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Sample records for prazosin treatment suppresses

  1. Prazosin in the treatment of PTSD.

    PubMed

    Green, Ben

    2014-07-01

    Posttraumatic stress disorder (PTSD) often follows a chronic course, and the disorder is resistant to treatment with antidepressants and cognitive-behavioral therapy in a proportion of patients. Prazosin, an a1-adrenoceptor blocker, has shown some promise in treating chronic PTSD. A review of this literature was conducted via a search of MEDLINE and SUMMON, using keywords such as PTSD, prazosin, treatment, and resistance. At least 10 clinical studies of prazosin in the treatment of PTSD, including open-label and randomized controlled trials, have been published. All of these studies support the efficacy of prazosin either for treating nightmares and improving sleep or for reducing the severity of PTSD. Treatment of PTSD with prazosin is usually initiated at a dose of 1 mg, with monitoring for hypotension after the first dose. The dose is then gradually increased to maintenance levels of 2-6 mg at night. Studies of military patients with PTSD have used higher doses (e.g., 10-16 mg at night). Prazosin has also been studied in younger and older adults with PTSD and in patients with alcohol problems, in whom it was found to reduce cravings and stress responses. Prazosin offers some hope for treating resistant cases of PTSD in which recurrent nightmares are problematic, with a relatively rapid response within weeks. It is suggested that large-scale civilian trials of prazosin be done, as well as studies concerning the use of prazosin in acute PTSD and as a potential preventive agent.

  2. Treatment of Nightmares With Prazosin: A Systematic Review

    PubMed Central

    Kung, Simon; Espinel, Zelde; Lapid, Maria I.

    2012-01-01

    Nightmares, frequently associated with posttraumatic stress disorder and clinically relevant in today's world of violence, are difficult to treat, with few pharmacologic options. We performed a systematic review to evaluate the evidence for the use of prazosin in the treatment of nightmares. A comprehensive search was performed using the databases EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systematic Reviews, from their inception to March 9, 2012, using keywords prazosin and nightmares/PTSD or associated terms (see text). Two authors independently reviewed titles and abstracts and selected relevant studies. Descriptive data and outcomes of interest from eligible studies were extracted by 1 author, and checked by 2 others. The risk of bias of randomized controlled trials (RCTs) was assessed independently by 2 reviewers. Articles met criteria for inclusion if prazosin was used to treat nightmares, and outcome measures included nightmares or related symptoms of sleep disorders. Our search yielded 21 studies, consisting of 4 RCTs, 4 open-label studies, 4 retrospective chart reviews, and 9 single case reports. The prazosin dose ranged from 1 to 16 mg/d. Results were mixed for the 4 RCTs: 3 reported significant improvement in the number of nightmares, and 1 found no reduction in the number of nightmares. Reduced nightmare severity with use of prazosin was consistently reported in the open-label trials, retrospective chart reviews, and single case reports. PMID:22883741

  3. Treatment of nightmares with prazosin: a systematic review.

    PubMed

    Kung, Simon; Espinel, Zelde; Lapid, Maria I

    2012-09-01

    Nightmares, frequently associated with posttraumatic stress disorder and clinically relevant in today's world of violence, are difficult to treat, with few pharmacologic options. We performed a systematic review to evaluate the evidence for the use of prazosin in the treatment of nightmares. A comprehensive search was performed using the databases EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systematic Reviews, from their inception to March 9, 2012, using keywords prazosin and nightmares/PTSD or associated terms (see text). Two authors independently reviewed titles and abstracts and selected relevant studies. Descriptive data and outcomes of interest from eligible studies were extracted by 1 author, and checked by 2 others. The risk of bias of randomized controlled trials (RCTs) was assessed independently by 2 reviewers. Articles met criteria for inclusion if prazosin was used to treat nightmares, and outcome measures included nightmares or related symptoms of sleep disorders. Our search yielded 21 studies, consisting of 4 RCTs, 4 open-label studies, 4 retrospective chart reviews, and 9 single case reports. The prazosin dose ranged from 1 to 16 mg/d. Results were mixed for the 4 RCTs: 3 reported significant improvement in the number of nightmares, and 1 found no reduction in the number of nightmares. Reduced nightmare severity with use of prazosin was consistently reported in the open-label trials, retrospective chart reviews, and single case reports.

  4. Prazosin treatment in the management of scorpion envenomation.

    PubMed

    Peker, Erdal; Oktar, Suleyman; Dogan, Murat; Kaya, Ergun; Duru, Mehmet

    2010-03-01

    Scorpion stings represent an important and serious public health problem worldwide due to their high incidence and potentially severe and often fatal clinical manifestations. Children are at greater risk of developing severe cardiac, respiratory, and neurological complications due to lesser body surface area. Alpha receptor stimulation plays important role in the pathogenesis of pulmonary edema. Prazosin, a post synaptic alpha blocker, can be recommended as an effective drug in the treatment of serious scorpion envenomations with significant sympathetic symptoms. Oral prazosin is fast acting, easily available, relatively cheap, free from any anaphylaxis and highly effective.

  5. Prazosin for Treatment of Patients with PTSD and Comorbid Alcohol Dependence

    DTIC Science & Technology

    2011-07-01

    08-2-0075 TITLE: Prazosin for Treatment of Patients With PTSD and Comorbid Alcohol Dependence PRINCIPAL INVESTIGATOR: Ismene...page. Subject terms on next page. 6 Prazosin for Treatment of Patients With PTSD and Comorbid Alcohol Dependence Ismene Petrakis Yale University New...PTSD. There is evidence of common neurobiological mechanisms that underlie both AD and PTSD. Prazosin is an alpha-! adrenergic •ceptor antagonist

  6. Treatment of Post-Traumatic Stress Disorders with the Alpha-1 Adrenergic Antagonist Prazosin.

    PubMed

    Simon, Philippe Yves Rémy; Rousseau, Pierre-François

    2017-03-01

    The present review aims to assess the clinical efficacy and safety of the α-1-adrenergic antagonist prazosin as primary pharmacologic treatment for post-traumatic stress disorder (PTSD). A systematic review was performed using keywords (i.e., prazosin, α-1-adrenergic antagonist, α-1-blocker, post-traumatic stress disorder) in the databases PubMed/Medline (1966-May 2016), Embase (1966-May 2016), ScienceDirect (1823-May 2016), OvidSP (1946-May 2016) and Nature (1845-May 2016). To be considered for inclusion, studies had to test the efficacy of prazosin either alone or added to ongoing treatment in adults with PTSD, use validated tools to assess and monitor the disorders, allow comparisons on the basis of univariate analyses (i.e., p-values of t-tests and effect sizes) and list the identified adverse reactions. 12 studies were included: 5 randomized controlled trials, 4 open-label prospective trials and 3 retrospective file reviews. The evaluation concerned 276 patients exposed to civilian trauma (19%) or war trauma (81%). Prazosin significantly decreases trauma nightmares, avoidance, hypervigilance and improves patient status in all studies. No significant difference of blood pressure was observed at the end of trials. Beyond the methodological and clinical biases of these studies, the present review not only confirms the effectiveness and good tolerability of prazosin, but also suggests its possible use as primary pharmacologic treatment for PTSD. Uncertainties remain, however, regarding the prescription modalities and dosages.

  7. Treatment of Post-Traumatic Stress Disorders with the Alpha-1 Adrenergic Antagonist Prazosin

    PubMed Central

    Rousseau, Pierre-François

    2016-01-01

    Objective: The present review aims to assess the clinical efficacy and safety of the α-1-adrenergic antagonist prazosin as primary pharmacologic treatment for post-traumatic stress disorder (PTSD). Method: A systematic review was performed using keywords (i.e., prazosin, α-1-adrenergic antagonist, α-1-blocker, post-traumatic stress disorder) in the databases PubMed/Medline (1966–May 2016), Embase (1966–May 2016), ScienceDirect (1823–May 2016), OvidSP (1946–May 2016) and Nature (1845–May 2016). To be considered for inclusion, studies had to test the efficacy of prazosin either alone or added to ongoing treatment in adults with PTSD, use validated tools to assess and monitor the disorders, allow comparisons on the basis of univariate analyses (i.e., p-values of t-tests and effect sizes) and list the identified adverse reactions. Results: 12 studies were included: 5 randomized controlled trials, 4 open-label prospective trials and 3 retrospective file reviews. The evaluation concerned 276 patients exposed to civilian trauma (19%) or war trauma (81%). Prazosin significantly decreases trauma nightmares, avoidance, hypervigilance and improves patient status in all studies. No significant difference of blood pressure was observed at the end of trials. Conclusions: Beyond the methodological and clinical biases of these studies, the present review not only confirms the effectiveness and good tolerability of prazosin, but also suggests its possible use as primary pharmacologic treatment for PTSD. Uncertainties remain, however, regarding the prescription modalities and dosages. PMID:27432823

  8. Comparison of terazosin and prazosin for treatment of vesico-urethral reflex dyssynergia in dogs.

    PubMed

    Haagsman, A N; Kummeling, A; Moes, M E; Mesu, S J; Kirpensteijn, J

    2013-07-13

    Nineteen dogs with vesico-urethral reflex dyssynergia (VURD) were treated with prazosin or terazosin 0.5 mg/kg twice daily to compare efficacy and side effects. Dogs were referred because of signs of (partial) urethral obstruction. Physical examination, abdominal ultrasonography, urinalysis and a radiographic contrast study of bladder and urethra (urethrocystography) were routinely performed. If no mechanical causes of obstruction or disease of the distal urinary tract were observed, the diagnosis VURD was presumed and the dogs were included in our study. Follow-up information was obtained from owners or referring veterinarians. Significantly more side effects were seen in the dogs treated with terazosin (n=14; 93 per cent) compared with the dogs treated with prazosin (n=5; 20 per cent; P=0.002). Effects of the treatment were comparable between prazosin and terazosin. Labradors and dogs that were castrated surgically had a significant better survival (P<0.01) compared with other breeds and animals that were castrated chemically. There was a moderate to good effect in 60 per cent of the dogs treated with prazosin, and in 64 per cent of the dogs treated with terazosin.

  9. PRAZOSIN REDUCES ALCOHOL DRINKING THROUGHOUT PROLONGED TREATMENT AND BLOCKS THE INITIATION OF DRINKING IN RATS SELECTIVELY BRED FOR HIGH ALCOHOL INTAKE

    PubMed Central

    Froehlich, Janice C; Hausauer, Brett J; Federoff, David L; Fischer, Stephen M; Rasmussen, Dennis D

    2013-01-01

    BACKGROUND This study examined whether prazosin reduces alcohol drinking over the course of prolonged treatment and whether it blocks initiation of alcohol drinking in rats with a genetic predisposition toward high alcohol drinking, i.e, alcohol-preferring (P) rats. METHODS In study one, alcohol-experienced P rats that had been drinking alcohol 2 hrs/day for several months were treated daily with prazosin (0, 0.5, 1.0 or 2.0 mg/kg BW) for 7 weeks. In study two, alcohol-naïve P rats were treated daily with prazosin (0, 1.0 or 2.0 mg/kg BW) for two weeks prior to, or concomitantly with, initiation of alcohol access and throughout 3 weeks of alcohol availability. Prazosin treatment and alcohol access were then discontinued for 2 weeks followed by reinstatement of alcohol access without prazosin treatment for 4 weeks, followed by resumption of daily prazosin treatment (2.0 mg/kg BW) for 3 weeks. RESULTS Prazosin reduced alcohol drinking throughout 7 weeks of treatment in P rats accustomed to drinking alcohol. Following termination of prazosin treatment, alcohol drinking slowly returned to pretreatment baseline. Reduced alcohol intake was accompanied by increased water intake. In alcohol-naïve P rats, prazosin administration prior to the first opportunity to drink alcohol and throughout 3 weeks of alcohol access retarded acquisition of alcohol drinking and reduced the amount of alcohol consumed. When prazosin was administered concomitantly with the first opportunity to drink alcohol, it abolished acquisition of alcohol drinking. Discontinuation of prazosin treatment allowed expression of a genetic predisposition toward high alcohol drinking to gradually emerge. Prazosin retained the ability to reduce alcohol intake with repeated treatments. CONCLUSIONS Prazosin decreased alcohol drinking during prolonged treatment and may be useful for treating alcoholism and alcohol use disorders. Prazosin may also be useful for deterring initiation of drinking in individuals with a

  10. Re-emergence of posttraumatic stress disorder nightmares with nursing home admission: treatment with prazosin.

    PubMed

    Johnson, Kim G; Rosen, Jules

    2013-02-01

    Seniors with a history of emotional trauma decades earlier can experience a recurrence of posttraumatic stress disorder symptoms when transitioning to a nursing home. We present the case of an 86-year-old male Holocaust survivor admitted to a nursing home for physical therapy and rehabilitation 6 weeks after the death of his wife; the patient was expressing a persistent death wish. Despite the multiple risk factors for depression, his distress was specifically related to the reemergence of nightly posttraumatic nightmares. Over the course of 1 week of treatment with 1 mg prazosin at bedtime, his nightmares and his death wish completely resolved. He achieved his rehabilitation goals and was discharged to a community setting. This report highlights the importance of considering posttraumatic stress disorder in nursing home residents with a history of emotional trauma, and understanding how to address these symptoms pharmacologically and nonpharmacologically.

  11. Preliminary findings concerning the use of prazosin for the treatment of posttraumatic nightmares in a refugee population.

    PubMed

    Boynton, Lorin; Bentley, Jacob; Strachan, Eric; Barbato, Anna; Raskind, Murray

    2009-11-01

    Prazosin, a centrally active alpha-1 adrenergic receptor antagonist, has reduced nightmares and sleep disturbances in placebo-controlled studies involving patients with combat and civilian related posttraumatic stress disorder (PTSD). In this retrospective chart review, we analyzed data from 23 refugees diagnosed with chronic PTSD who were treated with prazosin. The recurrent distressing dreams item of the Clinician Administered PTSD Scale (CAPS) was used to quantify nightmare severity. A Clinical Global Impressions-Change (CGI-C) score assessed change in overall PTSD severity exclusive of nightmares. Using a paired-samples t-test, we found that CAPS scores decreased significantly (p <0.0005) from baseline after 8 weeks of treatment with a stable dose of prazosin. Overall PTSD severity was "markedly improved" in 6 patients, "moderately improved" in 11 patients, and "minimally improved" in 6 patients. These data provide preliminary support for the use of prazosin in targeting reduction of trauma-related nightmares and promoting improvement of global clinical status within an international sample of severely traumatized refugee patients.

  12. Prazosin treatment of trauma nightmares and sleep disturbance in soldiers deployed in Iraq.

    PubMed

    Calohan, Jess; Peterson, Kris; Peskind, Elaine R; Raskind, Murray A

    2010-10-01

    Trauma nightmares and sleep disturbance impair combat soldiers' functioning. The alpha-1 adrenoreceptor antagonist prazosin has been demonstrated effective for these symptoms in Vietnam veterans. Thirteen soldiers seeking relief from distressing trauma nightmares impairing military function in northern Iraq in 2006 received prazosin alone or in combination with other psychotropics. Mean prazosin dose was 4.1 (SD = 2.2) mg before bed. Six soldiers improved markedly and 3 moderately on the Clinical Global Impression of Change Ratings of distressing dreams decreased from an average of 7.0 (SD = 0.7) to 2.9 (SD = 3.0, p < .001) and those of disturbed sleep from 6.7 (SD = 0.9) to 3.7 (SD = 2.4, p < .001). Prazosin appears effective and well tolerated in the desert warfare environment.

  13. Prazosin for Treatment of Patients with PTSD and Comorbid Alcohol Dependence

    DTIC Science & Technology

    2014-12-01

    placebo in reducing alcohol consumption and ecreasing symptoms of PTSD in patients with comorbid AD and PTSD. Methods: One hundred and twenty...prazosin or placebo . indings: No fmdings are yet available for this study. Significance: This project will be the first to compare prazosin to... placebo as effective eatments for reducing alcohol consumption and PTSD symptoms in patients with both AD and PTSD. 15. SUBJECT TERMS- PTSD, alcohol

  14. Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US Military Veterans.

    PubMed

    Germain, Anne; Richardson, Robin; Moul, Douglas E; Mammen, Oommen; Haas, Gretchen; Forman, Steven D; Rode, Noelle; Begley, Amy; Nofzinger, Eric A

    2012-02-01

    Pharmacological and cognitive-behavioral treatments targeting insomnia and nightmares have been shown to be effective in the treatment of military veterans with sleep complaints comorbid with symptoms of stress-related disorders, including Post-Traumatic Stress Disorder (PTSD), but the two approaches have not been directly compared. This randomized controlled trial compared the effects of prazosin vs. a behavioral sleep intervention (BSI), targeting nightmares and insomnia against a placebo pill control condition on sleep and daytime symptoms. Fifty United States military veterans (mean age 40.9years, SD=13.2years) with chronic sleep disturbances were randomized to prazosin (n=18), BSI (n=17), or placebo (n=15). Each intervention lasted 8weeks. Participants completed self-report measures of insomnia severity, sleep quality, and sleep disturbances. All kept a sleep diary throughout the intervention period. Polysomnographic studies were conducted pre- and post-intervention. Both active treatment groups showed greater reductions in insomnia severity and daytime PTSD symptom severity. Sleep improvements were found in 61.9% of those who completed the active treatments and 25% of those randomized to placebo. BSI and prazosin were both associated with significant sleep improvements and reductions in daytime PTSD symptoms in this sample of military veterans. Sleep-focused treatments may enhance the benefits of first-line PTSD treatments. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Prazosin Augmentation of Outpatient Treatment of Alcohol Use Disorders in Active Duty Soldiers with and without PTSD

    DTIC Science & Technology

    2015-10-01

    Substance Abuse Program (ASAP) at Madigan Health Care System/Joint Base Lewis McChord. The aims of this trial are 1) to determine prazosin’s efficacy...Augmentation of Outpatient Treatment of AUD in Active Duty Soldiers with and without PTSD. Presented at Joint Army/NIH Substance Abuse IP – September 29...randomized controlled trial (RCT) of prazosin for AUD in active duty soldiers both with and without comorbid PTSD enrolled in the Alcohol and Substance

  16. Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression.

    PubMed

    Wang, Lucy Y; Shofer, Jane B; Rohde, Kirsten; Hart, Kim L; Hoff, David J; McFall, Yun H; Raskind, Murray A; Peskind, Elaine R

    2009-09-01

    Agitation/aggression in Alzheimer disease (AD) is a major cause of patient distress, caregiver burden, and institutionalization. Enhanced behavioral responsiveness to central nervous system norepinephrine (NE) release may contribute to the pathophysiology of agitation/aggression in AD. Prazosin, a nonsedating generic medication used for hypertension and benign prostatic hypertrophy, antagonizes NE effects at brain postsynaptic alpha-1 adrenoreceptors. This pilot study examined the efficacy and tolerability of prazosin for behavioral symptoms in patients with agitation/aggression in AD. Double-blind, placebo controlled, parallel group study. A university AD center and a nursing home in Seattle, WA. Twenty-two nursing home and community-dwelling participants with agitation/aggression and probable or possible AD (mean age: 80.6 +/- 11.2). Randomization to placebo (N = 11) or prazosin (N = 11). Medication was initiated at 1 mg/day and increased up to 6 mg/day using a flexible dosing algorithm. The Brief Psychiatric Rating Scale (BPRS) and Neuropsychiatric Inventory (NPI) at Weeks 1, 2, 4, 6, and 8. The Clinical Global Impression of Change (CGIC) at Week 8. Participants taking prazosin (mean dose: 5.7 +/- 0.9 mg/day) had greater improvements than those taking placebo (mean dose: 5.6 +/- 1.2 mg/day) on the NPI (mean change: -19 +/- 21 versus -2 +/- 15, chi = 6.32, df = 1, p = 0.012) and BPRS (mean change: -9 +/- 9 versus -3 +/- 5, chi = 4.42, df = 1, p = 0.036) based on linear mixed effects models and the CGIC (mean: 2.6 +/- 1.0 versus 4.5 +/- 1.6, z = 2.57, p = 0.011 [Mann-Whitney test]). Adverse effects and blood pressure changes were similar between prazosin and placebo groups. Prazosin was well tolerated and improved behavioral symptoms in patients with agitation/aggression in AD.

  17. Adenosine 3',5'-cyclic monophosphate involvement in hepatic triacylglyceride lipase release from prazosin-stimulated primary cultured rat hepatocytes.

    PubMed

    Nakamura, Tetsuya; Morita, Tetsuo

    2014-01-01

    We recently found that hepatic triglyceride lipase (HTGL) was released from primary cultured rat hepatocytes after treatment with prazosin, an antagonist of alpha-1 adrenoceptors. However, the details of prazosin-induced HTGL release remain uncertain. Here we investigated whether changes in cAMP levels in hepatocytes were related to HTGL release from prazosin-stimulated hepatocytes. When hepatocytes were treated with prazosin, cAMP levels during stimulated release of HTGL increased in a time- and dose-dependent manner. Stimulated release of HTGL was suppressed by the adenylate cyclase inhibitors MDL-12,330A and 2',5'-dideoxyadenosine. Further, cAMP-dependent protein kinase A (PKA) activity in prazosin-stimulated hepatocytes also increased in a time- and dose-dependent manner. Moreover, prazosin-stimulated HTGL release was suppressed by the PKA inhibitors H-89 and KT5720. These results suggest that prazosin-stimulated HTGL release from hepatocytes was due to cAMP production and partly due to subsequent PKA activation in hepatocytes.

  18. Tracing the flow of knowledge: geographic variability in the diffusion of prazosin use for the treatment of posttraumatic stress disorder nationally in the Department of Veterans Affairs.

    PubMed

    Harpaz-Rotem, Ilan; Rosenheck, Robert A

    2009-04-01

    Passive diffusion of new medical innovations is an important mechanism by which knowledge transitions from research to clinical practice. Preliminary evidence has emerged about the effectiveness of the alpha(1)-adrenergic blocker prazosin hydrochloride in the treatment of nightmares and hyperarousal among patients with posttraumatic stress disorder (PTSD). This treatment has been neither widely accepted nor the subject of active dissemination efforts, and its efficacy was discovered in a discrete geographic location. To evaluate the pace and reach of the passive dissemination of a promising technology within a national health care system. Geographic surveillance data study. Academic research. We tracked the use of prazosin in the treatment of patients diagnosed as having PTSD in the Department of Veterans Affairs during fiscal years 2004 (n = 203 414) and 2006 (n = 319 670). The percentage of patients diagnosed as having PTSD who received a prescription for prazosin. Whereas 37.6% of patients with PTSD treated within the Veterans Affairs Puget Sound Health Care System, Tacoma, Washington, in 2004 were prescribed prazosin, only 18.2% were treated with prazosin at medical centers up to 499 miles (to convert miles to kilometers, multiply by 1.6) away, 6.7% at centers 500 to 999 miles away, 4.0% at centers 1000 to 2499 miles away, and 1.9% at centers 2500 miles away or farther. Adjusting for patient characteristics, patients with PTSD treated up to 499 miles from Puget Sound were about 49% less likely in 2006 and about 63% less likely in 2004 to be prescribed prazosin than their counterparts treated within Puget Sound, while those who were treated 2500 miles away or farther were about 94% less likely in 2006 and about 97% less likely in 2004 to be treated with prazosin than patients within Puget Sound. Passive diffusion of a new treatment can be rapid in the immediate area in which it is developed, but the geographic gradient of use seems to be steep and enduring even

  19. Prazosin Augmentation of Outpatient Treatment of Alcohol Use Disorders in Active Duty Soldiers with and without PTSD

    DTIC Science & Technology

    2014-10-01

    and N=2 (6%); and muscle weakness, N=1 (3%) and N=0. Miscellaneous TABLE 2. Demographic and Clinical Characteristics of Active-Duty Soldiers With...short duration of action (6 to 10 hours) (26), prazosin prescriptions in the medical management of hypertension or benign prostatic hypertrophy call

  20. Prazosin Can Prevent Glucocorticoid Mediated Capillary Rarefaction

    PubMed Central

    Mandel, Erin R.; Dunford, Emily C.; Trifonova, Anastassia; Abdifarkosh, Ghoncheh; Teich, Trevor; Riddell, Michael C.

    2016-01-01

    Glucocorticoids (GC) elicit skeletal muscle capillary rarefaction, which can subsequently impair blood distribution and muscle function; however, the mechanisms have not been established. We hypothesized that CORT would inhibit endothelial cell survival signals but that treatment with the alpha-1 adrenergic receptor inhibitor prazosin, which leads to angiogenesis in skeletal muscle of healthy rats, would reverse these effects and induce angiogenesis within the skeletal muscle of corticosterone (CORT)-treated rats. Male Sprague Dawley rats were implanted subcutaneously with CORT pellets (400 mg/rat), with or without concurrent prazosin treatment (50mg/L in drinking water), for 1 or 2 weeks. Skeletal muscle capillary rarefaction, as indicated by a significant reduction in capillary-to-fiber ratio (C:F), occurred after 2 weeks of CORT treatment. Concurrent prazosin administration prevented this capillary rarefaction in CORT-treated animals but did not induce angiogenesis or arteriogenesis as was observed with prazosin treatment in control rats. CORT treatment reduced the mRNA level of Angiopoietin-1 (Ang-1), which was partially offset in the muscles of rats that received 2 weeks of co-treatment with prazosin. In 2W CORT animals, prazosin treatment elicited a significant increase in vascular endothelial growth factor-A (VEGF-A) mRNA and protein. Conversely prazosin did not rescue CORT-induced reductions in transforming growth factor beta-1 (TGFβ1 and matrix metalloproteinase-2 (MMP-2) mRNA. To determine if CORT impaired shear stress dependent signaling, cultured rat skeletal muscle endothelial cells were pre-treated with CORT (600nM) for 48 hours, then exposed to 15 dynes/cm2 shear stress or maintained with no flow. CORT blunted the shear stress-induced increase in pSer473 Akt, while pThr308 Akt, ERK1/2 and p38 phosphorylation and nitric oxide (NO) production were unaffected. This study demonstrates that GC-mediated capillary rarefaction is associated with a reduction

  1. Prazosin Can Prevent Glucocorticoid Mediated Capillary Rarefaction.

    PubMed

    Mandel, Erin R; Dunford, Emily C; Trifonova, Anastassia; Abdifarkosh, Ghoncheh; Teich, Trevor; Riddell, Michael C; Haas, Tara L

    2016-01-01

    Glucocorticoids (GC) elicit skeletal muscle capillary rarefaction, which can subsequently impair blood distribution and muscle function; however, the mechanisms have not been established. We hypothesized that CORT would inhibit endothelial cell survival signals but that treatment with the alpha-1 adrenergic receptor inhibitor prazosin, which leads to angiogenesis in skeletal muscle of healthy rats, would reverse these effects and induce angiogenesis within the skeletal muscle of corticosterone (CORT)-treated rats. Male Sprague Dawley rats were implanted subcutaneously with CORT pellets (400 mg/rat), with or without concurrent prazosin treatment (50mg/L in drinking water), for 1 or 2 weeks. Skeletal muscle capillary rarefaction, as indicated by a significant reduction in capillary-to-fiber ratio (C:F), occurred after 2 weeks of CORT treatment. Concurrent prazosin administration prevented this capillary rarefaction in CORT-treated animals but did not induce angiogenesis or arteriogenesis as was observed with prazosin treatment in control rats. CORT treatment reduced the mRNA level of Angiopoietin-1 (Ang-1), which was partially offset in the muscles of rats that received 2 weeks of co-treatment with prazosin. In 2W CORT animals, prazosin treatment elicited a significant increase in vascular endothelial growth factor-A (VEGF-A) mRNA and protein. Conversely prazosin did not rescue CORT-induced reductions in transforming growth factor beta-1 (TGFβ1 and matrix metalloproteinase-2 (MMP-2) mRNA. To determine if CORT impaired shear stress dependent signaling, cultured rat skeletal muscle endothelial cells were pre-treated with CORT (600nM) for 48 hours, then exposed to 15 dynes/cm2 shear stress or maintained with no flow. CORT blunted the shear stress-induced increase in pSer473 Akt, while pThr308 Akt, ERK1/2 and p38 phosphorylation and nitric oxide (NO) production were unaffected. This study demonstrates that GC-mediated capillary rarefaction is associated with a reduction

  2. Combining the α1-Adrenergic Receptor Antagonist, Prazosin, with the β-Adrenergic Receptor Antagonist, Propranolol, Reduces Alcohol Drinking More Effectively Than Either Drug Alone

    PubMed Central

    Rasmussen, Dennis D; Beckwith, Lauren E; Kincaid, Carrie L; Froehlich, Janice C

    2014-01-01

    Background Evidence suggests that activation of the noradrenergic system may contribute to alcohol drinking in animals and humans. Our previous studies demonstrated that blocking α1-adrenergic receptors with the antagonist, prazosin, decreased alcohol drinking in rats under various conditions. Since noradrenergic activation is also regulated by β-adrenergic receptors, we now examine the effects of the β-adrenergic receptor antagonist, propranolol, alone or in combination with prazosin, on alcohol drinking in rats selectively bred for high voluntary alcohol intake and alcohol preference (P line). Methods Two studies were conducted with male P rats. In study one, rats were allowed to become alcohol-dependent during 14 weeks of ad libitum access to food, water and 20% alcohol and the effect of propranolol (5–15 mg/kg, IP) and prazosin (1–2 mg/kg, IP) on alcohol intake during withdrawal were assessed. In study two, the effect of propranolol (5 mg/kg, IP) and prazosin (2 mg/kg, IP) on alcohol intake following prolonged imposed abstinence was assessed. Results Alcohol drinking following propranolol treatment was variable, but the combination of propranolol + prazosin consistently suppressed alcohol drinking during both alcohol withdrawal and following prolonged imposed abstinence, and the combination of these two drugs was more effective than was treatment with either drug alone. Conclusions Treatment with prazosin + propranolol, or a combination of other centrally active α1- and β-adrenergic receptor antagonists, may assist in preventing alcohol relapse in some individuals. PMID:24891220

  3. Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits.

    PubMed

    Zubairi, Maysaa B; Ahmed, Jawad H; Al-Haroon, Sawsan S

    2014-01-01

    To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity. Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally), group 3, 4,5 and 6 were treated at a dose in (mg/kg/day) of the following: Carvedilol (10 mg), prazosin (0.5 mg), metoprolol (10 mg), and a combination of metoprolol (10 mg) and prazosin (0.5 mg) respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA) and glutathione (GSH) in serum and liver homogenates were estimated. Histopathological examinations of liver were performed. Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments. Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection.

  4. Two Case Reports on Use of Prazosin for Drug Dreams.

    PubMed

    Gopalakrishna, Ganesh; Popoola, Oluwole; Campbell, Austin; Nemetalla, Marina A

    2016-01-01

    Substance abuse and dependence is estimated to cost roughly $700 billion annually including direct and indirect care in the United States. Drug dreams (DD), or using dreams, are a reportedly common phenomenon among patients with substance abuse, and have been postulated as triggers for relapse. Prazosin is an alpha-1 receptor antagonist originally approved by the United States Food and Drug Administration for the treatment of hypertension. Prazosin passes the blood brain barrier easily, contributing to central and cognitive effects. Prazosin's efficacy has been demonstrated in the management of posttraumatic stress disorder (PTSD), and associated nightmares. We present the cases of two patients with substance use disorder experiencing DD which resolved after the addition of prazosin during an acute psychiatric hospitalization. To our knowledge, this is the first time treatment of DD with prazosin has been reported in the literature. Both patients reported an alleviation of their DD after the medication was initiated. The effect was immediate and results were seen on the same night of the initial dose. The precise mechanism of this effect is unclear, but we hypothesize it is related to the decrease in noradrenaline effects at α-1 adrenoreceptors in the brain, similar to the effect on nightmares in PTSD. The key limitation is the low number of patients and lack of follow up presented in this report. No causal relationship can be established between the use of prazosin and resolution of DD in our patients.

  5. Prazosin induces p53-mediated autophagic cell death in H9C2 cells.

    PubMed

    Yang, Yi-Fan; Wu, Chau-Chung; Chen, Wen-Pin; Chen, Yuh-Lien; Su, Ming-Jai

    2011-08-01

    Prazosin, a quinazoline-based α(1)-adrenoceptor antagonist, is known to induce cell death, and this effect is independent of its α-blockade activity. However, the detailed molecular mechanisms involved are still not fully understood. In this study, we found that prazosin, but not doxazosin, could induce patterns of autophagy in H9C2 cells, including intracellular vacuole formation, microtubule-associated protein 1 light chain 3 (LC3) conversion, and acidic vesicular organelle (AVO) augmentation. Western blot analysis of phosphorylated proteins showed that exposure to prazosin increased the levels of phospho-p53 and phospho-adenosine monophosphate-activated protein kinase (AMPK) but dramatically decreased the levels of phospho-mammalian target of rapamycin (mTOR), phospho-protein kinase B (Akt), and phospho-ribosomal protein S6 kinase (p70S6K). Furthermore, although pretreatments with the pharmacological autophagy inhibitor 3-methyladenine and the p53 inhibitor pifithrin-α suppressed prazosin-induced AVO formation, they did not reverse prazosin-induced decline in cell viability but enhanced prazosin-induced caspase-3 activation. From these results we suggest that prazosin induces autophagic cell death via a p53-mediated mechanism. When the autophagy pathway was inhibited, prazosin still induced programmed cell death, at least in part through apoptotic caspase-3 cascade enhancement. Thus, our results indicate a potential new target in prazosin-induced cell death.

  6. Haemodynamic and hormonal effects of prazosin on head-up tilt in essential hypertensive patients: comparison with those of propranolol.

    PubMed

    Kida, O; Morotomi, Y; Higa, T; Kodama, K; Someya, N; Tanaka, K

    1984-01-01

    To evaluate the haemodynamic and hormonal effects of prazosin, head-up tilt was performed in 10 essential hypertensive patients, and these effects of prazosin on the tilt were compared with those of propranolol. The tilts were performed in control phase and the last days of treatment for two weeks with propranolol (90 mg/day) or prazosin (3-6 mg/day). Each drug significantly lowered the mean blood pressure at rest, and also suppressed its rise on the tilt. Heart rates were significantly increased by the tilt in the control phase, in the propranolol phase and in the prazosin phase. Cardiac index was significantly reduced by the tilt from 2.66 (s.e.m. = 0.22) 1/min per m2 to 2.08 (s.e.m. = 0.20) in the propranolol phase. However, there were not significant changes in other phases. Total peripheral resistance indices were significantly increased by the tilt in all three phases. Plasma renin activity and plasma aldosterone were significantly increased by the tilt from 2.14 (s.e.m. = 0.47) ng/ml per h to 2.46 (s.e.m. = 0.54) and from 50.6 (s.e.m. = 12.9) pg/ml to 74.9 (s.e.m. = 14.9) respectively, in the control phase. And they were also significantly increased from 1.06 (s.e.m. = 0.29) to 1.65 (s.e.m. = 0.45) and from 41.4 (s.e.m. = 16.3) to 54.0 (s.e.m. = 17.4) in the prazosin phase. There were no significant increases during the administration of propranolol. We observed that prazosin did not alter heart rate and cardiac index, but suppressed the renin-angiotensin system at rest. It is suggested that prazosin did not influence haemodynamic and hormonal responses to the tilt.

