atsuta, Yoshiko; Kanda, Yoshinobu

2018-04-19

Compared with 4-times-daily infusion of intravenous busulfan (ivBU4), the safety and efficacy of once-daily infusion of ivBU (ivBU1) has not been fully clarified. We have been routinely using ivBU1 in a conditioning regimen in adult patients with myeloid malignancy who undergo allogeneic hematopoietic stem cell transplantation. In this study, a total of 91 patients who received ivBU1 for 2 days (n = 18) or 4 days (n = 73) in our institutions were compared with 273 control patients who received ivBU4, who were matched for age, sex, performance status, disease risk, conditioning regimen, and donor type, selected from the database of the Japanese Society for Hematopoietic Cell Transplantation using optimal matching algorithms. One-year overall survival (56.8% versus 57.1%, P = .94), disease-free survival (51.6% versus 50.8%, P = .73), relapse rate (28.5% versus 26.2%, P = .94), nonrelapse mortality (19.9% versus 23.0%, P = .71), and the incidence of graft-versus-host disease were not significantly different between the ivBU1 and ivBU4 groups. In patients who received ivBU1, neutrophil recovery was slower (median days: 22 versus 17, P = .001), and the incidence of veno-occlusive disease was lower (2.6% versus 17.4%, P = .04). In conclusion, ivBU1 can be safely administered with clinical outcomes similar to those with ivBU4. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Once-weekly exenatide as adjunct treatment of type 1 diabetes mellitus in patients receiving continuous subcutaneous insulin infusion therapy.

PubMed

Traina, Andrea N; Lull, Melinda E; Hui, Adrian C; Zahorian, Toni M; Lyons-Patterson, Jane

2014-08-01

The use of once-weekly exenatide in type 2 diabetes mellitus is well supported, but little is known about its effectiveness in type 1 diabetes. The objective of this study was to determine the clinical efficacy of once-weekly exenatide on glycemic control in patients with type 1 diabetes when added to basal-bolus insulin therapy. For this retrospective study, patients with type 1 diabetes, aged 18 years and older, receiving continuous subcutaneous insulin infusion, using a continuous glucose monitoring device or regularly measuring blood glucose levels and receiving 2 mg of exenatide once weekly for at least 3 months were included. Demographic information, glycated hemoglobin (A1C), body weight, body mass index, systolic and diastolic blood pressures, total daily insulin dose, basal and bolus insulin doses, 28-day continuous subcutaneous insulin infusion glucose average and incidence of hypoglycemia were collected at baseline and 3 months after beginning therapy with once-weekly exenatide. An electronic medical record search identified 11 patients with type 1 diabetes who met the inclusion criteria. Comparing baseline and 3 months after initiation of once-weekly exenatide revealed reductions of 0.6% in A1C (p=0.013), 3.7% in body weight (p=0.008), 1.7 kg/m(2) in body mass index (p=0.003), 13% in total daily insulin dose (p=0.011) and 9.3 units in bolus insulin dose (p=0.015). This study revealed that the addition of once-weekly exenatide to insulin therapy for type 1 diabetes patients leads to significant improvements in A1C, body weight, body mass index and insulin doses. Copyright © 2014 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Prophylactic Valacyclovir to Prevent Outbreaks of Primary Herpes Gladiatorum at a 28-Day Wrestling Camp: A 10-Year Review.

PubMed

Anderson, B J; McGuire, Dennis P; Reed, Megan; Foster, Monique; Ortiz, Deanna

2016-07-01

To determine efficacy of using oral antiviral medication to reduce herpes gladiatorum (HG) at summer high-school wrestling camps. Usage of antiviral medication hypothetically reduces the likelihood of HG outbreaks. This is an observational study examining the effectiveness of oral antiviral medications in reducing outbreaks of HG because of Herpes Simplex type-1 virus (HSV). A 28-day high-school summer wrestling camp at the University of Minnesota from 2003 to 2012. Each summer approximately 300 high-school wrestlers, age 13 to 18 years of age, participated in this camp. All athletes were recommended to take valacyclovir 1 g once a day for the duration of the camp. Athletes who did not use any antiviral medication comprised the comparison group for this study. Individuals were screened daily and those with outbreaks of HG were withheld from practice for 120 hours in accordance with National Collegiate Athletic Association/National Federation of State High School Associations guidelines. To measure viral outbreaks of HG due to HSV-1, determine level of compliance, and determine efficacy of antiviral medication in reducing the occurrence of HG at this 28-day wrestling camp. Of the 2793 athletes who completed camp, 1995 (71%) used antiviral medication, and 36 outbreaks occurred. Eighty-four athletes had a known history of HG/recurrent herpes labialis. Overall, prophylactic antiviral medication resulted in an 84.7% decrease in the probability of an outbreak. Prophylactic valacyclovir (1 g daily) lowered the incidence of individual outbreaks by 89.5%. Prophylactic use of valacyclovir 1 g once a day is efficacious in lowering the incidence of HSV outbreaks among adolescents at a 28-day wrestling camp.

STS-79 Flight Day 9

NASA Technical Reports Server (NTRS)

1996-01-01

On this ninth day of the STS-79 mission, the flight crew, Cmdr. William F. Readdy, Pilot Terrence W. Wilcutt, Mission Specialists, Thomas D. Akers, Shannon Lucid, Jay Apt, and Carl E. Walz having completed five days of joint operations between the American astronauts and the Russian cosmonauts are seen flying solo once again after undocking from the Mir Space Station. As Atlantis/Mir flew over the Ural Mountains of central Asia, the docking hooks and latches that joined the vehicles together were commanded open and Atlantis drifted slowly away from Mir. Wilcutt then initiated a tail-forward fly-around of the Russian space station. After one and one-half revolutions around Mir, Atlantis' jets were fired in a separation maneuver to enable Atlantis to break away from Mir. On board Atlantis, the six-member crew is settling back into its normal routine with a fairly light schedule for the remainder of the day. Early in the morning as Atlantis flew over the United States, the crew took time to talk with anchors for the CBS Up to the Minute' network news broadcast.

Once-daily USL255 as adjunctive treatment of partial-onset seizures: Randomized phase III study

PubMed Central

Chung, Steve S; Fakhoury, Toufic A; Hogan, R Edward; Nagaraddi, Venkatesh N; Blatt, Ilan; Lawson, Balduin; Arnold, Stephan; Anders, Bob; Clark, Annie M; Laine, Dawn; Meadows, R Shawn; Halvorsen, Mark B

2014-01-01

Objective To evaluate the efficacy and safety of USL255, Qudexy™ XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs. Methods In this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE-31-P) and clinical global impression of change (CGI-C), were evaluated. Results Across the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life. Significance The PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects. PMID:24902983

[Five days ceftibuten versus 10 days penicillin in the treatment of 2099 patients with A-streptococcal tonsillopharyngitis].

PubMed

Adam, D; Scholz, H; Helmerking, M

2001-07-19

Group A Streptococci have remained sensitive to penicillins and other betalactam antibiotics, e. g. cephalosporins. Since the beginning of the 1950s oral penicillin V given three times daily in a dose of 50,000 IU daily has been the drug of choice against Group A streptococcal infection. The German Society for Pediatric Infectious Diseases (DGPI) undertook a large scale multicenter randomized study of culture-proven A-streptococcal tonsillopharyngitis to compare the efficacy and safety of a five day regimen of ceftibuten (9 mg/kg KG, once daily) with 10 days of penicillin V (50,000 I.E./kg KG, divided in three doses), testing for equivalence of clinical and bacteriological efficacy. A one year follow-up served to assess poststreptococcal sequelae like rheumatic fever or glomerulonephritis. The clinical efficacy at the clinical end-point 7-9 days after end of treatment was 86.9% (419/482) for ceftibuten and 88.6% (1,198/1,352) for penicillin V. This result is statistically equivalent (P = 0.0152). Resolution of clinical symptoms was significantly faster in the ceftibuten group (P = 0.043/Fisher-Test) and compliance was significantly superior as well (P (0.001). Eradication of group A streptococci at an early control 2-4 days after end of treatment was not equivalent, 78.49% for ceftibuten and 84.42% for penicillin V (P = 0.5713). Both eradication rates were comparable 7-8 weeks after end of treatment (84.65%, 375/443 ceftibuten vs. 86.82%, 1,067/1,229 penicillin V), the difference not being significant. No cases of poststreptococcal sequelae, e.g. rheumatic fever or glomerulonephritis, attributable to either ceftibuten or penicillin were observed in the course of the study.

Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel.

PubMed

Kapitza, Christoph; Nosek, Leszek; Jensen, Lene; Hartvig, Helle; Jensen, Christine B; Flint, Anne

2015-05-01

The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80-1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0-24 h ) for semaglutide steady-state/semaglutide-free; 1.11 (1.06-1.15). AUC0-24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15-1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (-1.1 ± 0.6%) and weight (-4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel. © 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study.

PubMed

Johannsson, Gudmundur; Lennernäs, Hans; Marelli, Claudio; Rockich, Kevin; Skrtic, Stanko

2016-07-01

Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure-time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5-20mg and assess intrasubject variability. Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20-55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3×5), and 20mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography-tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration-time profiles. DR-HC 20mg provided higher than endogenous cortisol plasma concentrations 0-4h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (Cmax) was 82.0 and 178.1ng/mL, while mean area under the concentration-time curve (AUC)0-∞ was 562.8 and 1180.8h×ng/mL with DR-HC 5 and 20mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20mg. All exposure PK parameters were less than dose proportional (slope <1). PK differences between ethnicities were explained by body weight differences. DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional - an important consideration when managing intercurrent illness in patients with adrenal insufficiency. © 2016 The authors.

Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study

PubMed Central

Lennernäs, Hans; Marelli, Claudio; Rockich, Kevin; Skrtic, Stanko

2016-01-01

Objective Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure−time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5–20mg and assess intrasubject variability. Methods Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20−55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3×5), and 20mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography−tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration−time profiles. Results DR-HC 20mg provided higher than endogenous cortisol plasma concentrations 0−4h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (Cmax) was 82.0 and 178.1ng/mL, while mean area under the concentration−time curve (AUC)0−∞ was 562.8 and 1180.8h×ng/mL with DR-HC 5 and 20mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20mg. All exposure PK parameters were less than dose proportional (slope <1). PK differences between ethnicities were explained by body weight differences. Conclusions DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional – an important consideration when managing intercurrent illness in patients with adrenal insufficiency. PMID:27129362

The effect of orally administered ranitidine and once-daily or twice-daily orally administered omeprazole on intragastric pH in cats.

PubMed

Šutalo, S; Ruetten, M; Hartnack, S; Reusch, C E; Kook, P H

2015-01-01

Gastric acid suppressants frequently are used in cats with acid-related gastric disorders. However, it is not known if these drugs effectively increase intragastric pH in cats. To examine the effects of PO administered ranitidine and omeprazole on intragastric pH in cats and to compare the efficacy of once-daily versus twice-daily dosage regimens for omeprazole. Eight domestic shorthair cats. Using a randomized 4-way cross-over design, cats were given enteric-coated omeprazole granules (1.1-1.3 mg/kg q24h and q12h), ranitidine (1.5-2.3 mg/kg q12h), and placebo. Intragastric pH was monitored continuously for 96 hours using the Bravo(™) system, starting on day 4 of treatment, followed by a median washout period of 12 days. Mean percentage of time pH was ≥3 and ≥4 was compared among groups using repeated measures ANOVA. Mean ± SD percentage of time intragastric pH was ≥3 and ≥4 was 67.0 ± 24.0% and 54.6 ± 26.4% for twice-daily omeprazole, 24.4 ± 22.8% and 16.8 ± 19.3% for once-daily omeprazole, 16.5 ± 9.0% and 9.6 ± 5.9% for ranitidine, and 9.4 ± 8.0% and 7.0 ± 6.6% for placebo administration. Twice-daily omeprazole treatment significantly increased intragastric pH, whereas pH after once-daily omeprazole and ranitidine treatments did not differ from that of placebo-treated cats. Only twice-daily PO administered omeprazole significantly suppressed gastric acidity in healthy cats, whereas once-daily omeprazole and standard dosages of ranitidine were not effective acid suppressants in cats. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.

Safety and convenience of once-weekly somapacitan in adult GH deficiency: a 26-week randomized, controlled trial.

PubMed

Johannsson, Gudmundur; Feldt-Rasmussen, Ulla; Håkonsson, Ida Holme; Biering, Henrik; Rodien, Patrice; Tahara, Shigeyuki; Toogood, Andrew; Rasmussen, Michael Højby

2018-05-01

Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin ® . Local tolerability and treatment satisfaction were also assessed. 26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939). Male or female patients aged 18-79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan ( n  = 61) or once-daily Norditropin ( n  = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin ( P  = 0.0171). In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin. © 2018 The authors.

45 CFR 170.540 - ONC-ACB status.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Permanent Certification Program for HIT § 170.540 ONC-ACB status. (a...

45 CFR 170.540 - ONC-ACB status.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Permanent Certification Program for HIT § 170.540 ONC-ACB status. (a...

Number of pulses or number of sessions? An open-label study of trajectories of improvement for once-vs. twice-daily dorsomedial prefrontal rTMS in major depression.

PubMed

Schulze, Laura; Feffer, Kfir; Lozano, Christopher; Giacobbe, Peter; Daskalakis, Zafiris J; Blumberger, Daniel M; Downar, Jonathan

Repetitive transcranial magnetic stimulation (rTMS) shows efficacy in the treatment of major depressive episodes (MDEs), but can require ≥4-6 weeks for maximal effect. Recent studies suggest that multiple daily sessions of rTMS can accelerate response without reducing therapeutic efficacy. However, it is unresolved whether therapeutic effects track cumulative number of pulses, or cumulative number of sessions. This open-label study reviewed clinical outcomes over a 20-30 session course of high-frequency bilateral dorsomedial prefrontal cortex (DMPFC)-rTMS among patients receiving 6000 pulses/day delivered either in twice-daily sessions 80 min apart (at 20 Hz) or single, longer, once-daily sessions (at 10 Hz). A retrospective chart review identified 130 MDD patients who underwent 20-30 daily sessions of bilateral DMPFC-rTMS (Once-daily, n = 65; Twice-daily, n = 65) at a single Canadian clinic. Mixed-effects modeling revealed significantly faster improvement (group-by-time interaction) for twice-daily versus once-daily DMPFC-rTMS. Across both groups, the pace of improvement showed a consistent relationship with number of cumulative sessions, but not with cumulative number of pulses. Although the twice-daily group completed treatment in half as many days, final clinical outcomes did not differ significantly between groups on dichotomous measures (response/remission rates: once-daily, 35.4%/33.8%; twice-daily, 41.5%/35.4%), or continuous measures, or on overall response distribution. Twice-daily rTMS appears feasible, tolerable, and capable of achieving comparable results to once-daily rTMS, while also reducing course length approximately twofold. Therapeutic gains tracked the cumulative number of sessions, not pulses. Future randomized studies comparing once-daily to multiple-daily rTMS sessions, while controlling for number of pulses, may be warranted. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Comparison of a step-down dose of once-daily ciclesonide with a continued dose of twice-daily fluticasone propionate in maintaining control of asthma.

PubMed

Knox, A; Langan, J; Martinot, J-B; Gruss, C; Häfner, D

2007-10-01

To compare a step-down approach in well-controlled asthma patients, as recommended by treatment guidelines, from fluticasone propionate 250 microg twice daily (FP250 BID), or equivalent, to ciclesonide 160 microg once daily (CIC160 OD) with continued FP250 BID treatment. Patients with well-controlled asthma prior to study entry were included in two identical, randomized, double-blind, double-dummy, parallel-group studies. After a 2-week run-in period with FP250 BID, patients were randomized to CIC160 OD (n = 58) or FP250 BID (n = 53) for 12 weeks. Primary endpoints were percentage of days with asthma control, asthma symptom-free days, rescue medication-free days and nocturnal awakening-free days. Secondary endpoints included lung function variables, asthma symptom scores, rescue medication use and asthma exacerbations. Safety variables were also recorded. Patients had >or= 97% of days with asthma control, 98% asthma symptom-free days and 100% of days free from rescue medication use and nocturnal awakenings in both treatment groups (median values). There were no significant between-treatment differences for any of the primary or secondary efficacy variables. Overall, 42 treatment-emergent adverse events (TEAEs) were reported in the CIC160 OD group and 49 TEAEs were reported in the FP250 BID group. There were no clinically relevant changes from baseline in the safety variables in either treatment group. Patients well controlled on FP250 BID, or equivalent, who were stepped down to CIC160 OD, maintained similar asthma control compared with patients who received continued treatment standardized to FP250 BID.

The effect of implementation strength of basic emergency obstetric and newborn care (BEmONC) on facility deliveries and the met need for BEmONC at the primary health care level in Ethiopia.

PubMed

Tiruneh, Gizachew Tadele; Karim, Ali Mehryar; Avan, Bilal Iqbal; Zemichael, Nebreed Fesseha; Wereta, Tewabech Gebrekiristos; Wickremasinghe, Deepthi; Keweti, Zinar Nebi; Kebede, Zewditu; Betemariam, Wuleta Aklilu

2018-05-02

Basic emergency obstetric and newborn care (BEmONC) is a primary health care level initiative promoted in low- and middle-income countries to reduce maternal and newborn mortality. Tailored support, including BEmONC training to providers, mentoring and monitoring through supportive supervision, provision of equipment and supplies, strengthening referral linkages, and improving infection-prevention practice, was provided in a package of interventions to 134 health centers, covering 91 rural districts of Ethiopia to ensure timely BEmONC care. In recent years, there has been a growing interest in measuring program implementation strength to evaluate public health gains. To assess the effectiveness of the BEmONC initiative, this study measures its implementation strength and examines the effect of its variability across intervention health centers on the rate of facility deliveries and the met need for BEmONC. Before and after data from 134 intervention health centers were collected in April 2013 and July 2015. A BEmONC implementation strength index was constructed from seven input and five process indicators measured through observation, record review, and provider interview; while facility delivery rate and the met need for expected obstetric complications were measured from service statistics and patient records. We estimated the dose-response relationships between outcome and explanatory variables of interest using regression methods. The BEmONC implementation strength index score, which ranged between zero and 10, increased statistically significantly from 4.3 at baseline to 6.7 at follow-up (p < .05). Correspondingly, the health center delivery rate significantly increased from 24% to 56% (p < .05). There was a dose-response relationship between the explanatory and outcome variables. For every unit increase in BEmONC implementation strength score there was a corresponding average of 4.5 percentage points (95% confidence interval: 2.1-6.9) increase in

Introduction of cyclofem once-a-month injectable contraceptive in Mexico.

PubMed

Garza-Flores, J; Moraks del Olmo, A; Fuziwara, J L; Figueroa, J G; Alonso, A; Monroy, J; Perez, M; Urbina-Fuentes, M; Guevara, S J; Cedeno, E; Barrios, R; Ferman, J J; Medina, L M; Velazquez, E; Perez-Palacios, G

1998-07-01

A large introductory study of Cyclofem, a once-a-month injectable contraceptive, was conducted in three Mexican provinces. A total of 3457 healthy women participated: 640 women from rural areas (community-based component) and 2817 women from urban and suburban areas (health center-based component). A total of 20,316 women-months of treatment experience were accumulated during a one year period. Cyclofem proved its use-effectiveness (pregnancy rate of 0.03%) and its safety under routine service conditions of family planning facilities in Mexico. The overall life table continuation rate at 1 year was 26.1%. Higher continuation rates were observed in the community-based component (36.6%) as compared to the health center component (23.7%). The most common reason for method discontinuation was change of address. Only 15% of the discontinuations were attributable to the injectable contraceptive method, with the overall 1 year discontinuation rate for bleeding problems (including amenorrhea) was < 11%. These observations underscore the importance of appropriate counseling and follow-up measures, providing convenient access to repeat injections, and other service delivery issues related to continuation of Cyclofem. The results of this trial have once again demonstrated that Cyclofem is a highly effective method with an acceptable side effect profile. In addition, the study provided the elements for its approval by local health authorities and its inclusion into the Ministry of Health Family Planning Program.

45 CFR 170.560 - Good standing as an ONC-ACB.

Code of Federal Regulations, 2013 CFR

2013-10-01

....560 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.560 Good standing as an ONC...

45 CFR 170.560 - Good standing as an ONC-ACB.

Code of Federal Regulations, 2014 CFR

2014-10-01

....560 Public Welfare Department of Health and Human Services HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY ONC HIT Certification Program § 170.560 Good standing as an ONC...

49 CFR 238.305 - Interior calendar day mechanical inspection of passenger cars.

Code of Federal Regulations, 2014 CFR

2014-10-01

... passenger cars. 238.305 Section 238.305 Transportation Other Regulations Relating to Transportation... Interior calendar day mechanical inspection of passenger cars. (a) Except as provided in paragraph (e) of this section, each passenger car shall receive an interior mechanical inspection at least once each...

49 CFR 238.305 - Interior calendar day mechanical inspection of passenger cars.

Code of Federal Regulations, 2010 CFR

2010-10-01

... passenger cars. 238.305 Section 238.305 Transportation Other Regulations Relating to Transportation... Interior calendar day mechanical inspection of passenger cars. (a) Except as provided in paragraph (d) of this section, each passenger car shall receive an interior mechanical inspection at least once each...

Compliance, clinical outcome, and quality of life of patients with stable angina pectoris receiving once-daily betaxolol versus twice daily metoprolol: a randomized controlled trial

PubMed Central

Kardas, Przemyslaw

2007-01-01

Background A randomized, controlled trial was conducted in an outpatient setting to examine the effect of beta-blocker dosing frequency on patient compliance, clinical outcome, and health-related quality of life in patients with stable angina pectoris. Methods One hundred and twelve beta-blockers-naive outpatients with stable angina pectoris were randomized to receive betaxolol, 20 mg once daily or metoprolol tartrate, 50 mg twice daily for 8 weeks. The principal outcome measure was overall compliance measured electronically, whereas secondary outcome measures were drug effectiveness and health-related quality of life. Results The overall compliance was 86.5 ± 21.3% in the betaxolol group versus 76.1 ± 26.3% in the metoprolol group (p < 0.01), and the correct number of doses was taken on 84.4 ± 21.6% and 64.0 ± 31.7% of treatment days, respectively (p < 0.0001). The percentage of missed doses was 14.5 ± 21.5% in the once-daily group and 24.8 ± 26.4% in the twice-daily group (p < 0.01). The percentage of doses taken in the correct time window (58.6% vs 42.0%, p = 0.01), correct interdose intervals (77.4% v 53.1%, p < 0.0001), and therapeutic coverage (85.6% vs 73.7%, p < 0.001) were significantly higher in the once-daily group. Both studied drugs had similar antianginal effectiveness. Health-related quality of life improved in both groups, but this increase was more pronounced in the betaxolol arm in some dimensions. Conclusions The study demonstrates that patient compliance with once-daily betaxolol is significantly better than with twice daily metoprolol. Similarly, this treatment provides better quality of life. These results demonstrate possible therapeutic advantages of once-daily over twice-daily beta-blockers in the treatment of stable angina pectoris. PMID:17580734

Geomagnetic activity during the previous day is correlated with increased consumption of sucrose during subsequent days: is increased geomagnetic activity aversive?

PubMed

Galic, M A; Persinger, M A

2004-06-01

In five separate blocks over a period of several months for 33 female rats the amount of geomagnetic activity during the day before ad libitum access to 10% sucrose or water was positively correlated with the volume of sucrose consumed per 24-hr. period. The strength of the correlation (.62 to .77) declined over the subsequent 10 days from between .12 to -.18 and resembled an extinction curve. In a subsequent experiment four rats exposed to 5 nT to 8 nT, 0.5-Hz magnetic fields that ceased for 30 min. once every 4 hr. for 4 days consumed 11% more sucrose than the four rats exposed to no field. We suggest that the initial consumption of 10% sucrose may have been reinforced because it diminished the aversive physiological effects associated with the increased geomagnetic activity. However, over the subsequent days, as geomagnetic activity decreased or habituation occurred, negative reinforcement did not maintain this behavior.

ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells

PubMed Central

Yuan, Xun; Kho, Dhonghyo; Xu, Jing; Gajan, Ambikai; Wu, Kongming; Wu, Gen Sheng

2017-01-01

ONC201 was previously identified as a first-in-class antitumor agent and small-molecule inducer of the TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) gene that induces apoptosis in cancer cells. ONC201 has a safety profile and is currently in phase II clinical trials for the treatment of various malignancies. In the current study, we examine the effect of ONC201 on triple-negative breast cancer cells (TNBC), a subtype of breast cancer that is sensitive to TRAIL. We find that ONC201 inhibits the growth of TNBC cells including TNBC cells that have developed acquired TRAIL resistance. However, TNBC cells that have developed acquired ONC201 resistance are cross-resistant to TRAIL. Mechanistically, ONC201 triggers an integrated stress response (ISR) involving the activation of the transcription factor ATF4. Knockdown of ATF4 impairs ONC201-induced apoptosis of TNBC cells. Importantly, the activation of ATF4 is compromised in ONC201-resistant TNBC cells. Thus, our results indicate that ONC201 induces an ISR to cause TNBC cell death and suggest that TNBC patients may benefit from ONC201-based therapies. PMID:28423492

ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells.

PubMed

Yuan, Xun; Kho, Dhonghyo; Xu, Jing; Gajan, Ambikai; Wu, Kongming; Wu, Gen Sheng

2017-03-28

ONC201 was previously identified as a first-in-class antitumor agent and small-molecule inducer of the TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) gene that induces apoptosis in cancer cells. ONC201 has a safety profile and is currently in phase II clinical trials for the treatment of various malignancies. In the current study, we examine the effect of ONC201 on triple-negative breast cancer cells (TNBC), a subtype of breast cancer that is sensitive to TRAIL. We find that ONC201 inhibits the growth of TNBC cells including TNBC cells that have developed acquired TRAIL resistance. However, TNBC cells that have developed acquired ONC201 resistance are cross-resistant to TRAIL. Mechanistically, ONC201 triggers an integrated stress response (ISR) involving the activation of the transcription factor ATF4. Knockdown of ATF4 impairs ONC201-induced apoptosis of TNBC cells. Importantly, the activation of ATF4 is compromised in ONC201-resistant TNBC cells. Thus, our results indicate that ONC201 induces an ISR to cause TNBC cell death and suggest that TNBC patients may benefit from ONC201-based therapies.

A dose-finding, placebo-controlled study on extended-release felodipine once daily in treatment of hypertension.

PubMed

Cambell, L M; Ross, J R; Goves, J R; Lees, C T; McCullagh, A; Barnes, P; Timerick, S J; Richardson, P D

1989-12-01

Hypertensive patients received a beta-blocker plus placebo once daily for 4 weeks. If their diastolic blood pressure (DBP) was then 95-115 mm Hg, they were randomized to receive, in addition to the beta-blocker, placebo (n = 36), felodipine-extended release (ER) 10 mg (n = 36), or felodipine-ER 20 mg (n = 37) in a 4-week double-blind parallel-group trial. All medication was administered once daily and, when BP was measured 24 h after the last dose, felodipine-ER 10 mg reduced DBP by 14 +/- 9 mm Hg (mean +/- SD) from a mean of 103 mm Hg and felodipine-ER 20 mg reduced DBP by 18 +/- 9 mm Gg from 101 mm Hg. The reductions in DBP with both doses of felodipine were greater than reductions with placebo (5 +/- 8 mm Hg, from 102 mm Hg--both p less than 0.001). At the end of the study, 21% of patients receiving placebo had a DBP less than or equal to 90 mm Hg. In contrast, 69% of patients receiving felodipine-ER 10 mg and 82% receiving 20 mg attained this level. More than 90% of patients receiving 10 mg felodipine-ER once daily had a reduction in DBP greater than 5 mm Hg 24 h postdose. Felodipine-ER was well tolerated. Felodipine-ER once daily is an effective antihypertensive drug for patients who require therapy in addition to a beta-blocker; the tolerability in this study was good, and a starting dose greater than 10 mg once daily is not indicated.

25 CFR 1000.73 - Once a Tribe/Consortium has been awarded a grant, may the Tribe/Consortium obtain information...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 25 Indians 2 2013-04-01 2013-04-01 false Once a Tribe/Consortium has been awarded a grant, may the Tribe/Consortium obtain information from a non-BIA bureau? 1000.73 Section 1000.73 Indians OFFICE OF THE... § 1000.73 Once a Tribe/Consortium has been awarded a grant, may the Tribe/Consortium obtain information...

Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment.

PubMed

Wagner, Jessica; Kline, C Leah; Zhou, Lanlan; Campbell, Kerry S; MacFarlane, Alexander W; Olszanski, Anthony J; Cai, Kathy Q; Hensley, Harvey H; Ross, Eric A; Ralff, Marie D; Zloza, Andrew; Chesson, Charles B; Newman, Jenna H; Kaufman, Howard; Bertino, Joseph; Stein, Mark; El-Deiry, Wafik S

2018-06-01

ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy.

All Day Kindergarten Programs and Their Anticipated Benefit to Early Literacy Development--Real or Imagined

ERIC Educational Resources Information Center

Soiferman, L. Karen

2017-01-01

There has been increasing interest in both Canada and the United States in implementing all-day Kindergarten programs. Education policy makers stress the need for countries to take initiative in educating children so they are more successful once they begin their formal schooling process. But is a longer school day the only solution to the problem…

Use of acidifier and solubilizer in tadalafil solid dispersion to enhance the in vitro dissolution and oral bioavailability in rats.

PubMed

Choi, Jin-Seok; Kwon, Soon-Hyung; Lee, Sang-Eun; Jang, Woo Suk; Byeon, Jong Chan; Jeong, Hyeong Mo; Park, Jeong-Sook

2017-06-30

The purpose of this study is to improve the solubility, in vitro dissolution, and oral bioavailability in rats of tadalafil (TDF) by using SD technique with a weak acid and a copolymer. TDF-SD was prepared via solvent evaporation, coupled with the incorporation of an acidifier and solubilizer. Tartaric acid enhanced the solubility of TDF over 5-fold in DW, and Soluplus ® enhanced the solubility of TDF over 8.7-fold and 19.2-fold compared to that of TDF (pure) in DW and pH 1.2 for 1h, respectively. The optimal formulation of TDF-SD3 was composed of TDF vs Tartaric acid vs Soluplus ® vs Aerosil=1:1:3:3. The in vitro dissolution rate of TDF-SD3 in DW, pH 1.2 and pH 6.8 buffer (51.5%, 53.3%, and 33.2%, respectively) was significantly higher than that of the commercial product (Cialis ® ) powder (16.5%, 15.2%, and 14.8%, respectively). TDF was completely transformed to an amorphous form as shown in SEM, DSC and PXRD data. The stability of TDF-SD3 included drug contents and in vitro dissolution for 1 month were similar to those of Cialis ® , and the amorphous form of TDF-SD3 was well maintained for 6 months. The TDF-SD3 formulation improved the relative bioavailability (BA) and peak plasma concentration (C max ) compared to that of Cialis ® powder after oral administration in rats as 117.3% and 135.7%, respectively. From the results, we found that the acidifier increased the wettability of TDF, and the solubilizer improved solubility through hydrogen bonding with TDF, thereby increasing the solubility, dissolution and oral bioavailability of TDF in TDF-SD3. Copyright © 2017 Elsevier B.V. All rights reserved.

Randomized Double-Blind Study Comparing 3- and 6-Day Regimens of Azithromycin with a 10-Day Amoxicillin-Clavulanate Regimen for Treatment of Acute Bacterial Sinusitis

PubMed Central

Henry, Dan C.; Riffer, Ernie; Sokol, William N.; Chaudry, Naumann I.; Swanson, Robert N.

2003-01-01

A randomized, double-blind, multicenter study of adults with acute bacterial sinusitis (ABS) compared the efficacy and safety of two azithromycin (AZM) regimens, 500 mg/day once daily for 3 days (AZM-3) or 6 days (AZM-6) to the efficacy and safety of an amoxicillin-clavulanate (AMC) regimen of 500-125 mg three times daily for 10 days. A total of 936 subjects with clinically and radiologically documented ABS were treated (AZM-3, 312; AZM-6, 311; AMC, 313). Clinical success rates were equivalent among per-protocol subjects at the end of therapy (AZM-3, 88.8%; AZM-6, 89.3%; AMC, 84.9%) and at the end of the study (AZM-3, 71.7%; AZM-6, 73.4%; AMC, 71.3%). Subjects treated with AMC reported a higher incidence of treatment-related adverse events (AE) (51.1%) than AZM-3 (31.1%, P < 0.001) or AZM-6 (37.6%, P < 0.001). More AMC subjects discontinued the study (n = 28) than AZM-3 (n = 7) and AZM-6 (n = 11) subjects. Diarrhea was the most frequent treatment-related AE. AZM-3 and AZM-6 were each equivalent in efficacy and better tolerated than AMC for ABS. PMID:12936972

Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials.

PubMed

DeFronzo, Ralph A; Buse, John B; Kim, Terri; Burns, Colleen; Skare, Sharon; Baron, Alain; Fineman, Mark

2016-08-01

Delayed-release metformin (Metformin DR) was developed to maximise gut-based mechanisms of metformin action by targeting the drug to the ileum. Metformin DR was evaluated in two studies. Study 1 compared the bioavailability and effects on circulating glucose and gut hormones (glucagon-like peptide-1, peptide YY) of Metformin DR dosed twice-daily to twice-daily immediate-release metformin (Metformin IR). Study 2 compared the bioavailability and glycaemic effects of Metformin DR dosages of 1,000 mg once-daily in the morning, 1,000 mg once-daily in the evening, and 500 mg twice-daily. Study 1 was a blinded, randomised, crossover study (three × 5 day treatment periods) of twice-daily 500 mg or 1,000 mg Metformin DR vs twice-daily 1,000 mg Metformin IR in 24 participants with type 2 diabetes conducted at two study sites (Celerion Inc.; Tempe, AZ, and Lincoln, NE, USA). Plasma glucose and gut hormones were assessed over 10.25 h at the start and end of each treatment period; plasma metformin was measured over 11 h at the end of each treatment period. Study 2 was a non-blinded, randomised, crossover study (three × 7 day treatment periods) of 1,000 mg Metformin DR once-daily in the morning, 1,000 mg Metformin DR once-daily in the evening, or 500 mg Metformin DR twice-daily in 26 participants with type 2 diabetes performed at a single study site (Celerion, Tempe, AZ). Plasma glucose was assessed over 24 h at the start and end of each treatment period, and plasma metformin was measured over 30 h at the end of each treatment period. Both studies implemented centrally generated computer-based randomisation using a 1:1:1 allocation ratio. A total of 24 randomised participants were included in study 1; of these, 19 completed the study and were included in the evaluable population. In the evaluable population, all treatments produced similar significant reductions in fasting glucose (median reduction range, -0.67 to -0.81 mmol/l across treatments) and

Comparison of the pharmacokinetics of a new 30 mg modified-release tablet formulation of metoclopramide for once-a-day administration versus 10 mg immediate-release tablets: a single and multiple-dose, randomized, open-label, parallel study in healthy male subjects.

PubMed

Bernardo-Escudero, Roberto; Alonso-Campero, Rosalba; Francisco-Doce, María Teresa de Jesús; Cortés-Fuentes, Myriam; Villa-Vargas, Miriam; Angeles-Uribe, Juan

2012-12-01

The study aimed to assess the pharmacokinetics of a new, modified-release metoclopramide tablet, and compare it to an immediate-release tablet. A single and multiple-dose, randomized, open-label, parallel, pharmacokinetic study was conducted. Investigational products were administered to 26 healthy Hispanic Mexican male volunteers for two consecutive days: either one 30 mg modified-release tablet every 24 h, or one 10 mg immediate-release tablet every 8 h. Blood samples were collected after the first and last doses of metoclopramide. Plasma metoclopramide concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed through vital signs measurements, clinical evaluations, and spontaneous reports from study subjects. All 26 subjects were included in the analyses [mean (SD) age: 27 (8) years, range 18-50; BMI: 23.65 (2.22) kg/m², range 18.01-27.47)]. Peak plasmatic concentrations were not statistically different with both formulations, but occurred significantly later (p < 0.05) with the modified-release form [tmax: 3.15 (1.28) vs. 0.85 (0.32) h and tmax-ss: 2.92 (1.19) vs. 1.04 (0.43) h]. There was no difference noted in the average plasma concentrations [Cavgτ: 23.90 (7.90) vs. 20.64 (7.43) ng/mL after the first dose; and Cavg-ss: 31.14 (9.64) vs. 35.59 (12.29) ng/mL after the last dose, (p > 0.05)]. One adverse event was reported in the test group (diarrhea), and one in the reference group (headache). This study suggests that the 30 mg modified-release metoclopramide tablets show features compatible with slow-release formulations when compared to immediate-release tablets, and is suitable for once-a-day administration.

Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications

PubMed Central

Shen, Jie; Goodkin, Margot L; Tong, Warren; Attar, Mayssa

2017-01-01

Purpose Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed. Methods New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve. Results Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6–8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action) of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans), suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation. Conclusion Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid, especially in the iris-ciliary body. Key findings from previous clinical studies suggest that by varying the concentration of benzalkonium chloride (a preservative with corneal penetration-enhancing properties

Permanent certification program for health information technology; revisions to ONC-Approved Accreditor processes. Final rule.

PubMed

2011-11-25

Under the authority granted to the National Coordinator for Health Information Technology by section 3001(c)(5) of the Public Health Service Act (PHSA) as added by the Health Information Technology for Economic and Clinical Health (HITECH) Act, this final rule establishes a process for addressing instances where the ONC-Approved Accreditor (ONC-AA) engages in improper conduct or does not perform its responsibilities under the permanent certification program. This rule also addresses the status of ONC-Authorized Certification Bodies (ONC-ACBs) in instances where there may be a change in the accreditation organization serving as the ONC-AA and clarifies the responsibilities of the new ONC-AA.

45 CFR 170.440 - ONC-ATCB status.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Welfare Department of Health and Human Services HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.440 ONC-ATCB status...

45 CFR 170.440 - ONC-ATCB status.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.440 ONC-ATCB status...

45 CFR 170.440 - ONC-ATCB status.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.440 ONC-ATCB status...

45 CFR 170.440 - ONC-ATCB status.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.440 ONC-ATCB status...

45 CFR 170.440 - ONC-ATCB status.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.440 ONC-ATCB status...

Randomised clinical trial: alginate (Gaviscon Advance) vs. placebo as add-on therapy in reflux patients with inadequate response to a once daily proton pump inhibitor.

PubMed

Reimer, C; Lødrup, A B; Smith, G; Wilkinson, J; Bytzer, P

2016-04-01

Many reflux patients remain symptomatic on a standard dose of proton pump inhibitor (PPI). Alginates decrease the number of reflux events by forming a raft on top of the stomach content and thus offer a supplemental mechanism of action to acid suppression. To assess the efficacy of an alginate (Gaviscon Advance, Reckitt Benckiser, Slough, UK) on reflux symptoms in patients with persistent symptoms despite once daily PPI. This was a multicentre, randomised, placebo-controlled, 7-day double-blind trial preceded by a 7-day run-in period. Reflux symptoms were assessed using the Heartburn Reflux Dyspepsia Questionnaire (HRDQ). Based on symptom score during run-in, eligible patients were randomised to Gaviscon Advance 10 mL four times a day or placebo in addition to a once daily PPI. The primary endpoint was change in HRDQ score post-treatment compared to baseline. One hundred and thirty-six patients were randomised. Change in HRDQ reflux score was significantly greater for Gaviscon Advance (mean: -5.0, s.d.: 4.7) than for placebo (mean: -3.5, s.d.: 5.5) with an LS mean difference of 1.6 [95% CI -3.1 to -0.1], P = 0.03. A decrease in the mean (s.d.) number of nights with symptoms was observed from 3.6 (2.8) to 3.0 (3.0) in the placebo group and from 3.9 (2.8) to 2.2 (2.7) for the Gaviscon Advance group. This reduction was significantly greater in the Gaviscon Advance group than in the placebo group [LS mean difference = -0.9, 95% CI (-1.6 to -0.2), P < 0.01]. In patients with residual reflux symptoms despite PPI treatment, adding an alginate offers additional decrease in the burden of reflux symptoms (EudraCT/IND Number: 2011-005486-21). © 2016 John Wiley & Sons Ltd.

Pharmacokinetic evaluation of a sprinkle-dose regimen of a once-daily, extended-release morphine formulation.

PubMed

Eliot, Lise; Butler, Jackie; Devane, John; Loewen, Gordon

2002-02-01

Morphine sulfate extended-release (MSER) uses a drug-delivery technology that allows once-daily dosing. It is possible to open the MSER capsule and sprinkle the contents on soft food, a potentially useful alternative to the intact capsule in patients who have difficulty swallowing. This study compared the bioavailability of MSER and its metabolites morphine-3-glucuronide and morphine-6-glucuronide after administration of MSER in a sprinkle-dose regimen relative to an intact capsule swallowed whole. This was a randomized, open-label, single-dose, crossover study, with a 7-day washout period between the 2 dosing days. Healthy volunteers were randomized to receive an intact 60-mg MSER capsule swallowed whole or the contents of a 60-mg MSER capsule sprinkled on applesauce. Blood samples were collected and analyzed for concentrations of morphine and its active glucuronide metabolites. Pharmacokinetic (PK) parameters were calculated and bioequivalence assessed. Bioequivalence was concluded if the 90% CIs of the ratio of log-transformed values for maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were within 80% to 125%. Of 30 subjects enrolled, 28 completed the study and were eligible for PK evaluation. Two subjects were withdrawn for reasons unrelated to study treatment. The plasma concentration-time profiles of morphine and its metabolites were superimposable after administration of the 2 regimens. Cmax and total systemic exposure-based on AUC from time 0 to the last quantifiable concentration (AUC(last)) and AUC from time 0 to infinity (AUC(infinity))-were comparable between treatments. The 90% CIs for morphine AUC(last), AUC, and Cmax ratios were 98 to 109, 96 to 106, and 95 to 117, respectively. Similar 90% CIs were obtained for the morphine metabolites. In this study in healthy volunteers, sprinkling the entire contents of an MSER capsule onto applesauce and swallowing without chewing was bioequivalent to swallowing an intact

Technology of forced flow and once-through boiling: A survey. [pressure distribution

NASA Technical Reports Server (NTRS)

Poppendieck, H. F.; Sabin, C. M.

1975-01-01

Representative boiling heat transfer and pressure drop information obtained primarily from past NASA and AEC programs is presented which is applicable to forced flow and once-through boiler systems. The forced convection boiler has a number of advantages: little possibility of flow mal-distribution; heat transfer characteristics are usually consistent; and conductances are predictable, so that higher heat fluxes may be employed with safety (which leads to more compact, lighter weight equipment). It was found that in gas-fired systems particularly, the controlling heat transfer resistance may be on the hot side, so that increased fluxes would require extended surfaces. If in a power generation system the working fluid is very expensive, a forced flow boiler can be designed especially for small holdup volume. If the fluid is temperature sensitive, the boiling side wall temperatures can be tailored to maintain maximum heat transfer rates without overheating the fluid. The forced flow and once-through configurations may be the only type which can satisfy a specific need (such as the automotive Rankine cycle power plant design having a very short time-response boiler).

Market day midwives.

PubMed

1994-06-01

In August 1994 in Uganda, the Social Marketing for Change (SOMARC) project invited midwives to counsel clients and sell low-dose oral contraceptives (OCs), condoms, and the progestin-only OCs in local markets. They now sell these contraceptives from vendor stalls in busy markets, which allows clients to speak privately with the midwives. The midwives refer clients to their maternity clinics or to hospitals for other contraceptive methods and reproductive/maternal and child health (MCH) services. All Market Day Midwives have taken a 1-month family planning course and a course in quality of customer service. By the end of March 1994, 17 midwives served 22 marketplaces ranging from rural village markets operating once every 2 weeks to very busy, daily city markets. Some markets have 15 permanent stalls, while other midwives move within markets. Market Day Midwives have been able to add more than 1900 women to the list of women using the OC Pilplan. 65% of the new acceptors had not used any OC before Pilplan. 46% of them would be women considered to be high risk if they were to become pregnant (teenagers, women over 35, and women with many children). These midwives have been successful because they operate where the people are and they provide anonymity. Market Day Midwives have also brought in men who seek them out for family planning/sexually transmitted disease prevention services. They have sold more than 1000 Protector condoms. Another benefit of the market day approach is professional growth of the midwives. They often invest their earnings into new equipment and their private maternity clinics. They have learned the significance of advertising and the value of high-quality customer service. They look to expand into other markets and to integrate MCH products (e.g., oral rehydration) into their contraceptive business.

Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.