  7. Efficacy and safety of scorpion antivenom plus prazosin compared with prazosin alone for venomous scorpion (Mesobuthus tamulus) sting: randomised open label clinical trial

    PubMed Central

    2011-01-01

    Objective Envenomation by Mesobuthus tamulus scorpion sting can result in serious cardiovascular effects. Scorpion antivenom is a specific treatment for scorpion sting. Evidence for the benefit of scorpion antivenom and its efficacy compared with that of commonly used vasodilators, such as prazosin, is scarce. We assessed the efficacy of prazosin combined with scorpion antivenom, compared with prazosin alone, in individuals with autonomic storm caused by scorpion sting. Design Prospective, open label randomised controlled trial. Setting General hospital inpatients (Bawaskar Hospital and Research Centre Mahad Dist-Raigad Maharashtra, India). Participants Seventy patients with grade 2 scorpion envenomation, older than six months, with no cardiorespiratory or central nervous system abnormalities. Intervention Scorpion antivenom plus prazosin (n=35) or prazosin alone (n=35) assigned by block randomisation. Treatment was not masked. Analysis was by intention to treat. Main outcome measures The primary end point was the proportion of patients achieving resolution of the clinical syndrome (sweating, salivation, cool extremities, priapism, hypertension or hypotension, tachycardia) 10 hours after administration of study drugs. Secondary end points were time required for complete resolution of clinical syndrome, prevention of deterioration to higher grade, doses of prazosin required overall and within 10 hours, and adverse events. The study protocol was approved by the independent ethics committee of Mumbai. Results Mean (SD) recovery times in hours for the prazosin plus scorpion antivenom group compared with the prazosin alone groups were: sweating 3 (1.1) v 6.6 (2.6); salivation 1.9 (0.9) v 3 (1.9); priapism 4.7 (1.5) v 9.4 (1.5). Mean (SD) doses of prazosin in the groups were 2 (2.3) and 4 (3.5), respectively. 32 patients (91.4%, 95% confidence interval 76.9% to 97.8%) in the prazosin plus antivenom group showed complete resolution of the clinical syndrome within 10 hours

  8. Efficacy and safety of scorpion antivenom plus prazosin compared with prazosin alone for venomous scorpion (Mesobuthus tamulus) sting: randomised open label clinical trial.

    PubMed

    Bawaskar, Himmatrao Saluba; Bawaskar, Pramodini Himmatrao

    2011-01-05

    Envenomation by Mesobuthus tamulus scorpion sting can result in serious cardiovascular effects. Scorpion antivenom is a specific treatment for scorpion sting. Evidence for the benefit of scorpion antivenom and its efficacy compared with that of commonly used vasodilators, such as prazosin, is scarce. We assessed the efficacy of prazosin combined with scorpion antivenom, compared with prazosin alone, in individuals with autonomic storm caused by scorpion sting. Prospective, open label randomised controlled trial. General hospital inpatients (Bawaskar Hospital and Research Centre Mahad Dist-Raigad Maharashtra, India). Seventy patients with grade 2 scorpion envenomation, older than six months, with no cardiorespiratory or central nervous system abnormalities. Scorpion antivenom plus prazosin (n=35) or prazosin alone (n=35) assigned by block randomisation. Treatment was not masked. Analysis was by intention to treat. The primary end point was the proportion of patients achieving resolution of the clinical syndrome (sweating, salivation, cool extremities, priapism, hypertension or hypotension, tachycardia) 10 hours after administration of study drugs. Secondary end points were time required for complete resolution of clinical syndrome, prevention of deterioration to higher grade, doses of prazosin required overall and within 10 hours, and adverse events. The study protocol was approved by the independent ethics committee of Mumbai. Mean (SD) recovery times in hours for the prazosin plus scorpion antivenom group compared with the prazosin alone groups were: sweating 3 (1.1) v 6.6 (2.6); salivation 1.9 (0.9) v 3 (1.9); priapism 4.7 (1.5) v 9.4 (1.5). Mean (SD) doses of prazosin in the groups were 2 (2.3) and 4 (3.5), respectively. 32 patients (91.4%, 95% confidence interval 76.9% to 97.8%) in the prazosin plus antivenom group showed complete resolution of the clinical syndrome within 10 hours of administration of treatment compared with eight patients in the prazosin

  9. Prazosin

    MedlinePlus

    ... organs may cause heart disease, a heart attack, heart failure, stroke, kidney failure, loss of vision, and other ... hyperplasia (BPH, noncancerous enlargement of the prostate), congestive heart failure, pheochromocytoma (adrenal gland tumor), sleep problems associated with ...

  10. Prazosin in Children and Adolescents With Posttraumatic Stress Disorder Who Have Nightmares: A Systematic Review.

    PubMed

    Akinsanya, Adefolake; Marwaha, Raman; Tampi, Rajesh R

    2017-02-01

    The aim of this systematic review was to identify published articles that evaluated the use of prazosin for treating nightmares in children and adolescents who have posttraumatic stress disorder (PTSD). A literature search was conducted of PubMed, MEDLINE, EMBASE, Cochrane Collaboration, and PsycINFO databases for published articles in any language that evaluated the use of prazosin for treating nightmares in the context of PTSD in children and adolescents using the following key words: PTSD, nightmares, prazosin, children, adolescents, trauma, and sleep. A total of 9 published articles related to the use of prazosin for treatment of nightmares in PTSD in children and adolescents were identified. Six of the 9 articles that met our inclusion criteria were case reports. All of these 6 case reports showed marked improvement in nightmares when prazosin was used, although at a generally lower dose when compared with its use in adults, with dosing ranging from 1 to 4 mg/d. Prazosin has shown promising outcomes in treating nightmares associated with PTSD in children and adolescents, although this has not been well studied. Future placebo-controlled trials are needed to assess the efficacy and safety of prazosin in treating PTSD-related nightmares in children and adolescents.

  11. Rapid modulation of TRH and TRH-like peptide release in rat brain and peripheral tissues by prazosin.

    PubMed

    Sattin, Albert; Pekary, Albert Eugene; Blood, James

    2011-08-01

    Hyperresponsiveness to norepinephrine contributes to post-traumatic stress disorder (PTSD). Prazosin, a brain-active blocker of α(1)-adrenoceptors, originally used for the treatment of hypertension, has been reported to alleviate trauma nightmares, sleep disturbance and improve global clinical status in war veterans with PTSD. Thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH(2)) may play a role in the pathophysiology and treatment of neuropsychiatric disorders such as major depression, and PTSD (an anxiety disorder). To investigate whether TRH or TRH-like peptides (pGlu-X-Pro-NH(2), where "X" can be any amino acid residue) participate in the therapeutic effects of prazosin, male rats were injected with prazosin and these peptides then measured in brain and endocrine tissues. Prazosin stimulated TRH and TRH-like peptide release in those tissues with high α(1)-adrenoceptor levels suggesting that these peptides may play a role in the therapeutic effects of prazosin.

  12. Management of scorpion sting: prazosin or dobutamine.

    PubMed

    Gupta, B D; Parakh, M; Purohit, A

    2010-04-01

    To compare the efficacy of Dobutamine and Prazosin in the management of cases with scorpion sting. Pediatric intensive care unit of an affiliated hospital of a medical university. Forty-two children with scorpion sting. The involved victims were divided alternatively into two groups. Twenty-one patients were treated with intravenous Dobutamine infusion and other 21 received oral Prazosin. Percent-rise in left-ventricular ejection fraction in first 24 h after institution of the therapy, time taken in recovery from pulmonary edema, requirement of any additional drug and supportive measures, and mortality. The time taken in recovery from pulmonary edema was significantly shorter in cases treated with prazosin (28 +/- 18.3 vs. 72 +/- 0 h), the p-value being <0.05. Faster improvement of various parameters was observed in prazosin group in comparison to the dobutamine group. Mortality in both the groups was equal. Prazosin and dobutamine, both are useful drugs for management of cardiovascular features of scorpion envenomation, nevertheless, prazosin is slightly better than dobutamine in terms of faster recovery, and also because of its ease of administration and low cost of therapy.

  13. Prazosin for Trauma Nightmares and Sleep Disturbances in Combat Veterans with Post-Traumatic Stress Disorder

    PubMed Central

    Khazaie, Habibolah; Nasouri, Marzie; Ghadami, Mohammad Rasoul

    2016-01-01

    Background Prazosin is significantly effective to reduce sleep disturbance and trauma nightmare in patients with post-traumatic stress disorder (PTSD); however, results of different studies were evaluated. Objectives The current randomized clinical trial aimed to assess the effects of prazosin on sleep parameters and nightmares among veterans with chronic PTSD. Materials and Methods Thirty-two veterans with chronic war-induced PTSD and distressing nightmares were randomized into prazosin and placebo groups for eight weeks. The main symptoms were qualified using the recurrent distressing dreams item of the clinician administered PTSD scale (CAPS) and the daytime symptom severity was measured by PTSD checklist (PCL) and the objective sleep quality assessment by actigraphy. Results Compared with placebo, prazosin had no significant effects on reduction of daytime symptoms (P = 0.69) and frequency and intensity of trauma-related nightmares. Also, there were no significant differences between pre- and post-treatment actigraphy measurements (P > 0.05). Conclusions The study findings showed that prazosin had no significant effect on reduction of PTSD symptoms as well as nightmares among veterans with chronic PTSD. Further clinical trials are needed to define the effect of prazosin on sleep physiology and whether such effects regarding the therapeutic response. PMID:27822278

  14. Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations.

    PubMed

    Rasmussen, Dennis D; Kincaid, Carrie L; Froehlich, Janice C

    2017-01-01

    Stress-induced anxiety is a risk factor for relapse to alcohol drinking. The aim of this study was to test the hypothesis that the central nervous system (CNS)-active α1-adrenergic receptor antagonist, prazosin, would block the stress-induced increase in anxiety that occurs during alcohol deprivations. Selectively bred male alcohol-preferring (P) rats were given three cycles of 5 days of ad libitum voluntary alcohol drinking interrupted by 2 days of alcohol deprivation, with or without 1 h of restraint stress 4 h after the start of each of the first two alcohol deprivation cycles. Prazosin (1.0 or 1.5 mg/kg, IP) or vehicle was administered before each restraint stress. Anxiety-like behavior during alcohol deprivation following the third 5-day cycle of alcohol drinking (7 days after the most recent restraint stress ± prazosin treatment) was measured by performance in an elevated plus-maze and in social approach/avoidance testing. Rats that received constant alcohol access, or alcohol access and deprivations without stress or prazosin treatments in the first two alcohol deprivations did not exhibit augmented anxiety-like behavior during the third deprivation. In contrast, rats that had been stressed during the first two alcohol deprivations exhibited increased anxiety-like behavior (compared with control rats) in both anxiety tests during the third deprivation. Prazosin given before stresses in the first two cycles of alcohol withdrawal prevented increased anxiety-like behavior during the third alcohol deprivation. Prazosin treatment before stresses experienced during alcohol deprivations may prevent the increased anxiety during subsequent deprivation/abstinence that is a risk factor for relapse to alcohol drinking. Administration of prazosin before stresses during repetitive alcohol deprivations in male alcohol-preferring (P) rats prevents increased anxiety during a subsequent deprivation without further prazosin treatment. Prazosin treatment during repeated

  15. Erectile response to transurethral alprostadil, prazosin and alprostadil-prazosin combinations.

    PubMed

    Peterson, C A; Bennett, A H; Hellstrom, W J; Kaiser, F E; Morley, J E; Nemo, K J; Padma-Nathan, H; Place, V A; Prendergast, J J; Tam, P Y; Tanagho, E A; Todd, L K; Varady, J C; Gesundheit, N

    1998-05-01

    Transurethral alprostadil has been shown to be efficacious in many men with erectile dysfunction. We compared transurethral alprostadil and prazosin alone, and in combination to treat this disorder. In this double-blind, placebo controlled study the erectile responses to transurethral alprostadil, prazosin and alprostadil-prazosin combinations were assessed in 234 men 26.8 to 81.5 years old with complete organic erectile dysfunction. Patients self-administered a random sequence of 7 doses in the clinic in 4 weeks. The erectile response was assessed using categorical and visual analog scales. Full penile enlargement or rigidity was achieved by 165 of the 234 men (70.5%) after at least 1 active dose of medication. The most effective alprostadil dose (500 microg.) resulted in full penile enlargement or rigidity in 51.8% of administrations, whereas the most effective prazosin dose (2,000 microg.) and placebo resulted in a similar response in 12.7 and 2.7%, respectively (p <0.001). The 500/2,000 microg. alprostadil/prazosin combination, which resulted in full enlargement or rigidity in 58.9% of doses, was only slightly better than the most effective dose of alprostadil alone (500 microg.). However, combinations of 125/500 and 250/500 microg. alprostadil/prazosin were more effective (p <0.01) than 125 and 250 microg. alprostadil given alone, respectively. The most common side effect of therapy was penile pain, which rarely led to study discontinuation. Hypotension most commonly developed at the higher alprostadil-prazosin combination. Transurethral alprostadil and alprostadil-prazosin combinations produced erections in men with complete organic erectile dysfunction. This combination therapy may be an option in patients who do not respond to transurethral alprostadil alone.

  16. Metabolic effects of prazosin on skeletal muscle insulin resistance in glucocorticoid-treated male rats.

    PubMed

    Dunford, Emily C; Mandel, Erin R; Mohajeri, Sepideh; Haas, Tara L; Riddell, Michael C

    2017-01-01

    High-dose glucocorticoids (GC) induce skeletal muscle atrophy, insulin resistance, and reduced muscle capillarization. Identification of treatments to prevent or reverse capillary rarefaction and metabolic deterioration caused by prolonged elevations in GCs would be therapeutically beneficial. Chronic administration of prazosin, an α1-adrenergic antagonist, increases skeletal muscle capillarization in healthy rodents and, recently, in a rodent model of elevated GCs and hyperglycemia. The purpose of this study was to determine whether prazosin administration would improve glucose tolerance and insulin sensitivity, through prazosin-mediated sparing of capillary rarefaction, in this rodent model of increased GC exposure. Prazosin was provided in drinking water (50 mg/l) to GC-treated or control rats (400 mg implants of either corticosterone or a wax pellet) for 7 or 14 days (n = 5-14/group). Whole body measures of glucose metabolism were correlated with skeletal muscle capillarization (C:F) at 7 and 14 days in the four groups of rats. Individual C:F was found to be predictive of insulin sensitivity (r(2) = 0.4781), but not of glucose tolerance (r(2) = 0.1601) and compared with water only, prazosin treatment decreased insulin values during oral glucose challenge by approximately one-third in corticosterone (Cort)-treated animals. Cort treatment, regardless of duration, induced significant glycolytic skeletal muscle atrophy (P < 0.05), decreased IRS-1 protein content (P < 0.05), and caused elevations in FOXO1 protein expression (P < 0.05), which were unaffected with prazosin administration. In summary, it appears that α1-adrenergic antagonism improves Cort-induced skeletal muscle vascular impairments and reduces insulin secretion during an oral glucose tolerance test, but is unable to improve the negative alterations directly affecting the myocyte, including muscle size and muscle signaling protein expression. Copyright © 2017 the American Physiological Society.

  17. DEVELOPMENT OF NOVEL, ALTERNATIVE, FACILE, ECOFRIENDLY, HIGH YIELD SYNTHETIC PROCESS FOR PRAZOSIN

    PubMed Central

    Patil, D. A.; Jain, K. S.; Deodhar, M. N.; Patil, P. O.; Patil, G. B.; Patil, D. D.

    2010-01-01

    Industrial chemistry in the new millennium is widely adopting the concept of “Green chemistry” to meet the fundamental scientific challenges. Antihypertensive drugs include several of the most widely prescribed drugs like diuretics, beta-blockers, ACE inhibitors, calcium channel blockers, and α-1 adrenoreceptor blockers. The discovery of prazosin, with very high index of α1/α2 affinity has triggered off a renaissance of interest in α1-adrenoceptor antagonist drugs for treatment of hypertension. The three reported routes for synthesis and manufacture of the α-adrenoceptor antagonist- prazosin had some disadvantages. In present study we had developed new methods for the synthesis of prazosin by using microwave. The most important aspect is the overall yield of this process was ~25 % higher than the other reported methods excluding the use of banned substances PMID:24825992

  18. Prazosin for military combat-related PTSD nightmares: a critical review.

    PubMed

    Writer, Brian W; Meyer, Eric G; Schillerstrom, Jason E

    2014-01-01

    Military combat is a common trauma experience associated with posttraumatic stress disorder (PTSD). Trauma-related nightmares are a hallmark symptom of PTSD. They can be resistant to label-pharmacological PTSD treatment, and they are associated with a variety of adverse health outcomes. The purpose of this article is to review and evaluate prazosin therapy for combat-related PTSD nightmares. Consistent with available literature for all-causes PTSD nightmares, prazosin is an effective off-label option for combat-related PTSD nightmares. Future trials may further instruct use in specific combat-exposure profiles.

  19. Comparative Meta-Analysis of Prazosin and Imagery Rehearsal Therapy for Nightmare Frequency, Sleep Quality, and Posttraumatic Stress

    PubMed Central

    Seda, Gilbert; Sanchez-Ortuno, Maria M.; Welsh, Carolyn H.; Halbower, Ann C.; Edinger, Jack D.

    2015-01-01

    Study Objective: In this meta-analysis, we compare the short-term efficacy of prazosin vs. IRT on nightmares, sleep quality, and posttraumatic stress symptoms (PTSS). Methods: Reference databases were searched for randomized controlled trials using IRT or prazosin for nightmares, sleep disturbance, and/or PTSS. Effect sizes were calculated by subtracting the mean posttest score in the control group from the mean posttest score in the treatment group, and dividing the result by the pooled standard deviation of both groups. Mixed effects models were performed to evaluate effects of treatment characteristics, as well as sample characteristics (veteran vs. civilian) on treatment efficacy. Results: Four studies used prazosin, 10 used IRT alone or in combination with another psychological treatment, and 1 included a group receiving prazosin and another group receiving IRT. Overall effect sizes of both treatments were of moderate magnitude for nightmare frequency, sleep quality, and PTSS (p < 0.01). Effect size was not significantly different with type of treatment (psychological vs. pharmacological) on nightmare frequency (p = 0.79), sleep quality (p = 0.65), or PTSS, (p = 0.52). IRT combined with CBT for insomnia showed more improvement in sleep quality compared to prazosin (p = 0.03), IRT alone (p = 0.03), or IRT combined with another psychological intervention, (p < 0.01). Conclusion: Although IRT interventions and prazosin yield comparable acute effects for the treatment of nightmares, adding CBT for insomnia to IRT seems to enhance treatment outcomes pertaining to sleep quality and PTSS. More randomized clinical trials with long-term follow-up are warranted. Commentary: A commentary on this article appears in this issue on page 9. Citation: Seda G, Sanchez-Ortuno MM, Welsh CH, Halbower AC, Edinger JD. Comparative meta-analysis of prazosin and imagery rehearsal therapy for nightmare frequency, sleep quality, and posttraumatic stress. J Clin Sleep Med 2015;11(1):11

  20. Low-dose prazosin in combination with 5-HT6 antagonist PRX-07034 has antipsychotic effects.

    PubMed

    Abraham, Renny; Nirogi, Ramakrishna; Shinde, Anil; Irupannanavar, Shantaveer

    2015-01-01

    An extensive amount of research has focused on the development of new pharmacological agents to treat schizophrenia. Varying from person to person, schizophrenia is a heterogeneous disease with symptoms of positive, negative, and cognitive deficits. PRX-07034, a 5-hydroxytryptamine6 (5-HT6) receptor antagonist has been evaluated for its potential in treating obesity and cognitive deficits. This study evaluated PRX-07034 (0.1, 0.3, and 1.0 mg/kg body mass, by intraperitoneal (i.p.) injection), in combination with a low dose of prazosin (0.3 mg/kg, i.p.), for its antipsychotic potential. The research utilized a stereotypy assay, an open field test, an object recognition task, and prepulse inhibition. Dizocilpine, a non-competitive N-methyl-d-aspartate (NMDA) antagonist, was also administered in the above-mentioned assays as a psychomimetic. The combination of PRX-07034 and prazosin alleviated stereotypy and hyperlocomotor activity while enhancing memory in an object recognition task, and reversed sensory-gating deficits induced by dizocilpine. Examination of the medial prefrontal cortex revealed that a combination of PRX-07034 and prazosin reduced the dizocilpine-mediated increase of 5-HT. These results suggest that the combination of a 5-HT6 antagonist with low doses of prazosin could have therapeutic potential in the treatment of schizophrenia.

  1. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan.

    PubMed

    Raskind, Murray A; Peterson, Kris; Williams, Tammy; Hoff, David J; Hart, Kimberly; Holmes, Hollie; Homas, Dallas; Hill, Jeffrey; Daniels, Colin; Calohan, Jess; Millard, Steven P; Rohde, Kirsten; O'Connell, James; Pritzl, Denise; Feiszli, Kevin; Petrie, Eric C; Gross, Christopher; Mayer, Cynthia L; Freed, Michael C; Engel, Charles; Peskind, Elaine R

    2013-09-01

    The authors conducted a 15-week randomized controlled trial of the alpha-1 adrenoreceptor antagonist prazosin for combat trauma nightmares, sleep quality, global function, and overall symptoms in active-duty soldiers with posttraumatic stress disorder (PTSD) returned from combat deployments to Iraq and Afghanistan. Sixty-seven soldiers were randomly assigned to treatment with prazosin or placebo for 15 weeks. Drug was titrated based on nightmare response over 6 weeks to a possible maximum dose of 5 mg midmorning and 20 mg at bedtime for men and 2 mg midmorning and 10 mg at bedtime for women. Mean achieved bedtime doses were 15.6 mg of prazosin (SD=6.0) and 18.8 mg of placebo (SD=3.3) for men and 7.0 mg of prazosin (SD=3.5) and 10.0 mg of placebo (SD=0.0) for women. Mean achieved midmorning doses were 4.0 mg of prazosin (SD=1.4) and 4.8 mg of placebo (SD=0.8) for men and 1.7 mg of prazosin (SD=0.5) and 2.0 mg of placebo (SD=0.0) mg for women. Primary outcome measures were the nightmare item of the Clinician-Administered PTSD Scale (CAPS), the Pittsburgh Sleep Quality Index, and the change item of the Clinical Global Impressions Scale anchored to functioning. Secondary outcome measures were the 17-item CAPS, the Hamilton Depression Rating Scale, the Patient Health Questionnaire-9, and the Quality of Life Index. Maintenance psychotropic medications and supportive psychotherapy were held constant. Prazosin was effective for trauma nightmares, sleep quality, global function, CAPS score, and the CAPS hyperarousal symptom cluster. Prazosin was well tolerated, and blood pressure changes did not differ between groups. Prazosin is effective for combat-related PTSD with trauma nightmares in active-duty soldiers, and benefits are clinically meaningful. Substantial residual symptoms suggest that studies combining prazosin with effective psychotherapies might demonstrate further benefit.

  2. Prazosin lowers plasma triglyceride concentration in rats: a preliminary report.

    PubMed

    Reaven, G M; Dall'Aglio, E

    1982-01-01

    Prazosin was administered by intraperitoneal injection (0.3 or 3.0 mg/kg) to normal chow-fed male rats for 14 days. Mean +/- SEM plasma triglyceride levels were lower (p less than 0.001) in the prazosin-treated rats (74 +/- 12 mg/dl and 72 +/- 9 mg/dl) than in saline-injected control rats (115 +/- 11 mg/dl). This effect was associated with commensurate reductions in very low density lipoprotein-triglyceride secretion in prazosin-treated rats. No changes were noted in either plasma total or high density lipoprotein cholesterol concentrations. In addition, prazosin was capable of reducing by approximately 50% the elevation in plasma triglyceride concentration produced by a high glucose diet in control rats. The mechanism of the observed effect of prazosin on very low density lipoprotein metabolism in the rat remains to be defined.

  3. Sleep Disturbances and Nightmares in a Patient Treated with Prazosin.

    PubMed

    Kosari, Sam; Naunton, Mark

    2016-04-15

    Prazosin is increasingly being used off-label to treat nightmares in patients with posttraumatic stress disorder. The literature about the psychiatric adverse effects of prazosin is very limited. We present a case in which low-dose prazosin was associated with nightmares and sleep disturbances in an elderly patient without previously diagnosed mental illness or coexisting environmental risk factors for nightmares. Insomnia and hallucinations are listed as some of the rare side effects of prazosin by the manufacturer. Prazosin could be associated with rare psychiatric adverse effects and sleep disturbances. Particular attention is required in identifying these adverse effects, which can be difficult to distinguish from other drug-related side effects in the elderly particularly because they are often using multiple medications.

  4. Combining naltrexone and prazosin in a single oral medication decreases alcohol drinking more effectively than does either drug alone.

    PubMed

    Froehlich, Janice C; Hausauer, Brett J; Rasmussen, Dennis D

    2013-10-01

    Naltrexone (NTX) is underutilized in clinical treatment settings because its efficacy is modest, and it is not effective for all alcoholics and, when it is effective, a significant number of alcoholics fail to maintain initial treatment gains and subsequently relapse to heavy drinking. This has slowed acceptance of NTX by the treatment community, and there is a clear need for additional treatments for alcoholism and alcohol use disorders. Given that NTX and prazosin can each reduce alcohol drinking in rats selectively bred for alcohol preference and high voluntary alcohol drinking (alcohol-preferring "P" rats), we tested whether a combination of NTX + prazosin is more effective in decreasing alcohol drinking than is either drug alone. P rats were given access to a 15% (v/v) alcohol solution for 2 hours daily. Rats were fed NTX and prazosin, alone or in combination, prior to onset of the daily 2-hour alcohol access period for 4 weeks and the effect of drug treatment on alcohol and water intake was assessed. During the first week of treatment, neither a low dose of NTX, nor prazosin, was effective in decreasing alcohol intake when each drug was administered alone, but combining the 2 drugs in a single medication significantly reduced alcohol intake. The combination was as effective as was a higher dose of NTX. Using a low dose of NTX in combination with prazosin may reduce the potential for undesirable side effects early in treatment which, in turn, may improve patient compliance and result in a more successful outcome when NTX is used for treating alcoholism and alcohol use disorders. Combining low-dose NTX and prazosin in a single medication may be more useful than is either drug alone for treating both inpatient and outpatient alcoholics and heavy drinkers early in the treatment process. Copyright © 2013 by the Research Society on Alcoholism.

  5. Investigation of the atypical glass transition and recrystallization behavior of amorphous prazosin salts.

    PubMed

    Kumar, Lokesh; Popat, Dharmesh; Bansal, Arvind K

    2011-08-25

    This manuscript studied the effect of counterion on the glass transition and recrystallization behavior of amorphous salts of prazosin. Three amorphous salts of prazosin, namely, prazosin hydrochloride, prazosin mesylate and prazosin tosylate were prepared by spray drying, and characterized by optical-polarized microscopy, differential scanning calorimetry and powder X-ray diffraction. Modulated differential scanning calorimetry was used to determine the glass transition and recrystallization temperature of amorphous salts. Glass transition of amorphous salts followed the order: prazosin mesylate > prazosin tosylate ~ prazosin hydrochloride. Amorphous prazosin mesylate and prazosin tosylate showed glass transition, followed by recrystallization. In contrast, amorphous prazosin hydrochloride showed glass transition and recrystallization simultaneously. Density Functional Theory, however, suggested the expected order of glass transition as prazosin hydrochloride > prazosin mesylate > prazosin tosylate. The counterintuitive observation of amorphous prazosin hydrochloride having lower glass transition was explained in terms of its lower activation energy (206.1 kJ/mol) for molecular mobility at Tg, compared to that for amorphous prazosin mesylate (448.5 kJ/mol) and prazosin tosylate (490.7 kJ/mol), and was further correlated to a difference in hydrogen bonding strength of the amorphous and the corresponding recrystallized salts. This study has implications in selection of an optimal amorphous salt form for pharmaceutical development.

  6. Investigation of the Atypical Glass Transition and Recrystallization Behavior of Amorphous Prazosin Salts

    PubMed Central

    Kumar, Lokesh; Popat, Dharmesh; Bansal, Arvind K.

    2011-01-01

    This manuscript studied the effect of counterion on the glass transition and recrystallization behavior of amorphous salts of prazosin. Three amorphous salts of prazosin, namely, prazosin hydrochloride, prazosin mesylate and prazosin tosylate were prepared by spray drying, and characterized by optical-polarized microscopy, differential scanning calorimetry and powder X-ray diffraction. Modulated differential scanning calorimetry was used to determine the glass transition and recrystallization temperature of amorphous salts. Glass transition of amorphous salts followed the order: prazosin mesylate > prazosin tosylate ∼ prazosin hydrochloride. Amorphous prazosin mesylate and prazosin tosylate showed glass transition, followed by recrystallization. In contrast, amorphous prazosin hydrochloride showed glass transition and recrystallization simultaneously. Density Functional Theory, however, suggested the expected order of glass transition as prazosin hydrochloride > prazosin mesylate > prazosin tosylate. The counterintuitive observation of amorphous prazosin hydrochloride having lower glass transition was explained in terms of its lower activation energy (206.1 kJ/mol) for molecular mobility at Tg, compared to that for amorphous prazosin mesylate (448.5 kJ/mol) and prazosin tosylate (490.7 kJ/mol), and was further correlated to a difference in hydrogen bonding strength of the amorphous and the corresponding recrystallized salts. This study has implications in selection of an optimal amorphous salt form for pharmaceutical development. PMID:24310595

  7. Comparing the effect of prazosin and hydroxyzine on sleep quality in patients suffering from posttraumatic stress disorder.

    PubMed

    Ahmadpanah, Mohammad; Sabzeiee, Parasto; Hosseini, Seyed Mohammad; Torabian, Saadat; Haghighi, Mohammad; Jahangard, Leila; Bajoghli, Hafez; Holsboer-Trachsler, Edith; Brand, Serge

    2014-01-01

    In light of the high prevalence of sleep disorders in patients suffering from posttraumatic stress disorder (PTSD), this study sought to compare the effect of prazosin and hydroxyzine on sleep quality in this patient group. A total of 100 patients suffering from PTSD were assessed (mean age = 35.51 years, SD = 6.41; 28% females). Next, they were randomly assigned to one of three treatment groups: prazosin (33 patients), hydroxyzine (34 patients) or placebo (33 patients). The trial lasted for 8 weeks. The patients' sleep quality was assessed using the Pittsburgh Sleep Quality Index. Items taken from the Mini International Neuropsychiatric Interview were used to operationalize PTSD. Compared to controls, patients treated with prazosin and hydroxyzine reported improved sleep and less nightmares. Improvement was greatest in patients treated with prazosin compared to hydroxyzine and placebo. Improvement in sleep was associated with an amelioration of their PTSD symptoms. Both prazosin and hydroxyzine can be used to treat psychopharmacological sleep disorders and nightmares in patients suffering from PTSD, also leading to reductions in PTSD symptoms. © 2014 S. Karger AG, Basel.

  8. The alpha1-adrenergic receptor antagonists, benoxathian and prazosin, induce apoptosis and a switch towards megakaryocytic differentiation in human erythroleukemia cells.

    PubMed

    Fuchs, Robert; Stelzer, Ingeborg; Haas, Helga S; Leitinger, Gerd; Schauenstein, Konrad; Sadjak, Anton

    2009-10-01

    The erythroleukemia cell lines K562 and human erythroleukemia (HEL) are established models to study erythroid and megakaryocytic differentiation in vitro. In this study, we show that the alpha1-adrenergic antagonists, benoxathian and prazosin, inhibit the proliferation and induce apoptosis in K562 and HEL cells. Furthermore, both tested substances induced the expression of the megakaryocytic marker CD41a, whereas the expression of the erythroid marker glycophorin-a was decreased or unchanged. Even though the expression of differentiation markers was similar after benoxathian and prazosin treatment in both cell lines, endomitosis of erythroleukemia cells was observed only after prazosin treatment. So far, benoxathian and prazosin are the first described extracellular ligands, which cause megakaryocytic differentiation in K562 and HEL cells. In summary, these results indicate a possible role of alpha1-adrenergic receptor signaling in the regulation of erythroid and megakaryocytic differentiation, even though the receptor dependence of the observed effects needs further investigation.

  9. The effects of voluntary exercise and prazosin on capillary rarefaction and metabolism in streptozotocin-induced diabetic male rats.

    PubMed

    Dunford, Emily C; Leclair, Erwan; Aiken, Julian; Mandel, Erin R; Haas, Tara L; Birot, Olivier; Riddell, Michael C

    2017-03-01

    Type-1 diabetes mellitus (T1D) causes impairments within the skeletal muscle microvasculature. Both regular exercise and prazosin have been shown to improve skeletal muscle capillarization and metabolism in healthy rats through distinct angiogenic mechanisms. The aim of this study was to evaluate the independent and additive effects of voluntary exercise and prazosin treatment on capillary-to-fiber ratio (C:F) in streptozotocin (STZ)-treated diabetic rats. STZ (65 mg/kg) was intraperitoneally administered to male Sprague-Dawley rats (n = 36) to induce diabetes, with healthy, nondiabetic, sedentary rats (n = 10) as controls. The STZ-treated rats were then divided into sedentary (SED) or exercising (EX; 24-h access to running wheels) groups and then further subdivided into prazosin (Praz) or water (H2O) treatment groups: nondiabetic-SED-H2O, STZ-SED-H2O, STZ-EX-H2O, STZ-SED-Praz, and STZ-EX-Praz. After 3 wk, untreated diabetes significantly reduced the C:F in tibialis anterior (TA) and soleus muscles in the STZ-SED-H2O animals (both P < 0.05). Voluntary exercise and prazosin treatment independently resulted in a normalization of C:F within the TA (1.86 ± 0.12 and 2.04 ± 0.03 vs 1.71 ± 0.09, P < 0.05) and the soleus (2.36 ± 0.07 and 2.68 ± 0.14 vs 2.13 ± 0.12, P < 0.05). The combined STZ-EX-Praz group resulted in the highest C:F within the TA (2.26 ± 0.07, P < 0.05). Voluntary exercise volume was negatively correlated with fed blood glucose levels (r(2) = -0.7015, P < 0.01) and, when combined with prazosin, caused further enhanced nonfasted glucose (P < 0.01). Exercise and prazosin reduced circulating nonesterified fatty acids more than either stimulus alone (P < 0.05). These results suggest that the distinct stimulation of angiogenesis, with both regular exercise and prazosin treatment, causes a cooperative improvement in the microvascular complications associated with T1D.NEW & NOTEWORTHY It is currently well established that poorly controlled diabetes

  10. Effect of counterion on the solid state photodegradation behavior of prazosin salts.

    PubMed

    Kumar, Lokesh; Jog, Rajan; Singh, Saranjit; Bansal, Arvind

    2013-06-01

    The effect of counterion was evaluated on the photodegradation behavior of six prazosin salts, viz., prazosin hydrochloride anhydrous, prazosin hydrochloride polyhydrate, prazosin tosylate anhydrous, prazosin tosylate monohydrate, prazosin oxalate dihydrate, and prazosin camsylate anhydrous. The salts were subjected to UV-Visible irradiation in a photostability test chamber for 10 days. The samples were analyzed for chemical changes by a specific stability-indicating high-performance liquid chromatography method. pH of the microenvironment was determined in 10%w/v aqueous slurry of the salts. The observed order of photostability was: prazosin hydrochloride anhydrous>prazosin camsylate anhydrous~prazosin-free base>prazosin hydrochloride polyhydrate>prazosin tosylate anhydrous>prazosin oxalate dihydrate~prazosin tosylate monohydrate. Multivariate analysis of the photodegradation behavior suggested predominant contribution of the state of hydration and also intrinsic photosensitivity of the counterion. Overall, hydrated salts showed higher photodegradation compared to their anhydrous counterparts. Within the anhydrous salts, aromatic and carbonyl counterion-containing salts showed higher susceptibility to light. The pH of microenvironment furthermore contributed to photodegradation of prazosin salts, especially for drug counterions with inherent higher pH. The study reveals importance of selection of a suitable drug salt form for photosensitive drugs during preformulation stage of drug development.

  11. A retrospective analysis of a rural set up experience with special reference to dobutamine in prazosin-resistant scorpion sting cases.

    PubMed

    Patil, Suvarna Netaji

    2009-04-01

    Incidence of scorpion sting is high in west coast of Maharashtra. Scorpion sting gives rise to cardiotoxicity and it is our observation that in spite of using prazosin in initial phases, patients still developed severe cardiotoxicity and dobutamine was effective in reducing the mortality in these patients. So we want to convey this message to many of our doctor friends who practice in rural area. Death due to scorpion sting is common in rural parts of India. Prazosin is supposed to be a physiological & pharmalogical antidote of the scorpion venom but we studied efficacy of dobutamine in prazosin-resistant cardiotoxic cases. This study was a retrospective analysis of 242 patients admitted from January 1999 to December 2006. We classified these patients clinically in three groups Mild, Moderate and Severe Envenomation. For treatment plan 4 groups were made; where patients received Dobutamine + Prazosin / No Do + PR / No Pr + No Do / Do + No PR. Effect of these two drugs was compared on the basis of mortality ratio in all 4 groups. Out of 242 patients 141 patients developed cardiotoxicity. Out of them 96 had received prazosin as a first line of treatment. Out of 96, 23 needed dobutamine to treat cardiac complications. Mortality was highest in only prazosin, no dobutamine group and lowest in prazosin, dobutamine group. In initial phases of autonomic storm i.e. accelerated hypertension one can use prazosin but monitor the patient for left ventricular failure and clinically if patient develops LVF add dobutamine to prevent death. Addition of Dobutamine can be life-saving.

  12. Geographical diffusion of prazosin across Veterans Health Administration: Examination of regional variation in daily dosing and quality indicators among veterans with posttraumatic stress disorder.

    PubMed

    Abrams, Thad E; Lund, Brian C; Alexander, Bruce; Bernardy, Nancy C; Friedman, Matthew J

    2015-01-01

    Posttraumatic stress disorder (PTSD) is a high-priority treatment area for the Veterans Health Administration (VHA), and dissemination patterns of innovative, efficacious therapies can inform areas for potential improvement of diffusion efforts and quality prescribing. In this study, we replicated a prior examination of the period prevalence of prazosin use as a function of distance from Puget Sound, Washington, where prazosin was first tested as an effective treatment for PTSD and where prazosin use was previously shown to be much greater than in other parts of the United States. We tested the following three hypotheses related to prazosin geographic diffusion: (1) a positive geographical correlation exists between the distance from Puget Sound and the proportion of users treated according to a guideline recommended minimum therapeutic target dose (>/=6 mg/d), (2) an inverse geographic correlation exists between prazosin and benzodiazepine use, and (3) no geographical correlation exists between prazosin use and serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) use. Among a national sample of veterans with PTSD, overall prazosin utilization increased from 5.5 to 14.8% from 2006 to 2012. During this time period, rates at the Puget Sound VHA location declined from 34.4 to 29.9%, whereas utilization rates at locations a minimum of 2,500 miles away increased from 3.0 to 12.8%. Rates of minimum target dosing fell from 42.6 to 34.6% at the Puget Sound location. In contrast, at distances of at least 2,500 miles from Puget Sound, minimum threshold dosing rates remained stable (range, 18.6 to 17.7%). No discernible association was demonstrated between SSRI/SNRI or benzodiazepine utilization and the geographic distance from Puget Sound. Minimal threshold dosing of prazosin correlated positively with increased diffusion of prazosin use, but there was still a distance diffusion gradient. Although prazosin adoption has improved, geographic

  13. Terazosin, doxazosin, and prazosin: current clinical experience.

    PubMed

    Akduman, B; Crawford, E D

    2001-12-01

    Lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction are common in aging men. Nearly 25% of men >40 years of age have LUTS. Medical therapy with alpha-blockade is the most common method of medical therapy for benign prostatic obstruction. Multiple methods of minimally invasive surgical therapies have been introduced in the last decade. These methods include balloon dilatation, temporary and permanent urethral stents, various laser techniques, microwave thermotherapy, transurethral needle ablation, electrovaporization, and high-intensity focused ultrasound. alpha-Receptor blockers to reduce the sympathetic tone of the prostate are considered as first-line therapy to relieve the symptoms of benign prostatic hyperplasia. Selective alpha(1)-receptor blockers relax prostatic smooth muscle, relieve bladder outlet obstruction, and enhance urine flow with fewer side effects. In addition, it was determined that treating patients with alpha-blockers increases prostatic apoptosis. Pharmacokinetic activity, mode of action, clinical efficacy, and side effects of the selective alpha(1)-receptor blockers terazosin, doxazosin, and prazosin are reviewed.

  14. The α1 adrenoceptor antagonist prazosin enhances sleep continuity in fear-conditioned Wistar-Kyoto rats.

    PubMed

    Laitman, Benjamin M; Gajewski, Nicholas D; Mann, Graziella L; Kubin, Leszek; Morrison, Adrian R; Ross, Richard J

    2014-03-03

    Fragmentation of rapid eye movement sleep (REMS) is well described in individuals with posttraumatic stress disorder (PTSD) and likely has significant functional consequences. Fear-conditioned rodents may offer an attractive model of the changes in sleep that characterize PTSD. Following fear conditioning (FC), Wistar-Kyoto (WKY) rats, a strain known to be particularly stress-sensitive, have increased REMS fragmentation that can be quantified as a shift in the distribution of REMS episodes towards the more frequent occurrence of sequential REMS (inter-REMS episode interval≤3 min) vs. single REMS (interval>3 min). The α1 adrenoceptor antagonist prazosin has demonstrated efficacy in normalizing sleep in PTSD. To determine the utility of fear-conditioned WKY rats as a model of sleep disturbances typical of PTSD and as a platform for the development of new treatments, we tested the hypothesis that prazosin would reduce REMS fragmentation in fear-conditioned WKY rats. Sleep parameters and freezing (a standard measure of anxiety in rodents) were quantified at baseline and on Days 1, 7, and 14 following FC, with either prazosin (0.01mg/kg, i.p.) or vehicle injections administered prior to testing in a between-group design. Fear conditioning was achieved by pairing tones with a mild electric foot shock (1.0mA, 0.5s). One, 7, and 14 days following FC, prazosin or vehicle was injected, the tone was presented, freezing was measured, and then sleep was recorded from 11 AM to 3 PM. WKY rats given prazosin, compared to those given vehicle, had a lower amount of seq-REMS relative to total REMS time 14 days after FC. They also had a shorter non-REMS latency and fewer non-REMS arousals at baseline and on Days 1 and 7 after FC. Thus, in FC rats, prazosin reduced both REMS fragmentation and non-REMS discontinuity.

  15. Prazosin versus quetiapine for nighttime posttraumatic stress disorder symptoms in veterans: an assessment of long-term comparative effectiveness and safety.

    PubMed

    Byers, Melanie G; Allison, Kristen M; Wendel, Christopher S; Lee, Jeannie K

    2010-06-01

    Posttraumatic stress disorder (PTSD) is an anxiety disorder experienced by combat veterans. Nighttime symptoms are often unrelieved by selective serotonin reuptake inhibitor therapy, and increased use of prazosin or quetiapine for treatment is seen. The purpose of this study was to determine the short- and long-term effectiveness and safety of prazosin versus quetiapine for treating nighttime symptoms in veteran PTSD patients. This is a historical prospective cohort study using retrospective chart review. Three hundred twenty-four patients with a diagnosis of PTSD, based on International Classification of Diseases, Ninth Revision coding, who were initially prescribed prazosin or quetiapine for nighttime symptoms were screened for inclusion. Short-term effectiveness was determined by documentation of symptomatic improvement within 6 months, and long-term effectiveness if patients continued therapy to study end date. Safety was assessed by comparing incidence of adverse drug effects causing discontinuation of either study drug. This study included 237 patients: 62 received prazosin, and 175 received quetiapine. Short-term effectiveness was similar for prazosin (61.3%) and quetiapine (61.7%; P = 0.54). However, patients prescribed prazosin were significantly more likely to continue their therapy to study end date compared with quetiapine (48.4% vs 24%; P < 0.001; odds ratio, 3.0; 95% confidence interval, 1.62-5.45), thus achieving long-term effectiveness. Alternatively, patients in the quetiapine group were more likely to discontinue therapy because of adverse effects compared with the prazosin group (34.9% vs 17.7%; P = 0.008). Because of similar rate of short-term effectiveness, superior long-term effectiveness, and lower incidence of events leading to discontinuation, compared with quetiapine, prazosin should be used first-line for treating nighttime PTSD symptoms in a veteran population.

  16. Prazosin addition to fluvoxamine: A preclinical study and open clinical trial in OCD.

    PubMed

    Feenstra, Matthijs G P; Klompmakers, André; Figee, Martijn; Fluitman, Sjoerd; Vulink, Nienke; Westenberg, Herman G M; Denys, Damiaan

    2016-02-01

    The efficacy of selective serotonin reuptake inhibitors (SRIs) in psychiatric disorders may be "augmented" through the addition of atypical antipsychotic drugs. A synergistic increase in dopamine (DA) release in the prefrontal cortex has been suggested to underlie this augmentation effect, though the mechanism of action is not clear yet. We used in vivo microdialysis in rats to study DA release following the administration of combinations of fluvoxamine (10 mg/kg) and quetiapine (10 mg/kg) with various monoamine-related drugs. The results confirmed that the selective 5-HT1A antagonist WAY-100635 (0.05 mg/kg) partially blocked the fluvoxamine-quetiapine synergistic effect (maximum DA increase dropped from 325% to 214%). A novel finding is that the α1-adrenergic blocker prazosin (1 mg/kg), combined with fluvoxamine, partially mimicked the effect of augmentation (maximum DA increase 205%; area-under-the-curve 163%). As this suggested that prazosin augmentation might be tested in a clinical study, we performed an open clinical trial of prazosin 20 mg addition to SRI in therapy-resistant patients with obsessive-compulsive disorder applying for neurosurgery. A small, non-significant reduction in Yale Brown Obsessive Compulsive Scale (Y-BOCS) scores was observed in 10 patients and one patient was classified as a responder with a reduction in Y-BOCS scores of more than 25%. We suggest that future clinical studies augmenting SRIs with an α1-adrenergic blocker in less treatment resistant cases should be considered. The clinical trial "Prazosin in combination with a serotonin reuptake inhibitor for patients with Obsessive Compulsive disorder: an open label study" was registered at 24/05/2011 under trial number ISRCTN61562706: http://www.controlled-trials.com/ISRCTN61562706.

  17. The Specific α1-Adrenergic Receptor Antagonist Prazosin Influences the Urine Proteome

    PubMed Central

    Zhao, Mindi; Wu, Jianqiang; Gao, Youhe

    2016-01-01

    Urine, reflecting many changes in the body, is a better source than blood for biomarker discovery. However, even under physiological conditions, the urine proteome often varies. Understanding how various regulating factors affect urine proteome helps link changes to urine proteome with urinary biomarkers of physiological conditions as well as corresponding diseases. To evaluate the possible impact of α1-adrenergic receptor on urine proteome, this study investigated effects of the specific inhibitor prazosin on the urine proteome in a rat model by using tandem mass tagging and two-dimensional liquid chromatography-tandem mass spectrometry. A total of 775 proteins were identified, approximately half of which were influenced by prazosin treatment, indicating that the sympathetic nervous system exerts a significant impact on urine proteome. Eight significantly changed proteins were previously annotated as urinary candidate biomarkers. Angiotensinogen, haptoglobin, and beta-2 microglobulin, which were reported to be associated with blood pressure, were validated via Western blot. Prazosin is widely used in clinical practice; thus, these protein changes should be considered when studying corresponding diseases such as hypertension, post-traumatic stress disorder and benign prostatic hyperplasia. The related physiological activities of α1-receptors, controlling blood pressure and fear response might significantly affect the urine proteome and warrant further biomarker studies. PMID:27780262

  18. Effect of counterions on physicochemical properties of prazosin salts.

    PubMed

    Kumar, Lokesh; Meena, Chhuttan Lal; Pawar, Yogesh B; Wahlang, Banrida; Tikoo, Kulbhushan; Jain, Rahul; Bansal, Arvind K

    2013-03-01

    This study evaluated the effect of counterions on the physicochemical properties of prazosin salts. Salt forms of prazosin, namely, mesylate, besylate, tosylate, camsylate, oxalate, and maleate, were prepared and compared with the marketed anhydrous and polyhydrate forms of prazosin hydrochloride. Physicochemical characterization was performed in the order of crystallinity, hygroscopicity, solubility, and stability to select the optimal salt(s). Permeability study in Caco-2 cell lines and in vivo bioavailability study in rat model were investigated to ascertain their biopharmaceutical advantage. All salt forms were crystalline, nonhygroscopic (except the anhydrous hydrochloride salt), and had solubility in the range of 0.2 to 1.6 mg/ml. All salts were physically and chemically stable at 40°C/75% relative humidity, but degraded in UV-visible light, except the anhydrous hydrochloride salt. Prazosin mesylate was selected as the optimal salt, as it possessed higher solubility, permeability, and bioavailability, compared to the commercial hydrochloride salts. Hydrochloride salt is reported to have poor bioavailability that is partially attributed to its low solubility and extensive common-ion effect in the gastric region. Factors like hydrophilicity of the counterion, hydration state of the salt, and melting point of the salt contribute to the physicochemical properties of the salts. This study has implications in the selection of an optimal salt form for prazosin, which is suitable for further development.

  19. Prazosin, an α(1)-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease.

    PubMed

    Katsouri, Loukia; Vizcaychipi, Marcela P; McArthur, Simon; Harrison, Ian; Suárez-Calvet, Marc; Lleo, Alberto; Lloyd, Dafydd G; Ma, Daqing; Sastre, Magdalena

    2013-04-01

    Noradrenergic deficits have been described in the hippocampus and the frontal cortex of Alzheimer's disease brains, which are secondary to locus coeruleus degeneration. Locus coeruleus is the brain stem nucleus responsible for synthesis of noradrenaline and from where all noradrenergic neurons project. In addition, it has been suggested that noradrenaline might play a role in modulating inflammatory responses in Alzheimer's disease. In this study we aimed to investigate the effect of various agonists and antagonists for adrenergic receptors on amyloid precursor protein processing. Among them, we found that prazosin, an α(1)-adrenoceptor antagonist, was able to reduce the generation of amyloid β in N2a cells. Treatment of transgenic APP23 mice with prazosin prevented memory deficits over time. Although prazosin did not influence amyloid plaque load, it induced astrocytic proliferation and increased the release of apolipoprotein E and anti-inflammatory cytokines. These findings suggest that chronic treatment with prazosin leads to an anti-inflammatory response with potential beneficial effects on cognitive performance.

  20. Cytokine Treatment of Macrophage Suppression of T Cell Activation

    PubMed Central

    Silberman, Daniel; Bucknum, Amanda; Kozlowski, Megan; Matlack, Robin; Riggs, James

    2009-01-01

    High Mφ:T cell ratios suppress the immune response to the retroviral superantigen Mls by IFNγ-triggered production of the arg- and trp-consuming enzymes iNOS and IDO. Attempts to reverse suppression by treatment with pro-inflammatory cytokines revealed that IL-6 improved the T cell response to Mls and the pro-hematopoietic cyokines IL-3 and GM-CSF increased suppression. GM-CSF treatment increased Mφ expression of CD80, a ligand for the immune suppressive B7H1 and CTLA-4 receptors. These results illustrate potential strategies for reversing the suppression of cell-mediated immunity characteristic of the high Mφ:T cell ratios found in many tumors. PMID:19249120

  1. Cytokine treatment of macrophage suppression of T cell activation.

    PubMed

    Silberman, Daniel; Bucknum, Amanda; Kozlowski, Megan; Matlack, Robin; Riggs, James

    2010-01-01

    High Mphi:T cell ratios suppress the immune response to the retroviral superantigen Mls by IFNgamma-triggered production of the arg- and trp-consuming enzymes iNOS and IDO. Attempts to reverse suppression by treatment with pro-inflammatory cytokines revealed that IL-6 improved the T cell response to Mls and the pro-hematopoietic cyokines IL-3 and GM-CSF increased suppression. GM-CSF treatment increased Mphi expression of CD80, a ligand for the immune suppressive B7H1 and CTLA-4 receptors. These results illustrate potential strategies for reversing the suppression of cell-mediated immunity characteristic of the high Mphi:T cell ratios found in many tumors.

  2. A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma PTSD

    DTIC Science & Technology

    2012-06-01

    of Prazosin for Combat Trauma PTSD PRINCIPAL INVESTIGATOR: Murray Raskind, M.D...31 May 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma PTSD 5b. GRANT...controlled trial to evaluate the efficacy and tolerability of the alpha-1 adrenergic antagonist, prazosin , for reducing trauma nightmares and sleep

  3. Systemic or intra-prelimbic cortex infusion of prazosin impairs fear memory reconsolidation.

    PubMed

    Do Monte, Fabricio H; Souza, Rimenez R; Wong, Ting T; Carobrez, Antonio de Padua

    2013-05-01

    The alpha-1 adrenergic antagonist prazosin has been used to alleviate the symptoms of PTSD, but the mechanism remains unclear. One possibility is that prazosin may disrupt fear memory reconsolidation, leading to attenuation of fear responses. To test this hypothesis, we administered a single systemic injection of prazosin during the reconsolidation of olfactory fear conditioning in rats. We found that a post-retrieval injection of prazosin disrupted subsequent retrieval of fear. Similarly, intra-prelimbic cortex infusion of prazosin during the reconsolidation period also disrupted subsequent retrieval of fear. These findings suggest that fear memory undergoes reconsolidation through activation of alpha-1 adrenergic receptors in the prelimbic cortex.

  4. Hazardous fuel treatments, suppression cost impacts, and risk mitigation

    Treesearch

    Matthew P. Thompson; Michael S. Hand; Julie W. Gilbertson-Day; Nicole M. Vaillant; Darek J. Nalle

    2013-01-01

    Land management agencies face uncertain tradeoffs regarding investments in preparedness and fuels management versus future suppression costs and impacts to valued resources and assets. Prospective evaluation of fuel treatments allows for comparison of alternative treatment strategies in terms of socioeconomic and ecological impacts, and can facilitate tradeoff analysis...

  5. Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin.

    PubMed

    Boehnlein, James K; Kinzie, J David

    2007-03-01

    This article reviews the neurobiologic rationale for and presents clinical guidance concerning the use of medications that reduce central nervous system noradrenergic activity in the treatment of intrusive symptoms of posttraumatic stress disorder. The authors reviewed neurobiological studies, nonclinical studies using animal models, clinical case reports, open-label drug studies, and blinded, placebo-controlled drug studies. This review of the basic science and clinical literature, and the authors' clinical experience with culturally and demographically diverse populations, indicate that clonidine and prazosin can play a useful role in treating sleep disturbance and hyperarousal in posttraumatic stress disorder, with minimal adverse effects and low financial cost.

  6. Temperature dependence of the interaction of prazosin with lipid Langmuir monolayers.

    PubMed

    Gzyl-Malcher, Barbara; Handzlik, Jadwiga; Klekowska, Ewelina

    2013-12-01

    The influence of temperature on membrane-prazosin interactions was studied. Prazosin, a quinazoline derivative of 2-furoylpiperazine, is a classic antihypertensive and antiarrhythmic drug. A mixed cholesterol/phospholipid monolayer at the water/air interface was employed as a simplified biomembrane model. Brewster angle microscopy (BAM) was used to visualize the monolayer morphology. It was found that prazosin penetrates Langmuir monolayers and modifies the interactions between membrane components, causing monolayer fluidization. An increase in temperature facilitates penetration of prazosin into the monolayers. Prazosin interacts preferentially with phosphatidylcholine and modifies the morphology of the condensed phase domains of DPPC. In the presence of prazosin, monolayers collapse at lower surface pressures. The difference between the collapse pressures of monolayers on water with and without prazosin increases with temperature.

  7. Low-dose prazosin alone and in combination with propranolol or naltrexone: effects on ethanol and sucrose seeking and self-administration in the P rat.

    PubMed

    Verplaetse, Terril L; Czachowski, Cristine L

    2015-08-01

    Evidence suggests that the noradrenergic system mediates ethanol reinforcement. However, preclinical studies suggest that noradrenergic antagonists block other oral reinforcers indicating possible unwanted secondary medication effects. This study examined combinations of low-dose prazosin with propranolol or naltrexone using a behavioral paradigm that separately assesses reinforcer seeking and self-administration. Male alcohol-preferring (P) rats (n = 20/experiment) were trained to complete a response requirement (RR) resulting in access to 1 % sucrose (n = 10) or 10 % ethanol (n = 10) for 20 min. Rats received vehicle, prazosin alone (0.125, 0.25, 0.5, and 1.0 mg/kg, intraperitoneally (IP)), or prazosin in combination with propranolol (5 mg/kg (IP); Exp. 1) or in combination with naltrexone (0.03 mg/kg, subcutaneously (SC); Exp. 2). For Exp. 1, prazosin alone effectively decreased sucrose seeking more than ethanol seeking, but decreased ethanol self-administration only. Propranolol alone effectively decreased ethanol seeking more than sucrose seeking and decreased ethanol intake only. At some dose combinations, there was a greater attenuation of ethanol and sucrose intake relative to either drug alone. For Exp. 2, prazosin alone and naltrexone alone were effective in decreasing ethanol seeking and intake only. Combination treatment was more effective than either drug alone at decreasing ethanol seeking and consumption and sucrose intake, but not sucrose seeking. Propranolol and naltrexone alone were specific to ethanol indicating that low doses of either medication may be beneficial in treating alcohol use disorders. Prazosin in combination with propranolol or naltrexone was more effective than either drug alone and also reduced sucrose-reinforced behaviors. These data suggest that the noradrenergic system is a viable target for developing treatment approaches for problem drinkers.

  8. Low-Dose Prazosin Alone and in Combination with Propranolol or Naltrexone: Effects on Ethanol- and Sucrose-Seeking and Self-Administration in the P Rat

    PubMed Central

    Verplaetse, Terril L.; Czachowski, Cristine L.

    2015-01-01

    Rationale Evidence suggests that the noradrenergic system mediates ethanol-reinforcement. However, preclinical studies suggest that noradrenergic antagonists block other oral reinforcers indicating possible unwanted secondary medication effects. Methods This study examined combinations of low-dose prazosin with propranolol or naltrexone using a behavioral paradigm that separately assesses reinforcer-seeking and self-administration. Male alcohol-preferring (P) rats (n=20/experiment) were trained to complete a response requirement (RR) resulting in access to 1% sucrose (n=10) or 10% ethanol (n=10) for 20min. Rats received vehicle, prazosin alone (0.125, 0.25, 0.5, 1.0 mg/kg; intraperitoneally (IP)) or prazosin in combination with propranolol (5 mg/kg (IP); Exp1) or in combination with naltrexone (0.03 mg/kg (subcutaneously (SC); Exp2). Results For Exp1, prazosin alone effectively decreased sucrose-seeking more than ethanol-seeking, but decreased ethanol self-administration only. Propranolol alone effectively decreased ethanol-seeking more than sucrose-seeking and decreased ethanol intake only. At some dose combinations, there was a greater attenuation of ethanol and sucrose intake relative to either drug alone. For Exp2, prazosin alone and naltrexone alone were effective in decreasing ethanol-seeking and intake only. Combination treatment was more effective than either drug alone at decreasing ethanol-seeking and consumption and sucrose intake, but not sucrose-seeking. Conclusions Propranolol and naltrexone alone were specific to ethanol indicating that low doses of either medication may be beneficial in treating alcohol use disorders. Prazosin in combination with propranolol or naltrexone was more effective than either drug alone, but also reduced sucrose-reinforced behaviors. These data suggest that the noradrenergic system is a viable target for developing treatment approaches for problem drinkers. PMID:25743758

  9. The Measurement and Treatment of Suppression in Amblyopia

    PubMed Central

    Black, Joanna M.; Hess, Robert F.; Cooperstock, Jeremy R.; To, Long; Thompson, Benjamin

    2012-01-01

    performance advantage is a measure of the "balance point" and is a direct measure of suppression. This technique has been validated psychophysically both in control13,14 and patient6,9,11 populations. In addition to measuring suppression this technique also forms the basis of a novel form of treatment to decrease suppression over time and improve binocular and often monocular function in adult patients with amblyopia12,15,16 . This new treatment approach can be deployed either on the goggle system described above or on a specially modified iPod touch device15. PMID:23271400

  10. Targeting the Noradrenergic System in Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis of Prazosin Trials.

    PubMed

    De Berardis, Domenico; Marini, Stefano; Serroni, Nicola; Iasevoli, Felice; Tomasetti, Carmine; de Bartolomeis, Andrea; Mazza, Monica; Tempesta, Daniela; Valchera, Alessandro; Fornaro, Michele; Pompili, Maurizio; Sepede, Gianna; Vellante, Federica; Orsolini, Laura; Martinotti, Giovanni; Di Giannantonio, Massimo

    2015-01-01

    Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder that may develop after exposure to a life-threatening trauma. As veterans and armed forces may deal with diverse health problems compared with civilians, they have a greater risk for psychiatric disorders, including PTSD, than civilians, even if the disorder may be also frequent in the general population. PTSD is associated with significant comorbidity, especially with mood disorders and substance abuse. Moreover, the suicide risk is higher in PTSD patients than in the general population. Selective Serotonin Reuptake Inhibitors (SSRIs), atypical antipsychotics and benzodiazepines are commonly employed in the management of PTSD, but often these treatments fail or are discontinued due to adverse effects. It has been demonstrated that high noradrenergic activity may be associated with hyperarousal, trauma nightmares and sleep disturbances in PTSD subjects, probably through the stimulation of α -1 adrenergic receptors in the brain prefrontal cortex. The α -1 adrenoreceptor antagonist prazosin decreases noradrenaline effects at brain α-1 adrenoreceptors and may be a promising agent in the treatment of PTSD, as some studies have found it effective and well tolerated. Therefore, the present review is aimed to examine the role of noradrenergic system in the pathophysiology of PTSD. Moreover, we conducted a systematic review to evaluate the effectiveness and tolerability of prazosin in PTSD patients. Meta-analysis was used to combine data from multiple studies and better estimate the effect of prazosin on specific outcomes. We found prazosin to be significantly more efficacious than placebo in reducing distressing dreams in PTSD patients, even though our results should be interpreted with caution due to the small number of studies included in our quantitative synthesis.

  11. A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma PTSD

    DTIC Science & Technology

    2011-06-01

    08-2-0069 TITLE: A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma PTSD PRINCIPAL INVESTIGATOR: Murray...2011Annual01-06-2011 A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma PTSD Murray Raskind Seattle Institute for Biomedical/Clinical...and tolerability of the alpha-1 adrenergic antagonist, prazosin , for reducing trauma nightmares and sleep disturbance and improving global

  12. A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma PTSD

    DTIC Science & Technology

    2009-06-01

    of Prazosin for Combat Trauma PTSD PRINCIPAL INVESTIGATOR: Murray Raskind, M.D. Elaine Peskind, M.D. Kris Peterson...2008 – 31 May 2009 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma PTSD 5b...group, randomized placebo controlled trial to evaluate the efficacy and tolerability of the alpha-1 adrenergic antagonist, prazosin , for reducing trauma

  13. Molecular features of the prazosin molecule required for activation of Transport-P.

    PubMed

    da Silva, Joaquim Fernando Mendes; Walters, Marcus; Al-Damluji, Saad; Ganellin, C Robin

    2008-08-01

    Closely related structural analogues of prazosin have been synthesised and tested for inhibition and activation of Transport-P in order to identify the structural features of the prazosin molecule that appear to be necessary for activation of Transport-P. So far, all the compounds tested are less active than prazosin. It is shown that the structure of prazosin appears to be very specific for the activation. Only quinazolines have been found to activate, and the presence of the 6,7-dimethoxy and 4-amino groups appears to be critically important.

  14. Optimal Treatment Strategy for a Tumor Model under Immune Suppression

    PubMed Central

    Kim, Kwang Su; Cho, Giphil; Jung, Il Hyo

    2014-01-01

    We propose a mathematical model describing tumor-immune interactions under immune suppression. These days evidences indicate that the immune suppression related to cancer contributes to its progression. The mathematical model for tumor-immune interactions would provide a new methodology for more sophisticated treatment options of cancer. To do this we have developed a system of 11 ordinary differential equations including the movement, interaction, and activation of NK cells, CD8+T-cells, CD4+T cells, regulatory T cells, and dendritic cells under the presence of tumor and cytokines and the immune interactions. In addition, we apply two control therapies, immunotherapy and chemotherapy to the model in order to control growth of tumor. Using optimal control theory and numerical simulations, we obtain appropriate treatment strategies according to the ratio of the cost for two therapies, which suggest an optimal timing of each administration for the two types of models, without and with immunosuppressive effects. These results mean that the immune suppression can have an influence on treatment strategies for cancer. PMID:25140193

  15. Prazosin + naltrexone decreases alcohol drinking more effectively than does either drug alone in P rats with a protracted history of extensive voluntary alcohol drinking, dependence and multiple withdrawals

    PubMed Central

    Rasmussen, Dennis D; Kincaid, Carrie L; Froehlich, Janice C

    2015-01-01

    Background Prazosin (PRZ, an α1-adrenergic receptor antagonist) and naltrexone (NTX, a non-specific opioid receptor antagonist) each decrease alcohol drinking when administered to rats selectively-bred for high voluntary alcohol drinking (alcohol-preferring, or “P”), and the combination of PRZ+NTX decreases alcohol drinking more effectively than does either drug alone. Since drug responsiveness can depend on history of alcohol drinking and dependence, we investigated whether various schedules of PRZ and NTX administration, alone or in combination, are effective in decreasing alcohol drinking in male P rats with a history of protracted voluntary alcohol drinking, dependence and repeated withdrawals closely resembling human alcoholism. Methods Male P rats became alcohol-dependent during 1 year of ad libitum 24 h/day access to food, water and 20% alcohol with repetitive temporary alcohol withdrawals. Four sequential studies then addressed effects of oral PRZ (2 mg/kg) and NTX (10 mg/kg), alone or together, on alcohol drinking during: 1) daily alcohol access with daily drug treatment, 2) intermittent alcohol access with daily drug treatment, 3) intermittent alcohol access with occasional drug treatment, and 4) post-deprivation reinstatement of alcohol access. Results The combination of PRZ+NTX consistently suppressed alcohol drinking during daily or intermittent alcohol access conditions and when drug treatment was either daily or occasional. PRZ+NTX was consistently more effective than either drug alone. The reduction in alcohol drinking was not due to sedation, motor effects or malaise. Conclusions Both daily and “as-needed” treatment with PRZ+NTX are highly effective in suppressing daily, intermittent and post-deprivation alcohol drinking in male P rats with a protracted history of alcohol dependence and repeated withdrawals. This drug combination may be especially effective for treating individuals with long histories of heavy alcohol abuse, dependence and

  16. Prazosin + Naltrexone Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone in P Rats with a Protracted History of Extensive Voluntary Alcohol Drinking, Dependence, and Multiple Withdrawals.