PubMed

Faivre-Finn, Corinne; Snee, Michael; Ashcroft, Linda; Appel, Wiebke; Barlesi, Fabrice; Bhatnagar, Adityanarayan; Bezjak, Andrea; Cardenal, Felipe; Fournel, Pierre; Harden, Susan; Le Pechoux, Cecile; McMenemin, Rhona; Mohammed, Nazia; O'Brien, Mary; Pantarotto, Jason; Surmont, Veerle; Van Meerbeeck, Jan P; Woll, Penella J; Lorigan, Paul; Blackhall, Fiona

2017-08-01

Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0-2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up. Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our

Analysis of illicit dietary supplements sold in the Italian market: identification of a sildenafil thioderivative as adulterant using UPLC-TOF/MS and GC/MS.

PubMed

Damiano, Fabio; Silva, Claudia; Gregori, Adolfo; Vacondio, Federica; Mor, Marco; Menozzi, Mattia; Di Giorgio, Domenico

2014-05-01

Identification of pharmaceutical active ingredients sildenafil and tadalafil and the characterization of a dimethylated thio-derivative of sildenafil, called thioaildenafil or thiodimethylsildenafil, in illicit dietary supplements were described. A multi-residual ultra-performance liquid chromatography-time of flight mass spectrometry (UPLC-TOF/MS) method was developed to screen for the presence of the phosphodiesterase-5 (PDE-5) inhibitors sildenafil, tadalafil, and vardenafil and their analogues thioaildenafil and thiohomosildenafil in powders and pharmaceutical dosage forms. The study was developed in connection with an operation supervised by the Italian Medicines Agency (A.I.F.A.), aimed to monitor dietary supplements in the Italian market. In two of the eleven specimens under investigation, high-resolution mass spectrometry (HR-MS) allowed the identification of the PDE-5 inhibitors sildenafil and tadalafil, while another specimen proved to contain a unapproved dimethylated thioderivative of sildenafil, thioaildenafil or thiodimethylsildenafil, identified for the first time in Italy as adulterant in food supplements. Copyright © 2014 Forensic Science Society. Published by Elsevier Ireland Ltd. All rights reserved.

Formulation and evaluation of once-a-day transdermal gels of diclofenac diethylamine.

PubMed

Baboota, S; Shakeel, F; Kohli, K

2006-03-01

The present study was undertaken to prepare and evaluate transdermal gels of diclofenac diethylamine (DDEA) containing penetration enhancers such as olesan oil and dimethyl sulfoxide (DMSO). Transdermal gels were prepared using different polymers such as carbopol-940, polyvinyl alcohol (PVA), hydroxy propyl methyl cellulose-K(4) M, hydroxy propyl cellulose-M, and sodium carboxy methyl cellulose. The formulated gels were subjected to physicochemical studies, in vitro release studies and in vitro skin permeations studies and were evaluated for drug content, viscosity, extrudability, spreadability, and pH. The in vitro release studies of prepared gels were performed using specially designed Fites cell and in vitro skin permeation studies were performed using keshary-chien diffusion cell through rat skin. Selected formulations were evaluated for their antiinflammatory activity using the carrageenan-induced paw edema in rats. The carbopol-940 and PVA gels containing 10% DMSO showed best in vitro skin permeation of DDEA. In vivo study for the selected formulation showed a sustained reduction in inflammation in the carrageenan induced paw edema in rats. The efficacies of carbopol-940 and PVA gels were also compared with that of the marketed Voveran gel,(R) and it was found that carbopol and PVA gels produced better results than the Voveran gel. (c) 2006 Prous Science. All rights reserved. (c) 2006 Prous Science. All rights reserved.

Randomised controlled trial of three day versus 10 day intravenous antibiotics in acute pyelonephritis: effect on renal scarring

PubMed Central

Benador, D; Neuhaus, T; Papazyan, J; Willi, U; Engel-Bicik, I; Nadal, D; Slosman, D; Mermillod, B; Girardin, E

2001-01-01

BACKGROUND—Acute pyelonephritis often leaves children with permanent renal scarring.
AIMS—To compare the prevalence of scarring following initial treatment with antibiotics administered intravenously for 10 or three days.
METHODS—In a prospective two centre trial, 220 patients aged 3 months to 16 years with positive urine culture and acute renal lesions on initial DMSA scintigraphy, were randomly assigned to receive intravenous ceftriaxone (50 mg/kg once daily) for 10 or three days, followed by oral cefixime (4 mg/kg twice daily) to complete a 15 day course. After three months, scintigraphy was repeated in order to diagnose renal scars.
RESULTS—Renal scarring developed in 33% of the 110 children in the 10 day intravenous group and 36% of the 110 children in the three day group. Children older than 1 year had more renal scarring than infants (42% (54/129) and 24% (22/91), respectively). After adjustment for age, sex, duration of fever before treatment, degree of inflammation, presence of vesicoureteric reflux, and the patients' recruitment centres, there was no significant difference between the two treatments on renal scarring. During follow up, 15 children had recurrence of urinary infection with no significant difference between the two treatment groups.
CONCLUSION—In children with acute pyelonephritis, initial intravenous treatment for 10 days, compared with three days, does not significantly reduce the development of renal scarring.

 PMID:11207174

Pharmacokinetic profile and clinical efficacy of a once-daily ondansetron suppository in cyclophosphamide-induced emesis: a double blind comparative study with ondansetron tablets.

PubMed Central

de Wit, R.; Beijnen, J. H.; van Tellingen, O.; Schellens, J. H.; de Boer-Dennert, M.; Verweij, J.

1996-01-01

We investigated the pharmacokinetic profile and the efficacy of ondansetron (day 1) given as 16 mg suppository once a day, as compared with ondansetron 8 mg tablets twice daily, in patients receiving moderately emetogenic chemotherapy. The study was primarily aimed at investigating the pharmacokinetics and was part of a large multinational, randomised, double-blind, double-dummy efficacy trial. Pharmacokinetic data were obtained in a total of 20 patients, 11 of whom had received a suppository containing ondansetron, and nine patients had received the oral formulation. The median area under the plasma concentration curve (AUC) obtained with the oral formulation was 226 ng ml-1h-1 (range 91-750), and the median maximum plasma level (Cmax) was 50.5 ng ml-1 (range 24.7-199.6) after a dose of 8 mg. For the ondansetron suppository the median AUC was 140 ng ml-1h-1 range (77-405) and the median Cmax was 17.1 ng ml-1 (range 13-48.3) after a dose of 16 mg. The systemic exposure after correction for the dose difference after the suppository was on average 70% lower than after the tablet. The median time to reach the maximum level (Tmax) was 60 min (range 28-120) with the oral formulation and 209 min (range 90-420) with the suppository. For both the tablet and suppository, there was no apparent relationship between either Cmax or AUC, and efficacy. Although the patient numbers were too small for a formal exposure-response relationship to be derived, the slightly poorer pharmacokinetic performance of the suppository did not appear to be associated with a lessening of control of emesis following chemotherapy. The study demonstrates that the pharmacokinetic analysis of a once-daily 16 mg ondansetron suppository results in appropriate plasma concentrations and AUC, and that this rectal formulation is effective in the protection against nausea and vomiting associated with cyclophosphamide chemotherapy. This formulation will provide a useful alternative to the currently available

Pharmacokinetic profile and clinical efficacy of a once-daily ondansetron suppository in cyclophosphamide-induced emesis: a double blind comparative study with ondansetron tablets.

PubMed

de Wit, R; Beijnen, J H; van Tellingen, O; Schellens, J H; de Boer-Dennert, M; Verweij, J

1996-07-01

We investigated the pharmacokinetic profile and the efficacy of ondansetron (day 1) given as 16 mg suppository once a day, as compared with ondansetron 8 mg tablets twice daily, in patients receiving moderately emetogenic chemotherapy. The study was primarily aimed at investigating the pharmacokinetics and was part of a large multinational, randomised, double-blind, double-dummy efficacy trial. Pharmacokinetic data were obtained in a total of 20 patients, 11 of whom had received a suppository containing ondansetron, and nine patients had received the oral formulation. The median area under the plasma concentration curve (AUC) obtained with the oral formulation was 226 ng ml-1h-1 (range 91-750), and the median maximum plasma level (Cmax) was 50.5 ng ml-1 (range 24.7-199.6) after a dose of 8 mg. For the ondansetron suppository the median AUC was 140 ng ml-1h-1 range (77-405) and the median Cmax was 17.1 ng ml-1 (range 13-48.3) after a dose of 16 mg. The systemic exposure after correction for the dose difference after the suppository was on average 70% lower than after the tablet. The median time to reach the maximum level (Tmax) was 60 min (range 28-120) with the oral formulation and 209 min (range 90-420) with the suppository. For both the tablet and suppository, there was no apparent relationship between either Cmax or AUC, and efficacy. Although the patient numbers were too small for a formal exposure-response relationship to be derived, the slightly poorer pharmacokinetic performance of the suppository did not appear to be associated with a lessening of control of emesis following chemotherapy. The study demonstrates that the pharmacokinetic analysis of a once-daily 16 mg ondansetron suppository results in appropriate plasma concentrations and AUC, and that this rectal formulation is effective in the protection against nausea and vomiting associated with cyclophosphamide chemotherapy. This formulation will provide a useful alternative to the currently available

Once-daily treatment of rheumatoid arthritis with choline magnesium trisalicylate.

PubMed

Mann, C C; Boyer, J T

1984-01-01

A pilot study evaluated once-daily treatment of rheumatoid arthritis with choline magnesium trisalicylate (CMT) in patients diagnosed as having classical or definite rheumatoid arthritis, with morning stiffness as a major complaint. Twenty patients were selected who, in an earlier phase of the study, had found twice-daily treatment with CMT effective and tolerable. Efficacy was evaluated in 15 of these patients and safety was evaluated in all 20. Comparisons were made with the twice-daily regimen and with previous nonsteroidal anti-inflammatory drug (NSAID) therapy. Changes in clinical indicators (numbers of painful and swollen joints and the duration of morning stiffness) showed that once-daily treatment with CMT was as effective as twice-daily treatment with CMT or as treatment with other prior NSAIDs in controlling signs and symptoms of rheumatoid arthritis. Side effects in both the twice-daily and the once-daily treatment regimens were similar in incidence and nature.

40 CFR 35.4110 - What does EPA do once it receives the first LOI from a group?

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false What does EPA do once it receives the... to Apply for A Tag § 35.4110 What does EPA do once it receives the first LOI from a group? The following table shows what EPA does when it receives the first LOI from a group: If your site . . . Then EPA...

Protocol for the CONVERT trial-Concurrent ONce-daily VErsus twice-daily RadioTherapy: an international 2-arm randomised controlled trial of concurrent chemoradiotherapy comparing twice-daily and once-daily radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good performance status.

PubMed

Faivre-Finn, Corinne; Falk, Sally; Ashcroft, Linda; Bewley, Michelle; Lorigan, Paul; Wilson, Elena; Groom, Nicki; Snee, Michael; Fournel, Pierre; Cardenal, Felipe; Bezjak, Andrea; Blackhall, Fiona

2016-01-20

Concurrent ONce-daily VErsus twice-daily RadioTherapy (CONVERT) is the only multicentre, international, randomised, phase III trial open in Europe and Canada looking at optimisation of chemoradiotherapy (RT) in limited stage small cell lung cancer (LS-SCLC). Following on from the Turrisi trial of once-daily versus twice-daily (BD) concurrent chemoradiotherapy, there is a real need for a new phase III trial using modern conformal RT techniques and investigating higher once-daily radiation dose. This trial has the potential to define a new standard chemo-RT regimen for patients with LS-SCLC and good performance status. 447 patients with histologically or cytologically proven diagnosis of SCLC were recruited from 74 centres in eight countries between 2008 and 2013. Patients were randomised to receive either concurrent twice-daily RT(45 Gy in 30 twice-daily fractions over 3 weeks) or concurrent once-daily RT(66 Gy in 33 once-daily fractions over 6.5 weeks) both starting on day 22 of cycle 1. Patients are followed up until death. The primary end point of the study is overall survival and secondary end points include local progression-free survival, metastasis-free survival, acute and late toxicity based on the Common Terminology Criteria for Adverse Events V.3.0, chemotherapy and RTdose intensity. The trial received ethical approval from NRES Committee North West-Greater Manchester Central (07/H1008/229). There is a trial steering committee, including independent members and an independent data monitoring committee. Results will be published in a peer-reviewed journal and presented at international conferences. ISRCTN91927162; Pre-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Once a physicist: Nick Horvath

NASA Astrophysics Data System (ADS)

Horvath, Nick

2009-05-01

How did you get into basketball? That's an easy one: I was tall. I had zero interest in sport at a young age and was pushed into basketball against my will when I was about eight. I hated it. The next year, however, I was so much taller than everyone else that in my first game, even though I had no idea what I was doing, I could simply hold the ball above my head and shoot over everyone. I fell in love with basketball after that first game. If I had played badly that day, it is likely that I would not have played again in my entire life.

Chronic non-cancer pain: Focus on once-daily tramadol formulations

PubMed Central

Coluzzi, Flaminia; Mattia, Consalvo

2007-01-01

Despite progress in pain management, chronic non-cancer pain (CNCP) represents still a clinical challenge. The efficacy and safety profile of tramadol make it suitable as a long-term treatment in a variety of CNCP conditions. New once-daily (OD) formulations of tramadol have been marketed in various countries, in order to offer the advantage of a reduced dosing regimen and to improve patients’ compliance. This review focuses on the technology, pharmacology, clinical efficacy, and safety of different once-daily tramadol formulations. Hydrophilic vs hydrophobic matrix systems and newer technologies used in once-daily formulations to control drug delivery are discussed. Three randomized controlled trials (RCTs) established OD tramadol analgesic efficacy to be superior to that of placebo for pain management and functional improvement in patients with osteoarthritis. Three RCTs demonstrated similar rates of efficacy between OD tramadol and immediate-release (IR) or sustained-release (SR) formulations, with a better adverse events profile. An open trial on long term tolerability showed that OD tramadol is generally safe in rheumatological pain treatment. PMID:18473006

Increased medication compliance of liver transplant patients switched from a twice-daily to a once-daily tacrolimus-based immunosuppressive regimen.

PubMed

Eberlin, M; Otto, G; Krämer, I

2013-01-01

Compliance with immunosuppressive therapy plays a major role in the long-term success of liver transplantation. Thus, the development of strategies to promote compliance of liver transplant patients and its evaluation over time are of particular interest. The main objective of this study was to compare medication compliance rates among liver transplant patients over time after transplantation where switched from a twice- to once-daily tacrolimus-based regimen. Sixty-five liver transplant patients being administered tacrolimus-based therapy were classified into three subgroups with regard to time posttransplantation. Medication compliance with tacrolimus-based therapy was measured using an electronic medication event monitoring system over a 12-month period: for 6 months tacrolimus was administered twice-daily and for 6 months, once-daily. Dosing, taking, and timing compliance as well as drug holidays were compared intra-individually between twice- and once-daily intake and among the three subgroups. In addition, patient compliance and quality of life were evaluated using questionnaires. A per protocol analysis of electronically obtained data showed 63 patients to be eligible. The resulting dosing, taking, and timing compliance rates of the patients were higher during the once-daily dosing period. No significant differences in compliance rates with tacrolimus therapy were observed among three subgroups independent of the dosing regimen. More patients failed the correct timing of the evening compared to the morning dose. Missing doses occurred particularly during weekends. Compliance variables measured by questionnaires (Morisky score, self-report, Medication Experience Scale for Immunosuppressants (MESI) score) and the Hospital Anxiety and Depression Scale score were similar in the two dosing periods. The short-form health survey (SF-36) score was higher with once-daily intake. The high measured compliance rates did not vary significantly dependent upon the time

Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: A randomized controlled trial

PubMed Central

Beaulieu, André D; Peloso, Paul M; Haraoui, Boulos; Bensen, William; Thomson, Glen; Wade, John; Quigley, Patricia; Eisenhoffer, John; Harsanyi, Zoltan; Darke, Andrew C

2008-01-01

OBJECTIVE: The present study was a randomized, parallel, double-blind comparison between controlled-release (CR) tramadol and sustained-release (SR) diclofenac in patients with chronic pain due to osteoarthritis of the hips and/or knees. METHODS: Patients with at least moderate pain intensity, and having received analgesics over the past three months, underwent a two-to seven-day washout of current analgesics before initiation of 200 mg CR tramadol or 75 mg SR diclofenac. During the eight-week study, patients returned to the clinic biweekly. CR tramadol doses were titrated to a maximum of 200 mg, 300 mg or 400 mg per day. SR diclofenac doses were titrated to 75 mg or 100 mg once daily, or 75 mg twice a day based on pain relief and the presence of side effects. For rescue analgesic, patients took acetaminophen as needed, up to 650 mg three times a day. RESULTS: Forty-five patients on CR tramadol and 52 patients on SR diclofenac were evaluable. Significant improvements from prestudy treatment were shown for visual analogue scale pain (P=0.0001), stiffness (P<0.0005) and physical function (P=0.0001) scores for both treatments. There were no significant differences between the two treatments in the Western Ontario and McMaster Universities subscales, overall pain, pain and sleep, or the clinical effectiveness evaluation. Overall incidence of adverse events was similar in both groups, with more opioid-related adverse events with CR tramadol, and two serious adverse events occurring with the use of SR diclofenac. CONCLUSIONS: CR tramadol is as effective as SR diclofenac in the treatment of pain due to knee or hip osteoarthritis, with the potential for fewer of the serious side effects that characterize nonsteroidal anti-inflammatory drug administration. PMID:18443672

23 CFR 661.23 - How will a bridge project be programmed for funding once eligibility has been determined?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 23 Highways 1 2011-04-01 2011-04-01 false How will a bridge project be programmed for funding once... TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.23 How will a bridge project be programmed for funding once eligibility has been determined? (a) All projects will be...

23 CFR 661.23 - How will a bridge project be programmed for funding once eligibility has been determined?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 23 Highways 1 2010-04-01 2010-04-01 false How will a bridge project be programmed for funding once... TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.23 How will a bridge project be programmed for funding once eligibility has been determined? (a) All projects will be...

Twice-Daily versus Once-Daily Pramipexole Extended Release Dosage Regimens in Parkinson's Disease.

PubMed

Yun, Ji Young; Kim, Young Eun; Yang, Hui-Jun; Kim, Han-Joon; Jeon, Beomseok

2017-01-01

This open-label study aimed to compare once-daily and twice-daily pramipexole extended release (PER) treatment in Parkinson's disease (PD). PD patients on dopamine agonist therapy, but with unsatisfactory control, were enrolled. Existing agonist doses were switched into equivalent PER doses. Subjects were consecutively enrolled into either once-daily-first or twice-daily-first groups and received the prescribed amount in one or two, respectively, daily doses for 8 weeks. For the second period, subjects switched regimens in a crossover manner. The forty-four patients completed a questionnaire requesting preference during their last visit. We measured the UPDRS-III, Hoehn and Yahr stages (H&Y) in medication-on state, Parkinson's disease sleep scale (PDSS), and Epworth Sleepiness Scale. Eighteen patients preferred a twice-daily regimen, 12 preferred a once-daily regimen, and 14 had no preference. After the trial, 14 subjects wanted to be on a once-daily regimen, 25 chose a twice-daily regimen, and 5 wanted to maintain the prestudy regimen. Main reasons for choosing the twice-daily regimen were decreased off-duration, more tolerable off-symptoms, and psychological stability. The mean UPDRS-III, H&Y, and PDSS were not different. Daytime sleepiness was significantly high in the once-daily regimen, whereas nocturnal hallucinations were more common in the twice-daily. Multiple dosing should be considered if once-daily dosing is unsatisfactory. This study is registered as NCT01515774 at ClinicalTrials.gov.

Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study.

PubMed

Pratley, Richard E; Nauck, Michael A; Barnett, Anthony H; Feinglos, Mark N; Ovalle, Fernando; Harman-Boehm, Illana; Ye, June; Scott, Rhona; Johnson, Susan; Stewart, Murray; Rosenstock, Julio

2014-04-01

As new members of a drug class are developed, head-to-head trials are an important strategy to guide personalised treatment decisions. We assessed two glucagon-like peptide-1 receptor agonists, once-weekly albiglutide and once-daily liraglutide, in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs. We undertook this 32-week, open-label, phase 3 non-inferiority study at 162 sites in eight countries: USA (121 sites), Australia (9 sites), Peru (7 sites), Philippines (7 sites), South Korea (5 sites), UK (5 sites), Israel (4 sites), and Spain (4 sites). 841 adult participants (aged ≥18 years) with inadequately controlled type 2 diabetes and a BMI between 20 and 45 kg/m(2) were enrolled and randomised in a 1:1 ratio to receive albiglutide 30 mg once weekly titrated to 50 mg at week 6, or liraglutide 0·6 mg once daily titrated to 1·2 mg at week 1 and 1·8 mg at week 2. The randomisation schedule was generated by an independent randomisation team by the permuted block method with a fixed block size of 16. Participants and investigators were unmasked to treatment. The primary endpoint was change from baseline in HbA1c for albiglutide versus liraglutide, with a 95% CI non-inferiority upper margin of 0·3%. The primary analysis was by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT01128894. 422 patients were randomly allocated to the albigultide group and 419 to the liraglutide group; 404 patients in the abliglutide group and 408 in the liraglutide group received the study drugs. The primary endpoint analysis was done on the modified intention-to-treat population, which included 402 participants in the albiglutide group and 403 in the liraglutide group. Model-adjusted change in HbA1c from baseline to week 32 was -0·78% (95% CI -0·87 to -0·69) in the albigludite group and -0·99% (-1·08 to -0·90) in the liraglutide group; treatment difference was 0·21% (0·08-0·34; non-inferiority p value=0�

A Day at the Museums

ERIC Educational Resources Information Center

Hubel, Joy Alter

2009-01-01

The school field trip, once a supporting player in a well-rounded education, is slowly becoming endangered. Widespread budget cuts have made happily anticipated class trips to museums, zoos, and other cultural destinations increasingly scarce. A librarian may be able to rescue the field trip from extinction by transforming the school building into…

Comparison of therapy augmentation and deviation rates from the recommended once-daily dosing regimen between LDX and commonly prescribed long-acting stimulants for the treatment of ADHD in youth and adults.