    PubMed

    Rasmussen, Dennis D; Kincaid, Carrie L; Froehlich, Janice C

    2015-09-01

    Prazosin (PRZ; an α1 -adrenergic receptor antagonist) and naltrexone (NTX; a nonspecific opioid receptor antagonist) each decrease alcohol drinking when administered to rats selectively bred for high voluntary alcohol drinking (alcohol-preferring or "P"), and the combination of PRZ + NTX decreases alcohol drinking more effectively than does either drug alone. As drug responsiveness can depend on history of alcohol drinking and dependence, we investigated whether various schedules of PRZ and NTX administration, alone or in combination, are effective in decreasing alcohol drinking in male P rats with a history of protracted voluntary alcohol drinking, dependence, and repeated withdrawals closely resembling human alcoholism. Male P rats became alcohol-dependent during 1 year of ad libitum 24 h/d access to food, water, and 20% alcohol with repetitive temporary alcohol withdrawals. Four sequential studies then addressed effects of oral PRZ (2 mg/kg) and NTX (10 mg/kg), alone or together, on alcohol drinking during: (i) daily alcohol access with daily drug treatment, (ii) intermittent alcohol access with daily drug treatment, (iii) intermittent alcohol access with occasional drug treatment, and (iv) postdeprivation reinstatement of alcohol access. The combination of PRZ + NTX consistently suppressed alcohol drinking during daily or intermittent alcohol access conditions and when drug treatment was either daily or occasional. PRZ + NTX was consistently more effective than either drug alone. The reduction in alcohol drinking was not due to sedation, motor effects, or malaise. Both daily and "as-needed" treatment with PRZ + NTX are highly effective in suppressing daily, intermittent, and postdeprivation alcohol drinking in male P rats with a protracted history of alcohol dependence and repeated withdrawals. This drug combination may be especially effective for treating individuals with long histories of heavy alcohol abuse, dependence, and repeated relapse, as commonly

  17. A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma PTSD

    DTIC Science & Technology

    2013-08-01

    of Prazosin for Combat Trauma PTSD PRINCIPAL INVESTIGATOR: Murray Raskind, MD CONTRACTING ORGANIZATION: Seattle Institute for...Final Revised 3. DATES COVERED 1 June 2008 – 31 May 2013 4. TITLE AND SUBTITLE A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma ...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Trauma content nightmares and sleep disturbance are among the most

  18. Prazosin displays anticancer activity against human prostate cancers: targeting DNA and cell cycle.

    PubMed

    Lin, Ssu-Chia; Chueh, Shih-Chieh; Hsiao, Che-Jen; Li, Tsia-Kun; Chen, Tzu-Hsuan; Liao, Cho-Hwa; Lyu, Ping-Chiang; Guh, Jih-Hwa

    2007-10-01

    Quinazoline-based alpha1-adrenoceptor antagonists, in particular doxazosin and terazosin, are suggested to display antineoplastic activity against prostate cancers. However, there are few studies elucidating the effect of prazosin. In this study, prazosin displayed antiproliferative activity superior to that of other alpha1-blockers, including doxazosin, terazosin, tamsulosin, and phentolamine. Prazosin induced G2 checkpoint arrest and subsequent apoptosis in prostate cancer PC-3, DU-145, and LNCaP cells. In p53-null PC-3 cells, prazosin induced an increase in DNA strand breaks and ATM/ATR checkpoint pathways, leading to the activation of downstream signaling cascades, including Cdc25c phosphorylation at Ser216, nuclear export of Cdc25c, and cyclin-dependent kinase (Cdk) 1 phosphorylation at Tyr15. The data, together with sustained elevated cyclin A levels (other than cyclin B1 levels), suggested that Cdk1 activity was inactivated by prazosin. Moreover, prazosin triggered mitochondria-mediated and caspase-executed apoptotic pathways in PC-3 cells. The oral administration of prazosin significantly reduced tumor mass in PC-3-derived cancer xenografts in nude mice. In summary, we suggest that prazosin is a potential antitumor agent that induces cell apoptosis through the induction of DNA damage stress, leading to Cdk1 inactivation and G2 checkpoint arrest. Subsequently, mitochondria-mediated caspase cascades are triggered to induce apoptosis in PC-3 cells.

  19. High-performance liquid chromatography using electrochemical detection for the determination of prazosin in biological samples.

    PubMed

    Rathinavelu, A; Malave, A

    1995-08-04

    For the quantitation of prazosin a sensitive high-performance liquid chromatographic (HPLC) method was developed. This HPLC analysis method uses an electrochemical detection technique for the identification and quantitation of prazosin. In this assay the serum samples were deproteinized by using a simple acetonitrile precipitation technique that was followed by n-hexane extraction. Prazosin in the deproteinized serum sample was separated by an isocratic elution with an ODS Hypersil HPLC column (150 x 4.6 mm) using a mobile phase consisting of 0.05 M Na2HPO4-acetonitrile (60:40), pH 8.4. Prazosin that was eluted from the column was detected using a Coulochem II electrochemical detector. The precision of this assay method was assessed by performing inter- and intra-assay analyses by spiking prazosin free fetal bovine serum samples with 20 and 40 ng/ml concentrations of prazosin. In the intra-assay the recovery was 95.40 +/- 4.82% and 97.80 +/- 3.40%, respectively, for 20 and 40 ng/ml concentrations of prazosin that were used to spike the serum samples. This electrochemical detection HPLC assay method could be very useful in monitoring plasma levels of prazosin.

  20. A Placebo-Controlled Trial of Prazosin vs. Paroxetine in Combat Stress-Induced PTSD Nightmares and Sleep Disturbance

    DTIC Science & Technology

    2007-03-01

    AD_________________ Award Number: W81XWH-06-1-0014 TITLE: A Placebo-Controlled Trial of Prazosin ...06 – 22 Feb 07 4. TITLE AND SUBTITLE A Placebo-Controlled Trial of Prazosin vs. Paroxetine in Combat Stress-Induced 5a...adrenergic antagonist prazosin compared to placebo for combat trauma-related nightmares, sleep disturbance and overall function in recently combat

  1. Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS).

    PubMed

    Erve, J C L; Vashishtha, S C; Ojewoye, O; Adedoyin, A; Espina, R; Demaio, W; Talaat, R E

    2008-05-01

    1. Prazosin, 2-[4-(2-furanoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline, is an antihypertensive agent that has been used safely since 1976 and is currently being investigated for the treatment of post-traumatic stress disorder. The in vivo metabolism of prazosin in rat was first reported in 1977, although at the time analytical techniques were not as sophisticated, nor were the mass spectrometers as sensitive, as today. Recently, the in vitro metabolism of prazosin in rat liver microsomes and cryopreserved hepatocytes was investigated using liquid chromatography/mass spectrometry (LC/MS), which revealed new metabolic pathways. 2. In the present work, rat in vivo metabolism was reinvestigated using a quadrupole time-of-flight mass spectrometer coupled with ultra-performance liquid chromatography, or chip-based nanoflow electrospray ionization, with the aim of identifying metabolites revealed by the in vitro studies and any new metabolites. 3. It is reported that prazosin was metabolized in rats to produce the metabolites observed in vitro. In addition, new phase I metabolites, M18, M20 and M21, were formed and conjugation with glucose or taurine formed the new phase II metabolites, M16 and M19, respectively. 4. Evidence for bioactivation of prazosin included detection of ring-opened metabolites (M4 and M7) and a cysteinyl-glycine conjugate (M17). Further support to the structure of the ring-opened metabolite M7 was obtained by nuclear magnetic resonance (NMR) experiments on M7 isolated from urine.

  2. Long-term effect of prazosin administration on blood pressure, heart and structure of coronary artery of young spontaneously hypertensive rats.

    PubMed

    Kristek, F; Koprdova, R

    2011-06-01

    The sympathetic nervous system belongs to the essential systems participating in blood pressure (BP) regulation. Inhibitory intervention into the key point of its operation (alfa 1 adrenoceptors) in the prehypertensive period of spontaneously hypertensive rats (SHR) might affect the development of the hypertension in later ontogenic periods. We studied the long-term effect of prazosin administration on the cardiovascular system of young Wistar rats and SHR. Four-week-old animals were used: Wistar rats, SHR, and Wistar rats and SHR receiving prazosin (10 mg/kg/day in tap water) by gavage. Blood pressure (BP) was measured weekly by the plethysmographic method. After six weeks under anaesthesia, the carotid artery was cannulated for BP registration, and the jugular vein was cannulated for administration of drugs. Afterwards, the animals were perfused with a glutaraldehyde fixative at a pressure of 120 mmHg. The septal branch of the left descending coronary artery was processed using electron microscopy. The prazosin administration evoked the following results in both groups: a decrease of BP and heart/body weight ratio, enhancement of hypotensive responses to acetylcholine (0.1 μg, 1 μg, and 10 μg), and an increase in the inner diameter of the coronary artery without changes in wall thickness, cross sectional area (CSA) (tunica intima+media), CSA of smooth muscle cells, and extracellular matrix. In the SHR group, a reduction was observed in BP increase after noradrenaline (1 μg) application. CSA of endothelial cells which was decreased in the SHR (compared to the control Wistar rats) was increased after prazosin treatment (up to control value). Long-term prazosin administration from early ontogeny partially prevented some pathological alterations in the cardiovascular system of SHR.

  3. Efficacy of scorpion antivenom plus prazosin versus prazosin alone for Mesobuthus tamulus scorpion sting envenomation in children: a randomised controlled trial.

    PubMed

    Pandi, Karuppiah; Krishnamurthy, Sriram; Srinivasaraghavan, Rangan; Mahadevan, Subramanian

    2014-06-01

    To assess the efficacy of combined use of scorpion antivenom (SAV) with prazosin, compared with prazosin alone in children with Mesobuthus tamulus scorpion envenomation. Randomised controlled trial. A tertiary care hospital in south India. 50 children with definite history and/or systemic manifestations of scorpion envenomation were recruited from the paediatric emergency or outpatient department from February 2012 to July 2013. The children were randomised into two groups. In 25 children, SAV was administrated as a slow intravenous bolus combined with prazosin (group A). Others received prazosin alone (group B). Results were analysed by Student t test and χ(2) test. Time required for resolution of autonomic symptoms, total dose of prazosin, adverse events. Children in group A recovered earlier than those in group B (mean difference 9.1 h, 95% CI 6.0 to 12.2). 23 children (92%) in group A were clear of autonomic symptoms within 10 h, compared with 10 children (40%) in group B (mean difference 52%, 95% CI 29% to 75%). The proportion of children deteriorating to clinical grade 3 or 4 was 8% in group A as against 44% in group B (p<0.01). The mean dose of prazosin required was 54 µg/kg versus 130.8 µg/kg in group A and B, respectively (p<0.01). SAV was not associated with severe adverse reactions. Usage of SAV led to faster recovery and reduced the incidence of myocardial dysfunction. Combined therapy with SAV and prazosin is beneficial for children with M tamulus scorpion envenomation. CTRI/2013/09/004002 (Clinical Trials Registry of India). 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.

  4. [Suppression of cycling activity in sheep using parenteral progestagen treatment].

    PubMed

    Janett, F; Camponovo, L; Lanker, U; Hässig, M; Thun, R

    2004-03-01

    The objective of this study was to evaluate the effect of two synthetic progestagen preparations Chlormadinone acetate (CAP, Chronosyn, Veterinaria AG Zürich) and Medroxyprogesterone acetate (MPA, Nadigest, G Streuli & Co. Uznach) on cycling activity and fertility in sheep. A flock of 28 non pregnant white alpine sheep was randomly divided into three groups, A (n = 10), B (n = 9) and C (n = 9). During a period of 4 weeks the cycling activity was confirmed by blood progesterone analysis. Thereafter, the animals of group A were treated with 50 mg CAP, those of group B with 140 mg MPA and those of group C with physiological saline solution. All injections were given intramuscularly. Suppression of endogenous progesterone secretion lasted from 28 to 49 days (mean = 39 days) in group A and from 42 to 70 days (mean = 50 days) in group B. The synchronization effect of both preparations was unsatisfactory as the occurrence of first estrus was distributed over a period of 3 weeks in group A and 4 weeks in group B. These findings could also be confirmed by the lambing period which lasted 52 days in group A and 36 days in group B. Control animals lambed within 9 days due to the synchronizing effect of the ram. The first fertile estrus was observed 36 days (group A) and 45 days (group B) after the treatment. In group A all 10 animals and in groups B and C 8 of 9 ewes each became pregnant. Parenteral progestagen application with CAP and MPA is a simple, safe and reversible method of estrus suppression in the sheep. The minimal suppressive duration of 4 (CAP) and 5 weeks (MPA) is not sufficient when a period of 3 months (alpine pasture period) is desired.

  5. Prazosin for Treatment With PTSD And Comorbid Alcohol Dependence

    DTIC Science & Technology

    2010-07-01

    There is a high rate of comorbidity with alcohol dependence (AD) and post traumatic stress disorder (PTSD). The rates of PTSD among individuals with...AD are at least twice as high as those in the general population. In addition, alcohol dependence is the most common comorbid condition in men with...sleep disturbance in combat veterans with PTSD and alcohol dependence . The objective of this study is to evaluate the efficacy of prazosis (16mg

  6. The action of prazosin and propylene glycol on methoxamine-induced bronchoconstriction in asthmatic subjects.

    PubMed Central

    Black, J L; Salome, C; Yan, K; Shaw, J

    1984-01-01

    The effect of 1 mg inhaled prazosin on bronchoconstriction induced by methoxamine was investigated in seven asthmatic subjects. Prazosin caused significant inhibition of the methoxamine-induced bronchoconstriction in six of the seven patients. These findings suggest that methoxamine produces bronchoconstriction in asthmatic subjects via stimulation of alpha-adrenoceptors. In previous studies propylene glycol has been used as a vehicle for delivery of prazosin. This substance was found to cause significant inhibition of methoxamine effects and to shift the dose response curve to histamine to the right in four of seven patients. PMID:6487474

  7. Fire behavior, fuel treatments, and fire suppression on the Hayman Fire - Part 5: Fire suppression activities

    Treesearch

    Charles W. McHugh; Paul Gleason

    2003-01-01

    The purpose of this report is to document the suppression actions taken during the Hayman Fire. The long duration of suppression activities (June 8 through July 18), and multiple incident management teams assigned to the fire, makes this a challenging task. Original records and reports produced independently by the various teams assigned to different portions of the...

  8. Interaction of prazosin with model membranes--a Langmuir monolayer study.

    PubMed

    Gzyl-Malcher, Barbara; Handzlik, Jadwiga; Klekowska, Ewelina

    2012-10-01

    In this study, the effect of prazosin on the molecular interactions between cholesterol and 1,2-dipalmitoylphosphatidylcholine (DPPC) within a monolayer at an air-water interface was studied. A mixed cholesterol/DPPC monolayer was employed as a model lipid membrane. From a detailed analysis of surface pressure-area isotherms, it was concluded that DPPC and cholesterol were miscible and formed non-ideal monolayers on prazosin solution. The thermodynamic stability of the mixed monolayers was investigated by analyzing the free energy of mixing. It was found that the mixed monolayers were more stable than the single component monolayers. Monolayers spread over a subphase with prazosin were more compressible than those spread on pure water. To quantify the effect of prazosin on the monolayer stability, the Gibbs free energy due to the presence of prazosin in the water subphase was calculated. It was found that prazosin penetrated and destabilized mixed cholesterol/DPPC monolayers. However, a comparison of the drug penetration into the pure DPPC monolayer and the mixed cholesterol/DPPC monolayer showed that the presence of cholesterol in the DPPC monolayer considerably restricted the drug penetration.

  9. Inhibition of human ether-a-go-go-related gene potassium channels by alpha 1-adrenoceptor antagonists prazosin, doxazosin, and terazosin.

    PubMed

    Thomas, Dierk; Wimmer, Anna-Britt; Wu, Kezhong; Hammerling, Bettina C; Ficker, Eckhard K; Kuryshev, Yuri A; Kiehn, Johann; Katus, Hugo A; Schoels, Wolfgang; Karle, Christoph A

    2004-05-01

    Human ether-a-go-go-related gene (HERG) potassium channels are expressed in multiple tissues including the heart and adenocarcinomas. In cardiomyocytes, HERG encodes the alpha-subunit underlying the rapid component of the delayed rectifier potassium current, I(Kr), and pharmacological reduction of HERG currents may cause acquired long QT syndrome. In addition, HERG currents have been shown to be involved in the regulation of cell proliferation and apoptosis. Selective alpha 1-adrenoceptor antagonists are commonly used in the treatment of hypertension and benign prostatic hyperplasia. Recently, doxazosin has been associated with an increased risk of heart failure. Moreover, quinazoline-derived alpha 1-inhibitors induce apoptosis in cardiomyocytes and prostate tumor cells independently of alpha1-adrenoceptor blockade. To assess the action of the effects of prazosin, doxazosin, and terazosin on HERG currents, we investigated their acute electrophysiological effects on cloned HERG potassium channels heterologously expressed in Xenopus oocytes and HEK 293 cells.Prazosin, doxazosin, and terazosin blocked HERG currents in Xenopus oocytes with IC(50) values of 10.1, 18.2, and 113.2 microM respectively, whereas the IC(50) values for HERG channel inhibition in human HEK 293 cells were 1.57 microM, 585.1 nM, and 17.7 microM. Detailed biophysical studies revealed that inhibition by the prototype alpha 1-blocker prazosin occurred in closed, open, and inactivated channels. Analysis of the voltage-dependence of block displayed a reduction of inhibition at positive membrane potentials. Frequency-dependence was not observed. Prazosin caused a negative shift in the voltage-dependence of both activation (-3.8 mV) and inactivation (-9.4 mV). The S6 mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) HERG current blockade, indicating that prazosin binds to a common drug receptor within the pore-S6 region. In conclusion, this study demonstrates that HERG

  10. A Placebo-Controlled Trial of Prazosin vs. Paroxetine in Combat Stress-Induced PTSD Nightmares and Sleep Disturbance

    DTIC Science & Technology

    2008-03-01

    AD_________________ Award Number: W81XWH-06-2-0014 TITLE: A Placebo-Controlled Trial of Prazosin ...CONTRACT NUMBER A Placebo-Controlled Trial of Prazosin vs. Paroxetine in Combat Stress-Induced PTSD Nightmares and Sleep Disturbance 5b. GRANT...proposal is to evaluate the efficacy and tolerability of the alpha-1 adrenergic antagonist prazosin compared to placebo for combat trauma-related

  11. A Placebo-Controlled Trial of Prazosin vs. Paroxetine in Combat Stress-Induced PTSD Nightmares and Sleep Disturbance

    DTIC Science & Technology

    2009-03-01

    AD_________________ Award Number: W81XWH-06-2-0014 TITLE: A Placebo-Controlled Trial of Prazosin ...CONTRACT NUMBER A Placebo-Controlled Trial of Prazosin vs. Paroxetine in Combat Stress-Induced PTSD Nightmares and Sleep Disturbance 5b. GRANT NUMBER...proposal is to evaluate the efficacy and tolerability of the alpha-1 adrenergic antagonist prazosin compared to placebo for combat trauma-related

  12. Lgr4 Expression in Osteoblastic Cells Is Suppressed by Hydrogen Peroxide Treatment.

    PubMed

    Pawaputanon Na Mahasarakham, Chantida; Izu, Yayoi; Nishimori, Katsuhiko; Izumi, Yuichi; Noda, Masaki; Ezura, Yoichi

    2017-07-01

    LGR4 is expressed in bone and has been shown to be involved in bone metabolism. Oxidative stress is one of the key issues in pathophysiology of osteoporosis. However, the link between Lgr4 and oxidative stress has not been known. Therefore, effects of hydrogen peroxide on Lgr4 expression in osteoblasts were examined. Hydrogen peroxide treatment suppressed the levels of Lgr4 mRNA expression in an osteoblastic cell line, MC3T3-E1. The suppressive effects were not obvious at 0.1 mM, while 1 mM hydrogen peroxide suppressed Lgr4 expression by more than 50%. Hydrogen peroxide treatment suppressed Lgr4 expression within 12 h and this suppression lasted at least up to 48 h. Hydrogen peroxide suppression of Lgr4 expression was still observed in the presence of a transcription inhibitor but was no longer observed in the presence of a protein synthesis inhibitor. Although Lgr4 expression in osteoblasts is enhanced by BMP2 treatment as reported before, hydrogen peroxide treatment suppressed Lgr4 even in the presence of BMP2. Finally, hydrogen peroxide suppressed Lgr4 expression in primary cultures of osteoblasts similarly to MC3T3-E1 cells. These date indicate that hydrogen peroxide suppresses Lgr4 expression in osteoblastic cells. J. Cell. Physiol. 232: 1761-1766, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  13. Class I and III antiarrhythmic actions of prazosin in guinea-pig papillary muscles.

    PubMed Central

    Pérez, O.; Valenzuela, C.; Delpón, E.; Tamargo, J.

    1994-01-01

    1. The electrophysiological effects of prazosin, a highly specific alpha 1-adrenoceptor antagonist, on transmembrane action potential characteristics were studied in guinea-pig papillary muscles. 2. At concentrations between 10(-6) M and 10(-5) M, prazosin produced a concentration-dependent decrease in the maximum upstroke velocity (Vmax) and a progressive lengthening of the action potential duration at 50% (APD50) and 90% (APD90) of repolarization. The prolongation of the APD50 and APD90 values was independent of the frequency of stimulation. The prolongation of the ADP90 was accompanied by a parallel lengthening of the effective refractory period (ERP) and thus, the ERP/APD90 ratio remained unaltered at all drug concentrations tested. 3. In the presence of prazosin, 5 x 10(-6) M, the percentage of Vmax block increased with the frequency of stimulation, the inhibitory effect being more marked at fast driving rates (frequency-dependent Vmax block). At 3 Hz, the onset kinetics of the frequency-dependent Vmax block was better fitted by a biexponential function, the K values of the fast (K1) and slow components (K2) being 0.254 +/- 0.037 AP-1 and 0.045 +/- 0.010 AP-1, respectively. However, prazosin did not produce tonic Vmax block. 4. The recovery time constant (tau re) from the frequency-dependent Vmax block was prolonged from 19.6 +/- 2.5 ms to 24.4 +/- 5.5 s. This result indicated that prazosin can be considered as a slow kinetics Na channel blocker. 5. Prazosin, 5 x 10(-6) M, shifted the membrane responsiveness curve in a hyperpolarizing direction, which indicated that the blockade of sodium channels increased at less negative potentials (voltage-dependent Vmax block).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8019750

  14. Voltammetric and spectrophotometric techniques for the determination of the antihypertensive drug Prazosin in urine and formulations.

    PubMed

    Arranz, A; de Betoño, S F; Echevarria, C; Moreda, J M; Cid, A; Valentín, J F

    1999-12-01

    A sensitive method was developed to determine Prazosin using a nafion modified carbon paste electrode (NMCPE). Prazosin was accumulated at a potential of 750 mV in Britton-Robinson buffer (pH 6.0) and then a negative sweep was made obtaining a cathodic peak close to 0 V. Cyclic voltammetric studies indicated that the process was quasi-reversible, and fundamentally controlled by adsorption. To obtain a good sensitivity, the instrumental and accumulation variables were studied using differential pulse voltammetry (DPV). Adsorptive voltammetric peak currents showed a linear response for Prazosin concentrations in the range between 4.0 x 10(-11) and 4.0 x 10(-8) M with two different slopes, and a detection limit (LOD) of 3.1 x 10(-11)M was obtained. The variation coefficient (CV) for a 8.0 x 10(-10) M solution (n = 10) was 4.08%. A spectrophotometric study of Prazosin was also carried out and two absorption bands were obtained at 246 and 329 nm (pH 1.8). The band at 329 nm was pH-dependent and its height and position changed with the pH values, so this allowed the pK'a determination (7.14 +/- 0.20) using different methods. The detection limit reached by means of UV-spectrophotometry was 0.9 x 10(-7) M, and the variation coefficient for 1.5 x 10(-5) M Prazosin solutions was 1.14% (n = 10). Although the sensitivity of the UV-spectrophotometric method was lower than that obtained using adsorptive stripping-differential pulse voltammetry (AdS-DPV), it could be applied to the determination of Prazosin in Minipres tablets. The voltammetric method was used for the determination of the drug in human urine samples at trace levels with good recoveries.

  15. Quiet engine program: Turbine noise suppression. -Volume 1: General treatment evaluation and measurement techniques

    NASA Technical Reports Server (NTRS)

    Clemons, A.; Hehmann, H.; Radecki, K.

    1973-01-01

    Acoustic treatment was developed for jet engine turbine noise suppression. Acoustic impedance and duct transmission loss measurements were made for various suppression systems. An environmental compatibility study on several material types having suppression characteristics is presented. Two sets of engine hardware were designed and are described along with engine test results which include probe, farfield, near field, and acoustic directional array data. Comparisons of the expected and the measured suppression levels are given as well as a discussion of test results and design techniques.

  16. Binding of [3H]-prazosin and [3H]-dihydroergocryptine to rat cardiac alpha-adrenoceptors.

    PubMed Central

    Guicheney, P.; Meyer, P.

    1981-01-01

    1 [3H]-prazosin binds specifically to a single class of alpha-adrenoceptors in rat cardiac membranes (KD25 degrees C = 0.2 nM). 2 That these receptors are of the alpha 1-type was indicated by competition studies, i.e. alpha 1-antagonists such as prazosin and (2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1, 4-benzodioxane (WB 4101) were more potent than the alpha 2-antagonists, yohimbine and piperoxan in inhibiting [3H]-prazosin binding. 3 A comparative study of [3H]-prazosin binding and [3H]-dihydroergocryptine binding to cardiac membranes showed that both [3H]-prazosin and [3H]-dihydroergocryptine (at low concentrations) bind to alpha 2-adrenoceptors, while [3H]-dihydroergocryptine (at higher concentrations) also binds to another class of sites. PMID:6269682

  17. Effects of modafinil and prazosin on cognitive and physiological functions in healthy volunteers.

    PubMed

    Winder-Rhodes, S E; Chamberlain, S R; Idris, M I; Robbins, T W; Sahakian, B J; Müller, U

    2010-11-01

    Previous research has demonstrated cognitive-enhancing effects of modafinil in humans and generated evidence for its therapeutic potential in psychiatric disorders. The neurochemical basis of these effects remains unresolved although a role for α1-adrenoceptors has been hypothesised. In this within-subject, double-blind, placebo-controlled study, 12 healthy male adults received modafinil (300 mg), the α1-adrenoceptor antagonist prazosin (3 mg), both together and placebo on separate occasions at least 5 days apart. Cognitive effects were assessed using a well-validated testing battery focusing on executive and working memory functions. Blood pressure, heart rate and salivary α-amylase (sAA) were measured at hourly intervals. Cognitive effects of modafinil and prazosin were identified at the difficult levels of the One-Touch Stockings of Cambridge (OTSOC) planning task. Prazosin antagonized the error-reducing effect of modafinil when the agents were given together. In contrast, the combined agents acted synergistically to increase time taken to complete OTSOC problems compared with placebo. The tachycardic and sAA-elevating effects of prazosin were also potentiated by concurrent modafinil administration. The current data suggest that the cognitive effects of modafinil on performance accuracy and latency are dissociable in terms of their neurochemical mechanisms. Our findings support the hypothesised involvement of α1-adrenoceptors in some of the cognitive-enhancing effects of modafinil and warrant further investigation.

  18. Pharmacology of appetite suppression: implication for the treatment of obesity.

    PubMed

    Halford, J C

    2001-12-01

    Given the current global epidemic of obesity there is a demand for new anti-obesity drugs to overcome the problem. Many pharmacological agents reduce food intake and significantly decrease body mass when administered to animals but affect feeding behaviour in a profoundly different way indicating the variety of biological mechanisms by which such agents act (appetite verses non-appetite). More limited clinical data demonstrates that some of the same drugs produce decreases in food intake and weight loss in humans. A few of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). These drugs that modify the daily flux of appetite could be considered as 'appetite suppressants' with clinical potential as anti-obesity agents. Drugs that can be considered suitable candidates for appetite suppressants are agents that enhance peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin, CART and Melanocortins) or monoamine neurotransmitters (such as serotonin, nor-adrenaline and possibly dopamine). Recently, the hormone leptin has become regarded as a key hormonal signal linking adipose tissue status with a number of key central nervous system circuits (NPY, CART, CRF, Melanocortins and possibly Orexins). This tonic system may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i) psychological experience and behavioural expression of appetite, (ii) metabolism and peripheral physiology, and (iii) functioning of CNS neural pathways. In humans, such modulation of appetite will involve changes in total caloric consumption, subjective changes in feelings of hunger and fullness, preferences for specific food items, and general macronutrient preferences. These may be

  19. The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ-dependent inhibition of the AKT pathway.

    PubMed

    Assad Kahn, Suzana; Costa, Silvia Lima; Gholamin, Sharareh; Nitta, Ryan T; Dubois, Luiz Gustavo; Fève, Marie; Zeniou, Maria; Coelho, Paulo Lucas Cerqueira; El-Habr, Elias; Cadusseau, Josette; Varlet, Pascale; Mitra, Siddhartha S; Devaux, Bertrand; Kilhoffer, Marie-Claude; Cheshier, Samuel H; Moura-Neto, Vivaldo; Haiech, Jacques; Junier, Marie-Pierre; Chneiweiss, Hervé

    2016-05-01

    A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor-initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1- and α2B-adrenergic receptor antagonist, as the most potent inducer of patient-derived glioblastoma-initiating cell death. Prazosin triggered apoptosis of glioblastoma-initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient-derived glioblastoma-initiating cells, and increased survival of glioblastoma-bearing mice. We found that prazosin acted in glioblastoma-initiating cells independently from adrenergic receptors. Its off-target activity occurred via a PKCδ-dependent inhibition of the AKT pathway, which resulted in caspase-3 activation. Blockade of PKCδ activation prevented all molecular changes observed in prazosin-treated glioblastoma-initiating cells, as well as prazosin-induced apoptosis. Based on these data, we conclude that prazosin, an FDA-approved drug for the control of hypertension, inhibits glioblastoma growth through a PKCδ-dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients.

  20. High therapeutic concentration of prazosin up-regulates angiogenic IL6 and CCL2 genes in hepatocellular carcinoma cells.

    PubMed

    Lin, Zu-Yau; Chuang, Wan-Long

    2012-12-01

    Alteration of the oxidative stress of hepatocellular carcinoma (HCC) cells can influence the expressions of genes favored angiogenesis. Quinone reductase 2 which can activate quinones leading to reactive oxygen species production is a melatonin receptor known as MT3. Prazosin prescribed for benign prostate hyperplasia and hypertension is a potent antagonist for MT3. This study was to investigate the influence of therapeutic concentrations of prazosin (0.01 and 0.1μM) on cell proliferation and differential expressions of CCL2, CCL20, CXCL6, CXCL10, IL8 and IL6 genes related to inflammation and/or oxidative stress in human HCC cell lines. Two HCC cell lines including one without susceptible to amphotericin B-induced oxidative stress (cell line A; HCC24/KMUH) and one with this effect (cell line B; HCC38/KMUH) were investigated by 0.01 and 0.1μM prazosin. The premixed WST-1 cell proliferation reagent was applied for proliferation assay. Differential expressions of genes were examined by quantitative reverse transcriptase-polymerase chain reaction. Our results showed that both 0.01 and 0.1μM prazosin did not influence cell proliferation in both cell lines. Both 0.01 and 0.1μM prazosin in cell line A and 0.01μM prazosin in cell line B did not cause differential expressions of tested genes. However, 0.1μM prazosin caused remarkable up-regulation of IL6 gene and slightly up-regulation of CCL2 gene in cell line B. In conclusion, high therapeutic concentration of prazosin can up-regulate angiogenic IL6 and CCL2 genes in human HCC cells susceptible to amphotericin B-induced oxidative stress. Clinical application of prazosin in patients with HCC should consider this possibility.

  1. CD8+-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment

    PubMed Central

    Van Rompay, Koen K. A.; Singh, Raman P.; Pahar, Bapi; Sodora, Donald L.; Wingfield, Casey; Lawson, Jonathan R.; Marthas, Marta L.; Bischofberger, Norbert

    2004-01-01

    The ability of tenofovir to suppress viremia in simian immunodeficiency virus (SIV)-infected macaques for years despite the presence of virulent viral mutants with reduced in vitro susceptibility is unprecedented in this animal model. In vivo cell depletion experiments demonstrate that tenofovir's ability to suppress viremia during acute and chronic infection is significantly dependent on the presence of CD8+ lymphocytes. Continuous tenofovir treatment was required to maintain low viremia. Although it is unclear whether this immune-mediated suppression of viremia is linked to tenofovir's direct antiviral efficacy or is due to independent immunomodulatory effects, these studies prove the concept that antiviral immune responses can play a crucial role in suppressing viremia during anti-human immunodeficiency virus drug therapy. PMID:15113912

  2. Dopamine receptor D3 regulates endocytic sorting by a Prazosin-sensitive interaction with the coatomer COPI.

    PubMed

    Zhang, Xin; Wang, Wenchao; Bedigian, Anne V; Coughlin, Margaret L; Mitchison, Timothy J; Eggert, Ulrike S

    2012-07-31

    Macromolecules enter cells by endocytosis and are sorted to different cellular destinations in early/sorting endosomes. The mechanism and regulation of sorting are poorly understood, although transitions between vesicular and tubular endosomes are important. We found that the antihypertensive drug Prazosin inhibits endocytic sorting by an off-target perturbation of the G protein-coupled receptor dopamine receptor D(3) (DRD3). Prazosin is also a potent cytokinesis inhibitor, likely as a consequence of its effects on endosomes. Prazosin stabilizes a normally transient interaction between DRD3 and the coatomer COPI, a complex involved in membrane transport, and shifts endosomal morphology entirely to tubules, disrupting cargo sorting. RNAi depletion of DRD3 alone also inhibits endocytic sorting, indicating a noncanonical role for a G protein-coupled receptor. Prazosin is a powerful tool for rapid and reversible perturbation of endocytic dynamics.

  3. Antagonistic effects of atipamezole, yohimbine and prazosin on medetomidine-induced diuresis in healthy cats.

    PubMed

    Murahata, Yusuke; Yamamoto, Asami; Miki, Yuya; Hikasa, Yoshiaki

    2014-03-01

    This study aimed to investigate and compare the antagonistic effects of atipamezole, yohimbine and prazosin on medetomidine-induced diuresis in healthy cats. Five cats were repeatedly used in each of the 9 groups. One group was not medicated. Cats in the other groups received 40 µg/kg medetomidine intramuscularly and saline (as the control), 160 µg/kg prazosin, or 40, 160 or 480 µg/kg atipamezole or yohimbine intravenously 0.5 hr later. Volume, pH and specific gravity of urine; plasma arginine vasopressin (AVP) level; and creatinine, osmolality and electrolyte levels in both urine and plasma were measured. Both atipamezole and yohimbine, but not prazosin, antagonized medetomidine-induced diuresis. The antidiuretic effect of atipamezole was more potent than that of yohimbine, but was not dose dependent, in contrast to the effect of yohimbine at the tested doses. Both atipamezole and yohimbine reversed medetomidine-induced decreases in both urine specific gravity and osmolality and increases in plasma osmolality and free-water clearance. Antidiuresis of either atipamezole or yohimbine was not related to the area under the curve for AVP level, although the highest dose of both atipamezole and yohimbine initially and temporarily increased plasma AVP levels, suggesting that this may partly influence the antidiuretic effects of both agents. The diuretic effect of medetomidine in cats may be mediated by α2-adrenoceptors, but not α1-adrenoceptors. Atipamezole and yohimbine can be used as antagonistic agents against medetomidine-induced diuresis in healthy cats.

  4. Suppression of surface crystallization on borosilicate glass using RF plasma treatment

    NASA Astrophysics Data System (ADS)

    Yoo, Sunghyun; Ji, Chang-Hyeon; Jin, Joo-Young; Kim, Yong-Kweon

    2014-10-01

    Surface crystallization on a commercial grade borosilicate glass wafer, Borofloat® 33, is effectively prevented against 3 h of thermal reflow process at 850 °C. Surface plasma treatment with three different reactive gases, CF4, SF6, and Cl2, has been performed prior to the annealing. The effect of plasma treatment on surface ion concentration and nucleation of cristobalite were examined through optical microscope and x-ray photoemission spectroscopy. The dominant cause that suppresses crystallization was verified to be the increase of surface ion concentration of alumina during the plasma treatment. Both CF4 and SF6 treatment of no less than 30 s showed significant efficacy in suppressing crystallization by a factor of more than 112. Average surface roughness and the optical transparency were also enhanced by a factor of 15 and 3, respectively, compared to untreated sample.

  5. Development of Haemonchus contortus resistance in sheep under suppressive or targeted selective treatment with monepantel.

    PubMed

    de Albuquerque, Ana Cláudia Alexandre; Bassetto, Cesar Cristiano; de Almeida, Fabiana Alves; Amarante, Alessandro F T

    2017-11-15

    This study examined the development of resistance to anthelmintics in Haemonchus contortus in lambs under suppressive or selective treatment regimens that included monepantel. Twenty Ile de France and 20 Santa Ines lambs were allocated to two anthelmintic treatment regimens, based on body weight and nematode faecal egg counts (FEC): targeted selective treatment (TST) or suppressive treatment, both with monepantel. Lambs of the TST group were treated individually when they presented with a packed cell volume (PCV) ≤20%. On 7 October 2016, the lambs were allocated to clean pastures, where they grazed in separated paddocks by group until late February 2017. The experimental area was contaminated with nematodes that were introduced with the experimental Ile de France and Santa Ines lambs, naturally infected with gastrointestinal nematodes. To maintain the grazing lambs in the suppressive treatment group and their pasture as free of worms as possible, these lambs were treated with anthelmintics before being allocated to their paddock and then were periodically treated with monepantel. However, the use of a suppressive treatment regimen that included monepantel over a period of 3 months resulted in the emergence of a population of resistant H. contortus. In the TST group, there was a rapid and progressive reduction in the efficacy of monepantel, which at the end of the experiment was only 76%. The Ile de France lambs were all treated one or more times during the experiment, whereas only two Santa Ines lambs in the TST required treatment. In conclusion, a population of H. contortus resistant to monepantel emerged quickly during the rainy season, even when sheep were submitted to selective treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Treatment of NZB/NZW mice with total lymphoid irradiation: long-lasting suppression of disease without generalized immune suppression

    SciTech Connect

    Kotzin, B.L.; Arndt, R.; Okada, S.; Ward, R.; Thach, A.B.; Strober, S.

    1986-05-01

    We used total lymphoid irradiation (TLI; total dose = 3400 rad) to treat the lupus-like renal disease of 6-mo-old female NZB/NZW mice. Similar to our past studies, this treatment resulted in a marked prolongation of survival, decrease in proteinuria, and decrease in serum anti-DNA antibodies compared with untreated littermate controls. Although there was no evidence of disease recurrence in TLI-treated mice until after 12 mo of age, the in vitro proliferative response to phytohemagglutinin by NZB/NZW spleen cells recovered within 6 wk such that responses were greater than control NZB/NZW animals. A similar recovery and overshoot after TLI were evident in the primary antibody response to the T cell-dependent antigen sheep red blood cells (SRBC). Both the total and IgG anti-SRBC antibody responses after TLI were greater than those of untreated NZB/NZW controls, and were comparable with those of untreated non-autoimmune mice. Despite this increased response to mitogens and antigens after TLI, we noted a decrease in spontaneous splenic IgG-secreting cells and a decrease in IgG but not IgM antinuclear antibody production. Nonspecific suppressor cells of the mixed leukocyte response were detectable in the spleens of NZB/NZW mice early after TLI. However, the disappearance of suppressor cells was not associated with recrudescence of disease activity. Furthermore, transfer of large numbers of spleen cells from TLI-treated NZB/NZW mice did not result in disease suppression in untreated age-matched recipients. In summary, treatment of NZB/NZW mice with TLI results in a prolonged remission in autoimmune disease, which is achieved in the absence of generalized immunosuppression.

  7. The alpha1 adrenergic receptor antagonist prazosin reduces heroin self-administration in rats with extended access to heroin administration.

    PubMed

    Greenwell, Thomas N; Walker, Brendan M; Cottone, Pietro; Zorrilla, Eric P; Koob, George F

    2009-01-01

    Previous studies have reported that noradrenergic antagonists alleviate some of the symptoms of opiate withdrawal and dependence. Clinical studies also have shown that modification of the noradrenergic system may help protect patients from relapse. The present study tested the hypothesis that a dysregulated noradrenergic system has motivational significance in heroin self-administration of dependent rats. Prazosin, an alpha1-adrenergic antagonist (0.5, 1.0, 1.5 and 2.0 mg/kg, i.p.), was administered to adult male Wistar rats with a history of limited (1 h/day; short access) or extended (12 h/day; long access) access to intravenous heroin self-administration. Prazosin dose-dependently reduced heroin self-administration in long-access rats but not short-access rats, with 2 mg/kg of systemic prazosin significantly decreasing 1 h and 2 h heroin intake. Prazosin also reversed some changes in meal pattern associated with extended heroin access, including the taking of smaller and briefer meals (at 3 h), while also increasing total food intake and slowing the eating rate within meals (both 3 h and 12 h). Thus, prazosin appears to stimulate food intake in extended access rats by restoring meals to the normal size and duration. The data suggest that the alpha1 adrenergic system may contribute to mechanisms that promote dependence in rats with extended access.

  8. Time-dependent effects of prazosin on the development of methamphetamine conditioned hyperactivity and context-specific sensitization in mice.

    PubMed

    White, André O; Rauhut, Anthony S

    2014-04-15

    The present experiments examined the effects of prazosin, a selective α₁-adrenergic receptor antagonist, on the development of methamphetamine conditioned hyperactivity and context-specific sensitization. Mice received an injection of vehicle (distilled water) or prazosin (0.5, 1.0 or 2.0 mg/kg) 30 min prior to a second injection of vehicle (saline) or methamphetamine (1.0 mg/kg) during the conditioning sessions (Experiment 1). Following the conditioning sessions, mice were tested for conditioned hyperactivity and then tested for context-specific sensitization. In subsequent experiments, mice received an injection of vehicle (distilled water) or prazosin (2.0 mg/kg) immediately (Experiment 2) or 24 h (Experiment 3) after the conditioning sessions and then tested for conditioned hyperactivity and context-specific sensitization. Prazosin dose-dependently blocked the development of methamphetamine conditioned hyperactivity and context-specific sensitization when administered prior to the methamphetamine during the conditioning phase; however nonspecific motor impairments also were observed (Experiment 1). Immediate (Experiment 2), but not the 24-h delay (Experiment 3), post-session administration of prazosin attenuated the development of methamphetamine conditioned hyperactivity and context-specific sensitization. Nonspecific motor impairments were not observed in these latter experiments. Collectively, these results suggest that the α₁-adrenergic receptor mediates the development of methamphetamine-conditioned hyperactivity and context-specific sensitization, perhaps by altering memory consolidation and/or reconsolidation processes.

  9. Time-Dependent Effects of Prazosin on the Development of Methamphetamine Conditioned Hyperactivity and Context-Specific Sensitization in Mice

    PubMed Central

    White, André O.; Rauhut, Anthony S.

    2014-01-01

    The present experiments examined the effects of prazosin, a selective α1-adrenergic receptor antagonist, on the development of methamphetamine conditioned hyperactivity and context-specific sensitization. Mice received an injection of vehicle (distilled water) or prazosin (0.5, 1.0 or 2.0 mg/kg) 30 minutes prior to a second injection of vehicle (saline) or methamphetamine (1.0 mg/kg) during the conditioning sessions (Experiment 1). Following the conditioning sessions, mice were tested for conditioned hyperactivity and then tested for context-specific sensitization. In subsequent experiments, mice received an injection of vehicle (distilled water) or prazosin (2.0 mg/kg) immediately (Experiment 2) or 24 hours (Experiment 3) after the conditioning sessions and then tested for conditioned hyperactivity and context-specific sensitization. Prazosin dose-dependently blocked the development of methamphetamine conditioned hyperactivity and context-specific sensitization when administered prior to the methamphetamine during the conditioning phase; however nonspecific motor impairments also were observed (Experiment 1). Immediate (Experiment 2), but not the 24-hour delay (Experiment 3), post-session administration of prazosin attenuated the development of methamphetamine conditioned hyperactivity and context-specific sensitization. Nonspecific motor impairments were not observed in these latter experiments. Collectively, these results suggest that the α1-adrenergic receptor mediates the development of methamphetamine-conditioned hyperactivity and context-specific sensitization, perhaps by altering memory consolidation and/or reconsolidation processes. PMID:24487011

  10. Long-term treatment of obese Zucker rats with LY255582 and other appetite suppressants.

    PubMed

    Shaw, W N

    1993-11-01

    LY255582, administered subcutaneously, decreased food intake and body weight gain of fed obese Zucker rats during the entire 30-day period of treatment. No tolerance to these biologic effects of LY255582 could be demonstrated. d-Amphetamine and naltrexone, administered subcutaneously, and d,l-fenfluramine and salbutamol, administered orally, decreased food intake for no more than 6 to 12 days, in contrast to the long-lasting effects of LY255582. Salbutamol suppressed the appetite of obese rats for 3-4 days only. After an additional 12 days of treatment, weight gain decreased significantly accompanied by no appetite suppression. Thus, there is a difference in the duration of action of the opioid antagonist, LY255582, when compared to amphetamine, fenfluramine, naltrexone, and salbutamol, on food intake and body weight gain of obese rats.

  11. Antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats.

    PubMed

    Murahata, Yusuke; Miki, Yuya; Hikasa, Yoshiaki

    2014-10-01

    This study aimed to investigate and compare the antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats. Five cats were repeatedly used in each of the 9 groups. One group was not medicated. Cats in the other groups received 2 mg/kg BW xylazine intramuscularly, and saline (as the control); 160 μg/kg BW prazosin; or 40, 160, or 480 μg/kg BW atipamezole or yohimbine intravenously 0.5 h later. Urine and blood samples were collected 10 times over 8 h. Urine volume, pH, and specific gravity; plasma arginine vasopressin (AVP) concentration; and creatinine, osmolality, and electrolyte values in both urine and plasma were measured. Both atipamezole and yohimbine antagonized xylazine-induced diuresis, but prazosin did not. The antidiuretic effect of atipamezole was more potent than that of yohimbine but not dose-dependent, in contrast to the effect of yohimbine at the tested doses. Both atipamezole and yohimbine reversed xylazine-induced decreases in both urine specific gravity and osmolality, and the increase in free water clearance. Glomerular filtration rate, osmolar clearance, and plasma electrolyte concentrations were not significantly altered. Antidiuresis of either atipamezole or yohimbine was not related to the area under the curve for AVP concentration, although the highest dose of both atipamezole and yohimbine increased plasma AVP concentration initially and temporarily, suggesting that this may in part influence antidiuretic effects of both agents. The diuretic effect of xylazine in cats may be mediated by α2-adrenoceptors but not α1-adrenoceptors. Atipamezole and yohimbine can be used as antagonistic agents against xylazine-induced diuresis in clinically normal cats.

  12. Antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats

    PubMed Central

    Murahata, Yusuke; Miki, Yuya; Hikasa, Yoshiaki

    2014-01-01

    This study aimed to investigate and compare the antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats. Five cats were repeatedly used in each of the 9 groups. One group was not medicated. Cats in the other groups received 2 mg/kg BW xylazine intramuscularly, and saline (as the control); 160 μg/kg BW prazosin; or 40, 160, or 480 μg/kg BW atipamezole or yohimbine intravenously 0.5 h later. Urine and blood samples were collected 10 times over 8 h. Urine volume, pH, and specific gravity; plasma arginine vasopressin (AVP) concentration; and creatinine, osmolality, and electrolyte values in both urine and plasma were measured. Both atipamezole and yohimbine antagonized xylazine-induced diuresis, but prazosin did not. The antidiuretic effect of atipamezole was more potent than that of yohimbine but not dose-dependent, in contrast to the effect of yohimbine at the tested doses. Both atipamezole and yohimbine reversed xylazine-induced decreases in both urine specific gravity and osmolality, and the increase in free water clearance. Glomerular filtration rate, osmolar clearance, and plasma electrolyte concentrations were not significantly altered. Antidiuresis of either atipamezole or yohimbine was not related to the area under the curve for AVP concentration, although the highest dose of both atipamezole and yohimbine increased plasma AVP concentration initially and temporarily, suggesting that this may in part influence antidiuretic effects of both agents. The diuretic effect of xylazine in cats may be mediated by α2-adrenoceptors but not α1-adrenoceptors. Atipamezole and yohimbine can be used as antagonistic agents against xylazine-induced diuresis in clinically normal cats. PMID:25356000

  13. Prazosin modulates rapid eye movement sleep deprivation-induced changes in body temperature in rats.

    PubMed

    Jaiswal, Manoj K; Mallick, Birendra N

    2009-09-01

    Prolonged rapid eye movement sleep deprivation (REMSD) causes hypothermia and death; however, the effect of deprivation within 24 h and its mechanism(s) of action were unknown. Based on existing reports we argued that REMSD should, at least initially, induce hyperthermia and the death upon prolonged deprivation could be due to persistent hypothermia. We proposed that noradrenaline (NA), which modulates body temperature and is increased upon REMSD, may be involved in REMSD- associated body temperature changes. Adult male Wistar rats were REM sleep deprived for 6-9 days by the classical flower pot method; suitable free moving, large platform and recovery controls were carried out. The rectal temperature (Trec) was recorded every minute for 1 h, or once daily, or before and after i.p. injection of prazosin, an alpha-1 adrenergic antagonist. The Trec was indeed elevated within 24 h of REMSD which decreased steadily, despite continuation of deprivation. Prazosin injection into the deprived rats reduced the Trec within 30 min, and the duration of effect was comparable to its pharmacological half life. The findings have been explained on the basis of REMSD-induced elevated NA level, which has opposite actions on the peripheral and the central nervous systems. We propose that REMSD-associated immediate increase in Trec is due to increased Na-K ATPase as well as metabolic activities and peripheral vasoconstriction. However, upon prolonged deprivation, probably the persistent effect of NA on the central thermoregulatory sites induced sustained hypothermia, which if remained uncontrolled, results in death. Thus, our findings suggest that peripheral prazosin injection in REMSD would not bring the body temperature to normal, rather might become counterproductive.

  14. Fire suppression and fuels treatment effects on mixed-conifer carbon stocks and emissions.

    PubMed

    North, Malcolm; Hurteau, Matthew; Innes, James

    2009-09-01

    Depending on management, forests can be an important sink or source of carbon that if released as CO2 could contribute to global warming. Many forests in the western United States are being treated to reduce fuels, yet the effects of these treatments on forest carbon are not well understood. We compared the immediate effects of fuels treatments on carbon stocks and releases in replicated plots before and after treatment, and against a reconstruction of active-fire stand conditions for the same forest in 1865. Total live-tree carbon was substantially lower in modern fire-suppressed conditions (and all of the treatments) than the same forest under an active-fire regime. Although fire suppression has increased stem density, current forests have fewer very large trees, reducing total live-tree carbon stocks and shifting a higher proportion of those stocks into small-diameter, fire-sensitive trees. Prescribed burning released 14.8 Mg C/ha, with pre-burn thinning increasing the average release by 70% and contributing 21.9-37.5 Mg C/ha in milling waste. Fire suppression may have incurred a double carbon penalty by reducing stocks and contributing to emissions with fuels-treatment activities or inevitable wildfire combustion. All treatments reduced fuels and increased fire resistance, but most of the gains were achieved with understory thinning, with only modest increases in the much heavier overstory thinning. We suggest modifying current treatments to focus on reducing surface fuels, actively thinning the majority of small trees, and removing only fire-sensitive species in the merchantable, intermediate size class. These changes would retain most of the current carbon-pool levels, reduce prescribed burn and potential future wildfire emissions, and favor stand development of large, fire-resistant trees that can better stabilize carbon stocks.

  15. Factor structure and clinical correlates of the Food Thought Suppression Inventory within treatment seeking obese women with binge eating disorder

    PubMed Central

    Barnes, Rachel D.; Sawaoka, Takuya; White, Marney A.; Masheb, Robin M.; Grilo, Carlos M.

    2013-01-01

    Prior research on the relations among eating behaviors and thought suppression is limited to a measure of general thought suppression, the White Bear Suppression Inventory. To address this limitation, researchers recently validated the Food Thought Suppression Inventory (FTSI). Analyses using this measure suggest that food thought suppression is distinct from and is more predictive of eating disorder psychopathology than is general thought suppression. The FTSI, however, has not yet been validated in clinical samples. The purpose of the current study is to examine the factor structure and clinical correlates of the FTSI within treatment seeking obese women with binge eating disorder (BED; N = 128). Analyses revealed a valid and reliable one-factor measure of food thought suppression that was related to higher levels of eating and general psychopathology. The findings provide evidence for the use of the FTSI with obese women with BED. Future research should examine the psychometric properties of the FTSI within larger and more diverse samples. PMID:23265399

  16. Novel Burst Suppression Segmentation in the Joint Time-Frequency Domain for EEG in Treatment of Status Epilepticus

    PubMed Central

    Lee, Jaeyun; Song, Woo-Jin; Lee, Hyang Woon

    2016-01-01

    We developed a method to distinguish bursts and suppressions for EEG burst suppression from the treatments of status epilepticus, employing the joint time-frequency domain. We obtained the feature used in the proposed method from the joint use of the time and frequency domains, and we estimated the decision as to whether the measured EEG was a burst segment or suppression segment by the maximum likelihood estimation. We evaluated the performance of the proposed method in terms of its accordance with the visual scores and estimation of the burst suppression ratio. The accuracy was higher than the sole use of the time or frequency domains, as well as conventional methods conducted in the time domain. In addition, probabilistic modeling provided a more simplified optimization than conventional methods. Burst suppression quantification necessitated precise burst suppression segmentation with an easy optimization; therefore, the excellent discrimination and the easy optimization of burst suppression by the proposed method appear to be beneficial. PMID:27872655

  17. Pre-seasonal treatment with topical olopatadine suppresses the clinical symptoms of seasonal allergic conjunctivitis.

    PubMed

    Shimura, Masahiko; Yasuda, Kanako; Miyazawa, Akiko; Otani, Tetsuro; Nakazawa, Toru

    2011-04-01

    To evaluate the effectiveness of pre-seasonal treatment with topical olopatadine on the reduction of clinical symptoms of seasonal allergic conjunctivitis (SAC). Prospective interventional case series. Eleven patients with SAC received topical olopatadine in one eye at least two weeks before the onset of allergy symptoms, and the other eye served as the control. After the onset of allergic conjunctivitis, both eyes were treated with topical olopatadine. Visual analogue scale (VAS), which evaluated the subjective symptoms of ocular allergy, and the tear levels of histamine and substance P were measured up to six weeks. At the onset of allergy symptoms, the VAS score in the pretreatment eyes was statistically significantly lower than that in the control eyes. The VAS score in the control eyes decreased with time but did not decrease to the level seen in the pretreatment eyes until four weeks later. The tear level of substance P at the onset of allergy symptoms was significantly suppressed in the pretreatment eyes, while the level of histamine was not suppressed. Alteration of the VAS scores in the pretreatment eyes significantly correlated with the level of substance P, but not of histamine. To suppress clinical symptoms in patients with SAC, pre-seasonal treatment with topical olopatadine is effective. The effectiveness of treatment correlates with the tear level of substance P. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Suppression of ongoing experimental myasthenia by oral treatment with an acetylcholine receptor recombinant fragment.

    PubMed

    Im, S H; Barchan, D; Fuchs, S; Souroujon, M C

    1999-12-01

    Myasthenia gravis (MG) is an autoimmune disorder in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. In an attempt to develop an antigen-specific therapy for MG, we administered a nonmyasthenogenic recombinant fragment of AChR orally to rats. This fragment, corresponding to the extracellular domain of the human AChR alpha-subunit (Halpha1-205), protected rats from subsequently induced experimental autoimmune myasthenia gravis (EAMG) and suppressed ongoing EAMG when treatment was initiated during either the acute or chronic phases of disease. Prevention and suppression of EAMG were accompanied by a significant decrease in AChR-specific humoral and cellular responses. The underlying mechanism for the Halpha1-205-induced oral tolerance seems to be active suppression, mediated by a shift from a T-helper 1 (Th1) to a Th2/Th3 response. This shift was assessed by changes in the cytokine profile, a deviation of anti-AChR IgG isotypes from IgG2 to IgG1, and a suppressed AChR-specific delayed-type hypersensitivity response. Our results in experimental myasthenia suggest that oral administration of AChR-specific recombinant fragments may be considered for antigen-specific immunotherapy of myasthenia gravis.

  19. Suppression of ongoing experimental myasthenia by oral treatment with an acetylcholine receptor recombinant fragment

    PubMed Central

    Im, Sin-Hyeog; Barchan, Dora; Fuchs, Sara; Souroujon, Miriam C.

    1999-01-01

    Myasthenia gravis (MG) is an autoimmune disorder in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. In an attempt to develop an antigen-specific therapy for MG, we administered a nonmyasthenogenic recombinant fragment of AChR orally to rats. This fragment, corresponding to the extracellular domain of the human AChR α-subunit (Hα1-205), protected rats from subsequently induced experimental autoimmune myasthenia gravis (EAMG) and suppressed ongoing EAMG when treatment was initiated during either the acute or chronic phases of disease. Prevention and suppression of EAMG were accompanied by a significant decrease in AChR-specific humoral and cellular responses. The underlying mechanism for the Hα1-205–induced oral tolerance seems to be active suppression, mediated by a shift from a T-helper 1 (Th1) to a Th2/Th3 response. This shift was assessed by changes in the cytokine profile, a deviation of anti-AChR IgG isotypes from IgG2 to IgG1, and a suppressed AChR-specific delayed-type hypersensitivity response. Our results in experimental myasthenia suggest that oral administration of AChR-specific recombinant fragments may be considered for antigen-specific immunotherapy of myasthenia gravis. J. Clin. Invest. 104:1723–1730 (1999). PMID:10606626

  20. Preservation of androgen secretion during estrogen suppression with aminoglutethimide in the treatment of metastatic breast carcinoma.

    PubMed Central

    Samojlik, E; Veldhuis, J D; Wells, S A; Santen, R J

    1980-01-01

    We evaluated the comparative effects of aminoglutethimide (AG) on androgen and estrogen levels estrone ([E1], estradiol [E2], plasma dehydroepiandrosterone-sulfate [DHEA-S], testosterone [T], dihydrotestosterone [DHT], delta 4-androstenedione [delta 4-A]), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin in postmenopausal patients with breast cancer randomly allocated to either AG treatment or bilateral surgical adrenalectomy as a control group. In response to either treatment, the plasma levels of E1 fell 62-75% (P less than 0.001) and urine E1 85.7-88.7% (P less than 0.001) in all study days over a 12-wk period. Similarly, the concentrations of E2 in plasma and urine fell 40-72% without statistically significant differences between the two treatment modalities. The relatively weak androgen, DHEA-S, was reduced by 92% (877.3 +/- 184.6 to 71.8 +/- 14.5 ng/ml) at 12 wk in women treated with AG, but suppressed nearly 99% (1,151 +/- 262 to 5.8 +/- 3.3 ng/ml) in adrenalectomized women. At all time points after treatment, the DHEA-S levels were significantly higher in patients receiving AG. Plasma concentrations of the potent androgens, T and DHT, were also relatively preserved during AG treatment. T levels were never significantly reduced by AG, and DHT concentrations were decreased only at the 4th wk to a maximum of 20%. delta 4-A levels fell 56% in response to this drug only on the 12th wk of therapy (basal, 0.79 +/- 0.09 ng/ml; 12 wk, 0.35 +/- 0.07 ng/ml). In marked contrast, all androgens fell significantly at each time period in response to surgical adrenalectomy, with an 81% maximum suppression of T, 73% of DHT, and 97% of delta 4-A. In response to estrogen suppression, plasma levels of FSH, LH, and prolactin did not change significantly throughout the treatment period in either therapy group. To examine possible contributions of the postmenopausal ovary to hormone levels during therapy, data from surgically castrate and spontaneously

  1. Molecular exploration of the α(1A)-adrenoceptor orthosteric site: binding site definition for epinephrine, HEAT and prazosin.

    PubMed

    Maïga, Arhamatoulaye; Dupont, Mélanie; Blanchet, Guillaume; Marcon, Elodie; Gilquin, Bernard; Servent, Denis; Gilles, Nicolas

    2014-12-20

    Despite the physiological and pharmacological importance of the α1A-adrenoreceptor, the mode of interactions of classical agonists and radioactive ligands with this receptor is not yet clearly defined. Here, we used mutagenesis studies and binding experiments to evaluate the importance of 11 receptor sites for the binding of (125)I-HEAT, (3)H-prazosin and epinephrine. Only one residue (F312) commonly interacts with the three molecules, and, surprisingly, D106 interacts only with epinephrine in a moderate way. Our docking model shows that prazosin and HEAT are almost superimposed into the orthosteric pocket with their tetralone and quinazoline rings close to the phenyl ring of the agonist.

  2. Capsaicin treatment differentially affects feeding suppression by bombesin-like peptides.

    PubMed

    Ladenheim, Ellen E; Knipp, Susan

    2007-05-16

    Peripheral administration of bombesin (BN) and the related mammalian peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB), suppress food intake in rats. To examine whether all BN-like peptides utilize the same neural pathways to reduce feeding, rats were treated on postnatal day 2 with the injection vehicle or capsaicin, a neurotoxin that damages a subset of visceral afferent fibers. When rats reached adulthood, we compared the ability of a dose range of systemically administered BN, GRP18-27 and NMB to reduce intake of a 0.5 kcal/ml glucose solution in a short-term feeding test. Our results demonstrate that capsaicin treatment abolished or attenuated the suppression of glucose intake produced by BN and NMB but had no effect on the ability of GRP to reduce feeding. These results suggest that different neural substrates underlie the anorexic effects of peripherally administered BN-like peptides.

  3. Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment

    PubMed Central

    Lauriola, Mattia; Enuka, Yehoshua; Zeisel, Amit; D’Uva, Gabriele; Roth, Lee; Sharon-Sevilla, Michal; Lindzen, Moshit; Sharma, Kirti; Nevo, Nava; Feldman, Morris; Carvalho, Silvia; Cohen-Dvashi, Hadas; Kedmi, Merav; Ben-Chetrit, Nir; Chen, Alon; Solmi, Rossella; Wiemann, Stefan; Schmitt, Fernando; Domany, Eytan; Yarden, Yosef

    2014-01-01

    Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of EGFR, an RTK. The underlying mechanism entails suppression of EGFR’s positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our studies in mice reveal that the regulation of EGFR’s feedback loops by glucocorticoids translates to circadian control of EGFR signalling: EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy. PMID:25278152

  4. Is suppression of hypothalamic-pituitary-adrenal axis significant during clinical treatment of phimosis?

    PubMed

    Pileggi, F O; Martinelli, C E; Tazima, M F G S; Daneluzzi, J C; Vicente, Y A M V A

    2010-06-01

    Corticoids have been an option for phimosis treatment since 1993. However, long-term use or repeated cycles pose a concern regarding drug absorption and consequent systemic effects. The aim of this study was to investigate the effect of topical corticoids used in treating phimosis on the hypothalamus-pituitary-adrenal axis in children. A total of 31 children were included in the study. Cortisol secretion was evaluated by the measurement of salivary cortisol in saliva samples collected at 9:00 a.m. before starting treatment and after 8 weeks of topical treatment with 0.05% clobetasol propionate. Salivary cortisol was determined by radioimmunoassay. To confirm that use of clobetasol propionate was not detected by the assay, the presence of cortisol circadian rhythm was checked by an extra saliva sample obtained at 11:00 p.m. from 10 children, and was observed to be maintained in all of them. No significant difference in salivary cortisol levels was observed between samples obtained at 9:00 a.m. before starting treatment and after completing treatment when the entire group was analyzed. However, in 2 children the salivary cortisol levels after treatment were lower than the cutoff value (358 ng/dl) assumed to be suggestive of hypothalamus-pituitary-adrenal axis suppression. Topical clobetasol propionate used twice daily for clinical treatment of phimosis does not affect the hypothalamus-pituitary-adrenal axis in most patients. However, salivary cortisol level should be considered as a laboratory marker in long-term treatment or during repeated cycles to detect possible hypothalamus-pituitary-adrenal axis suppression. Copyright 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  5. Malonic acid suppresses mucin-type O-glycan degradation during hydrazine treatment of glycoproteins.

    PubMed

    Goso, Yukinobu

    2016-03-01

    Hydrazine treatment is frequently used for releasing mucin-type O-glycans (O-glycans) from glycoproteins because the method provides O-glycans that retain a reducible GalNAc at their reducing end, which is available for fluorescent labeling. However, many O-glycans are degraded by "peeling" during this treatment. In the current study, it was found that malonic acid suppressed O-glycan degradation during hydrazine treatment of bovine fetuin or porcine gastric mucin in both the gas and liquid phases. This is paradoxical because the release of O-glycans from glycoproteins occurs under alkaline conditions. However, malonic acid seems to prevent the degradation through its acidic property given that other weak acids also prevented the degradation. Accordingly, disodium malonate did not suppress O-glycan degradation. Application of this method to rat gastric mucin demonstrated that the majority of the major O-glycans obtained in the presence of malonic acid were intact, whereas those obtained in the absence of malonic acid were degraded. These results suggest that hydrazine treatment in the presence of malonic acid would allow glycomic analysis of native mucin glycoproteins.

  6. Synergistic suppression of autoimmune arthritis through concurrent treatment with tolerogenic DC and MSC.

    PubMed

    Li, Rong; Zhang, Yujuan; Zheng, Xiufen; Peng, Shanshan; Yuan, Keng; Zhang, Xusheng; Min, Weiping

    2017-02-23

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive immune-mediated joint deterioration. Current treatments are not antigen specific and are associated with various adverse. We have previously demonstrated that tolerogenic dendritic cells (Tol-DC) are potent antigen-specific immune regulators, which hold great promise in immunotherapy of autoimmune diseases. In this study, we aimed to develop new immunotherapy by combining Tol-DC and mesenchymal stem cells (MSC). We demonstrated that RelB gene silencing resulted in generation of Tol-DC that suppressed T cell responses and selectively promoted Treg generation. The combination of MSC synergized the tolerogenic capacity of Tol-DC in inhibition of T cell responses. In murine collagen-induced arthritis (CIA) model, we demonstrated that progression of arthritis was inhibited with administration of RelB gene-silenced Tol-DC or MSC. This therapeutic effect was remarkably enhanced with concurrent treatment of combination Tol-DC and MSC as demonstrated by improved clinical symptoms, decreased clinical scores and attenuated joint damage. These therapeutic effects were associated with suppression of CII-specific T cell responses, polarization of Th and inhibition of proinflammatory cytokines, and reduced cartilage degeneration. This study for the first time demonstrates a new approach to treat autoimmune inflammatory joint disease with concurrent treatment of RelB gene-silenced Tol-DC and MSC.

  7. Defective zoospore encystment and suppressed cyst germination of Phytophthora palmivora caused by transient leaching treatments.

    PubMed

    Dijksterhuis, J; Deacon, J W

    2003-01-01

    The behaviour of encysting zoospores of Phytophthora palmivora during leaching conditions was studied. Zoospores encysted and germinated successfully on polycarbonate membranes after mechanical agitation. Transient (10 min) leaching treatments with nutrient-free buffer underneath the membranes resulted in abnormal encystment and poor germination. The disruption was greatest when leaching was applied during the first minutes after start of encystment and not observed after 20 min. The early sensitivity of cells to leaching coincided with the period when alkali-resistant cell walls were formed (2-6 min after mechanical agitation). Effects of calcium and organic nutrients on encystment during leaching and germination after these treatments were studied. The disruption of encystment by early leaching treatments, but not the suppression of cyst germination, was overcome by adding calcium chloride during mechanical agitation of zoospores. Leaching with calcium containing buffer resulted in suppressed cyst germination as was the case with buffer alone. Leaching with 0.1% peptone containing buffer promoted consistently high encystment and germination.

  8. Synergistic suppression of autoimmune arthritis through concurrent treatment with tolerogenic DC and MSC

    PubMed Central

    Li, Rong; Zhang, Yujuan; Zheng, Xiufen; Peng, Shanshan; Yuan, Keng; Zhang, Xusheng; Min, Weiping

    2017-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive immune-mediated joint deterioration. Current treatments are not antigen specific and are associated with various adverse. We have previously demonstrated that tolerogenic dendritic cells (Tol-DC) are potent antigen-specific immune regulators, which hold great promise in immunotherapy of autoimmune diseases. In this study, we aimed to develop new immunotherapy by combining Tol-DC and mesenchymal stem cells (MSC). We demonstrated that RelB gene silencing resulted in generation of Tol-DC that suppressed T cell responses and selectively promoted Treg generation. The combination of MSC synergized the tolerogenic capacity of Tol-DC in inhibition of T cell responses. In murine collagen-induced arthritis (CIA) model, we demonstrated that progression of arthritis was inhibited with administration of RelB gene-silenced Tol-DC or MSC. This therapeutic effect was remarkably enhanced with concurrent treatment of combination Tol-DC and MSC as demonstrated by improved clinical symptoms, decreased clinical scores and attenuated joint damage. These therapeutic effects were associated with suppression of CII-specific T cell responses, polarization of Th and inhibition of proinflammatory cytokines, and reduced cartilage degeneration. This study for the first time demonstrates a new approach to treat autoimmune inflammatory joint disease with concurrent treatment of RelB gene-silenced Tol-DC and MSC. PMID:28230210

  9. Prazosin for Prophylaxis of Chronic Post Traumatic Headaches in OEF/OIF/OND Service Members and Veterans with Mild TBI

    DTIC Science & Technology

    2016-10-01

    compared to placebo on HA frequency, HA severity and duration, use of abortive /analgesic medications, and HA-related disability. Specific Aim 2: To...the effect of prazosin compared to placebo on post- traumatic HA frequency, severity, duration, use of abortive /analgesic medications, and HA-related

  10. The α1 Adrenergic Receptor Antagonist Prazosin Reduces Heroin Self-Administration in Rats with Extended Access to Heroin Administration

    PubMed Central

    Greenwell, Thomas N.; Walker, Brendan M.; Cottone, Pietro; Zorrilla, Eric P.; Koob, George F.