PubMed

Setyawan, Juliana; Hodgkins, Paul; Guérin, Annie; Gauthier, Geneviève; Cloutier, Martin; Wu, Eric; Erder, M Haim

2013-10-01

To compare therapy augmentation and deviation rates from the recommended once-daily dosing regimen in Attention Deficit Hyperactivity Disorder (ADHD) patients initiated on lisdexamfetamine (LDX) vs other once-daily Food and Drug Administration (FDA) approved stimulants. ADHD patients initiated on a long-acting ADHD stimulant medication (index medication) in/after 2007 were selected from a large U.S. administrative claims database. Patients were required to be persistent for ≥90 days and continuously enrolled in their healthcare plan for ≥12 months following treatment initiation date. Based on age and previous treatment status, patients were classified into treatment-naïve children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naïve adults (≥18 years old), and previously treated adults. Furthermore, patients were classified into four mutually exclusive treatment groups, based on index medication: lisdexamfetamine (LDX), osmotic release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate long-acting (MPH LA), and amphetamine/dextroamphetamine long-acting (AMPH LA). The average daily consumption was measured as the quantity of index medication supplied in the 12-month study period divided by the total number of days of supply. Therapy augmentation was defined as the use of another ADHD medication concomitantly with the index medication for ≥28 consecutive days. Therapy augmentation and deviation rates from the recommended once-daily dosing regimen were compared between treatment groups using multivariate logistic regression models. Compared to the other treatment groups, LDX patients were less likely to augment with another ADHD medication (range odds ratios [OR]; 1.28-3.30) and to deviate from the recommended once-daily dosing regimen (range OR; 1.73-4.55), except for previously treated adult patients, where therapy augmentation differences were not statistically

Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea.

PubMed

Thiboutot, Diane M; Fleischer, Alan B; Del Rosso, James Q; Graupe, Klaus

2008-06-01

Twice-daily azelaic acid (AzA) is the conventional regimen for papulopustular rosacea, but once-daily AzA may be equally effective, with greater convenience and dosing flexibility. In order to test this hypothesis, an exploratory study was conducted. The evaluable efficacy population of this 12-week double-blind, parallel-group study included 72 patients and the population that was used to report safety results included 92 patients. Baseline characteristics were comparable between the once-daily and twice-daily study groups. Evaluations were performed at baseline and at weeks 4, 8, and 12. No significant difference was found between the once-daily and twice-daily groups at the end of study therapy in mean investigator global assessment (IGA) scores, treatment success, or treatment response. The mean number of inflammatory lesions, the intensity of erythema intensity, and the intensity of telangiectasia at treatment end were likewise not significantly different (P>.205 for all). More than 90% of subjects in each group rated cosmetic acceptability of this AzA gel as satisfactory or better. Based on these findings and those of prior studies, once-daily AzA 15% gel can therefore be utilized as a safe, effective, and economical dosing option for the treatment of mild-to-moderate papulopustular rosacea. Once-daily dosing of AzA 15% gel was well accepted by patients and can offer considerable dosing flexibility and convenience for the patient as well as for the dermatologist.

Cerebrospinal fluid abacavir concentrations in HIV-positive patients following once-daily administration.

PubMed

Calcagno, A; Pinnetti, C; De Nicolò, A; Scarvaglieri, E; Gisslen, M; Tempestilli, M; D'Avolio, A; Fedele, V; Di Perri, G; Antinori, A; Bonora, S

2018-06-01

Abacavir is a widely used nucleotide reverse transcriptase inhibitor, for which cerebrospinal fluid (CSF) exposure has been previously assessed in twice-daily recipients. We studied abacavir CSF concentrations in 61 and nine HIV-positive patients taking abacavir once daily and twice daily, respectively. Patients on once-daily abacavir had higher plasma and CSF concentrations (96 vs. 22 ng ml -1 , P = 0.038 and 123 vs. 49 ng ml -1 , P = 0.038) but similar CSF-to-plasma ratios (0.8 vs. 0.5, P = 0.500). CSF abacavir concentrations were adequate in patients receiving once-daily treatment. © 2018 The British Pharmacological Society.

Altered metabolism of orally administered loxoprofen in human subjects after an oral administration of loxoprofen for three consecutive days followed by a seven-day washout.

PubMed

Kim, In-Wha; Chung, Suk-Jae; Shim, Chang-Koo

2002-04-01

The effect of pretreatment (i.e., oral administration of loxoprofen for 3 consecutive days followed by a 7-day washout) on the pharmacokinetics and metabolism of the drug was studied in humans. In a control study, a Loxonin tablet (60 mg as loxoprofen anhydrous) was administered orally to 6 healthy male Korean subjects. In a pretreatment study, a Loxonin tablet was administered orally to the subjects once daily for 3 consecutive days. On the 10(th) day, a Loxonin tablet was administered orally to the subjects, and the concentrations of loxoprofen and the trans- and cis-alcohol metabolites in the plasma and urine were measured as a function of time. Using this pretreatment, the area under the curve (AUC) of the trans-alcohol metabolite of loxoprofen in the plasma, but not those of loxoprofen and the cis-alcohol metabolite, was increased (1.5-fold, p < 0.05), leading to increased contribution of the trans-alcohol metabolite to the total urinary recovery of loxoprofen (1.3-fold, p < 0.05). The urinary recovery of total metabolites, which was largely (> 90%) comprised of conjugate metabolites, was also increased as a result of the pretreatment (1.5-fold, p < 0.05). These results indicate that stereoselective reduction to trans-alcohol metabolites as well as the phase II metabolism of loxoprofen may be increased by such a pretreatment in human subjects. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:973-979, 2002

Treatment patterns in patients with type 2 diabetes mellitus treated with glucagon-like peptide-1 receptor agonists: Higher adherence and persistence with dulaglutide compared with once-weekly exenatide and liraglutide.

PubMed

Alatorre, Carlos; Fernández Landó, Laura; Yu, Maria; Brown, Katelyn; Montejano, Leslie; Juneau, Paul; Mody, Reema; Swindle, Ralph

2017-07-01

To compare adherence (proportion of days covered [PDC]), persistence, and treatment patterns among patients with type 2 diabetes mellitus (T2DM) newly initiating glucagon-like peptide-1 receptor agonists (GLP-1RAs). More specifically, the main objectives were to compare dulaglutide vs exenatide once weekly and dulaglutide vs liraglutide. Patients with T2DM newly initiating dulaglutide, albiglutide, exenatide once weekly, exenatide twice daily and liraglutide between November 2014 and April 2015 were hierarchically selected from Truven Health's MarketScan Research Databases. Propensity score matching was used to account for selection bias. Adherence to and persistence with the index GLP-1RA, and switching and augmentation patterns were assessed during the 6-month post-index period. Mean adherence for the matched cohorts was significantly higher for dulaglutide than for exenatide once weekly (0.72 vs 0.61; P  < .0001) and liraglutide (0.71 vs 0.67; P  < .0001). The percentage of patients achieving PDC ≥ 0.80 was significantly higher for dulaglutide compared with exenatide once weekly (54.2% vs 37.9%; P  < .0001) and liraglutide (53.5% vs 44.3%; P  < .0001). The mean (standard deviation) days on treatment for all matched patients was significantly higher for patients in the dulaglutide cohort compared with those in the exenatide once-weekly (148.4 [55.4] vs 123.6 [61.6]; P  < .0001) and liraglutide cohorts (146.0 [56.9] vs 137.4 [60.1]; P  < .0001). A significantly lower proportion of patients on dulaglutide discontinued treatment compared with those on exenatide once weekly (26.2% vs 48.4%; P  < .0001) and those on liraglutide (28.0% vs 35.6%; P  < .0001). Dulaglutide initiators had significantly higher adherence, were more persistent, and had lower discontinuation rates compared with initiators of exenatide once weekly or liraglutide during the 6-month follow-up period. © 2017 Eli Lilly and Company. Diabetes, Obesity and

Comparison of twice-daily vs once-daily deferasirox dosing in a gerbil model of iron cardiomyopathy

PubMed Central

Otto-Duessel, Maya; Aguilar, Michelle; Nick, Hanspeter; Moats, Rex; Wood, John C.

2010-01-01

Objective Despite the availability of deferoxamine chelation therapy for more than 20 years, iron cardiomyopathy remains the leading cause of death in thalassemia major patients. Effective chelation of cardiac iron is difficult; cardiac iron stores respond more slowly to chelation therapy and require a constant gradient of labile iron species between serum and myocytes. We have previously demonstrated the efficacy of once-daily deferasirox in removing previously stored cardiac iron in the gerbil, but changes in cardiac iron were relatively modest compared with hepatic iron. We postulated that daily divided dosing, by sustaining a longer labile iron gradient from myocytes to serum, would produce better cardiac iron chelation than a comparable daily dose. Methods Twenty-four 8- to 10-week-old female gerbils underwent iron dextran—loading for 10 weeks, followed by a 1-week iron equilibration period. Animals were divided into three treatment groups of eight animals each and were treated with deferasirox 100 mg/kg/day as a single dose, deferasirox 100 mg/kg/day daily divided dose, or sham chelation for a total of 12 weeks. Following euthanasia, organs were harvested for quantitative iron and tissue histology. Results Hepatic and cardiac iron contents were not statistically different between the daily single-dose and daily divided-dose groups. However, the ratio of cardiac to hepatic iron content was lower in the divided-dose group (0.78% vs 1.11%, p = 0.0007). Conclusion Daily divided dosing of deferasirox changes the relative cardiac and liver iron chelation profile compared with daily single dosing, trading improvements in cardiac iron elimination for less-effective hepatic chelation. PMID:17588475

[Incremental approach to hemodialysis: twice a week, or once weekly hemodialysis combined with low-protein low-phosphorus diet?].

PubMed

Bolasco, Piergiorgio; Caria, Stefania; Egidi, Maria Francesca; Cupisti, Adamasco

2015-01-01

The start of dialysis treatment is a critical step in the care management of chronic renal failure patients. When hemodialysis is performed three times a week, rapid loss of kidney function and of urine volume output generally occur and this represents an unfavorable prognostic factor. Instead, reducing frequency of hemodialysis sessions, as well as peritoneal dialysis, can contribute to a lesser decrease of residual renal function. Unfortunately, the existing protocols for an incremental hemodialysis approach are not particularly common and they are generally limited to a twice a week hemodialysis schedule. In addition to clinical and economic reasons, an incremental approach to ESRD also contributes to better social and psychological adaptation by the patients to the dramatic change in living conditions linked to the maintenance dialysis treatment. In patients who have attitude for low-protein nutritional therapy, a once weekly dialysis schedule combined with low-protein, low-phosphorus, normal to high energy diet in the remaining six days of the week can be implemented in selected patients. In our experience, this kind of program produced important clinical results and reduction in costs and hospitalization. When compared with a three times a week dialysis schedule, a greater protection of residual renal function and of urine volume output, lower increase in 2 microglobulin, better control of phosphorus and less consumption of phosphate binders and erythropoietin were observed. Careful clinical monitoring and nutrition is essential for the safety and optimization of infrequent hemodialysis. Long-term follow-up analysis shows favorable effects on the overall survival. Furthermore, twice a week hemodialysis is not the only option for an incremental approach of dialysis commencing. In patients who have a good attitude for low-protein nutritional therapy, its arrangement with a program of once weekly dialysis represents a real and effective alternative.

Technical architecture of ONC-approved plans for statewide health information exchange.

PubMed

Barrows, Randolph C; Ezzard, John

2011-01-01

ONC-approved state plans for HIE were reviewed for descriptions and depictions of statewide HIE technical architecture. Review was complicated by non-standard organizational elements and technical terminology across state plans. Findings were mapped to industry standard, referenced, and defined HIE architecture descriptions and characteristics. Results are preliminary due to the initial subset of ONC-approved plans available, the rapid pace of new ONC-plan approvals, and continuing advancements in standards and technology of HIE, etc. Review of 28 state plans shows virtually all include a direct messaging component, but for participating entities at state-specific levels of granularity (RHIO, enterprise, organization/provider). About ½ of reviewed plans describe a federated architecture, and ¼ of plans utilize a single-vendor "hybrid-federated" architecture. About 1/3 of states plan to leverage new federal and open exchange technologies (DIRECT, CONNECT, etc.). Only one plan describes a centralized architecture for statewide HIE, but others combine central and federated architectural approaches.

Technical Architecture of ONC-Approved Plans For Statewide Health Information Exchange

PubMed Central

Barrows, Randolph C.; Ezzard, John

2011-01-01

ONC-approved state plans for HIE were reviewed for descriptions and depictions of statewide HIE technical architecture. Review was complicated by non-standard organizational elements and technical terminology across state plans. Findings were mapped to industry standard, referenced, and defined HIE architecture descriptions and characteristics. Results are preliminary due to the initial subset of ONC-approved plans available, the rapid pace of new ONC-plan approvals, and continuing advancements in standards and technology of HIE, etc. Review of 28 state plans shows virtually all include a direct messaging component, but for participating entities at state-specific levels of granularity (RHIO, enterprise, organization/provider). About ½ of reviewed plans describe a federated architecture, and ¼ of plans utilize a single-vendor “hybrid-federated” architecture. About 1/3 of states plan to leverage new federal and open exchange technologies (DIRECT, CONNECT, etc.). Only one plan describes a centralized architecture for statewide HIE, but others combine central and federated architectural approaches. PMID:22195059

Sexual life of Japanese patients with erectile dysfunction taking phosphodiesterase type 5 inhibitors: an Internet survey using the Psychological and Interpersonal Relationship Scales-Short Form questionnaire.

PubMed

Tsujimura, Akira; Kiuchi, Hiroshi; Soda, Tetsuji; Takezawa, Kentaro; Okuda, Hidenobu; Fukuhara, Shinichiro; Takao, Tetsuya; Nonomura, Norio; Miyagawa, Yasushi

2014-08-01

To investigate details of sexual function of erectile dysfunction in Japanese patients taking phosphodiesterase type 5 inhibitors. A Japanese version of the Psychological and Interpersonal Relationship Scales-Short Form was used to carry out a nationwide survey using the Internet. A total of 556 erectile dysfunction patients (age 30-70 years) who had been prescribed a phosphodiesterase type 5 inhibitor and had attempted sexual intercourse within the past 6 months were included in this survey. Scores were compared in relation to the phosphodiesterase type 5 inhibitors most frequently taken within the past 6 months. In the subdomains of self-confidence and spontaneity of the Psychological and Interpersonal Relationship Scales-Short Form, scores for vardenafil and tadalafil were significantly higher than those for sildenafil. In the subdomain of time concern of the Psychological and Interpersonal Relationship Scales-Short Form, the score for tadalafil was significantly lower than that for others. Our findings support the hypothesis that Japanese patients with erectile dysfunction have high sexual self-confidence, spontaneity and low time concerns when taking tadalafil. These characteristics of tadalafil could be associated with high patient satisfaction and high preference. © 2014 The Japanese Urological Association.

Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors.

PubMed

Prabhu, Varun V; Lulla, Amriti R; Madhukar, Neel S; Ralff, Marie D; Zhao, Dan; Kline, Christina Leah B; Van den Heuvel, A Pieter J; Lev, Avital; Garnett, Mathew J; McDermott, Ultan; Benes, Cyril H; Batchelor, Tracy T; Chi, Andrew S; Elemento, Olivier; Allen, Joshua E; El-Deiry, Wafik S

2017-01-01

Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1) known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3) significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies.

Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors

PubMed Central

Zhao, Dan; Kline, Christina Leah B.; Van den Heuvel, A. Pieter J.; Lev, Avital; Garnett, Mathew J.; McDermott, Ultan; Benes, Cyril H.; Batchelor, Tracy T.; Chi, Andrew S.; Elemento, Olivier; Allen, Joshua E.

2017-01-01

Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1) known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3) significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies. PMID:28767654

Pharmacokinetics/pharmacodynamics of levofloxacin 750 mg once daily in young women with acute uncomplicated pyelonephritis.

PubMed

Nicolle, Lindsay; Duckworth, Heather; Sitar, Dan; Bryski, Lisa; Harding, Godfrey; Zhanel, George

2008-03-01

This pilot study was undertaken to characterise the pharmacokinetics, pharmacodynamics and potential clinical efficacy of levofloxacin 750 mg once daily for 5 days for treatment of women with acute uncomplicated pyelonephritis. Four women diagnosed with acute pyelonephritis were enrolled. Following pre-therapy specimen collection, an initial oral dose of 750 mg levofloxacin was administered. The mean pharmacokinetic parameters for the first dose were: maximum serum concentration (C(max)) 12.5+/-4.7 mg/L (range 5.6-16.0mg/L) (fC(max) 8.8+/-3.3, where f indicates the levofloxacin free or non-protein-bound fraction), area under the serum concentration-time curve (AUC) 85.4+/-14.1 mgh/L (range 66.2-96.8 mgh/L) (fAUC 59.8+/-9.9) and serum half-life (t(1/2)) 6.7+/-0.5h. Mean urine concentrations were 88.0+/-100mg/L at the 0-3 h collection, 307+/-143 mg/L at 3-6 h, 170+/-107 mg/L at 6-12 h and 85+/-8 mg/L at 12-24 h. Mean levofloxacin serum pharmacodynamics for infecting Escherichia coli were: C(max)/minimum inhibitory concentration (MIC) 323+/-185(fC(max)/MIC 226+/-129); and AUC/MIC 2339+/-830(fAUC/MIC 1647+/-579). Mean urine levofloxacin concentration/MIC ratios were: 900+/-1389 for 0-3 h, 12100+/-4950 for 3-6 h, 5922+/-3912 for 6-12 h and 2233+/-1037 for 12-24 h. Levofloxacin eradicated E. coli from the urine by 3-6 h after the first dose. Levofloxacin 750 mg once daily for 5 days has pharmacodynamics that support further evaluation of this regimen for treatment of women with acute uncomplicated pyelonephritis.

Growth, behavior, and economics of group-fed dairy calves fed once or twice daily in an organic production system.

PubMed

Kienitz, M J; Heins, B J; Chester-Jones, H

2017-04-01

Heifer calves (n = 102) were used to evaluate the effect of once- or twice-daily feeding on growth, behavior, and economics of calves in an organic group management system. Calves were assigned to replicate feeding groups of 10 in superhutches by birth order, during 2 seasons from September to December 2013 and March to May 2014 at the University of Minnesota West Central Research and Outreach Center, Morris. Calves in groups were the experimental unit. Breed groups of calves were Holsteins (n = 26), crossbreds (n = 45) including combinations Holsteins, Montbéliarde, and Viking Red (selected for high production), and crossbreds (n = 31) including combinations of Holsteins, Jersey, Normande, and Viking Red (selected for robustness). Treatment groups were once-daily feeding (1×) or twice-daily feeding (2×). Calves in both groups were fed 6 L per calf/daily of organic milk with 13% total solids and then weaned at 60 d when the group consumption averaged 0.91 kg/d of starter per calf. Body weight and hip height were recorded at birth, once a week, at weaning, and at 90 and 120 d of age. Hobo Pendant G loggers (Onset Computer Corp., Bourne, MA) were applied to the right rear leg of calves to measure total lying and standing time. Data were analyzed using PROC MIXED of SAS (SAS Institute Inc., Cary, NC). Independent variables for analyses were the fixed effects of birth weight (co-variable), season of birth, and treatment group, along with replicate as a random effect. No significant differences were found between feeding groups for body weight, weight gain, average daily gain, hip height, or heart girth. For calves in 1× and 2× groups, respectively, weaning group performance was as follows: gain per day was 0.79 and 0.81 kg, weaning weight was 92.7 and 93.3 kg, and weaning hip height was 95.2 and 95.3 cm. Daily gain to 90 d was 0.85 and 0.85 kg, and daily gain to 120 d was 0.85 and 0.83 kg for 1× and 2× calves, respectively. For lying time, calves in groups 1�

Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial.

PubMed

Ostovaneh, M R; Saeidi, B; Hajifathalian, K; Farrokhi-Khajeh-Pasha, Y; Fotouhi, A; Mirbagheri, S S; Emami, H; Barzin, G; Mirbagheri, S A

2014-05-01

Patients with heartburn but without esophageal erosion respond less well to proton pump inhibitors (PPIs). There is a growing body of evidence implicating the role of psychological comorbidities in producing reflux symptoms. Pain modulators improve symptoms in patients with other functional gastrointestinal disorders. We aimed to compare the efficacy of fluoxetine with omeprazole and placebo to achieve symptomatic relief in patients with heartburn and normal endoscopy who failed once daily PPIs. Endoscopy-negative patients with heartburn who failed once daily PPIs were randomly allocated to receive 6 weeks treatment of fluoxetine, omeprazole, or placebo. Random allocation was stratified according to ambulatory pH monitoring study. Percentage of heartburn-free days and symptom severity was assessed. Sixty patients with abnormal and 84 patients with normal pH test were randomized. Subjects receiving fluoxetine experienced more improvement in percentage of heartburn-free days (median 35.7, IQR 21.4-57.1) than those on omeprazole (median 7.14, IQR 0-50, p < 0.001) or placebo (median 7.14, IQR 0-33.6, p < 0.001). In normal pH subgroup, fluoxetine was superior to both omeprazole and placebo regarding percentage of heartburn-free days (median improvement, 57.1, IQR 35.7-57.1 vs 13.9, IQR, 0-45.6 and 7.14, 0-23.8, respectively, p < 0.001), but no significant difference was observed between medications in abnormal pH subgroup. Fluoxetine was superior to omeprazole for improving the symptoms of patients with heartburn and normal endoscopy who failed once daily PPIs. The superiority of fluoxetine was mostly attributed to those with normal esophageal pH rather than those with abnormal pH (ClinicalTrials.gov, number NCT01269788). © 2014 John Wiley & Sons Ltd.

45 CFR 170.435 - ONC-ATCB application reconsideration.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Section 170.435 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.435 ONC...

45 CFR 170.435 - ONC-ATCB application reconsideration.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Section 170.435 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.435 ONC...

45 CFR 170.435 - ONC-ATCB application reconsideration.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Section 170.435 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.435 ONC...

45 CFR 170.435 - ONC-ATCB application reconsideration.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Section 170.435 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.435 ONC...

45 CFR 170.535 - ONC-ACB application reconsideration.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Section 170.535 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Permanent Certification Program for HIT § 170.535 ONC...

45 CFR 170.535 - ONC-ACB application reconsideration.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Section 170.535 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Permanent Certification Program for HIT § 170.535 ONC...

45 CFR 170.435 - ONC-ATCB application reconsideration.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Section 170.435 Public Welfare Department of Health and Human Services HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Temporary Certification Program for HIT § 170.435 ONC...

The efficacy and safety of a novel lipophilic formulation of methimazole for the once daily transdermal treatment of cats with hyperthyroidism.