    2009-01-01

    Previous studies have reported that noradrenergic antagonists alleviate some of the symptoms of opiate withdrawal and dependence. Clinical studies also have shown that modification of the noradrenergic system may help protect patients from relapse. The present study tested the hypothesis that a dysregulated noradrenergic system has motivational significance in heroin self-administration in dependent rats. Prazosin, an α1-adrenergic antagonist (0.5, 1.0, 1.5 and 2.0 mg/kg, i.p.), was administered to adult male Wistar rats with a history of limited (1 h/day; short access) or extended (12 h/day; long access) access to intravenous heroin self-administration. Prazosin dose-dependently reduced heroin self-administration in long-access rats but not short-access rats, with 2 mg/kg of systemic prazosin significantly decreasing 1 h and 2 h heroin intake. Prazosin also reversed some changes in meal pattern associated with extended heroin access, including the taking of smaller and briefer meals (at 3 h), while also increasing total food intake and slowing the eating rate within meals (both 3 h and 12 h). The data show that the α1-adrenergic system may contribute to mechanisms that promote dependence in rats with extended drug access, while also stimulating their food intake by restoring meals to the normal size and duration. PMID:18703080

  11. Blockade of noradrenaline-induced constrictions by yohimbine and prazosin differs between consecutive segments of cutaneous arteries in guinea-pig ears.

    PubMed Central

    Morris, J L

    1994-01-01

    1. The study has examined the receptors mediating constriction produced by brief local application of noradrenaline (NA) to cutaneous arteries and arterioles in the ear vasculature of anaesthetized guinea-pigs. The innervation of the corresponding vascular segments has been examined immunohistochemically at the conclusion of the pharmacological experiments. 2. Small arteries of branch order 4 (4 degrees, 40-110 microns internal diameter) were more sensitive to the vasoconstrictor action of NA than were more proximal arteries of branch order 3 (3 degrees, 60-150 microns internal diameter), or more distal arteries and arterioles of branch orders 5 to 7 (5 degrees-7 degrees, 18-85 microns internal diameter). This higher sensitivity of 4 degrees arteries was maintained after blockade of neuronal uptake with desipramine (1 microM), and after blockade of beta-adrenoceptors with propranolol (1 microM). 3. NA-induced vasoconstrictions of distal arterioles (5 degrees-7 degrees) were abolished or greatly reduced by yohimbine (1 microM). The blockade by yohimbine decreased progressively with increasing vessel diameter of proximal arteries, while the blockade by prazosin (1 microM) increased progressively in arteries > 40 microns diameter. 4. In 3 degrees and 4 degrees arteries, a substantial component (approximately 50%) of NA-induced vasoconstrictions remained after combined treatment with yohimbine and prazosin, in the presence or absence of desipramine. These constrictions were not further reduced by benextramine (1-10 microM), but were abolished by dihydroergotamine (1-10 microM). Constrictions induced by ATP (0.1-1 mM) were not affected by dihydroergotamine.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 4 Figure 5 PMID:7889261

  12. Treatment with recombinant Hsp72 suppresses collagen-induced arthritis in mice.

    PubMed

    Luo, Xinjing; Zuo, Xiaoxia; Mo, Xuanrong; Zhou, Yaou; Xiao, Xianzhong

    2011-10-01

    Although the level of heat shock protein (Hsp72) has been shown to be enhanced in rheumatoid arthritis (RA) synovial tissues and RA synovial fluid, it remains unclear what role extracellular Hsp72 plays in the pathogenesis of RA. This study was conducted to investigate the effects of recombinant human Hsp72 on collagen-induced arthritis (CIA) when administered therapeutically and elucidate its underlying mechanism. We demonstrated that recombinant Hsp72 significantly reduced disease severity. Hsp72-treated animals displayed significantly less cartilage and bone destruction than that in the controls. Hsp72 treatment also reduced the expression of tumor necrosis factor alpha and interleukin 6 in the sera. Furthermore, Hsp72 treatment significantly inhibited activation of nuclear factor kappa B (NF-κB) in synovial tissues of CIA mice. These findings suggest that recombinant Hsp72 effectively suppressed synovial inflammation and the development and progress of CIA, which is mediated through the reduction of production of proinflammatory cytokines and the suppression of activation of NF-κB pathway.

  13. Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice.

    PubMed

    Aharinejad, Seyedhossein; Abraham, Dietmar; Paulus, Patrick; Abri, Hojatollah; Hofmann, Michael; Grossschmidt, Karl; Schäfer, Romana; Stanley, E Richard; Hofbauer, Reinhold

    2002-09-15

    Matrix metalloproteinases (MMPs) foster cellular invasion by disrupting extracellular matrix barriers and thereby facilitate tumor development. MMPs are synthesized by both cancer cells and adjacent stromal cells, primarily macrophages. The production of macrophages is regulated by colony-stimulating factor-1 (CSF-1). Tissue CSF-1 expression increased significantly in embryonic and colon cancer xenografts. We, therefore, hypothesized that blocking CSF-1 may suppress tumor growth by decelerating macrophage-mediated extracellular matrix breakdown. Cells expressing CSF-1 and mice xenografted with CSF-1 receptor (c-fms)- and CSF-1-negative malignant human embryonic or colon cancer cells were treated with mouse CSF-1 antisense oligonucleotides. Two weeks of CSF-1 antisense treatment selectively down-regulated CSF-1 mRNA and protein tissue expression in tumor lysates. CSF-1 blockade suppressed the growth of embryonic tumors to dormant levels and the growth of the colon carcinoma by 50%. In addition, tumor vascularity and the expression of MMP-2 and angiogenic factors were reduced. Six-month survival was observed in colon carcinoma mice only after CSF-1 blockade, whereas controls were all dead at day 65. These results suggest that human embryonic and colon cancer cells up-regulate host CSF-1 and MMP-2 expression. Because the cancer cells used were CSF-1 negative, CSF-1 antisense targeted tumor stromal cell CSF-1 production. CSF-1 blockade could be a novel strategy in treatment of solid tumors.

  14. Photodynamic therapy with simultaneous suppression of multiple treatment escape pathways (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Spring, Bryan Q.; Sears, R. Bryan; Zheng, Lei Z.; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

    2016-03-01

    We introduce photoactivatable multi-inhibitor nanoliposomes (PMILs) for photodynamic tumor cell and microvessel damage in synchrony with photo-initiation of tumor-confined, multikinase inhibitor release. The PMIL is a biodegradable delivery system comprised of a nanoliposome carrying a photoactivable chromophore (benzoporphyrin derivative monoacid A, BPD) in its bilayer. A multikinase inhibitor-loaded PEG-PLGA nanoparticle is encapsulated within the liposome, which acts a barrier to nanoparticle erosion and drug release. Following intravenous PMIL administration, near infrared irradiation of tumors triggers photodynamic therapy and initiates tumor-confined drug release from the nanoparticle. This talk presents promising preclinical data in mouse models of pancreatic cancer utilizing this concept to suppress the VEGF and MET signaling pathways—both critical to cancer progression, metastasis and treatment escape. A single PMIL treatment using low doses of a multikanse inhibitor (cabozantinib, XL184) achieves sustained tumor reduction and suppresses metastatic escape, whereas combination therapy by co-administration of the individual agents has significantly reduced efficacy. The PMIL concept is amenable to a number of molecular inhibitors and offers new prospects for spatiotemporal synchronization of combination therapies whilst reducing systemic drug exposure and associated toxicities.

  15. Use and abuse of appetite-suppressant drugs in the treatment of obesity.

    PubMed

    Bray, G A

    1993-10-01

    Most of the available appetite-suppressant drugs act on noradrenergic and possibly dopaminergic receptors to produce satiety. A smaller number increase excess neuronal serotonin levels by blocking serotonin reuptake or by increasing its release. All these drugs produce significantly greater weight loss than does placebo in most studies. Abuse is a problem with amphetamine, methamphetamine, and benzphetamine, whereas other drugs have minimal or no potential for abuse. Weight loss can be sustained for up to 36 months. Net weight loss, compared with placebo, ranges from 2 to 10 kg, and weight regain after terminating drug treatment proves that drugs do not work when not taken. The stigma of obesity, the public opprobrium toward obese persons, and regulatory rigidity have led to unjustified distrust in the potential of drug treatment for obesity.

  16. Online Adaptive Hyperthermia Treatment Planning During Locoregional Heating to Suppress Treatment-Limiting Hot Spots.

    PubMed

    Kok, H Petra; Korshuize-van Straten, Linda; Bakker, Akke; de Kroon-Oldenhof, Rianne; Geijsen, Elisabeth D; Stalpers, Lukas J A; Crezee, Johannes

    2017-07-14

    Adequate tumor temperatures during hyperthermia are essential for good clinical response, but excessive heating of normal tissue should be avoided. This makes locoregional heating using phased array systems technically challenging. Online application of hyperthermia treatment planning could help to improve the heating quality. The aim of this study was to evaluate the clinical benefit of online treatment planning during treatment of pelvic tumors heated with the AMC-8 locoregional hyperthermia system. For online adaptive hyperthermia treatment planning, a graphical user interface was developed. Electric fields were calculated in a preprocessing step using our in-house-developed finite-difference-based treatment planning system. This allows instant calculation of the temperature distribution for user-selected phase-amplitude settings during treatment and projection onto the patient's computed tomographic scan for online visualization. Online treatment planning was used for 14 treatment sessions in 8 patients to reduce the patients' reports of hot spots while maintaining the same level of tumor heating. The predicted decrease in hot spot temperature should be at least 0.5°C, and the tumor temperature should decrease less than 0.2°C. These predictions were compared with clinical data: patient feedback about the hot spot and temperature measurements in the tumor region. In total, 17 hot spot reports occurred during the 14 sessions, and the alternative settings predicted the hot spot temperature to decrease by at least 0.5°C, which was confirmed by the disappearance of all 17 hot spot reports. At the same time, the average tumor temperature was predicted to change on average -0.01°C (range, -0.19°C to 0.34°C). The measured tumor temperature change was on average only -0.02°C (range, -0.26°C to 0.31°C). In only 2 cases the temperature decrease was slightly larger than 0.2°C, but at most it was 0.26°C. Online application of hyperthermia treatment planning is

  17. Facilitation of sodium intake by combining noradrenaline into the lateral parabrachial nucleus with prazosin peripherally.

    PubMed

    Gasparini, S; Gomide, J M C; Andrade-Franzé, G M F; Totola, L T; De Luca, L A; Colombari, D S A; De Paula, P M; Moreira, T S; Menani, J V

    2013-10-01

    Injections of noradrenaline into the lateral parabrachial nucleus (LPBN) increase arterial pressure and 1.8% NaCl intake and decrease water intake in rats treated with the diuretic furosemide (FURO) combined with a low dose of the angiotensin converting enzyme inhibitor captopril (CAP). In the present study, we investigated the influence of the pressor response elicited by noradrenaline injected into the LPBN on FURO+CAP-induced water and 1.8% NaCl intake. Male Holtzman rats with bilateral stainless steel guide-cannulas implanted into LPBN were used. Bilateral injections of noradrenaline (40 nmol/0.2 μl) into the LPBN increased FURO+CAP-induced 1.8% NaCl intake (12.2±3.5, vs., saline: 4.2±0.8 ml/180 min), reduced water intake and strongly increased arterial pressure (50±7, vs. saline: 1±1 mmHg). The blockade of the α1 adrenoceptors with the prazosin injected intraperitoneally abolished the pressor response and increased 1.8% NaCl and water intake in rats treated with FURO+CAP combined with noradrenaline injected into the LPBN. The deactivation of baro and perhaps volume receptors due to the cardiovascular effects of prazosin is a mechanism that may facilitate water and NaCl intake in rats treated with FURO+CAP combined with noradrenaline injected into the LPBN. Therefore, the activation of α2 adrenoceptors with noradrenaline injected into the LPBN, at least in dose tested, may not completely remove the inhibitory signals produced by the activation of the cardiovascular receptors, particularly the signals that result from the extra activation of these receptors with the increase of arterial pressure.

  18. The impact of transient combination antiretroviral treatment in early HIV infection on viral suppression and immunologic response in later treatment.

    PubMed

    Pantazis, Nikos; Touloumi, Giota; Meyer, Laurence; Olson, Ashley; Costagliola, Dominique; Kelleher, Anthony D; Lutsar, Irja; Chaix, Marie-Laure; Fisher, Martin; Moreno, Santiago; Porter, Kholoud

    2016-03-27

    Effects of transient combination antiretroviral treatment (cART) initiated during early HIV infection (EHI) remain unclear. We investigate whether this intervention affects viral suppression and CD4 cell count increase following its reinitiation in chronic infection (CHI). Longitudinal observational study. We identified adult patients from Concerted Action of Seroconversion to AIDS and Death in Europe who seroconverted after 1/1/2000, had a 12 months or less HIV test interval and initiated cART from naive. We classified individuals as 'pretreated in EHI' if treated within 6 months of seroconversion, interrupted for at least 12 weeks, and reinitiated during CHI. Statistical analysis was performed using survival analysis methods and mixed models. Pretreated and initiated in CHI groups comprised 202 and 4263 individuals, with median follow-up after CHI treatment 4.5 and 3 years, respectively. Both groups had similar virologic response and relapse rates (P = 0.585 and P = 0.206) but pretreated individuals restarted treatment with higher baseline CD4 cell count (∼80 cells/μl; P < 0.001) and retained significantly higher CD4 cell count for more than 3 years after treatment (re)initiation. Assuming common baseline CD4 cell count, differences in CD4 cell count slopes were nonsignificant. Immunovirologic response to CHI treatment was not associated with timing or duration of the transient treatment. Although treatment interruptions are not recommended, stopping cART initiated in EHI does not seem to reduce the chance of a successful outcome of treatment in CHI.

  19. Trehalose treatment suppresses inflammation, oxidative stress, and vasospasm induced by experimental subarachnoid hemorrhage

    PubMed Central

    2012-01-01

    Background Subarachnoid hemorrhage (SAH) frequently results in several complications, including cerebral vasospasm, associated with high mortality. Although cerebral vasospasm is a major cause of brain damages after SAH, other factors such as inflammatory responses and oxidative stress also contribute to high mortality after SAH. Trehalose is a non-reducing disaccharide in which two glucose units are linked by α,α-1,1-glycosidic bond, and has been shown to induce tolerance to a variety of stressors in numerous organisms. In the present study, we investigated the effect of trehalose on cerebral vasospasm, inflammatory responses, and oxidative stress induced by blood in vitro and in vivo. Methods Enzyme immunoassay for eicosanoids, pro-inflammatory cytokines, and endothelin-1, and western blotting analysis for cyclooxygenase-2, inducible nitric oxide synthase, and inhibitor of NF-κB were examined in macrophage-like cells treated with hemolysate. After treatment with hemolysate and hydrogen peroxide, the levels of lipid peroxide and amounts of arachidonic acid release were also analyzed. Three hours after the onset of experimental SAH, 18 Japanese White rabbits received an injection of saline, trehalose, or maltose into the cisterna magna. Angiographic and histological analyses of the basilar arteries were performed. In a separate study, the femoral arteries from 60 rats were exposed to fresh autologous blood. At 1, 3, 5, 7, 10, and 20 days after treatment, cryosections prepared from the femoral arteries were histologically analyzed. Results When cells were treated with hemolysate, trehalose inhibited the production of several inflammatory mediators and degradation of the inhibitor of NF-κB and also suppressed the lipid peroxidation, the reactive oxygen species-induced arachidonic acid release in vitro. In the rabbit model, trehalose produced an inhibitory effect on vasospasm after the onset of experimental SAH, while maltose had only a moderate effect. When the

  20. Treatment with FGFR2-IIIc monoclonal antibody suppresses weight gain and adiposity in KKAy mice

    PubMed Central

    Nonogaki, K; Kaji, T; Yamazaki, T; Murakami, Mari

    2016-01-01

    Expression of β-Kotho, fibroblast growth factor receptor (FGFR)-1c and 2c, which bind FGF21, is decreased in the white adipose tissue of obese mice. The aim of the present study was to determine the role of FGFR2c in the development of obesity and diabetes in KKAy mice. Treatment with mouse monoclonal FGFR2-IIIc antibody (0.5 mg kg−1) significantly suppressed body weight gain and epididymal white adipose tissue weight in individually housed KKAy mice while having no effect on daily food intake. In addition, treatment with FGFR2-IIIc antibody significantly increased plasma-free fatty acid levels while having no effect on blood glucose or plasma FGF21 levels. Moreover, treatment with FGFR2-IIIc antibody had no significant effect on the expression of uncoupling protein-1, uncoupling protein-2 or peroxisome proliferator-activated receptor-γ coactivator 1α in the epididymal white adipose tissue. The treatment with FGFR2-IIIc antibody had no significant effects on daily food intake and body weight gain in individually housed KK mice. These findings suggest that FGFR2-IIIc upregulates the adiposity induced by social isolation in KKAy mice, and that decreased expression and/or function of FGFR2c might be a compensatory response to enhanced adiposity. Inhibition of FGFR2-IIIc function might be a novel therapeutic approach for obesity. PMID:27892934

  1. Adverse events in IBD: to stop or continue immune suppressant and biologic treatment

    PubMed Central

    McLean, Leon P; Cross, Raymond K

    2014-01-01

    Crohn’s disease and ulcerative colitis affect an increasing number of patients. A variety of medical options exist for the treatment of these diseases including immune suppressants and biologic therapies. Unfortunately, these agents are associated with adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. This review discusses adverse events associated with azathioprine, mercaptopurine, and methotrexate as well as anti-TNF-α and anti-integrin antibodies. In addition, adverse events associated with combination therapy are discussed as are clinical scenarios in which it may be reasonable to discontinue or de-escalate drug therapy. It is the responsibility of the treating gastroenterologist to effectively communicate the benefits and risks of therapy with patients; this review offers strategies that may assist providers in communicating risk with patients in addition to offering our perspective on whether modification or cessation of therapy can be considered. PMID:24490595

  2. Optimization of suppression for two-element treatment liners for turbomachinery exhaust ducts

    NASA Technical Reports Server (NTRS)

    Motsinger, R. E.; Kraft, R. E.; Zwick, J. W.; Vukelich, S. I.; Minner, G. L.; Baumeister, K. J.

    1976-01-01

    Sound wave propagation in a soft-walled rectangular duct with steady uniform flow was investigated at exhaust conditions, incorporating the solution equations for sound wave propagation in a rectangular duct with multiple longitudinal wall treatment segments. Modal analysis was employed to find the solution equations and to study the effectiveness of a uniform and of a two-sectional liner in attenuating sound power in a treated rectangular duct without flow (M = 0) and with uniform flow of Mach 0.3. Two-segment liners were shown to increase the attenuation of sound as compared to a uniform liner. The predicted sound attenuation was compared with measured laboratory results for an optimized two-segment suppressor. Good correlation was obtained between the measured and predicted suppressions when practical variations in the modal content and impedance were taken into account. Two parametric studies were also completed.

  3. [Persistence of suppression after treatment for strabismic amblyopia: some remarks on two particular cases (authors' transl)].

    PubMed

    Nardi, M

    1981-01-01

    The dominant eye of these patients, successfully treated for strabismic amblyopia, has become myopic, while the previous amblyopic eye is now emmetropic: monocular visual acuity of the latter is good, but binocular vision, without correction, is equal to that of the non-corrected dominant myopic eye. During binocular vision the dominant eye maintains fixation even though its visual acuity is reduced with respect to the other eye: indeed the latter cannot be utilized to the best of its functional possibility, due to the presence of a suppressive central scotoma. A similar situation may be present during treatment with penalization of a strabismic amblyopia: it may not, therefore, be sufficient to lower the visual acuity of the dominant eye to a value less than that of the amblyopic eye (monocularly determined) to ensure utilization and exercise of this latter.

  4. Slow-release oral morphine for maintenance treatment of opioid addicts intolerant to methadone or with inadequate withdrawal suppression.

    PubMed

    Kastelic, Andrej; Dubajic, Goran; Strbad, Ervin

    2008-11-01

    Evaluation of the efficacy, safety and acceptability of slow-release oral morphine (SROM) in opioid addicts intolerant to methadone or with inadequate withdrawal suppression. Prospective, open, non-comparative multi-centre study. Twelve out-patient Centres for Prevention and Treatment of Drug Addiction in Slovenia. Male and female opioid addicts (age>18 years) under methadone maintenance therapy requiring a change of treatment in order to continue more effectively with maintenance. Maintenance therapy with methadone was switched to once-daily SROM. Efficacy evaluations were based on the reduction of side effects and on the degree of suppression of opiate craving, signs and symptoms of withdrawal. In addition, self-reported somatic and psychic symptoms (SCL-27) as well as World Health Organization quality of life-related (WHO QOL) parameters were monitored. Thirty-nine subjects intolerant to methadone and 28 subjects showing inadequate withdrawal suppression under methadone>or=90 mg/day were included as two separate groups in the efficacy analyses. Treatment was switched easily from methadone to SROM on a 1:8 ratio. Four-week SROM treatment resulted in significant reduction of side effects reported under methadone. Signs and symptoms of opioid withdrawal as well as craving for opiates were improved significantly in patients with inadequate response to methadone. Physical and psychological wellbeing improved significantly under SROM treatment. SROM was tolerated very well. Maintenance treatment with SROM appears to be a clinically useful alternative treatment in subjects not tolerating methadone or with inadequate withdrawal suppression.

  5. The effect of omeprazole pre-treatment on rafts formed by reflux suppressant tablets containing alginate.

    PubMed

    Dettmar, P W; Little, S L; Baxter, T

    2005-01-01

    Alginate-based reflux suppressant preparations provide symptom relief by forming a physical barrier on top of the stomach contents in the form of a neutral floating gel or raft. This study investigated whether reduced acidity in the stomach brought about by omeprazole pre-treatment affected the formation and gastric residence time of alginate rafts. It was a balanced, cross-over study in 12 healthy non-patient volunteers following a single dose of two indium-111-labelled alginate tablets in the presence or absence of 3 days' pre-treatment with omeprazole. Raft formation and gastric residence, in the presence of a technetium-99m-labelled meal, were assessed by gamma scintigraphy for 3 h after alginate tablet administration. The relative raft-forming ability of alginate tablets after omeprazole compared with alginate tablets alone was 0.950 with 95% confidence intervals of 0.882 and 1.018. Pre-treatment and co-administration with omeprazole has no significant effect on the raft-forming ability of alginate tablets.

  6. Increased long-term remission after adequate medical cortisol suppression therapy as presurgical treatment in Cushing's disease.

    PubMed

    van den Bosch, O F C; Stades, A M E; Zelissen, P M J

    2014-02-01

    In the last decade, pre-operative medical cortisol suppression therapy has frequently been used in Cushing's disease to normalize cortisol concentrations pre-operatively. Our aim was to assess the efficacy of presurgical medical cortisol suppression therapy in Cushing's disease. We retrospectively assessed the medical files of all patients with Cushing's disease that received presurgical cortisol suppression therapy with ketoconazole or metyrapone and underwent subsequent transsphenoidal surgery between 1990 and 2010 at our centre. We retrieved the pretreatment regimen, adequacy of pretreatment, early postoperative serum cortisol levels, adverse effects and long-term remission status. Nineteen of 33 patients (58%) obtained long-term remission after pituitary surgery without additional postoperative therapy. Thirteen of 16 patients with adequate presurgical cortisol suppression therapy had postoperative cortisol concentrations <50 nmol/l. The 16 patients with adequate presurgical cortisol suppression had a higher long-term remission rate after primary surgery compared with the 13 patients with borderline or inadequate pretreatment (81% vs 38%; P < 0·05). Adequate presurgical cortisol suppression treatment with ketoconazole or metyrapone in Cushing's disease seems to be associated with suppressed postoperative cortisol concentrations and an increased long-term remission rate. © 2013 John Wiley & Sons Ltd.

  7. Factor structure and clinical correlates of the Food Thought Suppression Inventory within treatment seeking obese women with binge eating disorder.

    PubMed

    Barnes, Rachel D; Sawaoka, Takuya; White, Marney A; Masheb, Robin M; Grilo, Carlos M

    2013-01-01

    Prior research on the relations among eating behaviors and thought suppression is limited to a measure of general thought suppression, the White Bear Suppression Inventory. To address this limitation, researchers recently validated the Food Thought Suppression Inventory (FTSI). Analyses using this measure suggest that food thought suppression is distinct from and is more predictive of eating disorder psychopathology than is general thought suppression. The FTSI, however, has not yet been validated in clinical samples. The purpose of the current study is to examine the factor structure and clinical correlates of the FTSI within treatment seeking obese women with binge eating disorder (BED; N=128). Analyses revealed a valid and reliable one-factor measure of food thought suppression that was related to higher levels of eating and general psychopathology. The findings provide evidence for the use of the FTSI with obese women with BED. Future research should examine the psychometric properties of the FTSI within larger and more diverse samples. Copyright © 2012. Published by Elsevier Ltd.

  8. Proton Radiotherapy for Prostate Cancer Is Not Associated With Post-Treatment Testosterone Suppression

    SciTech Connect

    Nichols, R. Charles; Morris, Christopher G.; Hoppe, Bradford S.; Henderson, Randal H.; Marcus, Robert B.; Mendenhall, William M.; Li Zuofeng; Williams, Christopher R.; Costa, Joseph A.; Mendenhall, Nancy P.

    2012-03-01

    Purpose: Three independent studies of photon (x-ray) radiotherapy (RT) for prostate cancer have demonstrated evidence of testosterone suppression after treatment. The present study was undertaken to determine whether this would also be the case with conformal protons. Methods and Materials: Between August 2006 and October 2007, 171 patients with low- and intermediate-risk prostate cancer were enrolled and underwent treatment according to University of Florida Proton Therapy Institute institutional review board-approved PR01 and PR02 protocols. Of the 171 patients, 18 were excluded because they had received androgen deprivation therapy either before (n = 17) or after (n = 1) RT. The pretreatment serum testosterone level was available for 150 of the remaining 153 patients. These 150 patients were included in the present study. The post-treatment levels were compared with the pretreatment levels. Results: The median baseline pretreatment serum testosterone level was 357.9 ng/dL. The median post-treatment testosterone value was 375.5 ng/dL at treatment completion (p = .1935) and 369.9 ng/dL (p = .1336), 348.7 ng/dL (p = .7317), 353.4 ng/dL (p = .6996), and 340.9 ng/dL (p = .1669) at 6, 12, 18, and 24 months after proton therapy, respectively. Conclusions: Conformal proton therapy to the prostate, as delivered using University of Florida Proton Therapy Institute PR01 and PR02 protocols, did not appear to significantly affect the serum testosterone levels within 24 months after RT.

  9. Examining the relative effects of fire weather, suppression and fuel treatment on fire behaviour--a simulation study.

    PubMed

    Penman, T D; Collins, L; Price, O F; Bradstock, R A; Metcalf, S; Chong, D M O

    2013-12-15

    Large budgets are spent on both suppression and fuel treatments in order to reduce the risk of wildfires. There is little evidence regarding the relative contribution of fire weather, suppression and fuel treatments in determining the risk posed from wildfires. Here we undertake a simulation study in the Sydney Basin, Australia, to examine this question using a fire behaviour model (Phoenix Rapidfire). Results of the study indicate that fire behaviour is most strongly influenced by fire weather. Suppression has a greater influence on whether a fire reaches 5 ha in size compared to fuel treatments. In contrast, fuel treatments have a stronger effect on the fire size and maximum distance the fire travels. The study suggests that fire management agencies will receive additional benefits from fuel treatment if they are located in areas which suppression resources can respond rapidly and attempt to contain the fires. No combination of treatments contained all fires, and the proportion of uncontained fires increased under more severe fire weather when the greatest number of properties are lost. Our study highlights the importance of alternative management strategies to reduce the risk of property loss.

  10. Bindings of /sup 3/H-prazosin and /sup 3/H-yohimbine to alpha adrenoceptors in the guinea-pig stomach

    SciTech Connect

    Taniguchi, T.; Nishikawa, H.

    1988-01-01

    Alpha adrenoceptor subtypes have been investigated by radioligand binding study in guinea-pig stomach using /sup 3/H-prazosin and /sup 3/H-yohimbine. The specific /sup 3/H-prazosin binding to guinea-pig stomach was saturable and of high affinity with a Bmax of 33 fmol/mg protein. Specific /sup 3/H-yohimbine binding to the tissue was also saturable and of high affinity with a Bmax of 150 fmol/mg protein. Adrenergic drugs competed for /sup 3/H-prazosin binding in order of prazosin > phentolamine > methoxamine > norepinephrine > clonidine > epinephrine > yohimbine. These drugs competed for /sup 3/H-yohimbine binding in order of yohimbine > phentolamine > clonidine > epinephrine > norepinephrine > prazosin > methoxamine. They also examined whether dopamine receptors exist in guinea-pig stomach, using radioligand binding study. Specific binding of /sup 3/H-spiperone, /sup 3/H-apomorphine, /sup 3/H-dopamine and /sup 3/H-domperidone was not detectable in the stomach. Dopaminergic drugs such as dopamine, haloperidol, domperidone and sulpiride competed for /sup 3/H-prazosin binding in order of haloperidol > domperidone > dopamine > sulpiride. Metoclopramide, sulpiride and dopamine competed for /sup 3/H-yohimbine binding in order of metoclopramide > sulpiride > dopamine.

  11. Impairment of contextual conditioned fear extinction after microinjection of alpha-1-adrenergic blocker prazosin into the medial prefrontal cortex.

    PubMed

    Do-Monte, Fabrício H M; Allensworth, Melody; Carobrez, Antônio P

    2010-07-29

    Long-lasting memories of aversive or stressful events have been associated with the noradrenergic system activation. Alpha-1-adrenergic antagonist prazosin has successfully been used in the last years to treat anxiety disorders related to aversive memories recurrence in humans. Contextual conditioned fear extinction paradigm in rats has been used to better understand the mechanisms involved in the attenuation of defensive behaviour after a traumatic situation. Here we investigated the effects of systemic administration of prazosin in the fear extinction processes. Rats were previously paired in a contextual fear conditioning box (1 footshock, 1 mA, 2s duration), further returning to the same box during three consecutive days receiving an intraperitoneal injection of vehicle or prazosin 30 min before (acquisition of extinction; 0.1 or 0.5mg/kg) or immediately after (consolidation of extinction, 0.5 or 1.5mg/kg) each extinction session (10 min). On the last day, all animals were re-exposed undrugged to the apparatus. Since the medial prefrontal cortex (mPFC) has been described as a key structure in the modulation of conditioned fear extinction, the effects of intra-mPFC microinjection (0.2 microl per side) of vehicle (PBS) or prazosin (0.75 or 2.5 nmol) in the acquisition of fear extinction (10 min before extinction session 1) were further evaluated. Subjects were drug-free re-exposed to the same box in the next day (extinction session 2). The percentage of freezing time was used as the memory retention parameter. The results showed that either systemic or intra-mPFC-alpha-1-adrenergic blockade increased the freezing time in the last extinction sessions, suggesting impairment of the extinction of contextual conditioned fear in rats.

  12. Prazosin differentially affects extinction of cocaine conditioned place preference on the basis of dose and initial preference.

    PubMed

    Bernardi, Rick E; Lattal, K Matthew

    2012-12-19

    Recent work has shown that α1-adrenergic receptor blockade impairs extinction in fear conditioning paradigms in rodents. However, studies of the role of α1-adrenergic receptors in extinction using other conditioning paradigms, such as those examining the conditioned effects of drug of abuse, have yielded inconsistent results. In this article, we reanalyze and extend previously reported findings of the effect of prazosin, an α1-adrenergic receptor antagonist, on the extinction of a cocaine-induced conditioned place preference in rats, using a median split of performance during the initial test for preference. This new reanalysis, which includes further extinction testing, indicated a paradoxical dose effect. A single post-test administration of a lower dose of prazosin, 0.3 mg/kg intraperitoneally, impaired extinction in rats that showed a below-median preference during initial testing, but had no effect on extinction in rats that showed an above-median preference during initial testing. In contrast, a single post-test administration of a higher dose of prazosin, 1.0 mg/kg intraperitoneally, enhanced extinction in rats that showed an above-median preference during initial testing, but had no effect on extinction in rats that showed a below-median preference during initial testing. Consistent with other studies of fear and drug conditioning, these results suggest the involvement of the α1-adrenergic receptor in the formation of extinction memories, but also indicate a potentially important differential effect on extinction on the basis of the dose of prazosin and the strength of the initial learning.

  13. Novel Americium Treatment Process for Surface Water and Dust Suppression Water

    SciTech Connect

    Tiepel, E.W.; Pigeon, P.; Nesta, S.; Anderson, J.

    2006-07-01

    -241 contaminated pond water, surface run-off and D and D dust suppression water during the later stages of the D and D effort at Rocky Flats. This novel chemical treatment system allowed for highly efficient, high-volume treatment of all contaminated waste waters to the very low stream standard of 0.15 pCi/1 with strict compliance to the RFCA discharge criteria for release to off-site surface waters. The rapid development and implementation of the treatment system avoided water management issues that would have had to be addressed if contaminated water had remained in Pond A-4 into the Spring of 2005. Implementation of this treatment system for the Pond A-4 waters and the D and D waters from Buildings 776 and 371 enabled the site to achieve cost-effective treatment that minimized secondary waste generation, avoiding the need for expensive off-site water disposal. Water treatment was conducted for a cost of less than $0.20/gal which included all development costs, capital costs and operational costs. This innovative and rapid response effort saved the RFETS cleanup program well in excess of $30 million for the potential cost of off-site transportation and treatment of radioactive liquid waste. (authors)

  14. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption.

    PubMed

    Scheid, Johannes F; Horwitz, Joshua A; Bar-On, Yotam; Kreider, Edward F; Lu, Ching-Lan; Lorenzi, Julio C C; Feldmann, Anna; Braunschweig, Malte; Nogueira, Lilian; Oliveira, Thiago; Shimeliovich, Irina; Patel, Roshni; Burke, Leah; Cohen, Yehuda Z; Hadrigan, Sonya; Settler, Allison; Witmer-Pack, Maggi; West, Anthony P; Juelg, Boris; Keler, Tibor; Hawthorne, Thomas; Zingman, Barry; Gulick, Roy M; Pfeifer, Nico; Learn, Gerald H; Seaman, Michael S; Bjorkman, Pamela J; Klein, Florian; Schlesinger, Sarah J; Walker, Bruce D; Hahn, Beatrice H; Nussenzweig, Michel C

    2016-07-28

    Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117,a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein, during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions,separated by 3 or 2 weeks, respectively, are generally well tolerated.Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals,emerging viruses show increased resistance, indicating escape.However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks.We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans.