PubMed

Hill, K E; Gieseg, M A; Kingsbury, D; Lopez-Villalobos, N; Bridges, J; Chambers, P

2011-01-01

Previous studies on transdermal methimazole have used pluronic lecithin organogel as the vehicle. This might not be the most suitable vehicle for a lipophilic drug, such as methimazole. Once daily transdermal administration of a novel lipophilic formulation of methimazole is as safe and effective as oral carbimazole in treating hyperthyroidism in cats. Forty-five client-owned cats diagnosed with hyperthyroidism. Prospective study. Cats with newly diagnosed, untreated hyperthyroidism were treated with carbimazole (5 mg p.o., q12h) or methimazole (10 mg) applied to the inner pinnae q24h. Cats were examined after 0, 1, 4, 8, and 12 weeks of treatment. Clinical signs, body weight, systolic blood pressure, hematologic, serum biochemical and urine parameters, total serum thyroxine concentrations (TT4), and serum methimazole concentrations were recorded. No significant differences between groups were detected at day 0. Both formulations were effective in treating hyperthyroidism. No significant differences were detected in thyroxine concentrations, body weight, blood pressure, heart rate, alkaline phosphatase, alanine aminotransferase, creatinine, urea, and urine specific gravity (USG) between groups. The serum methimazole concentrations correlated poorly with TT4-concentrations in both groups. In this 12-week trial, once daily application of a novel formulation of transdermal methimazole applied to the pinnae was as effective and safe as twice daily oral carbimazole in the treatment of cats with hyperthyroidism. This novel formulation and transdermal application could have practical advantages to some pet owners. Copyright © 2011 by the American College of Veterinary Internal Medicine.

A polymer/semiconductor write-once read-many-times memory

NASA Astrophysics Data System (ADS)

Möller, Sven; Perlov, Craig; Jackson, Warren; Taussig, Carl; Forrest, Stephen R.

2003-11-01

Organic devices promise to revolutionize the extent of, and access to, electronics by providing extremely inexpensive, lightweight and capable ubiquitous components that are printed onto plastic, glass or metal foils. One key component of an electronic circuit that has thus far received surprisingly little attention is an organic electronic memory. Here we report an architecture for a write-once read-many-times (WORM) memory, based on the hybrid integration of an electrochromic polymer with a thin-film silicon diode deposited onto a flexible metal foil substrate. WORM memories are desirable for ultralow-cost permanent storage of digital images, eliminating the need for slow, bulky and expensive mechanical drives used in conventional magnetic and optical memories. Our results indicate that the hybrid organic/inorganic memory device is a reliable means for achieving rapid, large-scale archival data storage. The WORM memory pixel exploits a mechanism of current-controlled, thermally activated un-doping of a two-component electrochromic conducting polymer.

Can Palliative Home Care Reduce 30-Day Readmissions? Results of a Propensity Score Matched Cohort Study

PubMed Central

Ranganathan, Anjana; Dougherty, Meredith; Waite, David

2013-01-01

Abstract Objective This study examined the impact of palliative home nursing care on rates of hospital 30-day readmissions. Methods The electronic health record based retrospective cohort study was performed within home care and palliative home care programs. Participants were home care patients discharged from one of three urban teaching hospitals. Outcome measures were propensity score matched rates of hospital readmissions within 30 days of hospital discharge. Results Of 406 palliative home care patients, matches were identified for 392 (96%). Of 15,709 home care patients, 890 were used at least once as a match for palliative care patients, for a total final sample of 1282. Using the matched sample we calculated the average treatment effect for treated patients. In this sample, palliative care patients had a 30-day readmission probability of 9.1% compared to a probability of 17.4% in the home care group (mean ATT: 8.3%; 95% confidence interval [CI] 8.0%–8.6%). This effect persisted after adjustment for visit frequency. Conclusions Palliative home care may offer benefits to health systems by allowing patients to remain at home and thereby avoiding 30-day rehospitalizations. PMID:24007348

Small molecule ONC201/TIC10 targets chemotherapy-resistant colorectal cancer stem-like cells in an Akt/Foxo3a/TRAIL-dependent manner

PubMed Central

Prabhu, Varun V.; Allen, Joshua E.; Dicker, David T.; El-Deiry, Wafik S.

2015-01-01

Self-renewing colorectal cancer stem/progenitor cells (CSCs) contribute to tumor maintenance and resistance to therapy. Therapeutic targeting of CSCs could improve treatment response and prolong patient survival. ONC201/TIC10 is a first-in-class anti-tumor agent that induces TRAIL pathway mediated cell death in cancer cells without observed toxicity. We have previously described that ONC201/TIC10 exposure leads to transcriptional induction of the TRAIL gene via transcription factor Foxo3a, which is activated by dual inactivation of Akt and ERK. The Akt and ERK pathways serve as important targets in CSCs. Foxo3a is a key mediator of Akt and ERK-mediated CSC regulation. We hypothesized that the potent anti-tumor effect of ONC201/TIC10 in colorectal cancer involves targeting CSCs and bulk tumor cells. ONC201/TIC10 depletes CD133(+), CD44(+) and Aldefluor(+) cells in vitro and in vivo. TIC10 significantly inhibits colonosphere formation of unsorted and sorted 5-Fluorouracil-resistant CSCs. ONC201/TIC10 significantly reduces CSC-initiated xenograft tumor growth in mice and prevents the passage of these tumors. ONC201/TIC10 treatment also decreased xenograft tumor initiation and was superior to 5-Fluorouracil treatment. Thus, ONC201/TIC10 inhibits CSC self-renewal in vitro and in vivo. ONC201/TIC10 inhibits Akt and ERK, consequently activating Foxo3a and significantly induces cell surface TRAIL and DR5 expression in both CSCs and non-CSCs. ONC201/TIC10-mediated anti-CSC effect is significantly blocked by the TRAIL sequestering antibody RIK-2. Overexpression of Akt, DR5 knockdown and Foxo3a knockdown rescues ONC201/TIC10-mediated depletion of CD44(+) cells and colonosphere inhibition. In conclusion, ONC201/TIC10 is a promising agent for colorectal cancer therapy that targets both non-CSCs and CSCs in an Akt-Foxo3a-TRAIL-dependent manner. PMID:25712124

Small-Molecule ONC201/TIC10 Targets Chemotherapy-Resistant Colorectal Cancer Stem-like Cells in an Akt/Foxo3a/TRAIL-Dependent Manner.

PubMed

Prabhu, Varun V; Allen, Joshua E; Dicker, David T; El-Deiry, Wafik S

2015-04-01

Self-renewing colorectal cancer stem/progenitor cells (CSC) contribute to tumor maintenance and resistance to therapy. Therapeutic targeting of CSCs could improve treatment response and prolong patient survival. ONC201/TIC10 is a first-in-class antitumor agent that induces TRAIL pathway-mediated cell death in cancer cells without observed toxicity. We have previously described that ONC201/TIC10 exposure leads to transcriptional induction of the TRAIL gene via transcription factor Foxo3a, which is activated by dual inactivation of Akt and ERK. The Akt and ERK pathways serve as important targets in CSCs. Foxo3a is a key mediator of Akt and ERK-mediated CSC regulation. We hypothesized that the potent antitumor effect of ONC201/TIC10 in colorectal cancer involves targeting CSCs and bulk tumor cells. ONC201/TIC10 depletes CD133(+), CD44(+), and Aldefluor(+) cells in vitro and in vivo. TIC10 significantly inhibits colonosphere formation of unsorted and sorted 5-fluorouracil-resistant CSCs. ONC201/TIC10 significantly reduces CSC-initiated xenograft tumor growth in mice and prevents the passage of these tumors. ONC201/TIC10 treatment also decreased xenograft tumor initiation and was superior to 5-fluorouracil treatment. Thus, ONC201/TIC10 inhibits CSC self-renewal in vitro and in vivo. ONC201/TIC10 inhibits Akt and ERK, consequently activating Foxo3a and significantly induces cell surface TRAIL and DR5 expression in both CSCs and non-CSCs. ONC201/TIC10-mediated anti-CSC effect is significantly blocked by the TRAIL sequestering antibody RIK-2. Overexpression of Akt, DR5 knockdown, and Foxo3a knockdown rescues ONC201/TIC10-mediated depletion of CD44(+) cells and colonosphere inhibition. In conclusion, ONC201/TIC10 is a promising agent for colorectal cancer therapy that targets both non-CSCs and CSCs in an Akt-Foxo3a-TRAIL-dependent manner. ©2015 American Association for Cancer Research.

A double-blind, placebo-controlled, randomised, parallel-group, dose-escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days.

PubMed

Bell, D; Duffin, A; Jacobs, A; Pediconi, C; Gruss, H J

2014-03-01

The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α-adrenergic effect. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial.

PubMed

Kelsey, Douglas K; Sumner, Calvin R; Casat, Charles D; Coury, Daniel L; Quintana, Humberto; Saylor, Keith E; Sutton, Virginia K; Gonzales, Jill; Malcolm, Sandra K; Schuh, Kory J; Allen, Albert J

2004-07-01

Atomoxetine seems to be as effective for treating attention-deficit/hyperactivity disorder (ADHD) when the daily dose is administered once in the morning as when the dose is divided and administered in the morning and evening. In the present study, the efficacy of atomoxetine administered once daily among children with ADHD was assessed throughout the day, including the evening and early morning. Another goal was to determine how early in treatment it was possible to discern a specific effect of the drug on ADHD symptoms. This study was a randomized, multicenter, double-blind, placebo-controlled trial conducted at 12 outpatient sites in the United States. A total of 197 children, 6 to 12 years of age, who had been diagnosed as having ADHD, on the basis of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria, were randomized to receive 8 weeks of treatment with atomoxetine or placebo, dosed once daily in the mornings. ADHD symptoms were assessed with parent and investigator rating scales. The primary outcome measure was the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score. Daily parent assessments of children's home behaviors in the evening and early morning were recorded with an electronic data entry system. This instrument measures 11 specific morning or evening activities, including getting up and out of bed, doing or completing homework, and sitting through dinner. Seventy-one percent of the children enrolled were male, 69% met criteria for the combined subtype (both inattentive and hyperactive/impulsive symptoms), and the most common psychiatric comorbidity was oppositional defiant disorder (35%). Once-daily atomoxetine (final mean daily dose of 1.3 mg/kg) was significantly more effective than placebo in treating core symptoms of ADHD. Mean reductions in the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored

High energy ball milling and supercritical carbon dioxide impregnation as co-processing methods to improve dissolution of tadalafil.

PubMed

Krupa, Anna; Descamps, Marc; Willart, Jean-François; Jachowicz, Renata; Danède, Florence

2016-12-01

Tadalafil (TD) is a crystalline drug of a high melting point (T m =299°C) and limited solubility in water (<5μg/mL). These properties may result in reduced and variable bioavailability after oral administration. Since the melting of TD is followed by its decomposition, the drug processing at high temperatures is limited. The aim of the research is, therefore, to improve the dissolution of TD by its co-processing with the hydrophilic polymer Soluplus® (SL) at temperatures below 40°C. In this study, two methods, i.e. high energy ball-milling and supercritical carbon dioxide impregnation (scCO 2 ) are compared, with the aim to predict their suitability for the vitrification of TD. The influence of the amount of SL and the kind of co-processing method on TD thermal properties is analyzed. The results show that only the high energy ball milling process makes it possible to obtain a completely amorphous form of TD, with the characteristic X-ray 'halo' pattern. The intensity of the Bragg peaks diminishes for all the formulations treated with scCO 2 , but these samples remain crystalline. The MDSC results show that high energy ball milling is capable of forcing the mixing of TD and SL at a molecular level, providing a homogeneous amorphous solid solution. The glass transition temperatures (T g ), determined for the co-milled formulations, range from 79°C to 139°C and they are higher than T g of pure SL (ca. 70°C) and lower than T g of pure TD (ca. 149°C). In contrast to the co-milled formulations which are in the form of powder, all the formulations after scCO 2 impregnation form a hard residue, sticking to the reaction vessel, which needs to be ground before analysis or further processing. Finally, the dissolution studies show that not only has SL a beneficial effect on the amount of TD dissolved, but also both co-processing methods make the dissolution enhancement of TD possible. After co-processing by scCO 2 , the amount of TD dissolved increases with the

Clinical evaluation of a novel liquid formulation of L-thyroxine for once daily treatment of dogs with hypothyroidism.

PubMed

Le Traon, G; Brennan, S F; Burgaud, S; Daminet, S; Gommeren, K; Horspool, L J I; Rosenberg, D; Mooney, C T

2009-01-01

A liquid solution of levothyroxine (L-T4) is available for treatment of canine hypothyroidism. Once daily oral administration of a liquid L-T4 solution is effective and safe for controlling hypothyroidism in dogs. Thirty-five dogs with naturally occurring hypothyroidism. Dogs received L-T4 solution PO once daily at a starting dosage of 20 microg/kg body weight (BW). The dose was adjusted every 4 weeks, based on clinical signs and peak serum total T4 (tT4) concentrations. Target peak serum tT4 and thyroid stimulating hormone (TSH) concentrations, 4-6 hours posttreatment, were 35-95 nmol/L and < 0.68 ng/mL, respectively. Dogs were followed for up to 22 weeks after establishment of the maintenance dose. Clinical signs of hypothyroidism improved or resolved in 91% of dogs after 4 weeks of L-T4 treatment at 20 microg/kg once daily. The maintenance dose was established in 76, 94, and 100% of dogs after 4, 8, and 12 weeks of treatment, respectively. This was 20 microg L-T4/kg BW for 79% of the dogs, 30 microg/kg BW for 15%, and 10-15 microg/kg BW in the remaining 6%, once daily. Thereafter, median peak tT4 and TSH concentrations were 51 nmol/L and 0.18 ng/mL, respectively, and remained stable during the 22-week follow-up; clinical signs did not recur. All of the hypothyroid dogs had rapid clinical and hormonal responses to supplementation with the PO-administered L-T4 solution. The starting dosage of 20 microg L-T4/kg BW once daily was suitable for 79% of dogs.

Discharges with surgical procedures performed less often than once per month per hospital account for two-thirds of hospital costs of inpatient surgery.

PubMed

O'Neill, Liam; Dexter, Franklin; Park, Sae-Hwan; Epstein, Richard H

2017-09-01

Most surgical discharges (54%) at the average hospital are for procedures performed no more often than once per month at that hospital. We hypothesized that such uncommon procedures would be associated with an even greater percentage of the total cost of performing all surgical procedures at that hospital. Observational study. State of Texas hospital discharge abstract data: 4th quarter of 2015 and 1st quarter of 2016. Inpatients discharged with a major therapeutic ("operative") procedure. For each of N=343 hospitals, counts of discharges, sums of lengths of stay (LOS), sums of diagnosis related group (DRG) case-mix weights, and sums of charges were obtained for each procedure or combination of procedures, classified by International Classification of Diseases version 10 Procedure Coding System (ICD-10-PCS). Each discharge was classified into 2 categories, uncommon versus not, defined as a procedure performed at most once per month versus those performed more often than once per month. Major procedures performed at most once per month per hospital accounted for an average among hospitals of 68% of the total inpatient costs associated with all major therapeutic procedures. On average, the percentage of total costs associated with uncommon procedures was 26% greater than expected based on their share of total discharges (P<0.00001). Average percentage differences were insensitive to the endpoint, with similar results for the percentage of patient days and percentage of DRG case-mix weights. Approximately 2/3rd (mean 68%) of inpatient costs among surgical patients can be attributed to procedures performed at most once per month per hospital. The finding that such uncommon procedures account for a large percentage of costs is important because methods of cost accounting by procedure are generally unsuitable for them. Copyright © 2017 Elsevier Inc. All rights reserved.

Initial inflight calibration for Hayabusa2 optical navigation camera (ONC) for science observations of asteroid Ryugu

NASA Astrophysics Data System (ADS)

Suzuki, H.; Yamada, M.; Kouyama, T.; Tatsumi, E.; Kameda, S.; Honda, R.; Sawada, H.; Ogawa, N.; Morota, T.; Honda, C.; Sakatani, N.; Hayakawa, M.; Yokota, Y.; Yamamoto, Y.; Sugita, S.

2018-01-01

Hayabusa2, the first sample return mission to a C-type asteroid was launched by the Japan Aerospace Exploration Agency (JAXA) on December 3, 2014 and will arrive at the asteroid in the middle of 2018 to collect samples from its surface, which may contain both hydrated minerals and organics. The optical navigation camera (ONC) system on board the Hayabusa2 consists of three individual framing CCD cameras, ONC-T for a telescopic nadir view, ONC-W1 for a wide-angle nadir view, and ONC-W2 for a wide-angle slant view will be used to observe the surface of Ryugu. The cameras will be used to measure the global asteroid shape, local morphologies, and visible spectroscopic properties. Thus, image data obtained by ONC will provide essential information to select landing (sampling) sites on the asteroid. This study reports the results of initial inflight calibration based on observations of Earth, Mars, Moon, and stars to verify and characterize the optical performance of the ONC, such as flat-field sensitivity, spectral sensitivity, point-spread function (PSF), distortion, and stray light of ONC-T, and distortion for ONC-W1 and W2. We found some potential problems that may influence our science observations. This includes changes in sensitivity of flat fields for all bands from those that were measured in the pre-flight calibration and existence of a stray light that arises under certain conditions of spacecraft attitude with respect to the sun. The countermeasures for these problems were evaluated by using data obtained during initial in-flight calibration. The results of our inflight calibration indicate that the error of spectroscopic measurements around 0.7 μm using 0.55, 0.70, and 0.86 μm bands of the ONC-T can be lower than 0.7% after these countermeasures and pixel binning. This result suggests that our ONC-T would be able to detect typical strength (∼3%) of the serpentine absorption band often found on CM chondrites and low albedo asteroids with ≥ 4�

Once-Daily Radiation Therapy for Inflammatory Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Lindsay; Harmsen, William; Blanchard, Miran

2014-08-01

Purpose: Inflammatory breast cancer (IBC) is a rare and aggressive breast cancer variant treated with multimodality therapy. A variety of approaches intended to escalate the intensity and efficacy of radiation therapy have been reported, including twice-daily radiation therapy, dose escalation, and aggressive use of bolus. Herein, we examine our outcomes for patients treated with once-daily radiation therapy with aggressive bolus utilization, focusing on treatment technique. Methods and Materials: A retrospective review of patients with nonmetastatic IBC treated from January 1, 2000, through December 31, 2010, was performed. Locoregional control (LRC), disease-free survival (DFS), overall survival (OS) and predictors thereof weremore » assessed. Results: Fifty-two women with IBC were identified, 49 (94%) of whom were treated with neoadjuvant chemotherapy. All underwent mastectomy followed by adjuvant radiation therapy. Radiation was delivered in once-daily fractions of 1.8 to 2.25 Gy (median, 2 Gy). Patients were typically treated with daily 1-cm bolus throughout treatment, and 33 (63%) received a subsequent boost to the mastectomy scar. Five-year Kaplan Meier survival estimates for LRC, DFS, and OS were 81%, 56%, and 64%, respectively. Locoregional recurrence was associated with poorer OS (P<.001; hazard ratio [HR], 4.1). Extracapsular extension was associated with worse LRC (P=.02), DFS (P=.007), and OS (P=.002). Age greater than 50 years was associated with better DFS (P=.03). Pathologic complete response was associated with a trend toward improved LRC (P=.06). Conclusions: Once-daily radiation therapy with aggressive use of bolus for IBC results in outcomes consistent with previous reports using various intensified radiation therapy regimens. LRC remains a challenge despite modern systemic therapy. Extracapsular extension, age ≤50 years, and lack of complete response to chemotherapy appear to be associated with worse outcomes. Novel strategies are

The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity

PubMed Central

Wagner, Jessica; Kline, Christina Leah; Pottorf, Richard S.; Nallaganchu, Bhaskara Rao; Olson, Gary L.; Dicker, David T.; Allen, Joshua E.; El-Deiry, Wafik S.

2014-01-01

We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anti-cancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers. PMID:25587031

The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity.

PubMed

Wagner, Jessica; Kline, Christina Leah; Pottorf, Richard S; Nallaganchu, Bhaskara Rao; Olson, Gary L; Dicker, David T; Allen, Joshua E; El-Deiry, Wafik S

2014-12-30

We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anti-cancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers.

Pharmacokinetics of a once-daily extended-release formulation of pramipexole in healthy male volunteers: three studies.

PubMed

Jenner, Peter; Könen-Bergmann, Michael; Schepers, Cornelia; Haertter, Sebastian

2009-11-01

-dose ER 0.375 mg administered in the fasted state in study 2, in vivo bioavailability was predictable from in vitro dissolution data, with internal mean absolute percent prediction errors of 3.18% for AUC(0-30h) and 4.87% for C(max), and external mean absolute prediction errors of 6.61% and 3.34%, respectively, satisfying current guidelines for a level A IVIVC. For single-dose ER 0.375 mg administered in the fed state, the upper bound of the 90% CI for fed:fasted values was 119.8 for AUC(0-30h) (within the bioequivalence limits of 80%-125%) and 134.1 for C(max). At steady state in study 3 (subjects' 5th treatment day), dosing at 0.375 to 4.5 mg in the fasted state was associated with a linear, dose-proportional increase in pharmacokinetic parameters, including AUC(0-24h,ss) and C(max,ss). At the highest fasted dose (4.5 mg), the geometric coefficient of variation for interindividual variability at steady state was 30.1% for AUC(0-24h,ss) (vs 21.4% for IR pramipexole 1.5 mg TID) and 22.3% for C(max,ss) (vs 19.0%). At steady state, the upper bounds of the 90% CIs for fed:fasted values with ER 4.5 mg were 122.1 for AUC(0-24h) and 126.8 for C(max). No serious AEs occurred, and the dropout rate was low. In these studies in healthy male volunteers, an ER pramipexole formulation was identified that resembled the IR formulation in terms of both pharmacokinetics and tolerability. In patients with Parkinson's disease, once-daily use of an ER formulation may improve the convenience of treatment relative to the IR formulation taken 3 times daily and thus increase compliance. Copyright 2009 Excerpta Medica Inc. All rights reserved.

A Day of Silence, a Day of Truth, and a Lawsuit

ERIC Educational Resources Information Center

Fusarelli, Bonnie C.; Eaton, Lucy E.

2011-01-01

This case study focuses on issues of freedom of speech and freedom of religion in public schools. It involves a rural, southern high school where a group of students participated in a Day of Silence. The school allowed the students to participate based on the principal's understanding of the students' First Amendment rights. However, the next day,…

34 CFR 300.11 - Day; business day; school day.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 34 Education 2 2011-07-01 2010-07-01 true Day; business day; school day. 300.11 Section 300.11... CHILDREN WITH DISABILITIES General Definitions Used in This Part § 300.11 Day; business day; school day. (a) Day means calendar day unless otherwise indicated as business day or school day. (b) Business day...

Study on Bidding Strategy and Market Clearing Price in Electric Power Day-ahead Market using Market Simulation

NASA Astrophysics Data System (ADS)

Sasaki, Tetsuo; Kadoya, Toshihisa

In an electric power day-ahead market, market prices are not always cleared at marginal cost caused by the strategic bidding of generators. This paper presents the results of day-ahead market simulation that analyzes profits depending upon bidding strategies in an electric power day-ahead market. It is clarified that MCP (Market Clearing Price) is easily managed by only one player and does not easily decline after it has gone up once. Moreover the mutual interference among day-ahead markets, future markets, increase of generators, etc. are also discussed.

Once More to the Essay: Prose Models, Textbooks, and Teaching.

ERIC Educational Resources Information Center

Root, Robert L., Jr.

1995-01-01

Examines the ways in which composition essay anthologies shape and reflect the beliefs and teaching approaches of composition teachers. Focuses on how anthologies treat a widely reproduced essay, E.B. White's "Once More to the Lake." (TB)

Design and evaluation of the ONC health information technology curriculum.

PubMed

Mohan, Vishnu; Abbott, Patricia; Acteson, Shelby; Berner, Eta S; Devlin, Corkey; Hammond, William E; Kukafka, Rita; Hersh, William

2014-01-01

As part of the Heath Information Technology for Economic and Clinical Health (HITECH) Act, the Office of the National Coordinator for Health Information Technology (ONC) implemented its Workforce Development Program, which included initiatives to train health information technology (HIT) professionals in 12 workforce roles, half of them in community colleges. To achieve this, the ONC tasked five universities with established informatics programs with creating curricular materials that could be used by community colleges. The five universities created 20 components that were made available for downloading from the National Training and Dissemination Center (NTDC) website. This paper describes an evaluation of the curricular materials by its intended audience of educators. We measured the quantity of downloads from the NTDC site and administered a survey about the curricular materials to its registered users to determine use patterns and user characteristics. The survey was evaluated using mixed methods. Registered users downloaded nearly half a million units or components from the NTDC website. We surveyed these 9835 registered users. 1269 individuals completed all or part of the survey, of whom 339 identified themselves as educators (26.7% of all respondents). This paper addresses the survey responses of educators. Successful aspects of the curriculum included its breadth, convenience, hands-on and course planning capabilities. Several areas were identified for potential improvement. The ONC HIT curriculum met its goals for community college programs and will likely continue to be a valuable resource for the larger informatics community in the future.

Exenatide Once-Weekly Clinical Development: Safety and Efficacy Across a Range of Background Therapies

PubMed Central

Stonehouse, Anthony; Walsh, Brandon

2011-01-01

Abstract In patients with type 2 diabetes mellitus (T2DM), the physiologic glucagon-like peptide-1 (GLP-1) response, which is involved in glucose regulation through several mechanisms, is dysfunctional. GLP-1 receptor agonists can fill an unmet therapeutic need in the treatment of T2DM: improving glycemic control without increasing the risk of hypoglycemia (except with concomitant sulfonylureas) and reducing weight in a substantial proportion of patients. GLP-1 receptor agonists have impacted established disease treatment algorithms for T2DM. For example, in 2009 the American Diabetes Association and European Association for the Study of Diabetes revised their consensus treatment algorithm to incorporate GLP-1 receptor agonists. GLP-1 receptor agonists were originally represented by exenatide BID (ExBID), a short-acting agent requiring twice-daily injections at mealtime. The longer-acting agent liraglutide, requiring once-daily injections, recently received regulatory approval. Several other long-acting agents are in clinical development, one of which is the once-weekly formulation of exenatide (exenatide once weekly [ExQW]). This article reviews the clinical development of ExQW in the DURATION program. Patients in theses clinical trials were receiving various background treatments, ranging from lifestyle therapy to combination oral therapy, although the majority (68%) received metformin monotherapy. Specifically, safety, glycemic control, and weight were compared in patients treated with ExQW versus ExBID, sitagliptin, pioglitazone, or insulin glargine. Moreover, measures of β-cell function, cardiovascular risk, inflammation, and hepatic health were investigated. During ExQW clinical development, consistent clinical efficacy (glycosylated hemoglobin, −1.5% to −1.9%; weight, −2 kg to −4 kg) and safety data were observed in patients with T2DM treated with ExQW. PMID:21732798

45 CFR 170.575 - Removal of the ONC-AA.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH INFORMATION TECHNOLOGY HEALTH INFORMATION TECHNOLOGY STANDARDS, IMPLEMENTATION SPECIFICATIONS, AND CERTIFICATION CRITERIA AND CERTIFICATION PROGRAMS FOR HEALTH INFORMATION TECHNOLOGY Permanent Certification Program for HIT § 170.575 Removal of the ONC...

El Dia de la Independencia, September 16, 1810: El Grito de Dolores (Independence Day, September 16, 1810: The Cry of Dolores).

ERIC Educational Resources Information Center

Oakland Unified School District, CA.

Each year on the eve of September 16, when the President of the Republic of Mexico has rung the church bell that once hung in the belfry at the Church of Our Lady of Sorrows in the small town of Dolores Hidalgo, he has once more proclaimed Independence Day. When Father Miguel Hidalgo y Costilla rang that same bell on September 16, 1810, he rang it…

STS-82 Flight Day 01 Highlights

NASA Technical Reports Server (NTRS)

1997-01-01

The first day of the STS-82 mission begins with the crew, Commander Kenneth D. Bowersox, Pilot Scott J. Horowitz, Payload Commander Mark C. Lee, and Mission Specialists Gregory J. Harbaugh, Steven L. Smith, Joseph R. Tanner, and Steven A. Hawley performing pre-launch activities such as eating the traditional breakfast, being suited up, and riding out to the launch pad. Also, included are various panoramic views of the shuttle on the pad. The crew is readied in the 'white room' for their mission. After the closing of the hatch, and arm retraction, launch activities are shown including the countdown, engine ignition, launch, shuttle roll maneuver, and then the separation of the Solid Rocket Boosters (SRB) from the shuttle. Once in orbit the cargo bay doors are seen opening.

Efficacy of twice-daily vs once-daily sessions of repetitive transcranial magnetic stimulation in the treatment of major depressive disorder: a retrospective study

PubMed Central

Modirrousta, Mandana; Meek, Benjamin P; Wikstrom, Sara L

2018-01-01

Purpose There is no clinical consensus on the optimal protocol for the treatment of major depressive disorder (MDD) using repetitive transcranial magnetic stimulation (rTMS). Accelerated protocols using more than a single session of treatment per day have been suggested as a means to reduce the overall length of time required for rTMS therapy. The objective of this study is to compare the treatment outcomes of patients with MDD who received two sessions of rTMS per day vs those who received one session per day, keeping the overall number of delivered pulses constant. Patients and methods In a retrospective study, we compared treatment outcomes of 36 patients with MDD who received 30 sessions of high-frequency (10 Hz) rTMS over the left dorsolateral prefrontal cortex. Patients received 3,000 pulses per session (5 s trains, 25 s intertrain interval) at 110% of resting motor threshold using a figure-eight coil. Patients received either two rTMS sessions per day (n=17) or one session per day (n=19). Depression symptoms were assessed by a psychiatrist using the Hamilton Rating Scale for Depression at baseline and after every 10 sessions of rTMS. Results The majority of patients in both groups responded to treatment, and there was a trend toward greater response rate in the twice-daily (TD) group (82.4%) compared to the once-daily (OD) group (52.6%). TD stimulation was tolerable for patients and produced no adverse side effects. Patients in the TD group experienced an improvement in symptoms faster than the OD group due to the accelerated therapy period. Conclusion Administration of two rTMS treatment sessions per day is tolerable for patients and does not seem to be inferior in efficacy to a OD protocol. TD administration has the benefit of producing symptom improvement over a shorter time span and requires fewer visits to the clinic. PMID:29398915

Cassini Scientist for a Day: a tactile experience

NASA Astrophysics Data System (ADS)

Canas, L.; Altobelli, N.

2012-09-01

In September 2011, the Cassini spacecraft took images of three targets and a challenge was launched to all students: to choose the one target they thought would provide the best science and to write an essay explaining their reasons (more information on the "Cassini Scientist for a Day" essay contest official webpage in: http://saturn.jpl.nasa.gov/education/scientistforaday10thedition/, run by NASA/JPL) The three targets presented were: Hyperion, Rhea and Titan, and Saturn. The idea behind "Cassini Scientist for a Day: a tactile experience" was to transform each of these images into schematic tactile images, highlighting relevant features apprehended through a tactile key, accompanied by a small text in Braille with some additional information. This initial approach would allow reach a broader community of students, more specifically those with visual impairment disabilities. Through proper implementation and careful study cases the adapted images associated with an explanatory key provide more resources in tactile astronomy. As the 2012 edition approaches a new set of targeted objet images will be once again transformed and adapted to visually impaired students and will aim to reach more students into participate in this international competition and to engage them in a quest to expand their knowledge in the amazing Cassini discoveries and the wonders of Saturn and its moons. As the winning essays will be published on the Cassini website and contest winners invited to participate in a dedicated teleconference with Cassini scientists from NASA's Jet Propulsion Laboratory, this initiative presents a great chance to all visually impaired students and teachers to participate in an exciting experience. These initiatives must be complemented with further information to strengthen the learning experience. However they stand as a good starting point to tackle further astronomical concepts in the classroom, especially this field that sometimes lacks the resources. Although

Once versus three times daily dosing of oral budesonide for active Crohn's disease: a double-blind, double-dummy, randomised trial.

PubMed

Dignass, Axel; Stoynov, Simeon; Dorofeyev, Andrey E; Grigorieva, Galina A; Tomsová, Eva; Altorjay, István; Tuculanu, Daniel; Bunganič, Ivan; Pokrotnieks, Juris; Kupčinskas, Limas; Dilger, Karin; Greinwald, Roland; Mueller, Ralph

2014-09-01

Oral budesonide 9 mg/day represents first-line treatment of mild-to-moderately active ileocolonic Crohn's disease. However, there is no precise recommendation for budesonide dosing due to lack of comparative data. A once-daily (OD) 9 mg dose may improve adherence and thereby efficacy. An eight-week, double-blind, double-dummy randomised trial compared budesonide 9 mg OD versus 3mg three-times daily (TID) in patients with mild-to-moderately active ileocolonic Crohn's disease. Primary endpoint was clinical remission defined as CDAI <150 at week 8 (last observation carried forward). The final intent-to-treat population comprised 471 patients (238 [9 mg OD], 233 [3 mg TID]). The confirmatory population for the primary endpoint analysis was the interim per protocol population (n=377; 188 [9 mg OD], 189 [3mg TID]), in which the primary endpoint was statistically non-inferior with budesonide 9 mg OD versus 3 mg TID. Clinical remission was achieved in 71.3% versus 75.1%, a difference of -3.9% (95% CI [-14.6%; 6.4%]; p=0.020 for non-inferiority). The mean (SD) time to remission was 21.9 (13.8) days versus 21.4 (14.6) days with budesonide 9 mg OD versus 3 mg TID, respectively. In a subpopulation of 122 patients with baseline SES-CD ulcer score ≥1, complete mucosal healing occurred in 32.8% (21/64) on 9 mg OD and 41.4% (24/58) on 3mg TID; deep remission (mucosal healing and clinical remission) was observed in 26.6% (17/64) and 32.8% (19/58) of patients, respectively. Treatment-emergent suspected adverse drug reactions were reported in 4.6% of 9 mg OD and 4.7% of 3 mg TID patients. Budesonide at the recommended dose of 9 mg/day can be administered OD without impaired efficacy and safety compared to 3mg TID dosing in mild-to-moderately active Crohn's disease. Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Effect of horticultural therapy on wellbeing among dementia day care programme participants: A mixed-methods study (Innovative Practice).

PubMed

Hall, Jodi; Mitchell, Gary; Webber, Catherine; Johnson, Karen

2016-04-11

Fourteen people attending an adult day programme were recruited to a structured horticultural therapy programme which took place over 10 weeks. The effects were assessed using Dementia Care Mapping and questionnaires completed by family carers. High levels of wellbeing were observed while the participants were engaged in horticultural therapy, and these were sustained once the programme was completed. This study adds to the growing evidence on the benefits of horticultural therapy for people with dementia who have enjoyed gardening in the past. © The Author(s) 2016.

New once-a-month injectable contraceptives, with particular reference to Cyclofem/Cyclo-Provera.

PubMed

Hall, P E

1998-08-01

Once-a-month injectable contraceptives containing a progestogen and an estrogen have been developed that disrupt vaginal bleeding patterns less than the widely used progestogen-only preparations. Pharmacokinetic studies were undertaken of dosages and ratios of the progestogens and the respective estrogens. In Phase III clinical trials, annual pregnancy rates were below 0.4% for Mesigyna (norethisterone enanthate/estradiol valerate, Schering AG, Berlin, Germany) and below 0.2% for Cyclofem (MPA/E2C) (medroxyprogesterone acetate/estradiol cypionate, Aplicaciones Farmaceuticas, SA, Mexico and PT Tunggal, Indonesia). More than two-thirds of women had predictable, regular cycles, and discontinuation due to bleeding-related problems occurred less than half as often as with progestogen-only injectables. With MPA/E2C, return to fertility is similar to that observed with other hormonal or intrauterine methods, and both products have little effect on lipids or hemostasis. Introductory trials of MPA/E2C in 12000 women with 100000 woman-months of experience confirmed the high efficacy of the product in routine use. The use of MPA/E2C in a non-reusable injection device, Uniject (Becton Dickinson, Franklin Lakes, NJ) is discussed. Once-a-month hormonal contraceptives have been shown to provide a safe contraceptive option for all women and an alternative for women who wish to use injectable formulations that cause less disruption in vaginal bleeding and minimal side effects.

Treatment of Hypertension: Favourable Effect of the Twice-Daily Compared to the Once-Daily (Evening) Administration of Perindopril and Losartan.

PubMed

Szauder, Ipoly; Csajági, Eszter; Major, Zsuzsanna; Pavlik, Gabor; Ujhelyi, Gabriella

2015-01-01

Little is known about the effect of twice daily administration of same dose of ACE inhibitor and ARB on the diurnal/nocturnal blood pressure (BP) ratio. We aimed to assess the effect of two widely used long-acting drugs: perindopril and losartan in the treatment of hypertension comparing the once-daily (evening) vs. twice-daily (morning and evening) administration with the same daily doses. Untreated primary hypertensive patients without complaints (a total of 164: 65 men, 99 women, 55.7 ± 13.7 years of age, 41-41 patients per treated groups) were selected with non-dipper phenomenon, estimated by diurnal index (DI) <10%. The effect of evening (8 mg perindopril or 100 mg losartan) vs morning and evening (4-4 mg perindopril or 50-50 mg losartan) administration was determined on a 14-day treatment by ABPM. The mean BP, the percent time elevation index, and the hyperbaric impact decreased in both drug groups. Significant difference was observed in the DI in the case of twice-daily administration vs once-daily evening dosing. The twice-daily administration with the same daily dose of perindopril or losartan seems to be more effective compared to the once daily evening administration in eliminating the non-dipper phenomenon. According to some authors the non-dipping phenomenon increases cardiovascular risk, while others are of the opinion that the association of non-dipping with cardiovascular events does not necessarily mean that selective treatment of non-dipping improves cardiovascular outcomes. © 2015 S. Karger AG, Basel.

Medical treatment of lower urinary tract symptoms/benign prostatic hyperplasia: anything new in 2015.

PubMed

Schauer, Ingrid; Madersbacher, Stephan

2015-01-01

The purpose of this study is to provide an update on recent developments regarding the medical management of male lower urinary tract symptoms (LUTS). Silodosin improves storage/voiding symptoms and nocturia and is effective within the framework of a trial without a catheter. 5α-reductase inhibitors (5ARIs) are not associated with male breast cancer development. Alcohol consumption seems to increase the risk of high-grade prostate cancer under 5ARIs. The combination of α-blocker and 5ARIs remains a well established concept for benign prostatic hyperplasia/LUTS patients with an enhanced risk of disease progression. Tadalafil 5 mg/day monotherapy is a valid option particularly for men with LUTS and erectile dysfunction; the combination of Tadalafil 5 mg/day with a 5ARI is an interesting approach. The fixed-dose combination of α-blocker and antimuscarinic provides advantages regarding storage symptom improvement. This approach is currently primarily recommended as an add-on strategy. Mirabegron opens new horizons in the management of male LUTS and has no negative (but also no positive) urodynamic effects. Several encouraging novel approaches are currently in the experimental phase and might enhance our therapeutic armamentarium in the near future. The recent literature refines our knowledge on current therapeutic options and provides further evidence for an individualized, risk-adapted approach for male LUTS mainly depending on symptoms status, comorbidities (i.e. erectile dysfunction) and risk of disease progression.

A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma.

PubMed

Arrillaga-Romany, Isabel; Chi, Andrew S; Allen, Joshua E; Oster, Wolfgang; Wen, Patrick Y; Batchelor, Tracy T

2017-10-03

ONC201 is an oral, small molecule selective antagonist of the G protein-coupled receptor DRD2 that causes p53-independent apoptosis in tumor cells via integrated stress response activation and Akt/ERK inactivation. We performed a Phase II study that enrolled 17 patients with recurrent, bevacizumab-naïve, IDH1/2 WT glioblastoma who received 625mg ONC201 every three weeks. Median OS was 41.6 weeks with OS6 of 71% and OS9 of 53%. Seven of 17 patients are alive. PFS6 was 11.8% with two patients remaining on study who continue to receive ONC201 for >12 months. One of these patients had a durable objective response with a secondary glioblastoma possessing a H3.3 K27M mutation, exhibiting regression by 85% in one lesion and 76% in the second lesion. The second patient who continues to receive ONC201 for >12 months remains disease-free after enrolling on this trial following a re-resection. No drug-related SAEs or treatment discontinuation due to toxicity occurred. Plasma PK at 2 hours post-dose was 2.6 ug/mL, serum prolactin induction was observed as a surrogate marker of target engagement, and DRD2 was expressed in all evaluated archival tumor specimens. In summary, ONC201 is well tolerated and may have single agent activity in recurrent glioblastoma patients.

Comparison of once-daily versus twice-daily combination of ropinirole prolonged release in Parkinson's disease.

PubMed

Yun, Ji Young; Kim, Han-Joon; Lee, Jee-Young; Kim, Young Eun; Kim, Ji Seon; Kim, Jong-Min; Jeon, Beom S

2013-09-02

Ropinirole prolonged release (RPR) is a once-daily formulation. However, there may be individual pharmacokinetic differences so that multiple dosing may be preferred in some individuals. This study compares once-daily and twice-daily RPR in patients with Parkinson's disease. This study was an open-label crossover study. We enrolled Parkinson's disease patients on dopamine agonist therapy with unsatisfactory control such as motor fluctuation, dyskinesia and sleep-related problems. Agonists were switched into equivalent dose of RPR. Subjects were consecutively enrolled into either once-daily first or twice-daily first groups, and received the same amount of RPR in a single and two divided dosing for 8 weeks respectively in a crossover manner without a washout period.The primary outcome was a questionnaire of the preference completed by patients in the last visit. The secondary outcome measures included the Unified Parkinson's Disease Rating Scale part 3 (mUPDRS), Hoehn and Yahr stage (H&Y); sleep questionnaire including overall quality of sleep, nocturnal off symptoms and early morning symptoms; Epworth Sleep Scale (ESS); compliances and patient global impression (PGI). A total of 82 patients were enrolled and 61 completed the study. 31 patients preferred twice-daily regimen, 17 preferred the once-daily regimen, and 13 had no preference. Their mean mUPDRS, H&Y, ESS, sleep quality, compliance and adverse events were not statistically different in both regimens. PGI-improvement on wearing off defined was better in twice-daily dosing regimen. RPR is a once-daily formulation, but multiple dosing was preferred in many patients. Multiple dosing of RPR might be a therapeutic option if once-daily dosing is unsatisfactory.

Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers.

PubMed

Chien, S C; Wong, F A; Fowler, C L; Callery-D'Amico, S V; Williams, R R; Nayak, R; Chow, A T

1998-04-01

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0-24) following a single 750-mg dose were 7.1 microg/ml and 71.3 microg x h/ml, respectively, compared to 8.6 microg/ml and 90.7 microg x h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0-24 values were 8.9 microg/ml and 95.4 microg x h/ml, respectively; corresponding values at steady state were 11.8 microg/ml and 118 microg x h/ml. These Cmax and AUC0-24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CL[R]) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CL(R) following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8

Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers

PubMed Central

Chien, Shu-Chean; Wong, Frank A.; Fowler, Cynthia L.; Callery-D’Amico, Susan V.; Williams, R. Rex; Nayak, Ramchandra; Chow, Andrew T.

1998-01-01

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These Cmax and AUC0–24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CLR) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CLR following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml

Design and evaluation of the ONC health information technology curriculum

PubMed Central

Mohan, Vishnu; Abbott, Patricia; Acteson, Shelby; Berner, Eta S; Devlin, Corkey; Hammond, William E; Kukafka, Rita; Hersh, William

2014-01-01

Objective As part of the Heath Information Technology for Economic and Clinical Health (HITECH) Act, the Office of the National Coordinator for Health Information Technology (ONC) implemented its Workforce Development Program, which included initiatives to train health information technology (HIT) professionals in 12 workforce roles, half of them in community colleges. To achieve this, the ONC tasked five universities with established informatics programs with creating curricular materials that could be used by community colleges. The five universities created 20 components that were made available for downloading from the National Training and Dissemination Center (NTDC) website. This paper describes an evaluation of the curricular materials by its intended audience of educators. Methods We measured the quantity of downloads from the NTDC site and administered a survey about the curricular materials to its registered users to determine use patterns and user characteristics. The survey was evaluated using mixed methods. Registered users downloaded nearly half a million units or components from the NTDC website. We surveyed these 9835 registered users. Results 1269 individuals completed all or part of the survey, of whom 339 identified themselves as educators (26.7% of all respondents). This paper addresses the survey responses of educators. Discussion Successful aspects of the curriculum included its breadth, convenience, hands-on and course planning capabilities. Several areas were identified for potential improvement. Conclusions The ONC HIT curriculum met its goals for community college programs and will likely continue to be a valuable resource for the larger informatics community in the future. PMID:23831832

Aripiprazole once-monthly long-acting injectable for the treatment of schizophrenia.