  15. Treatment of self-injurious behavior using a water mist: initial response suppression and generalization.

    PubMed Central

    Dorsey, M F; Iwata, B A; Ong, P; McSween, T E

    1980-01-01

    This study evaluated the effects of a fine mist of water applied to the face contingent upon self-injurious behavior (SIB) exhibited by profoundly retarded persons. In Experiment 1, results of individual reversal designs showed substantial reductions in a variety of SIB's (mouthing, hand biting, skin tearing, and head banging) for seven participants. In Experiment 2, two participants who frequently bit their hands were each observed in two different settings. Following initial baselines in each setting, a series of manipulations was undertaken to compare the effects of mild verbal punishment ("No") with those of a combined treatment ("No" plus mist procedure). Results in one setting indicated that "No" suppressed SIB only after it was first paired with the water mist. Data also suggested that, once acquired, the punishing properties of "No" could be extended to a second setting in which the mist was never applied, and that these effects could be generalized across therapists. Results of these experiments indicate that the water mist procedure may be an effective alternative to traditional punishment techniques. Although conclusions regarding generalization are limited due to the brevity of the maintenance conditions, the data suggest that treatment gains may be transferred to more acceptable forms of social punishment and reinforcement. PMID:7380756

  16. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

    PubMed Central

    Scheid, Johannes F.; Horwitz, Joshua A.; Bar-On, Yotam; Kreider, Edward F.; Lu, Ching-Lan; Lorenzi, Julio C. C.; Feldmann, Anna; Braunschweig, Malte; Nogueira, Lilian; Oliveira, Thiago; Shimeliovich, Irina; Patel, Roshni; Burke, Leah; Cohen, Yehuda Z.; Hadrigan, Sonya; Settler, Allison; Witmer-Pack, Maggi; West, Anthony P.; Juelg, Boris; Keler, Tibor; Hawthorne, Thomas; Zingman, Barry; Gulick, Roy M.; Pfeifer, Nico; Learn, Gerald H.; Seaman, Michael S.; Bjorkman, Pamela J.; Klein, Florian; Schlesinger, Sarah J.; Walker, Bruce D.; Hahn, Beatrice H.; Nussenzweig, Michel C.; Caskey, Marina

    2016-01-01

    Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env1, in the setting of analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg kg−1 infusions of 3BNC117, separated by 3 or 2 weeks, respectively, are generally well tolerated. Infusions are associated with a delay in viral rebound for 5–9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals, emerging viruses show increased resistance, indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg ml−1, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9–19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans. PMID:27338952

  17. Short-term sertraline treatment suppresses sympathetic nervous system activity in healthy human subjects.

    PubMed

    Shores, M M; Pascualy, M; Lewis, N L; Flatness, D; Veith, R C

    2001-05-01

    Increased sympathetic nervous system (SNS) activity has been associated with stress, major depression, aging, and several medical conditions. This study assessed the effect of the selective serotonin reuptake inhibitor (SSRI), sertraline, on sympathetic nervous system (SNS) activity in healthy subjects. Twelve healthy volunteers participated in a double-blind, placebo-controlled, norepinephrine (NE) kinetic study, in which the effects of sertraline on SNS activity were ascertained by determining NE plasma concentrations and NE plasma appearance rates and clearance rates in sertraline or placebo conditions. Subjects received 50 mg of sertraline or placebo for two days and then one week later underwent the same protocol with the other drug. By single compartmental analysis, plasma NE appearance rates were significantly lower in the sertraline compared to the placebo condition (0.26+/-0.10 vs 0.40+/-0.23 microg/m(2)/min; P=0.04). Our study found that the net effect of short-term SSRI treatment is an apparent suppression of SNS activity as indicated by a decreased plasma NE appearance rate in the sertraline condition. If this preliminary finding can be extended to long-term treatment of patients, this could have significant therapeutic relevance for treating depression in elderly patients or those with cardiac disease, in which elevated SNS activity may exacerbate underlying medical conditions.

  18. Terazosin for the treatment of trauma-related nightmares: a report of 4 cases.

    PubMed

    Nirmalani-Gandhy, Anjali; Sanchez, Deborah; Catalano, Glenn

    2015-01-01

    The selective α1-adrenergic antagonist prazosin has been shown in multiple studies to be effective in targeting trauma-related nightmares in posttraumatic stress disorder. There are limited data regarding the effectiveness of another selective α1-adrenergic antagonist terazosin for the treatment of trauma-related nightmares. We present 4 cases in which terazosin was effectively used to treat nightmares as a second-line agent after prazosin failure. Further studies are needed to validate terazosin as an alternative to prazosin for the treatment of posttraumatic stress disorder-related nightmares.

  19. Ginger Treatment Ameliorates Alcohol-induced Myocardial Damage by Suppression of Hyperlipidemia and Cardiac Biomarkers in Rats.

    PubMed

    Subbaiah, Ganjikunta Venkata; Mallikarjuna, Korivi; Shanmugam, Bhasha; Ravi, Sahukari; Taj, Patan Usnan; Reddy, Kesireddy Sathyavelu

    2017-01-01

    Alcohol-induced hyperlipidemia is positively correlated with cardiovascular diseases. Several herbal extracts have been reported to protect the cardiac injury and suppress the hyperlipidemia. However, the effect of ginger extracts on alcohol-induced hyperlipidemia and associated myocardial damage remains unclear. This study investigated the cardio-protective properties of ginger ethanolic extract (Gt) against alcohol-induced myocardial damage, and further distinguished the association between hyperlipidemia and occurrence of myocardial damage in rats. Twenty four Wistar male albino rats (250 ± 20 g) were divided into four groups including, Normal control (NC) (0.9% NaCl), Ginger treated (Gt) (200 mg/Kg b.w.), Alcohol treated (At) (20% of 6g/kg b.w. alcohol), and Alcohol along with Ginger treatment (At+Gt). In this study, lipid profiles such as fatty acids, triglycerides, total cholesterol, phospholipids, low density lipoprotein and high density lipoproteins, and cardiac biomarkers, including LDH, AST, CK-MB, cTn-T and cTn-I were examined in rats. Furthermore, histopathological studies were also conducted. We found that alcohol-induced myocardial damage was associated with increased lipid profile except high density lipoprotein in alcohol treated (20%, 6g/kg b.w.) rats compared with control. Ginger treatment significantly reduced the alcohol-induced lipid profiles except high density lipoproteins. Furthermore, elevated cardiac biomarkers activity with alcohol intoxication was substantially suppressed by ginger treatment. In addition, ginger treatment for 7-weeks significantly minimized the alcohol-induced myocardial damage. Our results concluded that ginger could protect alcohol-induced myocardial damage by suppression of hyperlipidemia and cardiac biomarkers. Ginger extract could alleviate the myocardial injury partially due to the suppression of circulating FFAs and TG levels.Increased circulating cholesterol, LDL and phospholipids with alcohol intake were

  20. Ginger Treatment Ameliorates Alcohol-induced Myocardial Damage by Suppression of Hyperlipidemia and Cardiac Biomarkers in Rats

    PubMed Central

    Subbaiah, Ganjikunta Venkata; Mallikarjuna, Korivi; Shanmugam, Bhasha; Ravi, Sahukari; Taj, Patan Usnan; Reddy, Kesireddy Sathyavelu

    2017-01-01

    Background: Alcohol-induced hyperlipidemia is positively correlated with cardiovascular diseases. Several herbal extracts have been reported to protect the cardiac injury and suppress the hyperlipidemia. However, the effect of ginger extracts on alcohol-induced hyperlipidemia and associated myocardial damage remains unclear. Objective: This study investigated the cardio-protective properties of ginger ethanolic extract (Gt) against alcohol-induced myocardial damage, and further distinguished the association between hyperlipidemia and occurrence of myocardial damage in rats. Materials and Methods: Twenty four Wistar male albino rats (250 ± 20 g) were divided into four groups including, Normal control (NC) (0.9% NaCl), Ginger treated (Gt) (200 mg/Kg b.w.), Alcohol treated (At) (20% of 6g/kg b.w. alcohol), and Alcohol along with Ginger treatment (At+Gt). In this study, lipid profiles such as fatty acids, triglycerides, total cholesterol, phospholipids, low density lipoprotein and high density lipoproteins, and cardiac biomarkers, including LDH, AST, CK-MB, cTn-T and cTn-I were examined in rats. Furthermore, histopathological studies were also conducted. Results: We found that alcohol-induced myocardial damage was associated with increased lipid profile except high density lipoprotein in alcohol treated (20%, 6g/kg b.w.) rats compared with control. Ginger treatment significantly reduced the alcohol-induced lipid profiles except high density lipoproteins. Furthermore, elevated cardiac biomarkers activity with alcohol intoxication was substantially suppressed by ginger treatment. In addition, ginger treatment for 7-weeks significantly minimized the alcohol-induced myocardial damage. Conclusion: Our results concluded that ginger could protect alcohol-induced myocardial damage by suppression of hyperlipidemia and cardiac biomarkers. SUMMARY Ginger extract could alleviate the myocardial injury partially due to the suppression of circulating FFAs and TG levels

  1. The cytotoxicity of the α1-adrenoceptor antagonist prazosin is linked to an endocytotic mechanism equivalent to transport-P.

    PubMed

    Fuchs, Robert; Stracke, Anika; Ebner, Nadine; Zeller, Christian Wolfgang; Raninger, Anna Maria; Schittmayer, Matthias; Kueznik, Tatjana; Absenger-Novak, Markus; Birner-Gruenberger, Ruth

    2015-12-02

    Since the α1-adrenergic antagonist prazosin (PRZ) was introduced into medicine as a treatment for hypertension and benign prostate hyperplasia, several studies have shown that PRZ induces apoptosis in various cell types and interferes with endocytotic trafficking. Because PRZ is also able to induce apoptosis in malignant cells, its cytotoxicity is a focus of interest in cancer research. Besides inducing apoptosis, PRZ was shown to serve as a substrate for an amine uptake mechanism originally discovered in neurones called transport-P. In line with our hypothesis that transport-P is an endocytotic mechanism also present in non-neuronal tissue and linked to the cytotoxicity of PRZ, we tested the uptake of QAPB, a fluorescent derivative of PRZ, in cancer cell lines in the presence of inhibitors of transport-P and endocytosis. Early endosomes and lysosomes were visualised by expression of RAB5-RFP and LAMP1-RFP, respectively; growth and viability of cells in the presence of PRZ and uptake inhibitors were also tested. Cancer cells showed co-localisation of QAPB with RAB5 and LAMP1 positive vesicles as well as tubulation of lysosomes. The uptake of QAPB was sensitive to transport-P inhibitors bafilomycin A1 (inhibits v-ATPase) and the antidepressant desipramine. Endocytosis inhibitors pitstop(®) 2 (general inhibitor of endocytosis), dynasore (dynamin inhibitor) and methyl-β-cyclodextrin (cholesterol chelator) inhibited the uptake of QAPB. Bafilomycin A1 and methyl-β-cyclodextrin but not desipramine were able to preserve growth and viability of cells in the presence of PRZ. In summary, we confirmed the hypothesis that the cellular uptake of QAPB/PRZ represents an endocytotic mechanism equivalent to transport-P. Endocytosis of QAPB/PRZ depends on a proton gradient, dynamin and cholesterol, and results in reorganisation of the LAMP1 positive endolysosomal system. Finally, the link seen between the cellular uptake of PRZ and cell death implies a still unknown pro

  2. Prazosin for Treatment of Patients With PTSD and Comorbid Alcohol Dependence

    DTIC Science & Technology

    2013-07-01

    GA (June, 2011) comparing demographic characteristics of patients with dual diagnosis of AD and PTSD (from this study) and patients with only AD...stimuli. The data showed that those with dual diagnosis had significantly stronger reactions to stress than those with diagnosis of AD alone. A...currently under review in the journal of " Addictive Disorders". The paper explored differences in the pretreatment characteristics of veterans with

  3. Caspase-resistant vimentin suppresses apoptosis after photodynamic treatment with a silicon phthalocyanine in Jurkat cells.

    PubMed

    Belichenko, I; Morishima, N; Separovic, D

    2001-06-01

    Oxidative stress, such as photodynamic therapy, is an apoptosis inducer. Apoptosis, as well as photosensitization, have been associated with disruption of the cytoskeletal network. The purpose of the present study was to assess the role of vimentin, a major cytoskeletal protein, in apoptosis after photodynamic treatment (PDT) with the silicon phthalocyanine Pc 4 in human Jurkat T cells. Here we show for the first time that photosensitization with Pc 4 initiates vimentin cleavage and that this event precedes poly(ADP-ribose) polymerase (PARP) degradation. Similar findings were obtained in the presence of C2-ceramide, an inducer of oxidative stress and apoptosis. In the presence of benzyloxycarbonyl-Val-Ala-Asp(O-methyl)-fluoromethylketone, a pan-caspase inhibitor, Pc 4-PDT-induced vimentin and PARP cleavage were abolished. In Jurkat cells transfected with a caspase-resistant vimentin apoptosis was partly suppressed and delayed post-Pc 4-PDT. We suggest that the full-length vimentin confers resistance to nuclear apoptosis after PDT with Pc 4.

  4. Paroxetine treatment, following behavioral suppression of PTSD-like symptoms in mice, prevents relapse by activating the infralimbic cortex.

    PubMed

    Bentefour, Yassine; Rakibi, Youness; Bennis, Mohamed; Ba-M'hamed, Saadia; Garcia, René

    2016-02-01

    Clinical studies have shown that post-traumatic stress disorder (PTSD) remission, induced by selective serotonin reuptake inhibitor (SSRI) treatment, is associated with increased prefrontal activation during post-treatment symptom provocation. Other studies have shown that continuation SSRI treatment after remitting from PTSD reduces the rate of relapse. The aim of the present preclinical study was to investigate the relationship between post-treatment prefrontal changes and PTSD relapse prevention. Avoidance conditioning (with a 1.5-mA foot-shock), avoidance extinction and a trauma priming exposure (with a 0.3-mA foot-shock) were used in mice to induce, suppress and reactivate PTSD-like symptoms (including avoidance, fear sensitization, enhanced contextual fear, and anxiety-like behavior), respectively. Paroxetine, injected at 8 mg/kg/day (7 days), was used as SSRI treatment. PTSD-like symptoms were present for at least 30 days and resistant to paroxetine treatment. However, after extinction training (suppressing all PTSD-like symptoms), paroxetine treatment prevented symptom reactivation. Paroxetine treatment also induced infralimbic neuronal activation. However, infralimbic functional tetrodotoxin inactivation abolished the preventive effect of paroxetine treatment on symptom reactivation. The data reveal a potential ability of treatments inducing infralimbic activation to provide prophylactic protection against PTSD relapse.

  5. Using Topography to Meet Wildlife and Fuels Treatment Objectives in Fire-Suppressed Landscapes

    NASA Astrophysics Data System (ADS)

    Underwood, Emma C.; Viers, Joshua H.; Quinn, James F.; North, Malcolm

    2010-11-01

    Past forest management practices, fire suppression, and climate change are increasing the need to actively manage California Sierra Nevada forests for multiple environmental amenities. Here we present a relatively low-cost, repeatable method for spatially parsing the landscape to help the U.S. Forest Service manage for different forest and fuel conditions to meet multiple goals relating to sensitive species, fuels reduction, forest products, water, carbon storage, and ecosystem restoration. Using the Kings River area of the Sierra Nevada as a case study, we create areas of topographically-based units, Landscape Management Units (LMUs) using a three by three matrix (canyon, mid-slope, ridge-top and northerly, southerly, and neutral aspects). We describe their size, elevation, slope, aspect, and their difference in inherent wetness and solar radiation. We assess the predictive value and field applicability of LMUs by using existing data on stand conditions and two sensitive wildlife species. Stand conditions varied significantly between LMUs, with canyons consistently having the greatest stem and snag densities. Pacific fisher ( Martes pennanti) activity points (from radio telemetry) and California spotted owl ( Strix occidentalis occidentalis) nests, roosts, and sightings were both significantly different from uniform, with a disproportionate number of observations in canyons, and fewer than expected on ridge-tops. Given the distinct characteristics of the LMUs, these units provide a relatively simple but ecologically meaningful template for managers to spatially allocate forest treatments, thereby meeting multiple National Forest objectives. These LMUs provide a framework that can potentially be applied to other fire-dependent western forests with steep topographic relief.

  6. Using topography to meet wildlife and fuels treatment objectives in fire-suppressed landscapes.

    PubMed

    Underwood, Emma C; Viers, Joshua H; Quinn, James F; North, Malcolm

    2010-11-01

    Past forest management practices, fire suppression, and climate change are increasing the need to actively manage California Sierra Nevada forests for multiple environmental amenities. Here we present a relatively low-cost, repeatable method for spatially parsing the landscape to help the U.S. Forest Service manage for different forest and fuel conditions to meet multiple goals relating to sensitive species, fuels reduction, forest products, water, carbon storage, and ecosystem restoration. Using the Kings River area of the Sierra Nevada as a case study, we create areas of topographically-based units, Landscape Management Units (LMUs) using a three by three matrix (canyon, mid-slope, ridge-top and northerly, southerly, and neutral aspects). We describe their size, elevation, slope, aspect, and their difference in inherent wetness and solar radiation. We assess the predictive value and field applicability of LMUs by using existing data on stand conditions and two sensitive wildlife species. Stand conditions varied significantly between LMUs, with canyons consistently having the greatest stem and snag densities. Pacific fisher (Martes pennanti) activity points (from radio telemetry) and California spotted owl (Strix occidentalis occidentalis) nests, roosts, and sightings were both significantly different from uniform, with a disproportionate number of observations in canyons, and fewer than expected on ridge-tops. Given the distinct characteristics of the LMUs, these units provide a relatively simple but ecologically meaningful template for managers to spatially allocate forest treatments, thereby meeting multiple National Forest objectives. These LMUs provide a framework that can potentially be applied to other fire-dependent western forests with steep topographic relief.

  7. Using Topography to Meet Wildlife and Fuels Treatment Objectives in Fire-Suppressed Landscapes

    PubMed Central

    Viers, Joshua H.; Quinn, James F.; North, Malcolm

    2010-01-01

    Past forest management practices, fire suppression, and climate change are increasing the need to actively manage California Sierra Nevada forests for multiple environmental amenities. Here we present a relatively low-cost, repeatable method for spatially parsing the landscape to help the U.S. Forest Service manage for different forest and fuel conditions to meet multiple goals relating to sensitive species, fuels reduction, forest products, water, carbon storage, and ecosystem restoration. Using the Kings River area of the Sierra Nevada as a case study, we create areas of topographically-based units, Landscape Management Units (LMUs) using a three by three matrix (canyon, mid-slope, ridge-top and northerly, southerly, and neutral aspects). We describe their size, elevation, slope, aspect, and their difference in inherent wetness and solar radiation. We assess the predictive value and field applicability of LMUs by using existing data on stand conditions and two sensitive wildlife species. Stand conditions varied significantly between LMUs, with canyons consistently having the greatest stem and snag densities. Pacific fisher (Martes pennanti) activity points (from radio telemetry) and California spotted owl (Strix occidentalis occidentalis) nests, roosts, and sightings were both significantly different from uniform, with a disproportionate number of observations in canyons, and fewer than expected on ridge-tops. Given the distinct characteristics of the LMUs, these units provide a relatively simple but ecologically meaningful template for managers to spatially allocate forest treatments, thereby meeting multiple National Forest objectives. These LMUs provide a framework that can potentially be applied to other fire-dependent western forests with steep topographic relief. PMID:20872142

  8. Gain media edge treatment to suppress amplified spontaneous emission in a high power laser

    DOEpatents

    Hackel, Lloyd A [Livermore, CA; Soules, Thomas F [Livermore, CA; Fochs, Scott N [Livermore, CA; Rotter, Mark D [San Ramon, CA; Letts, Stephan A [San Ramon, CA

    2011-02-22

    A novel method and apparatus for suppressing ASE and/or parasitic oscillation modes in a laser is introduced. By roughening one or more peripheral edges of a solid-state crystal or ceramic laser gain media and by bonding such edges to a predetermined electromagnetic absorbing material arranged adjacent to the entire outer surface of the peripheral edges of the roughened laser gain media, ASE, parasitic oscillation modes and/or residual pump energy can be effectively suppressed.

  9. Gain media edge treatment to suppress amplified spontaneous emission in a high power laser

    DOEpatents

    Hackel, Lloyd A.; Soules, Thomas F.; Fochs, Scott N.; Rotter, Mark D.; Letts, Stephan A.

    2008-12-09

    A novel method and apparatus for suppressing ASE and parasitic oscillation modes in a high average power laser is introduced. By roughening one or more peripheral edges of a solid-state crystal or ceramic laser gain media and by bonding such edges using a substantially high index bonding elastomer or epoxy to a predetermined electromagnetic absorbing arranged adjacent to the entire outer surface of the peripheral edges of the roughened laser gain media, ASE and parasitic oscillation modes can be effectively suppressed.

  10. Evidence for Using Doxazosin in the Treatment of Posttraumatic Stress Disorder

    PubMed Central

    Smith, Cherish; Koola, Maju Mathew

    2016-01-01

    There is evidence that doxazosin is effective in the treatment of posttraumatic stress disorder (PTSD). Doxazosin is a “me-too” drug of prazosin. Doxazosin has an improved absorption profile and this likely minimizes the risk for unintended adverse hypotensive effects. The availability of doxazosin in the gastrointestinal therapeutic system (GITS) form permits a higher initial daily dose (4 mg/day) while avoiding significant first-dose side effects. The treatment of PTSD with prazosin has several disadvantages due to its short duration of action (6–8 hours), which results in multiple doses being required. Prazosin may wear off and this may lead to nightmares in the latter half of the sleep. Doxazosin has significant advantages over prazosin in clinical practice because it has a long half-life and requires only once-daily dosing. This may lead to better adherence and greater effectiveness in the treatment of PTSD. PMID:27667865

  11. Prazosin-Conjugated Matrices Based on Biodegradable Polymers and α-Amino Acids--Synthesis, Characterization, and in Vitro Release Study.

    PubMed

    Oledzka, Ewa; Sawicka, Anna; Sobczak, Marcin; Nalecz-Jawecki, Grzegorz; Skrzypczak, Agata; Kolodziejski, Waclaw

    2015-08-12

    Novel and promising macromolecular conjugates of the α1-adrenergic blocker prazosin were directly synthesized by covalent incorporation of the drug to matrices composed of biodegradable polymers and α-amino acids for the development of a polymeric implantable drug delivery carrier. The cyto- and genotoxicity of the synthesized matrices were evaluated using a bacterial luminescence test, protozoan assay, and Salmonella typhimurium TA1535. A new urethane bond was formed between the hydroxyl end-groups of the synthesized polymer matrices and an amine group of prazosin, using 1,1'-carbonyldiimidazole (CDI) as a coupling agent. The structure of the polymeric conjugates was characterized by various spectroscopy techniques. A study of hydrogen nuclear magnetic resonance ((1)H-NMR) and differential scanning calorimetry (DSC) thermodiagrams indicated that the presence of prazosin pendant groups in the macromolecule structures increased the polymer's rigidity alongside increasing glass transition temperature. It has been found that the kinetic release of prazosin from the obtained macromolecular conjugates, tested in vitro under different conditions, is strongly dependent on the physicochemical properties of polymeric matrices. Furthermore, the presence of a urethane bond in the macromolecular conjugates allowed for obtaining a relatively controlled release profile of the drug. The obtained results confirm that the pharmacokinetics of prazosin might be improved through the synthesis of polymeric conjugates containing biomedical polymers and α-amino acids in the macromolecule.

  12. Efficacy and Safety of Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric Adolescents.

    PubMed

    Schagen, Sebastian E E; Cohen-Kettenis, Peggy T; Delemarre-van de Waal, Henriette A; Hannema, Sabine E

    2016-07-01

    Puberty suppression using gonadotropin-releasing hormone agonists (GnRHas) is recommended by current guidelines as the treatment of choice for gender dysphoric adolescents. Although GnRHas have long been used to treat precocious puberty, there are few data on the efficacy and safety in gender dysphoric adolescents. Therefore, the Endocrine Society guideline recommends frequent monitoring of gonadotropins, sex steroids, and renal and liver function. To evaluate the efficacy and safety of GnRHa treatment to suppress puberty in gender dysphoric adolescents. Forty-nine male-to-female and 67 female-to-male gender dysphoric adolescents treated with triptorelin were included in the analysis. Physical examination, including assessment of Tanner stage, took place every 3 months and blood samples were drawn at 0, 3, and 6 months and then every 6 months. Body composition was evaluated using dual energy x-ray absorptiometry. GnRHa treatment caused a decrease in testicular volume in 43 of 49 male-to-female subjects. In one of four female-to-male subjects who presented at Tanner breast stage 2, breast development completely regressed. Gonadotropins and sex steroid levels were suppressed within 3 months. Treatment did not have to be adjusted because of insufficient suppression in any subject. No sustained abnormalities of liver enzymes or creatinine were encountered. Alkaline phosphatase decreased, probably related to a slower growth velocity, because height SD score decreased in boys and girls. Lean body mass percentage significantly decreased during the first year of treatment in girls and boys, whereas fat percentage significantly increased. Triptorelin effectively suppresses puberty in gender dysphoric adolescents. These data suggest routine monitoring of gonadotropins, sex steroids, creatinine, and liver function is not necessary during treatment with triptorelin. Further studies should evaluate the extent to which changes in height SD score and body composition that occur

  13. Differential Interaction of Dantrolene, Glafenine, Nalidixic Acid, and Prazosin with Human Organic Anion Transporters 1 and 3.

    PubMed

    Burckhardt, Birgitta C; Henjakovic, Maja; Hagos, Yohannes; Burckhardt, Gerhard

    2017-09-01

    In renal proximal tubule cells, the organic anion transporters 1 and 3 (OAT1 and OAT3) in the basolateral membrane and the multidrug resistance-associated protein 4 (MRP4) in the apical membrane share substrates and co-operate in renal drug secretion. We hypothesized that recently identified MRP4 inhibitors dantrolene, glafenine, nalidixic acid, and prazosin also interact with human OAT1 and/or OAT3 stably transfected in human embryonic kidney 293 cells. These four drugs were tested as possible inhibitors of p-[(3)H]aminohippurate (PAH) and [(14)C]glutarate uptake by OAT1, and of [(3)H]estrone-3-sulfate (ES) uptake by OAT3. In addition, we explored whether these drugs decrease the equilibrium distribution of radiolabeled PAH, glutarate, or ES, an approach intended to indirectly suggest drug/substrate exchange through OAT1 and OAT3. With OAT3, a dose-dependent inhibition of [(3)H]ES uptake and a downward shift in [(3)H]ES equilibrium were observed, indicating that all four drugs bind to OAT3 and may possibly be translocated. In contrast, the interaction with OAT1 was more complex. With [(14)C]glutarate as substrate, all four drugs inhibited uptake but only glafenine and nalidixic acid shifted glutarate equilibrium. Using [(3)H]PAH as a substrate of OAT1, nalidixic acid inhibited but dantrolene, glafenine, and prazosin stimulated uptake. Nalidixic acid decreased equilibrium content of [(3)H]PAH, suggesting that it may possibly be exchanged by OAT1. Taken together, OAT1 and OAT3 interact with the MRP4 inhibitors dantrolene, glafenine, nalidixic acid, and prazosin, indicating overlapping specificities. At OAT1, more than one binding site must be assumed to explain substrate and drug-dependent stimulation and inhibition of transport activity. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  14. Using topography to meet wildlife and fuels treatment objectives in fire-suppressed landscapes

    Treesearch

    Emma C. Underwood; Joshua H. Viers; James F. Quinn; Malcolm. North

    2010-01-01

    Past forest management practices, fire suppression, and climate change are increasing the need to actively manage California Sierra Nevada forests for multiple environmental amenities. Here we present a relatively low-cost, repeatable method for spatially parsing the landscape to help the U.S. Forest Service manage for different forest and fuel conditions to meet...

  15. Highly Sensitive Fluorescence Methods for the Determination of Alfuzosin, Doxazosin, Terazosin and Prazosin in Pharmaceutical Formulations, Plasma and Urine.

    PubMed

    Guo, Xiaozhen; Wu, Hao; Guo, Shiwen; Shi, Yating; DU, Juanli; Zhu, Panpan; DU, Liming

    2016-01-01

    Polymeric ionic liquid-coated magnetic nanoparticles have been successfully prepared as adsorbents for the magnetic solid-phase extraction of four drugs, namely alfuzosin, doxazosin, terazosin and prazosin, from pharmaceutical preparations, urine samples and plasma samples. The four drugs were detected by fluorescence spectrophotometer. Several extraction parameters, including the pH of the solution; the type, ratio and volume of the desorbing reagent; the amount of adsorbent; the time of the extraction and desorption processes; and the addition of NaCl, were investigated and optimized. Linear responses were determined for the four drugs in the concentration range of 0.5 - 45 ng mL(-1). The limit of detection values for alfuzosin, doxazosin, terazosin and prazosin, which were defined as three times the standard deviation of a blank sample, were determined to be 0.035, 0.034, 0.027 and 0.028 ng mL(-1) (n = 11), respectively. Furthermore, this new method gave preconcentration factors of 114.5, 111.3, 111.1 and 108.5 for these four drugs.

  16. Transplacental pharmacokinetics of glyburide, rhodamine 123, and BODIPY FL prazosin: effect of drug efflux transporters and lipid solubility.

    PubMed

    Cygalova, Lenka Hahnova; Hofman, Jakub; Ceckova, Martina; Staud, Frantisek

    2009-12-01

    Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are the most abundantly expressed ATP-binding cassette (ABC) drug transporters in the placenta. They recognize a large, partly overlapping spectrum of chemically unrelated compounds and affect their transplacental passage. In this study we investigate the effect of Bcrp and P-gp on the transplacental pharmacokinetics of their specific and common substrates employing the technique of dually perfused rat placenta. We show that the clearance of rhodamine 123 (P-gp substrate), glyburide (BCRP substrate) and BODIPY FL prazosin (P-gp and BCRP substrate) in fetal-to-maternal direction is 11, 11.2 and 4 times higher, respectively, than that in the maternal-to-fetal direction. In addition, all of these substances were found to be transported from the fetal compartment even against concentration gradient. We thus demonstrate the ability of placental ABC transporters to hinder maternal-to-fetal and accelerate fetal-to-maternal transport in a concentration-dependent manner. However, by means of pharmacokinetic modeling we describe the inverse correlation between lipid solubility of a molecule and its active transport by placental ABC efflux transporters. Therefore, in the case of highly lipophilic substrates, such as BODIPY FL prazosin in this study, the efficacy of efflux transporters to pump the molecule back to the maternal circulation is markedly limited.

  17. Suppression of tumour metastasis in a murine osteosarcoma model with anti-CD25 monoclonal antibody treatment.

    PubMed

    Kozawa, Eiji; Sugiura, Hideshi; Wasa, Junshi; Kohyama, Keishi; Yamada, Kenji; Nishioka, Akiko; Nishida, Yoshihiro; Ishiguro, Naoki; Taguchi, Osamu

    2010-12-01

    Mouse regulatory T cells (Treg) may be deleted by intraperitoneal injection of anti-CD25 monoclonal antibody (mAb) (PC61). When Treg populations are thus suppressed, the immune system attacks tumours in autoimmune reactions. An osteosarcoma (LM8) was transplanted subcutaneously into C3H/He mice. Serial injections of PC61 were conducted from seven days before (pre-PC61 group) or from two days thereafter (post-PC61 group) and tumour growth and metastasis were examined four weeks later. A control group received PBS injections. Subcutaneous tumours were reduced in size and the numbers of lung and liver metastatic colonies were significantly decreased in both pre- and post-PC61 groups compared to the control group. Tumour suppression was effective even when injection of PC61 was performed two days after LM8 transplantation. These results indicate that such treatments might be suitable to be applied in the clinic after surgical operations.

  18. Estrogen suppression in premenopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone.

    PubMed

    Jannuzzo, Maria Gabriella; Di Salle, Enrico; Spinelli, Riccardo; Pirotta, Nicoletta; Buchan, Peter; Bello, Akintunde

    2009-02-01

    Luteinizing hormone-releasing hormone (LHRH) agonists (e.g., triptorelin) reduce ovarian estrogen production in premenopausal women with hormone-sensitive breast cancer. Aromatase inhibitors (e.g., exemestane) inhibit extraovarian production of estrogen and may further reduce circulating estrogens when combined with an LHRH agonist. Healthy premenopausal women were randomized to receive 3.75 mg triptorelin (T) on days 1 and 29 with 25 mg exemestane (EX) or matched placebo once daily for 8 weeks, from day 1 to day 56. The primary objective was to evaluate the effect of T +/- EX on estradiol (E(2)) suppression by comparing the AUC(day 36-57 )for the 2 treatments. Secondary objectives included evaluation of estrone (E(1)), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) suppression; effects of EX on the T-induced gonadotrophin and estrogen flare; pharmacokinetics (PK); and safety. Twenty-eight (14 in each arm) were evaluable for efficacy and PK. Mean plasma estrogen levels (AUC(day 36-57)) were significantly lower for subjects who received T + EX than for subjects who received T alone (20.6 vs. 54.0 pg d/ml [-62%; P < 0.05], and 38.9 vs. 198.0 pg d/ml [-80%; P < 0.01] for E(2) and E(1), respectively). Coadministration of EX did not affect the initial flare or subsequent suppression of LH and FSH following the first dose of T, or the PK of T. Both treatments were well tolerated. Coadministration of T and EX resulted in greater estrogen suppression than when T was given alone. These findings could translate into improved clinical outcomes for premenopausal breast cancer patients receiving LHRH agonists.

  19. Pre-treatment with mild UV irradiation suppresses reproductive toxicity induced by subsequent cadmium exposure in nematodes.

    PubMed

    Wang, Dayong; Xing, Xiaojuan

    2010-03-01

    In nematodes, 10 J/m(2)/min of UV irradiation induced a mild reproductive toxicity. Pre-treatment with UV irradiation at 10 J/m(2)/min suppressed the formation of reproductive defects, and activated a noticeable reduction of percentage of population with hsp-16.2::gfp expression, an obvious elevation of superoxide dismutase activities, and decrease of oxidative damage in 50 and 100 microM Cd exposed nematodes; however, pre-treatment with UV irradiation at 20 J/m(2)/min caused a significant decrease of brood sizes or increase of generation times in Cd-exposed nematodes. Pre-treatment with mild UV irradiation did not suppress the formation of reproductive defects in 150 microM Cd-exposed nematodes. Furthermore, the adaptive response to reproductive toxicity from Cd exposure was not observed in a reactive oxygen species sensitive mev-1(kn1) mutant. Therefore, pre-treatment with mild UV irradiation triggers the resistance to reproductive toxicity from Cd exposure by at least partially inducing adaptation to oxidative stress and through a mev-1-dependent pathway. (c) 2009 Elsevier Inc. All rights reserved.