PubMed

Potkin, Steven G; Preda, Adrian

2016-01-01

Patient non-adherence increases the risk for relapse and the long-term care of schizophrenia. Long-acting injectable (LAI) antipsychotics can decrease this risk by ensuring adherence. An extended formulation, aripiprazole 400 mg once-monthly (AOM 400) LAI (AOM LAI), received regulatory approval in the year 2013 for the treatment of schizophrenia. AOM LAI is the first dopamine D2 partial agonist available in a long-acting formulation for the treatment of schizophrenia. This review covers data on the efficacy and tolerability/safety of AOM LAI. AOM LAI is a lyophilized powder of aripiprazole, with an elimination half-life of 29.9 - 46.5 days, allowing for a 4-week injection interval. Antipsychotic efficacy was documented in a 12-week double-blind trial (n = 340) and in two maintenance-of-effect trials: a 38-week trial (n = 662) and a 52-week trial (n = 403). The side effect profile is similar to that of oral aripiprazole. Adverse events (≥5% and at least twice that for placebo) were typically mild or moderate and did not lead to discontinuation: increased weight, akathisia, injection site pain and sedation. The 400 mg dose is tolerated by >90% of patients. Injection does not require additional training of health personnel or post-injection observation. AOM LAI is an efficacious and well-tolerated antipsychotic treatment for schizophrenia.

RUSTING ORE TRAIN, ONCE PART OF NEW YORK ELEVATED LINE ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

RUSTING ORE TRAIN, ONCE PART OF NEW YORK ELEVATED LINE (TWO LOCOMOTIVES, SHOWING RAILROAD TRUCKS IN FOREGROUND) - Council City & Solomon River Railroad, Locomotives, Nome Vicinity, Nome, Nome Census Area, AK

30 CFR 241.76 - Can MMS reduce my penalty once it is assessed?

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false Can MMS reduce my penalty once it is assessed? 241.76 Section 241.76 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR... Provisions § 241.76 Can MMS reduce my penalty once it is assessed? Under 30 U.S.C. 1719(g), the Director or...

Predicting 7-day, 30-day and 60-day all-cause unplanned readmission: a case study of a Sydney hospital.

PubMed

Maali, Yashar; Perez-Concha, Oscar; Coiera, Enrico; Roffe, David; Day, Richard O; Gallego, Blanca

2018-01-04

The identification of patients at high risk of unplanned readmission is an important component of discharge planning strategies aimed at preventing unwanted returns to hospital. The aim of this study was to investigate the factors associated with unplanned readmission in a Sydney hospital. We developed and compared validated readmission risk scores using routinely collected hospital data to predict 7-day, 30-day and 60-day all-cause unplanned readmission. A combination of gradient boosted tree algorithms for variable selection and logistic regression models was used to build and validate readmission risk scores using medical records from 62,235 live discharges from a metropolitan hospital in Sydney, Australia. The scores had good calibration and fair discriminative performance with c-statistic of 0.71 for 7-day and for 30-day readmission, and 0.74 for 60-day. Previous history of healthcare utilization, urgency of the index admission, old age, comorbidities related to cancer, psychosis, and drug-abuse, abnormal pathology results at discharge, and being unmarried and a public patient were found to be important predictors in all models. Unplanned readmissions beyond 7 days were more strongly associated with longer hospital stays and older patients with higher number of comorbidities and higher use of acute care in the past year. This study demonstrates similar predictors and performance to previous risk scores of 30-day unplanned readmission. Shorter-term readmissions may have different causal pathways than 30-day readmission, and may, therefore, require different screening tools and interventions. This study also re-iterates the need to include more informative data elements to ensure the appropriateness of these risk scores in clinical practice.

Health in Day Care: A Training Guide for Day Care Providers.

ERIC Educational Resources Information Center

Pokorni, Judith L.; Kaufmann, Roxane K.

Written for trainers of day care staff, this guide provides help in communicating to day care personnel the information presented in "Health in Day Care: A Manual for Day Care Providers," originally developed by a division of the Massachusetts Department of Health and adapted for national use by the Georgetown University Child Development Center.…

Once or twice daily versus three times daily amoxicillin with or without clavulanate for the treatment of acute otitis media.

PubMed

Thanaviratananich, Sanguansak; Laopaiboon, Malinee; Vatanasapt, Patravoot

2013-12-13

Acute otitis media (AOM) is a common problem in children, for which amoxicillin, with or without clavulanate, is frequently prescribed as a treatment of choice. The conventional recommendation is either three or four daily doses. However, nowadays it is frequently prescribed as once or twice daily doses. If once or twice daily amoxicillin, with or without clavulanate, is as effective for acute otitis media as three or four times a day, it may be more convenient to give the medication once or twice a day to children and hence improve compliance. To compare the effectiveness of one or two daily doses with three or four daily doses of amoxicillin, with or without clavulanate, for the treatment of AOM in children; and to compare complication rates and adverse reactions. We searched CENTRAL 2013, Issue 2, MEDLINE (January 1950 to March week 1, 2013), EMBASE (1974 to March 2013) and the Science Citation Index (2001 to March 2013). We included randomised controlled trials (RCTs) of children aged 12 years or younger with AOM, diagnosed by acute ear pain (otalgia) and inflamed ear drum (confirmed by positive tympanocentesis or tympanogram of type B or C). Two review authors independently extracted data on treatment outcomes from individual trials and assessed trial quality based on selection bias, performance bias and detection bias, attrition bias, reporting bias and other biases. We defined the quality grading as low risk of bias, high risk of bias or unclear risk of bias. We summarised the results as risk ratio (RR) with 95% confidence intervals (CI). We included five studies with 1601 children in the review. Pooled analysis demonstrated that the following outcomes were comparable between the two groups: clinical cure at the end of therapy (RR 1.03, 95% CI 0.99 to 1.07); during therapy (RR 1.06, 95% CI 0.85 to 1.33) and at follow-up (RR 1.02, 95% CI 0.95 to 1.09); recurrent AOM (RR 1.21, 95% CI 0.52 to 2.81); compliance rate (RR 1.04, 95% CI 0.98 to 1.10) and overall

Eradication of common pathogens at days 2, 3 and 4 of moxifloxacin therapy in patients with acute bacterial sinusitis

PubMed Central

Ariza, Horacio; Rojas, Ramon; Johnson, Peter; Gower, Richard; Benson, Alice; Herrington, Janet; Perroncel, Renee; Pertel, Peter

2006-01-01

Background Acute bacterial sinusitis (ABS) is a common infection in clinical practice. Data on time to bacteriologic eradication after antimicrobial therapy are lacking for most agents, but are necessary in order to optimize therapy. This was a prospective, single-arm, open-label, multicenter study to determine the time to bacteriologic eradication in ABS patients (maxillary sinusitis) treated with moxifloxacin. Methods Adult patients with radiologically and clinically confirmed ABS received once-daily moxifloxacin 400 mg for 10 days. Middle meatus secretion sampling was performed using nasal endoscopy pre-therapy, and repeated on 3 consecutive days during treatment. Target enrollment was 30 bacteriologically evaluable patients (pre-therapy culture positive for Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis and evaluable cultures for at least Day 2 and Day 3 during therapy visits), including at least 10 each with S. pneumoniae or H. influenzae. Results Of 192 patients enrolled, 42 were bacteriologically evaluable, with 48 pathogens isolated. Moxifloxacin was started on Day 1. Baseline bacteria were eradicated in 35/42 (83.3%) patients by day 2, 42/42 (100%) patients by day 3, and 41/42 (97.6%) patients by day 4. In terms of individual pathogens, 12/18 S. pneumoniae, 22/23 H. influenzae and 7/7 M. catarrhalis were eradicated by day 2 (total 41/48; 85.4%), and 18/18 S. pneumoniae and 23/23 H. influenzae were eradicated by day 3. On Day 4, S. pneumoniae was isolated from a patient who had negative cultures on Days 2 and 3. Thus, the Day 4 eradication rate was 47/48 (97.9%). Clinical success was achieved in 36/38 (94.7%) patients at the test of cure visit. Conclusion In patients with ABS (maxillary sinusitis), moxifloxacin 400 mg once daily for 10 days resulted in eradication of baseline bacteria in 83.3% of patients by Day 2, 100% by Day 3 and 97.6% by Day 4. PMID:16646958

34 CFR 300.11 - Day; business day; school day.

Code of Federal Regulations, 2012 CFR

2012-07-01

... has the same meaning for all children in school, including children with and without disabilities... 34 Education 2 2012-07-01 2012-07-01 false Day; business day; school day. 300.11 Section 300.11... CHILDREN WITH DISABILITIES General Definitions Used in This Part § 300.11 Day; business day; school day. (a...

34 CFR 300.11 - Day; business day; school day.

Code of Federal Regulations, 2014 CFR

2014-07-01

... has the same meaning for all children in school, including children with and without disabilities... 34 Education 2 2014-07-01 2013-07-01 true Day; business day; school day. 300.11 Section 300.11... CHILDREN WITH DISABILITIES General Definitions Used in This Part § 300.11 Day; business day; school day. (a...

34 CFR 300.11 - Day; business day; school day.

Code of Federal Regulations, 2013 CFR

2013-07-01

... has the same meaning for all children in school, including children with and without disabilities... 34 Education 2 2013-07-01 2013-07-01 false Day; business day; school day. 300.11 Section 300.11... CHILDREN WITH DISABILITIES General Definitions Used in This Part § 300.11 Day; business day; school day. (a...

Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Single- and multiple-dose Once-daily Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, in Chinese Patients With Type 2 Diabetes Mellitus.

PubMed

Zhao, Xia; Cui, Yimin; Zhao, Shuai; Lang, Benjamin; Broedl, Uli C; Salsali, Afshin; Pinnetti, Sabine; Macha, Sreeraj

2015-07-01

The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties and tolerability of the oral once-daily sodium glucose cotransporter 2 inhibitor empagliflozin, given in single and multiple 10 and 25 mg doses in Chinese patients with type 2 diabetes mellitus (T2DM). In a double-blind, placebo-controlled, parallel-group study, Chinese patients with T2DM were randomly assigned to receive a single dose of empagliflozin 10 or 25 mg or placebo on day 1 and once daily on days 3 to 9. A total of 24 patients were enrolled (14 men, 10 women; median age, 53.5 years; empagliflozin 10 mg, n = 9; empagliflozin 25 mg, n = 9; and placebo, n = 6). After both single- and multiple-dose administration, empagliflozin 10 and 25 mg were rapidly absorbed, reaching peak plasma concentrations within 1 to 1.5 hours (median), with plasma levels declining biphasically. Empagliflozin exposure increased roughly dose proportionally between 10 and 25 mg. Mean terminal elimination half-life values at steady state were 13.9 and 12.1 hours with empagliflozin 10 and 25 mg, respectively. Mean (SD) changes from baseline in 24-hour urinary glucose excretion (UGE) on day 1 were +87.7 (22.9) and +82.8 (18.8) g with empagliflozin 10 and 25 mg, respectively, compared with -1.0 (2.8) g with placebo, and on day 9 were +95.8 (24.1), +82.6 (34.8) g with empagliflozin 10 and 25 mg, respectively, compared with -4.1 (6.4) g with placebo. Mean (SD) changes from baseline in fasting plasma glucose (FPG) on day 2 were -18.7 (17.2) mg/dL and -25.8 (19.6) mg/dL with empagliflozin 10 and 25 mg, respectively, compared with -4.2 (15.2) mg/dL with placebo, and on day 9, were -25.6 (20.7) mg/dL and -31.4 (26.9) mg/dL with empagliflozin 10 and 25 mg, respectively, compared to -3.7 (7.5) mg/dL with placebo. On day 10, mean changes in weight were -1.1, -1.6, and +0.5 kg with empagliflozin 10 and 25 mg and placebo, respectively. Overall, empagliflozin 10 and 25 mg had safety profiles similar to that of

76 FR 31272 - Permanent Certification Program for Health Information Technology; Revisions to ONC-Approved...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-31

... Permanent Certification Program for Health Information Technology; Revisions to ONC-Approved Accreditor Processes AGENCY: Office of the National Coordinator for Health Information Technology (ONC), Department of... Coordinator for Health Information Technology (the National Coordinator) by section 3001(c)(5) of the Public...

Once More to the Essay: Prose Models, Textbooks, and Teaching.

ERIC Educational Resources Information Center

Root, Robert L., Jr.

A study of 24 composition anthologies that reprinted E. B. White's "Once More to the Lake" reveals a number of disturbing assumptions among the editors of these anthologies. Four areas of examinations were concentrated on: (1) classifications of White's essay; (2) thematic categories; (3) suggestions for writing; (4) study apparatuses;…

VIEW OF MORTARED ROCK FOOTING THAT ONCE SUPPORTED THE TWIN ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

VIEW OF MORTARED ROCK FOOTING THAT ONCE SUPPORTED THE TWIN FLUME'S OUTLET TO TUMALO FEED CANAL, WITH BRIDGE. LOOKING NORTHWEST - Tumalo Irrigation District, Tumalo Project, West of Deschutes River, Tumalo, Deschutes County, OR

76 FR 72636 - Permanent Certification Program for Health Information Technology; Revisions to ONC-Approved...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-25

... Permanent Certification Program for Health Information Technology; Revisions to ONC-Approved Accreditor Processes AGENCY: Office of the National Coordinator for Health Information Technology (ONC), Department of... Coordinator for Health Information Technology by section 3001(c)(5) of the Public Health Service Act (PHSA) as...

Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies.

PubMed

Prabhu, Varun V; Talekar, Mala K; Lulla, Amriti R; Kline, C Leah B; Zhou, Lanlan; Hall, Junior; Van den Heuvel, A Pieter J; Dicker, David T; Babar, Jawad; Grupp, Stephan A; Garnett, Mathew J; McDermott, Ultan; Benes, Cyril H; Pu, Jeffrey J; Claxton, David F; Khan, Nadia; Oster, Wolfgang; Allen, Joshua E; El-Deiry, Wafik S

2018-01-01

ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.

How 6 Colleges Once in Decline Reversed Their Fortunes.

ERIC Educational Resources Information Center

Gose, Ben; van der Werf, Martin; June, Audrey Wiliams; Pulley, John L.

2003-01-01

Provides descriptions of the policies and practices that enabled six colleges, once in danger of closing, to achieve turnarounds and regain financial health. The institutions profiled are: (1) Rocky Mountain College, Montana; (2) Bellevue University, Washington; (3) Muskingum College, Ohio; (4) University of the Ozarks, Arkansas; (5) University of…

(+/-)-3,4-Methylenedioxymethamphetamine treatment in adult rats impairs path integration learning: a comparison of single vs once per week treatment for 5 weeks.

PubMed

Skelton, Matthew R; Able, Jessica A; Grace, Curtis E; Herring, Nicole R; Schaefer, Tori L; Gudelsky, Gary A; Vorhees, Charles V; Williams, Michael T

2008-12-01

3,4-Methlylenedioxymethamphetamine (MDMA) administration (4 x 15 mg/kg) on a single day has been shown to cause path integration deficits in rats. While most animal experiments focus on single binge-type models of MDMA use, many MDMA users take the drug on a recurring basis. The purpose of this study was to compare the effects of repeated single-day treatments with MDMA (4 x 15 mg/kg) once weekly for 5 weeks to animals that only received MDMA on week 5 and saline on weeks 1-4. In animals treated with MDMA for 5 weeks, there was an increase in time spent in the open area of the elevated zero maze suggesting a decrease in anxiety or increase in impulsivity compared to the animals given MDMA for 1 week and saline treated controls. Regardless of dosing regimen, MDMA treatment produced path integration deficits as evidenced by an increase in latency to find the goal in the Cincinnati water maze. Animals treated with MDMA also showed a transient hypoactivity that was not present when the animals were re-tested at the end of cognitive testing. In addition, both MDMA-treated groups showed comparable hyperactive responses to a later methamphetamine challenge. No differences were observed in spatial learning in the Morris water maze during acquisition or reversal but MDMA-related deficits were seen on reduced platform-size trials. Taken together, the data show that a single-day regimen of MDMA induces deficits similar to that of multiple weekly treatments.

Radiation-Free Weekend Rescued! Continuous Accelerated Irradiation of 7-Days per Week Is Equal to Accelerated Fractionation With Concomitant Boost of 7 Fractions in 5-Days per Week: Report on Phase 3 Clinical Trial in Head-and-Neck Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skladowski, Krzysztof, E-mail: skladowski@io.gliwice.pl; Hutnik, Marcin; Wygoda, Andrzej

2013-03-01

Purpose: To report long-term results of randomized trial comparing 2 accelerated fractionations of definitive radiation therapy assessing the need to irradiate during weekend in patients with head and neck squamous cell carcinoma. Methods and Materials: A total of 345 patients with SCC of the oral cavity, larynx, and oro- or hypo-pharynx, stage T2-4N0-1M0, were randomized to receive continuous accelerated irradiation (CAIR: once per day, 7 days per week) or concomitant accelerated boost (CB: once per day, 3 days per week, and twice per day, 2 days per week). Total dose ranged from 66.6-72 Gy, dose per fraction was 1.8 Gy,more » number of fractions ranged from 37-40 fractions, and overall treatment time ranged from 37-40 days. Results: No differences for all trial end-points were noted. At 5 and 10 years, the actuarial rates of local-regional control were 63% and 60% for CAIR vs 65% and 60% for CB, and the corresponding overall survival were 40% and 25% vs 44% and 25%, respectively. Confluent mucositis was the main acute toxicity, with an incidence of 89% in CAIR and 86% in CB patients. The 5-year rate of grade 3-4 late radiation morbidity was 6% for both regimens. Conclusions: Results of this trial indicate that the effects of accelerated fractionation can be achieve by delivering twice-per-day irradiation on weekday(s). This trial has also confirmed that an accelerated, 6-weeks schedule is a reasonable option for patients with intermediate-stage head-and-neck squamous cell carcinoma because of the associated high cure rate and minimal severe late toxicity.« less

Quality standards in a rheumatology Day-Care Hospital Unit. The proposal of the Spanish Society of Rheumatology Day Hospitals' Working Group.

PubMed

García-Vicuña, Rosario; Montoro, María; Egües Dubuc, César Antonio; Bustabad Reyes, Sagrario; Gómez-Centeno, Antonio; Muñoz-Fernández, Santiago; Pérez Pampín, Eva; Román Ivorra, Jose Andrés; Balsa, Alejandro; Loza, Estíbaliz

2014-01-01

In recent years, the Rheumatology Day-Care Hospital Units (DHU have undergone extensive development. However, the quality standards are poorly documented and mainly limited to structure items rather than including broad and specific areas of this specialty. To develop specific quality standards for Rheumatology DHU. After a systematic review of the literature and related documents, a working group (WG) involving 8 DHU-experienced rheumatologists developed an initial proposal of the quality standards, under the supervision of an expert methodologist. A second round was held by the WG group to review the initial proposal and to consider further suggestions. Once the content was agreed upon by consensus, a final report was prepared. 17 structure standards, 25 process standards and 10 results standards were defined, with special emphasis on specific aspects of the Rheumatology DHU. The proposal includes: 1) essential standards to 2) excellent standards, 3) a Rheumatology DHU services portfolio and 4) performance criteria. The proposed quality standards are the basis for developing the indicators and other management tools for Rheumatology DHU, thereby ensuring a patient-oriented practice based on both the evidence and the experience. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

25 CFR 1000.106 - Once a Tribe/Consortium establishes a base budget, are funding amounts renegotiated each year?

Code of Federal Regulations, 2010 CFR

2010-04-01

... Bureau of Indian Affairs Programs Establishing Self-Governance Base Budgets § 1000.106 Once a Tribe... renegotiates funding levels: (a) It must negotiate all funding levels in the AFA using the process for determining residuals and funding amounts on the same basis as other Tribes; and (b) It is eligible for...

Helicobacter pylori eradication with either seven-day or 10-day triple therapies, and with a 10-day sequential regimen

PubMed Central

Scaccianoce, Giuseppe; Hassan, Cesare; Panarese, Alba; Piglionica, Donato; Morini, Sergio; Zullo, Angelo

2006-01-01

BACKGROUND Helicobacter pylori eradication rates achieved by standard seven-day triple therapies are decreasing in several countries, while a novel 10-day sequential regimen has achieved a very high success rate. A longer 10-day triple therapy, similar to the sequential regimen, was tested to see whether it could achieve a better infection cure rate. METHODS Patients with nonulcer dyspepsia and H pylori infection were randomly assigned to one of the following three therapies: esomeprazole 20 mg, clarithromycin 500 mg and amoxycillin 1 g for seven days or 10 days, or a 10-day sequential regimen including esomeprazole 20 mg plus amoxycillin 1 g for five days and esomeprazole 20 mg, clarithromycin 500 mg and tinidazole 500 mg for the remaining five days. All drugs were given twice daily. H pylori eradication was checked four to six weeks after treatment by using a 13C-urea breath test. RESULTS Overall, 213 patients were enrolled. H pylori eradication was achieved in 75.7% and 77.9%, in 81.7% and 84.1%, and in 94.4% and 97.1% of patients following seven-day or 10-day triple therapy and the 10-day sequential regimen, at intention-to-treat and per protocol analyses, respectively. The eradication rate following the sequential regimen was higher than either seven-day (P=0.002) or 10-day triple therapy (P=0.02), while no significant difference emerged between the latter two regimens (P=0.6). CONCLUSIONS The 10-day sequential regimen was significantly more effective than both triple regimens, while 10-day triple therapy failed to significantly increase the H pylori eradication rate achieved by the standard seven-day regimen. PMID:16482238

Insulin lispro low mixture twice daily versus basal insulin glargine once daily and prandial insulin lispro once daily in patients with type 2 diabetes requiring insulin intensification: a randomized phase IV trial.

PubMed

Tinahones, F J; Gross, J L; Onaca, A; Cleall, S; Rodríguez, A

2014-10-01

To compare the efficacy and safety of two insulin intensification strategies in patients with type 2 diabetes inadequately controlled on basal insulin glargine with metformin and/or pioglitazone. A multinational, randomized, open-label trial that compared insulin lispro low mixture (LM25; n = 236) twice daily with a basal-prandial regimen of insulin glargine once daily and insulin lispro once daily (IGL; n = 240) over 24 weeks in patients with HbA1c 7.5-10.5% and fasting plasma glucose ≤ 6.7 mmol/l. The primary objective was to assess non-inferiority [per-protocol (PP) population], and then superiority [intention-to-treat (ITT) population], of LM25 versus IGL according to change in HbA1c after 24 weeks (non-inferiority margin 0.4%, two-sided significance level 0.05). Estimated change [least squares (LS) mean (95% CI)] in HbA1c after 24 weeks: -1.30 (-1.44, -1.16)% with LM25 and -1.08 (-1.22, -0.94)% with IGL. Non-inferiority was shown [LS mean (95% CI) HbA1c treatment difference -0.21 (-0.38, -0.04) (PP population)]; gated superiority assessment showed a statistically significant advantage for LM25 (p = 0.010; ITT population). Mean blood glucose, glycaemic variability, overall tolerability and hypoglycaemic episodes per patient-year did not show significant differences between treatments during the study. In patients with type 2 diabetes inadequately controlled on once-daily basal insulin glargine and metformin and/or pioglitazone, intensification with LM25 was superior to a basal-prandial approach in terms of reduction in HbA1c after 24 weeks and did not increase hypoglycaemia episodes. © 2014 The Authors. Diabetes, Obesity and Metabolism published by JohnWiley & Sons Ltd.

Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway.

PubMed

Allen, Joshua E; Krigsfeld, Gabriel; Patel, Luv; Mayes, Patrick A; Dicker, David T; Wu, Gen Sheng; El-Deiry, Wafik S

2015-05-01

We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models. We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds. Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro-apoptotic death receptor DR5. These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5.

Once daily maraviroc 300 mg or 150 mg in combination with ritonavir-boosted darunavir 800/100 mg.

PubMed

Okoli, Chinyere; Siccardi, Marco; Thomas-William, Sathish; Dufty, Ngozi; Khonyongwa, Kirstin; Ainsworth, Jonathan; Watson, John; Cook, Roseanne; Gandhi, Kate; Hickinbottom, Geraldine; Owen, Andrew; Taylor, Stephen

2012-03-01

To describe the pharmacokinetics of maraviroc when dosed at 150 or 300 mg once daily with 800/100 mg of darunavir/ritonavir. A retrospective case-note review of HIV-infected adults taking maraviroc was conducted. Patients on a maraviroc-based regimen for a minimum of 5 weeks were grouped as receiving: (i) 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine; (ii) 300 mg of maraviroc once daily with 800/100 mg of darunavir/ritonavir once daily; and (iii) 150 mg of maraviroc once daily with 800/100 mg of darunavir/ritonavir once daily. C(trough) and C(peak) data were collected at 2, 12 or 24 h post-dose. Sixty-six patients were included, providing 115 samples. The median (IQR) C(peak) was 378 (350-640) ng/mL for 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine (n=9), 728 (378-935) ng/mL for 300 mg of maraviroc once daily with darunavir/ritonavir (n=29) and 364 (104-624) ng/mL for 150 mg of maraviroc once daily with darunavir/ritonavir (n=2; P=0.24). The median (IQR) C(trough) was 46 (33-61) ng/mL for 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine (n=12), 70 (49-97) ng/mL for 300 mg of maraviroc once daily with darunavir/ritonavir (n=34) and 43 (35-55) ng/mL for 150 mg of maraviroc once daily with darunavir/ritonavir (n=17; P=0.001). The maraviroc C(trough) in black patients (n=34) was 61 (45-110) ng/mL and in white patients (n=29) it was 49 (42-70) ng/mL (P=0.04). The C(peak) in black patients (n=20) was 800 (397-1060) ng/mL versus 387 (336-723) ng/mL in white patients (n=20; P=0.02). Once daily coadministration of 300 mg of maraviroc with 800/100 mg of darunavir/ritonavir was well tolerated and had favourable pharmacokinetics when compared with 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine. A 24% higher C(trough) and 107% higher C(peak) was seen in black patients compared with white patients.

Day-to-Day Variability in Self-Reported Cigarettes Per Day.

PubMed

Hughes, John R; Shiffman, Saul; Naud, Shelly; Peters, Erica N

2017-09-01

Nicotine addiction theory predicts small day-to-day variability in cigarettes/day (CPD) whereas social learning theory predicts large variability. A description of the variability in CPD over multiple days is not available. We conducted secondary analyses of two natural history studies with daily smokers-one of smokers not intending to quit, and one of smokers intending to quit sometime in the next 3 months. In the former, smokers recorded their smoking during the day by Ecological Momentary Assessment, using a palm-top computer. In the latter, participants reported CPD nightly via a phone Interactive Voice Response system. Analyses were based on smokers who reported averaging ≥10 CPD, and on days in which there was no attempt to stop or reduce smoking. Across the two studies, on average, smokers had small changes in day-to-day CPD (mean changes were 2.2 and 2.9 CPD). However a minority averaged changing by ≥5 CPD from one day to the next (7% and 11%), and many changed by ≥5 CPD on at least 10 of the 90 days (8% and 31%). Neither smoking restrictions, dependence, stereotypy ratings, nor interest in quitting predicted variability. Although on average, smokers have little change day-to-day CPD, a substantial minority of smokers often change by 5 CPD from day-to-day. We did not find potential causes of this variability. Across day variability in CPD is larger than implied in prior studies. Determining causes of day-to-day variability should increase our understanding of the determinants of smoking. © The Author 2017. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

1. ONLY SURVIVING BUILDING OF WHAT ONCE WAS AN EXTENSIVE ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. ONLY SURVIVING BUILDING OF WHAT ONCE WAS AN EXTENSIVE COMPLEX OF FREIGHT CAR CONSTRUCTION AND REPAIR SHOPS, (GENERAL VIEW) - Lehigh Valley Railroad, Packerton Shops, Between Packerton Yards of Lehigh Valley Railroad & Lehigh River, Packerton, Carbon County, PA

Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model.

PubMed

Liljebäck, Hanna; Grapensparr, Liza; Olerud, Johan; Carlsson, Per-Ola

2016-01-01

Clinical islet transplantation is characterized by a progressive deterioration of islet graft function, which renders many patients once again dependent on exogenous insulin administration within a couple of years. In this study, we aimed to investigate possible engraftment factors limiting the survival and viability of experimentally transplanted human islets beyond the first day after their transplantation to the liver. Human islets were transplanted into the liver of nude mice and characterized 1 or 30 days after transplantation by immunohistochemistry. The factors assessed were endocrine mass, cellular death, hypoxia, vascular density and amyloid formation in the transplanted islets. One day posttransplantation, necrotic cells, as well as apoptotic cells, were commonly observed. In contrast to necrotic death, apoptosis rates remained high 1 month posttransplantation, and the total islet mass was reduced by more than 50% between 1 and 30 days posttransplantation. Islet mass at 30 days posttransplantation correlated negatively to apoptotic death. Vascular density within the transplanted islets remained less than 30% of that in native human islets up to 30 days posttransplantation and was associated with prevailing hypoxia. Amyloid formation was rarely observed in the 1-day-old transplants, but was commonly observed in the 30-day-old islet transplants. We conclude that substantial islet cell death occurs beyond the immediate posttransplantation phase, particularly through apoptotic events. Concomitant low vascularization with prevailing hypoxia and progressive amyloid development was observed in the human islet grafts. Strategies to improve engraftment at the intraportal site or change of implantation site in the clinical setting are needed.

DNA adenine methylation is required to replicate both Vibrio cholerae chromosomes once per cell cycle.

PubMed

Demarre, Gaëlle; Chattoraj, Dhruba K

2010-05-06

DNA adenine methylation is widely used to control many DNA transactions, including replication. In Escherichia coli, methylation serves to silence newly synthesized (hemimethylated) sister origins. SeqA, a protein that binds to hemimethylated DNA, mediates the silencing, and this is necessary to restrict replication to once per cell cycle. The methylation, however, is not essential for replication initiation per se but appeared so when the origins (oriI and oriII) of the two Vibrio cholerae chromosomes were used to drive plasmid replication in E. coli. Here we show that, as in the case of E. coli, methylation is not essential for oriI when it drives chromosomal replication and is needed for once-per-cell-cycle replication in a SeqA-dependent fashion. We found that oriII also needs SeqA for once-per-cell-cycle replication and, additionally, full methylation for efficient initiator binding. The requirement for initiator binding might suffice to make methylation an essential function in V. cholerae. The structure of oriII suggests that it originated from a plasmid, but unlike plasmids, oriII makes use of methylation for once-per-cell-cycle replication, the norm for chromosomal but not plasmid replication.

Spectral analysis of skeletal muscle changes resulting from 59 days of weightlessness in Skylab 2

NASA Technical Reports Server (NTRS)

Lafevers, E. V.; Nicogossian, A. E.; Hoffler, G. W.; Hursta, W.; Baker, J.

1975-01-01

During stressful exercise of the m. gastrocnemius, preflight and postflight surface electromyograms (EMG) were taken from each of the Skylab II astronauts. Measurements on the muscle were made once 5 days before launch, and four times postflight on recovery day, 4 days after recovery, 16 days after recovery and 29 days after recovery. It was hypothesized that the disused gastrocnemius would exhibit dysfunction characteristics similar to those found in laboratory studies on disuse and of pathologically astrophied muscle, and that physical stress would be associated with heightened fatigability in the muscle. Both hypotheses were sustained. The results showed significant shifts of the predominant frequency of the gastrocnemius into higher than normal bands which suggests a relationship between muscle disuse characteristics and pathologic dysfunction characteristics. It was concluded that the spectrally analyzed EMG is a sensitive measure of muscle dsyfunction that is associated with disuse. Antigravity muscles exhibit heightened susceptibility to fatigue when subjected to lengthy weightlessness.

Efficacy and safety of prophylaxis with once-weekly BAY 79-4980 compared with thrice-weekly rFVIII-FS in haemophilia A patients. A randomised, active-controlled, double-blind study.

PubMed

Powell, Jerry; Martinowitz, Uri; Windyga, Jerzy; Di Minno, Giovanni; Hellmann, Andrzej; Pabinger, Ingrid; Maas Enriquez, Monika; Schwartz, Lawrence; Ingerslev, Jørgen

2012-11-01

The benefits of prophylaxis of haemophilia A patients regarding joint health and quality-of-life are well established. However, adherence to an up to every-other-day infusion regimen is a barrier to widespread adoption of prophylaxis. BAY 79-4980 is an investigational drug consisting of rFVIII-FS (sucrose-formulated recombinant FVIII) reconstituted with liposome solvent. Previous clinical studies showed extended protection from bleeding after a single injection of BAY 79-4980 (13.3 ± 6.2 days) compared with rFVIII-FS (7.2 ± 1.7 days). The effect of once-a-week prophylaxis with BAY 79-4980 (35 IU/kg) compared with three times-per-week rFVIII-FS (25 IU/kg) in previously treated, severe haemophilia A patients was evaluated in a 52-week, double-blind, two-arm, randomised, controlled study. The primary and secondary endpoints were protection from total bleeds and joint bleeds, respectively. Short- and long-term safety and tolerability of BAY 79-4980 including effects on lipid levels were assessed. A total of 139 and 131 subjects were evaluable for safety and efficacy analyses, respectively. A large difference in efficacy between treatment groups was observed with 72.1% (49/68) in the rFVIII-FS control group demonstrating <9 bleeds/year compared with 38.1% (24/63) of BAY 79-4980-treated subjects. A similar difference was seen in annualised joint bleeds, with 43 subjects (63.2%) in the control group demonstrating <5 joint bleeds/year compared with 24 subjects (38.1%) treated with BAY 79-4980. The distribution of bleeds seven days post-prophylactic treatment with BAY 79-4980 showed that 61% of bleeds occurred after day 4 post dosing. There were no safety concerns identified. The investigational treatment arm was prematurely discontinued due to failure to achieve the primary endpoint.

Baghdad University: A Day in the Life

ERIC Educational Resources Information Center

Ali, M. H.; Al-Mukhtar, Jenan

2004-01-01

Once, Baghdad University was one of the most prominent institutions of higher education among all the Arab countries, perhaps second only to Cairo University. In all Iraq, built up about thirteen universities, fifty-five specialized colleges, and more than a hundred scientific centers. Each academic year, more than 250,000 students attended these…

A Day as a Scientist: Take Your Child to Work Day | Poster

Cancer.gov

Do you ever dream you could fight a fire, conduct fascinating experiments, and eat ice cream all in one day? A record number of kids—285 in all—got to do just that during the NCI at Frederick’s annual Take Your Child to Work Day.

STS-77 Flight Day 10

NASA Technical Reports Server (NTRS)

1996-01-01

On this tenth day of the STS-77 mission, the flight crew, Cmdr. John H. Casper, Pilot Curtis L. Brown, Jr., and Mission Specialists Andrew S.W. Thomas, Ph.D., Daniel W. Bursch, Mario Runco, Jr., and Marc Garneau, Ph.D., perform a routine check of the shuttle's flight control surfaces and reaction control system jets, wrap up work with a number of scientific investigations, and begin securing the cabin for the trip back to Earth. Most experiments aboard the shuttle have been completed and stowed away, although a few will operate throughout the night and be deactivated once the crew wakes. Crew members Andy Thomas, a native of Australia, and Marc Garneau, a Canadian, each receive special greetings today as STS-77 nears its end. South Australia Premier Dean Brown called Thomas with congratulations early this morning as the shuttle passed above Brown's office in Adelaide, Australia, Thomas' hometown. Later, Canadian Prime Minister Jean Chretien called Garneau to congratulate him on the mission and the joint Canadian Space Agency and NASA experiments that were conducted.

Randomized clinical trial of extended use of a hydrophobic condenser humidifier: 1 vs. 7 days.

PubMed

Thomachot, Laurent; Leone, Marc; Razzouk, Karim; Antonini, François; Vialet, Renaud; Martin, Claude

2002-01-01

To determine whether extended use (7 days) would affect the efficiency on heat and water preservation of a hydrophobic condenser humidifier as well as the rate of ventilation-acquired pneumonia, compared with 1 day of use. Prospective, controlled, randomized, not blinded, clinical study. Twelve-bed intensive care unit of a university hospital. One hundred and fifty-five consecutive patients undergoing mechanical ventilation for > or = 48 hrs. After randomization, patients were allocated to one of the two following groups: a) heat and moisture exchangers (HMEs) changed every 24 hrs; b) HMEs changed only once a week. Devices in both groups could be changed at the discretion of the staff when signs of occlusion or increased resistance were identified. Efficient airway humidification and heating were assessed by clinical variables (numbers of tracheal suctionings and instillations required, peak and mean airway pressures). The frequency rates of bronchial colonization and ventilation-acquired pneumonia were evaluated by using clinical and microbiological criteria. Endotracheal tube occlusion, ventilatory support variables, duration of mechanical ventilation, length of intensive care, acquired multiorgan dysfunction, and mortality rates also were recorded. The two groups were similar at the time of randomization. Endotracheal tube occlusion never occurred. In the targeted population (patients ventilated for > or = 7 days), the frequency rate of ventilation-acquired pneumonia was 24% in the HME 1-day group and 17% in the HME 7-day group (p > .05, not significant). Ventilation-acquired pneumonia rates per 1000 ventilatory support days were 16.4/1000 in the HME 1-day group and 12.4/1000 in the HME 7-day group (p > .05, not significant). No statistically significant differences were found between the two groups for duration of mechanical ventilation, intensive care unit length of stay, acquired organ system derangements, and mortality rate. There was indirect evidence of

Medication-related osteonecrosis of the jaws from once per year intravenous zoledronic acid (Reclast): report of 4 cases.

PubMed

Lee, Cameron Y S; Suzuki, Jon B

2015-04-01

Osteonecrosis of the jaws is a commonly reported side effect with patients prescribed oral antiresorptive medications to treat osteoporosis and osteopenia. Oral antiresorptive agents are considered as the standard of care for the prevention and treatment of women with postmenopausal osteoporosis. Because of patient's noncompliance of the antiresorptive medications, which may require once-weekly or once-monthly oral ingestion, a new once a year intravenous (IV) infusion of zoledronic acid was recently introduced in the management of osteoporosis. Reports of medication-related osteonecrosis of the jaw (MRONJ) have been reported in patients with cancer treated with multiple doses of IV zoledronic acid. However, there is a paucity of reports occurring with the once-yearly infusion of zoledronic acid (Reclast) for the management of osteoporosis. In this article, we report 4 cases of patients who had a history of long-term oral antiresorptive therapy and now were taking the once-yearly IV zoledronic acid (Reclast) and soon developed MRONJ after completing surgery of the maxilla and mandible.

"Once-Upon-A-Time" Reconsidered: The Developmental Dialectic between Function and Form. Technical Report No. 36.

ERIC Educational Resources Information Center

Dyson, Anne Haas

A case study traces the evolution of "once-upon-a-time" in a child's classroom story writing, drawing upon data collected in a three-year study of writing development in an urban magnet school. The subject, Mitzi, is observed from kindergarten through second grade. The study assumes that stories are cultural discourse forms that serve…

The case of David: on the couch for sixty minutes, nine years of once-a-week treatment.

PubMed

Kavaler-Adler, Susan

2005-06-01

This paper illustrates a unique case of object relations psychoanalytic psychotherapy on a once-a-week treatment basis. The work of developmental mourning that would be thought to require two to five sessions a week was accomplished on a once-a-week basis. The analyst adjusted the treatment hour, in this one case, to 60 minutes, as opposed to the 45- or 50-minute hour. When treatment began, the analyst made an intuitive judgment to increase the patient's one session a week--which the patient made clear was all he was ready to do--to 60 minutes. The analyst made time in her practice for this 60-minute session and has continued with the patient using this format for 9 years of treatment. This had led up to the current stage of treatment, which has been so critical to the patient's self-integration process.

Efficacy and safety of once-weekly oral trelagliptin switched from once-daily dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: An open-label, phase 3 exploratory study.

PubMed

Inagaki, Nobuya; Sano, Hiroki; Seki, Yoshifumi; Kuroda, Shingo; Kaku, Kohei

2018-03-01

Trelagliptin, a novel once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor, has shown favorable efficacy and safety in type 2 diabetes mellitus patients. Trelagliptin was launched in Japan, and is expected to be initially used for switchover from a daily DPP-4 inhibitor in the clinical setting. Thus, the present study was carried out to explore the efficacy and safety of trelagliptin after a daily DPP-4 inhibitor was switched to it. This was an open-label, phase 3 exploratory study to evaluate the efficacy and safety of trelagliptin in Japanese type 2 diabetes mellitus patients who had stable glycemic control on once-daily sitagliptin therapy. Eligible patients received trelagliptin 100 mg orally before breakfast once a week for 12 weeks. The primary end-point was blood glucose by the meal tolerance test, and additional end-points were glycemic control (efficacy) and safety. Altogether, 14 patients received the study drug. The blood glucose did not markedly change from baseline at major assessment points in the meal tolerance test, and a decrease in blood glucose was observed at several other assessment points. Adverse events were reported in 42.9% (6/14) of patients, but all adverse events were mild or moderate in severity, and most were not related to the study drug. No cases of death, serious adverse events or hypoglycemia were reported. It is considered possible to switch a once-daily DPP-4 inhibitor to trelagliptin in type 2 diabetes mellitus patients with stable glycemic control in combination with diet and exercise therapy without any major influences on glycemic control or safety. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Effects of a long-day light programme on the motility and membrane integrity of cooled-stored and cyropreserved semen in Shetland pony stallions.

PubMed

Deichsel, Katharina; Schrammel, Nadine; Aurich, Jörg; Aurich, Christine

2016-04-01

Increasing day length in spring stimulates reproductive functions in horses. In this study, we have analysed the effect of artificial long days on the quality of cooled-stored and cryopreserved semen in Shetland stallions. Stallions of the treatment group (AL, n = 8) were exposed to 16 h light and 8h darkness from 15th December to 20th March while control stallions (CON, n = 7) were kept under natural photoperiod. Semen was collected once weekly and processed for cooled-storage and cryopreservation once per month. Total and progressive motility and percentage of membrane intact spermatozoa were analysed at 24, 48 and 72 h of cooled-storage and after freezing-thawing, respectively. Total and progressive motility and membrane integrity decreased during cooled-storage for 72 h in each month and both groups (p < 0.001). All these parameters were lower in CON versus AL stallions (p < 0.05) and the decrease was more pronounced in group CON (storage time x group p < 0.05). Differences between groups decreased throughout the observation period from January (p < 0.05 between groups) to July (e.g. total motility after 72 h of cooled-storage in January for group AL 80 ± 3 and group CON 49 ± 12%, respective values in July, 83 ± 2 and 72 ± 6%). Neither total and progressive motility nor percentage of membrane-intact and morphologically defect spermatozoa in frozen-thawed semen differed between groups and months. In conclusion, motility of cooled-stored semen was reduced in January and increased in stallions kept under a long day light programme for at least 30 days. Copyright © 2016 Elsevier B.V. All rights reserved.

Once-daily Mesalamine Formulation for Maintenance of Remission in Ulcerative Colitis: A Randomized, Placebo-controlled Clinical Trial.

PubMed

Gordon, Glenn L; Zakko, Salam; Murthy, Uma; Sedghi, Shahriar; Pruitt, Ronald; Barrett, Andrew C; Bortey, Enoch; Paterson, Craig; Forbes, William P; Lichtenstein, Gary R

2016-04-01

To evaluate the efficacy and safety of mesalamine granules 1.5 g once daily for maintenance of ulcerative colitis (UC) remission. Mesalamine is a first-line treatment for induction and maintenance of UC remission. A phase 3, randomized, double-blind, placebo-controlled trial of patients with a history of mild to moderate UC, currently in remission, who received mesalamine granules once daily for 6 months. The primary efficacy endpoint was percentage of patients maintaining UC remission at 6 months. A significantly greater percentage of patients receiving mesalamine granules versus placebo were in remission at 6 months (79.9% vs. 66.7%; P=0.03). A greater percentage of patients receiving mesalamine granules maintained a revised Sutherland Disease Activity Index (SDAI)≤2 with no individual component of revised SDAI>1 and rectal bleeding=0 at 6 months (72.0% vs. 58.1%; P=0.04). No significant differences between groups were observed for change from baseline to 6 months for total SDAI score or its components (ie, stool frequency, rectal bleeding, mucosal appearance, physician's rating of disease). Mesalamine granules treatment resulted in a significantly longer remission duration versus placebo (P=0.02) and decreased patients' risk of relapse by 43% (hazard ratio=0.57; 95% confidence interval, 0.35-0.93; P=0.02). Mesalamine granules were well tolerated, and adverse events related to hepatic, renal, and pancreatic function-potential concerns with long-term treatment-occurred at a rate similar to placebo. Once-daily mesalamine granules are efficacious and safe for the maintenance of UC remission.

76 FR 53524 - Culturally Significant Objects Imported for Exhibition Determinations: “Once Upon Many Times...

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