  20. Suppression of bovine lymphocyte function by treatment with physiologic concentrations of cortisone

    SciTech Connect

    Ojo-Amaize, E.A.; Paape, M.J.; Guidry, A.J.; Mayer, H.K.

    1986-03-01

    The blastogenic response of peripheral blood lymphocytes (PBL) (8 cows) to capsular antigen extract of Staphylococcus aureus, PHA and LPS was measured in vitro using /sup 5/H-thymidine pulse labelling. isolated PBL were treated in vitro for 6-8 days with 10, 25 and 45 ng/ml cortisone. These concentrations simulate serum corticosteroid levels during environmental stress, acute clinical mastitis and ACTH therapy, respectively. To determine the minimal concentration of cortisone that would induce suppression, PBL were also incubated with increasing concentrations of cortisone starting at 10 pg/ml. All concentrations of cortisone caused a significant (P<0.01) depression of lymphocyte blastogenic response to S. aureus, PHA and LPS. Macrophage depletion experiments showed no macrophage suppressor effects. Both the blastogenic response of untreated peripheral blood lymphocytes to S. aureus, PHA and LPS and the degree to which that response was suppressed by cortisone differed significantly among cows. Results indicate that cortisone levels found during physiological stress and after therapeutic administration of ACTH can suppress lymphocyte function.

  1. A Randomized Trial of Comparing the Efficacy of Two Neurofeedback Protocols for Treatment of Clinical and Cognitive Symptoms of ADHD: Theta Suppression/Beta Enhancement and Theta Suppression/Alpha Enhancement

    PubMed Central

    Mohagheghi, Arash; Moghaddasi Bonab, Nafiseh; Chalabianloo, Gholamreza; Noorazar, Seyed Gholamreza; Tabatabaei, Seyed Mahmoud; Farhang, Sara

    2017-01-01

    Introduction. Neurofeedback (NF) is an adjuvant or alternative therapy for children with Attention Deficit Hyperactivity Disorder (ADHD). This study intended to compare the efficacy of two different NF protocols on clinical and cognitive symptoms of ADHD. Materials and Methods. In this clinical trial, sixty children with ADHD aged 7 to 10 years old were randomly grouped to receive two different NF treatments (theta suppression/beta enhancement protocol and theta suppression/alpha enhancement protocol). Clinical and cognitive assessments were conducted prior to and following the treatment and also after an eight-week follow-up. Results. Both protocols alleviated the symptoms of ADHD in general (p < 0.001), hyperactivity (p < 0.001), inattention (p < 0.001), and omission errors (p < 0.001); however, they did not affect the oppositional and impulsive scales nor commission errors. These effects were maintained after an eight-week intervention-free period. The only significant difference between the two NF protocols was that high-frequency alpha enhancement protocol performed better in suppressing omission errors (p < 0.001). Conclusion. The two NF protocols with theta suppression/beta enhancement and theta suppression/alpha enhancement have considerable and comparable effect on clinical symptoms of ADHD. Alpha enhancement protocol was more effective in suppressing omission errors. PMID:28321406

  2. Fuel Treatment Effects on Water Use Efficiency in Western Pine Forests Under Fire Suppression Evaluated Using Tree Ring Carbon Isotopes

    NASA Astrophysics Data System (ADS)

    Taylor, A. H.; Belmecheri, S.; Harris, L. B.

    2016-12-01

    We identified variation on water use efficiency interpreted from carbon 13 in tree ring cellulose in dense ponderosa pines forests in Washington and Arizona. Historically, these forests burned every decade until fires were suppressed beginning in the early twentieth century. The reduction in fire caused large increases in forest density and forest biomass and potential for intense fire. Forests with hazardous fuels are common in the western United States and these types of forests are treated with mechanical thinning and mechanical thinning and burning to reduce hazardous fuels and fire intensity. At each site we extracted tree ring samples from five trees in each treatment type and a control to identify the effects of fuel treatment of concentration of carbon 13 in tree ring cellulose. Water use efficiency as measured by carbon 13 increased after fuel treatments. Treatment effects were larger for the mechanical plus burn treatment than for the mechanical treatment in each study area compared to the control stands Our results suggest that fuel treatments reduce sensitivity of tree growth to climate and increase water use efficiency. Since tree ring carbon 13 is related to plant productivity, carbon 13 in tree rings can be used as a metric of change in ecosystem function for evaluating fuel treatments.

  3. Rapid suppression of Onchocerca volvulus transmission in two communities of the Southern Chiapas focus, Mexico, achieved by quarterly treatments with Mectizan.

    PubMed

    Rodríguez-Pérez, Mario A; Lutzow-Steiner, Miguel A; Segura-Cabrera, Aldo; Lizarazo-Ortega, Cristian; Domínguez-Vázquez, Alfredo; Sauerbrey, Mauricio; Richards, Frank; Unnasch, Thomas R; Hassan, Hassan K; Hernández-Hernández, Raymundo

    2008-08-01

    The impact of quarterly Mectizan (ivermectin) treatments on transmission, microfiladermia, and ocular lesions was evaluated in two formerly hyperendemic communities (Las Golondrinas and Las Nubes II) located in the main endemic focus for onchocerciasis in Southern Chiapas, Mexico. The data suggest that Onchocerca volvulus transmission has been suppressed after elimination of microfiladermia in these two communities. Increasing the frequency of Mectizan treatment to four times per year appears to have resulted in the rapid suppression of transmission in communities with residual transmission.

  4. White matter structure alterations in HIV-1-infected men with sustained suppression of viraemia on treatment.

    PubMed

    Su, Tanja; Caan, Matthan W A; Wit, Ferdinand W N M; Schouten, Judith; Geurtsen, Gert J; Cole, James H; Sharp, David J; Vos, Frans M; Prins, Maria; Portegies, Peter; Reiss, Peter; Majoie, Charles B

    2016-01-01

    Cognitive impairment is highly prevalent in HIV-1-infected (HIV+) patients, despite adequate suppression of viral replication by combination antiretroviral therapy (cART). Cerebral white matter structure alterations are often associated with cognitive impairment and have commonly been reported in the natural course of HIV infection. However, the existence of these alterations in adequately treated HIV+ patients remains unknown, as well as its possible association with cognitive impairment. We used diffusion tensor imaging (DTI) to investigate whether white matter structure alterations exist in HIV+ patients with sustained suppressed viral replication on cART, and if such alterations are related to HIV-associated cognitive deficits. We compared 100 aviraemic HIV+ men on cART with 70 HIV-uninfected, otherwise comparable men. Clinical and neuropsychological assessments were performed. From DTI data, white matter fractional anisotropy and mean diffusion were calculated. Subsequently, tract-based spatial statistics (TBSS) was performed, with and without masking out white matter lesions. HIV+ patients showed diffuse white matter structure alterations as compared with HIV-uninfected controls, observed as widespread decreased fractional anisotropy and an increased mean diffusion. These white matter structure alterations were associated with the number of years spent with a CD4 cell count below 500 cells/μl, but not with HIV-associated cognitive deficits. Cerebral white matter structure alterations are found in middle-aged HIV+ men with sustained suppression of viraemia on cART, and may result from periods with immune deficiency when viral toxicity and host-inflammatory responses were at their peak. These white matter structure alterations were not associated with the observed subtle HIV-associated cognitive deficits. .

  5. Treatment of vomiting and of gastric emptying suppression in primates after gamma irradiation

    SciTech Connect

    Dubois, A.; Dorval, E.D.; O'Connell, L.; Durakovic, A.; Conklin, J.J.

    1984-01-01

    Total body irradiation is followed within minutes by nausea and vomiting. In dogs, the authors found that gastric emptying was suppressed for at least 3 hours after exposure to 8 Gy Cobalt-60; in addition, pretreatment with domperidone (D) could prevent vomiting without improving gastric emptying. In the present studies, the authors used a primate model to further investigate the possibility of treating radiation induced vomiting and delayed gastric emptying. Gastric emptying was measured using either (1) radionuclide imaging after intragastric administration of chicken liver tagged in vivo with 1 mCi Tc-99m sulfur colloid and water containing 0.2 mCi In-111-DTPA; or (2) a Tc-99 m-DPTA dilution technique. Chair-adapted rhesus monkeys were studied in the basal state receiving either saline (S; 1.0 ml), D (0.1 mg/kg) or metoclopramide (M; 0.15 mg/kg). All monkeys were then exposed to total body irradiation (8 Gy, Cobalt-60) after receiving either S, D or M. Vomiting was observed in 5 of 6 monkeys receiving S or D but in only one of 5 animals pretreated with M. Gastric emptying was unaffected by any drug in the basal state (S: 5.54 +- 0.86; D: 6.21 +- 1.01; P: 6.52 +- 0.95%/min; means +- SE). After irradiation, emptying was completely abolished in animals treated with S (0.2 +- 0.2%/min) or D (0.1 +- 0.1%/min; in contrast, pretreatment with M improved gastric emptying significantly (1.81 +- 0.52%/min. Thus, gastric emptying is suppressed in monkeys who vomit after exposure to total body irradiation. In addition, vomiting is prevented and suppression of gastric emptying is improved by M, a dopamine antagonist that acts centrally but not by D, a peripherally acting dopamine antagonist.

  6. Prazosin has low potency at α1A-adrenoceptors and high potency at α1D -adrenoceptors in rat vas deferens.

    PubMed

    Docherty, J R

    2013-10-01

    (1) We have investigated α1 -adrenoceptor subtypes mediating contractions to noradrenaline in epididymal portions of rat vas deferens. (2) Contractions to noradrenaline were investigated in the absence or presence of the noradrenaline transporter blocker cocaine. (3) In the absence of cocaine, contractions to noradrenaline were potently antagonized by RS100329, but not by BMY7378, and so are mediated mainly by α1A -adrenoceptors. (4) In the presence of cocaine, noradrenaline potency was increased, particularly in terms of low concentrations and phasic contractions. Contractions to low concentrations of noradrenaline in the presence of cocaine were resistant to RS100329 but potently antagonized by BMY7378, demonstrating that α1D-adrenoceptors are additionally involved in contractions amplified by cocaine. (5) In the absence of cocaine, prazosin exhibited relatively low potency as an antagonist against the α1A-adrenoceptor-mediated component to the response. In the presence of cocaine, prazosin exhibited higher potency against the α1D-adrenoceptor-mediated component. (6) In conclusion, prazosin has previously unreported selectivity for α1D-over α1A -adrenoceptors in functional studies of rat vas deferens. Contractions of rat vas deferens are mediated by α1A-and α1D -adrenoceptors. The range of prazosin potencies and of receptor subtypes previously reported in rat vas deferens may be explained by the presence of these two subtypes.

  7. Body composition and bone mineral density after ovarian hormone suppression with or without estradiol treatment.

    PubMed

    Shea, Karen L; Gavin, Kathleen M; Melanson, Edward L; Gibbons, Ellie; Stavros, Anne; Wolfe, Pamela; Kittelson, John M; Vondracek, Sheryl F; Schwartz, Robert S; Wierman, Margaret E; Kohrt, Wendy M

    2015-10-01

    Suppression of ovarian hormones in premenopausal women on gonadotropin-releasing hormone agonist (GnRH(AG)) therapy can cause fat mass (FM) gain and fat-free mass (FFM) loss. Whether this is specifically caused by a decline in serum estradiol (E2) is unknown. This study aims to evaluate the effects of GnRH(AG) with placebo (PL) or E2 add-back therapy on FM, FFM, and bone mineral density (BMD). Our exploratory aim was to evaluate the effects of resistance exercise training on body composition during the drug intervention. Seventy healthy premenopausal women underwent 5 months of GnRH(AG) therapy and were randomized to receive transdermal E2 (GnRH(AG) + E2, n = 35) or PL (GnRH(AG) + PL, n = 35) add-back therapy. As part of our exploratory aim to evaluate whether exercise can minimize the effects of hormone suppression, some women within each drug arm were randomized to undergo a resistance exercise program (GnRH(AG) + E2 + Ex, n = 12; GnRH(AG) + PL + Ex, n = 12). The groups did not differ in mean (SD) age (36 [8] and 35 [9] y) or mean (SD) body mass index (both 28 [6] kg/m). FFM declined in response to GnRH(AG) + PL (mean, -0.6 kg; 95% CI, -1.0 to -0.3) but not in response to GnRH(AG) + E2 (mean, 0.3 kg; 95% CI, -0.2 to 0.8) or GnRH(AG) + PL + Ex (mean, 0.1 kg; 95% CI, -0.6 to 0.7). Although FM did not change in either group, visceral fat area increased in response to GnRH(AG) + PL but not in response to GnRH(AG) + E2. GnRH(AG) + PL induced a decrease in BMD at the lumbar spine and proximal femur that was prevented by E2. Preliminary data suggest that exercise may have favorable effects on FM, FFM, and hip BMD. Suppression of ovarian E2 results in loss of bone and FFM and expansion of abdominal adipose depots. Failure of hormone suppression to increase total FM conflicts with previous studies of the effects of GnRH(AG). Further research is necessary to understand the role of estrogen in energy balance regulation and fat distribution.

  8. Acid Treatment Enables Suppression of Electron-Hole Recombination in Hematite for Photoelectrochemical Water Splitting.

    PubMed

    Yang, Yi; Forster, Mark; Ling, Yichuan; Wang, Gongming; Zhai, Teng; Tong, Yexiang; Cowan, Alexander J; Li, Yat

    2016-03-01

    We report a strategy for efficient suppression of electron-hole recombination in hematite photoanodes. Acid-treated hematite showed a substantially enhanced photocurrent density compared to untreated samples. Electrochemical impedance spectroscopy studies revealed that the enhanced photocurrent is partly due to improved efficiency of charge separation. Transient absorption spectroscopic studies coupled to electrochemical measurements indicate that, in addition to improved bulk electrochemical properties, acid-treated hematite has significantly decreased surface electron-hole recombination losses owing to a greater yield of the trapped photoelectrons being extracted to the external circuit.

  9. Quantifying the potential impacts of fuel treatments on wildfire suppression costs volume

    Treesearch

    Matthew P. Thompson; Nicole M. Vaillant; Jessica R. Haas; Krista M. Gebert; Keith D. Stockmann

    2013-01-01

    Modeling the impacts and effects of hazardous fuel reduction treatments is a pressing issue within the wildfire management community. Prospective evaluation of fuel treatments allows for comparison of alternative treatment strategies in terms of socioeconomic and ecological impacts and facilitates analysis of tradeoffs across land management objectives (Stockmann et al...

  10. A fuel treatment reduces fire severity and increases suppression efficiency in a mixed conifer forest

    Treesearch

    Jason J. Moghaddas; Larry Craggs

    2007-01-01

    Fuel treatments are being implemented on public and private lands across the western United States. Although scientists and managers have an understanding of how fuel treatments can modify potential fire behaviour under modelled conditions, there is limited information on how treatments perform under real wildfire conditions in Sierran mixed conifer forests. The Bell...

  11. Quantifying the potential impacts of fuel treatments on wildfire suppression costs

    Treesearch

    Matthew P. Thompson; Nicole M. Vaillant; Jessica R. Haas; Krista M. Gebert; Keith D. Stockmann

    2013-01-01

    Modeling the impacts and effects of hazardous fuel reduction treatments is a pressing issue within the wildfire management community. Prospective evaluation of fuel treatment effectiveness allows for comparison of alternative treatment strategies in terms of socioeconomic and ecological impacts and facilitates analysis of tradeoffs across land-management objectives....

  12. PEITC treatment suppresses myeloid derived tumor suppressor cells to inhibit breast tumor growth.

    PubMed

    Gupta, Parul; Wright, Stephen E; Srivastava, Sanjay K

    2015-02-01

    Breast tumors are heterogeneous with a complex etiology. The immune system plays a crucial role in the development of tumors and can facilitate tumor growth pleiotropically. Myeloid derived suppressor cells (MDSCs) generate reactive oxygen species (ROS) and cytokines to suppress T cells, dendritic cells and natural killer (NK) cells. Hence, the inhibition of MDSCs could be an important strategy for anticancer therapeutics. Phenethyl isothiocyanate (PEITC), a bioactive compound present in cruciferous vegetables, is known to have anticancer properties. However, the effects of PEITC administration on the immune system have not been previously reported. In the current study, we evaluated the effects of administering PEITC to immunocompromised NOD-SCID IL2Rγ(-/-) (SCID/NSG) host mice bearing MDA-MB-231 xenografts on MDSCs in the peripheral blood. Our results reveal that oral administration of 12 μmol PEITC attenuated tumor growth by 76%. This was marked tumor-inhibitory phenotype was associated with a significant reduction in the levels of MDSCs bearing the surface markers CD33, CD34 and CD11b in PEITC treated mice, indicating that overall tumor growth suppression by PEITC correlates with inhibition of MDSCs. To the best of our knowledge, this is the first study showing effects of PEITC on MDSCs.

  13. The effects of the co-administration of the α₁-adrenoreceptor antagonist prazosin on the anxiolytic effect of citalopram in conditioned fear stress in the rat.

    PubMed

    Takamura, Naoki; Masuda, Takahiro; Inoue, Takeshi; Nakagawa, Shin; Koyama, Tsukasa

    2012-10-01

    Several studies have shown that the α₁-adrenoreceptor is involved in controlling extracellular serotonin levels. The administration of the α₁-adrenoreceptor antagonist prazosin was shown to decrease extracellular serotonin levels in the hippocampus, the prefrontal cortex and the raphe nucleus, while the administration of the α₁-adrenoreceptor agonist cirazoline was shown to increase serotonin levels. Furthermore, the elevation of serotonin levels induced by the selective serotonin reuptake inhibitor (SSRI) citalopram was attenuated by prazosin. Thus, α₁-adrenoreceptor antagonists may affect SSRI-induced increases in extracellular serotonin levels and their antidepressive and anxiolytic effects. However, little is known about the influence of α₁-adrenoreceptor antagonists on the behavioral pharmacological effects of SSRIs. The conditioned fear stress-induced freezing behavior is an animal model of anxiety and can detect the anxiolytic effect of SSRIs. To clarify whether an α₁-adrenoreceptor antagonist affects the anxiolytic action of SSRIs, we examined the effects of the co-administration of the α₁-adrenoreceptor antagonist prazosin and the SSRI citalopram using the contextual conditioned fear stress model. Low-dose prazosin (0.03 mg/kg) significantly attenuated the citalopram (3 mg/kg)-induced decrease in conditioned freezing. Moreover, high-dose (0.5 mg/kg), but not low-dose (0.03 mg/kg), prazosin significantly attenuated citalopram (10 mg/kg)-induced decreases in conditioned freezing. These drugs did not affect the spontaneous motor activity of the rats. Therefore, these results suggest that blocking the α₁-adrenoreceptor decreases the anxiolytic effect of citalopram.

  14. The peripubertal gender-dysphoric child: puberty suppression and treatment paradigms.

    PubMed

    Olson, Johanna; Garofalo, Robert

    2014-06-01

    Gender-nonconforming youth are emerging at increasingly younger ages, and those experiencing gender dysphoria are seeking medical care at, or sometimes even before, the onset of puberty. Youth with gender dysphoria are at high risk for depression, anxiety, isolation, self-harm, and suicidality at the onset of a puberty that feels wrong. Medical providers would benefit from understanding interventions that help gender-nonconforming children and youth thrive. The use of gonadotropin-releasing hormone (GnRH) agonists to block the onset of an undesired puberty in youth with gender dysphoria is a relatively new practice, particularly in the United States. These medications shut down the hypothalamic-pituitary-gonadal axis (HPG), and the production of either testosterone or estrogen is temporarily halted. Puberty blocking allows a young person to explore gender and participate more fully in the mental health therapy process without being consumed by the fear of an impending developmental process that will result in the acquisition of undesired secondary sexual characteristics. GnRH agonists have been used safely for decades in children with other medical conditions, including central precocious puberty. Potential side effects of GnRH agonists include diminished bone density, injection site problems, emotional instability, and weight gain. Preliminary data have shown GnRH agonists to be very helpful in improving behavioral and overall functioning outcomes. Puberty suppression should ideally begin in the first stages of pubertal development and can be given via intramuscular or subcutaneous injections, or via an implant that is inserted in the upper arm. Monitoring to assure suppression of the HPG axis should occur regularly. Gender-nonconforming youth who remain gender dysphoric can go on to receive cross-sex hormones for phenotypic gender transition when they are older. GnRH agonists have changed the landscape of medical intervention for youth with gender dysphoria and

  15. Bilirubin treatment suppresses pulmonary inflammation in a rat model of smoke-induced emphysema.

    PubMed

    Wei, Jingjing; Zhao, Hui; Fan, Guoquan; Li, Jianqiang

    2015-09-18

    Cigarette smoking is a significant risk factor for emphysema, which is characterized by airway inflammation and oxidative damage. To assess the capacity of bilirubin to protect against smoke-induced emphysema. Smoking status and bilirubin levels were recorded in 58 patients with chronic obstructive pulmonary diseases (COPD) and 71 non-COPD participants. The impact of smoking on serum bilirubin levels and exogenous bilirubin (20 mg/kg/day) on pulmonary injury was assessed in a rat model of smoking-induced emphysema. At sacrifice lung histology, airway leukocyte accumulation and cytokine and chemokine levels in serum, bronchoalveolar lavage fluid (BALF) and lung were analyzed. Oxidative lipid damage and anti-oxidative components was assessed by measuring malondialdehyde, superoxide dismutase (SOD) activity and glutathione. Total serum bilirubin levels were lower in smokers with or without COPD than non-smoking patients without COPD (P < 0.05). Indirect serum bilirubin levels were lower in COPD patients than patients without COPD (P < 0.05). In rats, cigarette smoke reduced serum total and indirect bilirubin levels. Administration of bilirubin reduced mean linear intercept and mean alveoli area, increased mean alveoli number, reduced macrophage, neutrophil and TNF-α content of BALF, and increased BALF and serum IL-10 level, but lowered local and systemic CCL2, CXCL2, CXCL8 and IL-17 levels. Bilirubin suppressed the smoke-induced systemic and regional oxidative lipid damage associated with increased SOD activity. Bilirubin attenuated smoking-induced pulmonary injury by suppressing inflammatory cell recruitment and pro-inflammatory cytokine secretion, increasing anti-inflammatory cytokine levels, and anti-oxidant SOD activity in a rat model of smoke-induced emphysema. Copyright © 2015. Published by Elsevier Inc.

  16. CXCR4 antibody treatment suppresses metastatic spread to the lung of intratibial human osteosarcoma xenografts in mice.

    PubMed

    Brennecke, Patrick; Arlt, Matthias J E; Campanile, Carmen; Husmann, Knut; Gvozdenovic, Ana; Apuzzo, Tiziana; Thelen, Marcus; Born, Walter; Fuchs, Bruno

    2014-03-01

    Current combined surgical and neo-adjuvant chemotherapy of primary metastatic osteosarcoma (OS) is ineffective, reflected by a 5-year survival rate of affected patients of less than 20 %. Studies in experimental OS metastasis models pointed to the CXCR4/CXCL12 homing axis as a novel target for OS metastasis-suppressive treatment. The present study investigated for the first time the CXCR4-blocking principle in a spontaneously metastasizing human 143B OS cell line-derived orthotopic xenograft mouse model. The highly metastatic 143B cells, unlike the parental non-metastatic HOS cells, express functional CXCR4 receptors at the cell surface, as revealed in this study by RT/PCR of gene transcripts, by FACS analysis with the monoclonal anti CXCR4 antibody 12G5 (mAb 12G5) and by CXCL12 time- and dose-dependent stimulation of AKT and ERK phosphorylation. A significantly (p < 0.05) higher CXCL12 dose-dependent chemotactic response of 143B compared to HOS cells in a Boyden chamber trans-well migration assay suggested a crucial role of the CXCL12/CXCR4 homing axis in 143B cell lung metastasis. Repetitive treatment of mice with 143B cell-derived intratibial tumors given intravenous bolus injections of mAb12G5 indeed inhibited significantly (p < 0.01) the number of X-gal-stainable lung micrometastases of lacZ-transduced 143B cells. Antibody treatment had also a mild inhibitory effect on primary tumor growth associated with remarkably less osteolysis, but it did not affect the number of developing lung macrometastases. In conclusion, these results demonstrate considerable potential of high-affinity CXCR4-blocking agents for OS tumor cell homing suppressive treatment in metastasizing OS complementary to current (neo)-adjuvant chemotherapy.

  17. Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction.

    PubMed

    Soraya, Hamid; Clanachan, Alexander S; Rameshrad, Maryam; Maleki-Dizaji, Nasrin; Ghazi-Khansari, Mahmoud; Garjani, Alireza

    2014-08-15

    Acute treatment with metformin has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of AMP-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with metformin on cardiac dysfunction and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected isoproterenol after chronic pre-treatment with 0, 25, 50, or 100mg/kg of metformin twice daily for 14 days. Isoproterenol (100mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dtmax and LVdp/dtmin. The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50mg/kg of metformin. Metfromin markedly lowered isoproterenol-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-α and IL-6. However, the lower doses of 25 and 50mg/kg were more effective than 100mg/kg. Phosphorylated AMPKα (p-AMPK) in the myocardium was significantly elevated by 25mg/kg of metformin, slightly by 50mg/kg, but not by 100mg/kg. Chronic pre-treatment with metformin reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium.

  18. Suppression of Phytophthora ramorum infestations through silvicultural treatment in California's north coast

    Treesearch

    Yana Valachovic; Chris Lee; Brendan Twieg; David Rizzo; Richard Cobb; Radoslaw Glebocki

    2013-01-01

    In 2006, three forested sites infested with Phytophthora ramorum in Humboldt County, California were subjected to different combinations of treatments designed to reduce inoculum and control spread. One treatment, consisting of removal of all California bay laurel (Umbellularia californica (Hook. & Arn.) Nutt.) and tanoak...

  19. Fire suppression and fuels treatment effects on mixed-conifer carbon stocks and emissions

    Treesearch

    M. North; M Hurteau; J Innes

    2009-01-01

    Depending on management, forests can be an important sink or source of carbon that if released as CO2 could contribute to global warming. Many forests in the western United States are being treated to reduce fuels, yet the effects of these treatments on forest carbon are not well understood. We compared the immediate effects of fuels treatments on carbon stocks and...

  20. Effects of single and repeated treatment with antidepressants on apomorphine-induced yawning in the rat: the implication of alpha-1 adrenergic mechanisms in the D-2 receptor function.

    PubMed

    Delini-Stula, A; Hunn, C

    1990-01-01

    Acute (10 or 20 mg/kg IP) and subchronic (2 x 5 or 10 mg/kg IP daily for 7 days) effects of desipramine, imipramine, maprotiline, (+)- and (-)-oxaprotiline enantiomers as well as selective 5-HT-uptake inhibitors citalopram and ifoxetine on yawning, induced by low doses of apomorphine, were investigated in the rat. In addition, the effects of alpha-1 receptor agonist adrafinil and antagonist prazosin were also tested. After acute treatment, desipramine, the stereoselective NA-uptake inhibiting (+)-enantiomer of oxaprotiline, and the alpha-1 agonist adrafinil, markedly and significantly suppressed yawning. Prazosin, in contrast, clearly potentiated it. This potentiating effect was abolished by the pretreatment with (+)-oxaprotiline and adrafinil. Other drugs were inactive. After subchronic administration, yawning was antagonized by NA-uptake-inhibiting antidepressants, including imipramine and maprotiline. By comparison to the acute treatment, the inhibitory effects of desipramine and (+)-oxaprotiline were considerably enhanced. Neither selective 5-HT-uptake inhibitors nor (-)-oxaprotiline (levoprotiline) were active. Antidepressants therefore modulate the functional activity of D-2 receptors, activated by low doses of apomorphine, predominantly by the virtue of their noradrenergic enhancing properties. This modulatory effect appears to be mediated by alpha-1 adrenergic receptors.

  1. A Single-Day Treatment with Mifepristone Is Sufficient to Normalize Chronic Glucocorticoid Induced Suppression of Hippocampal Cell Proliferation

    PubMed Central

    Hu, Pu; Oomen, Charlotte; van Dam, Anne-Marie; Wester, Jordi; Zhou, Jiang-Ning

    2012-01-01

    Background Chronic stress or prolonged administration of glucocorticoids suppresses proliferation and/or survival of newborn cells in adult rat dentate gyrus. Earlier we showed that administration of the glucocorticoid receptor antagonist mifepristone during the final 4 days of a 21 days period of corticosterone treatment fully normalized the number of newborn cells. Here we aimed to better understand how mifepristone achieves this effect and questioned whether an even shorter (single day) mifepristone treatment (instead of 4 days) also suffices to normalize neurogenesis. Methods We investigated various steps of the neurogenic process, using the immunohistochemical markers BrdU, doublecortin, proliferating cell nuclear antigen as well as glial fibrillary acidic protein, after 17 or 21 days of corticosterone (versus vehicle) treatment. Results Corticosterone primarily attenuates the proliferation of cells which subsequently develop into neurons; this is fully reversed by mifepristone. Surprisingly, the corticosteroid effects on neurogenesis can even be fully re-set by a single-day treatment with mifepristone (on day 18), despite the continued corticosterone exposure on subsequent days. Conclusions Our results emphasize that studies into the therapeutical efficacy of new antidepressants, especially those targeting HPA-activity or the glucocorticoid receptor, should explore the possibility to reduce treatment duration. PMID:23049985

  2. An Artesunate-Containing Antimalarial Treatment Regimen Did Not Suppress Cytomegalovirus Viremia

    PubMed Central

    Gantt, Soren; Huang, Meei-Li; Magaret, Amalia; Bunts, Lisa; Selke, Stacy; Wald, Anna; Rosenthal, Philip J.; Dorsey, Grant; Casper, Corey

    2014-01-01

    Background Additional drugs are needed for the treatment of cytomegalovirus (CMV) infection. Artesunate is an antimalarial drug that has activity against CMV in vitro and in a rodent model. Only a small number of case reports are available describing the clinical effects of artesunate on CMV infection, and these yielded inconsistent results. Objective To evaluate the effect of artesunate on CMV infection, using blood samples collected from children who participated in malaria treatment trials. Study design Quantitative CMV DNA PCR was performed on dried blood spots collected from 494 Ugandan children, who were randomized either to artesunate plus amodiaquine or sulfadoxine-pyrimethamine plus amodiaquine for acute malaria infection. Poisson regression was used to compare treatment regimens with respect to the change in the frequency and quantity of CMV detected that occurred before and after treatment. Results CMV was detected in 11.4% of children immediately prior to treatment and 10.7% 3 days later (p=0.70). The average quantity of CMV was 0.30 log10 copies per million cells higher on day 3 than at treatment initiation (95% CI 0.01 to 0.58, p=0.041). There was no measurable difference in either the frequency or quantity of CMV detected in blood between children randomized to the two treatment arms. Conclusions A standard 3-day artesunate-containing antimalarial regimen had no detectable effect on CMV viremia in children with malaria. Longer treatment courses and/or higher doses of artesunate than those routinely used for malaria may be required for effective treatment of CMV infection. PMID:23827788

  3. An artesunate-containing antimalarial treatment regimen did not suppress cytomegalovirus viremia.

    PubMed

    Gantt, Soren; Huang, Meei-Li; Magaret, Amalia; Bunts, Lisa; Selke, Stacy; Wald, Anna; Rosenthal, Philip J; Dorsey, Grant; Casper, Corey

    2013-09-01

    Additional drugs are needed for the treatment of cytomegalovirus (CMV) infection. Artesunate is an antimalarial drug that has activity against CMV in vitro and in a rodent model. Only a small number of case reports are available describing the clinical effects of artesunate on CMV infection, and these yielded inconsistent results. To evaluate the effect of artesunate on CMV infection, using blood samples collected from children who participated in malaria treatment trials. Quantitative CMV DNA PCR was performed on dried blood spots collected from 494 Ugandan children, who were randomized either to artesunate plus amodiaquine or sulfadoxine-pyrimethamine plus amodiaquine for acute malaria infection. Poisson regression was used to compare treatment regimens with respect to the change in the frequency and quantity of CMV detected that occurred before and after treatment. CMV was detected in 11.4% of children immediately prior to treatment and 10.7% 3 days later (p=0.70). The average quantity of CMV was 0.30 log10 copies per million cells higher on day 3 than at treatment initiation (95% CI 0.01-0.58, p=0.041). There was no measurable difference in either the frequency or quantity of CMV detected in blood between children randomized to the two treatment arms. A standard 3-day artesunate-containing antimalarial regimen had no detectable effect on CMV viremia in children with malaria. Longer treatment courses and/or higher doses of artesunate than those routinely used for malaria may be required for effective treatment of CMV infection. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Xylanase Treatment Suppresses Light- and Heat-Induced Yellowing of Pulp

    PubMed Central

    Zhang, Daolei; Li, Xuezhi; Wang, Meimei; Ye, Yanxin; Du, Jian; Lu, Xianqin; Zhao, Jian

    2016-01-01

    Xylanase is commonly applied in pulp and paper industries to ease cost-related and environmental pressures. The effect of xylanase treatment on pulp bleaching is well-established, however, few studies were conducted on the effects of xylanase treatment in pulp yellowing, especially the mechanism of pulp yellowing inhibition by xylanase treatment. In this study, pure xylanase (EC 3.2.1.8) was applied to treat wheat straw chemical pulp (CP) and poplar chemi-thermo-mechanical pulp (CTMP) to determine their effects on pulp brightness and on light- and heat-induced yellowing. The xylanase treatment decreased the post-color number of the pulps during light- and heat-induced yellowing. However, differences were observed in the yellowing inhibition between the wheat straw CP and poplar CTMP. The changes in chemical components of pulps after the xylanase treatment, for example, lignin, hemicellulose, and HexA contents, and analysis of UV–vis absorption spectra and Fourier transform infrared-attenuated total reflectance spectrum were used to explore the pulp yellowing inhibition causes by the xylanase treatment. PMID:27917912

  5. Sulfasalazine Treatment Suppresses the Formation of HLA-B27 Heavy Chain Homodimer in Patients with Ankylosing Spondylitis.

    PubMed

    Yu, Hui-Chun; Lu, Ming-Chi; Huang, Kuang-Yung; Huang, Hsien-Lu; Liu, Su-Qin; Huang, Hsien-Bin; Lai, Ning-Sheng

    2015-12-29

    Human leukocytic antigen-B27 heavy chain (HLA-B27 HC) has the tendency to fold slowly, in turn gradually forming a homodimer, (B27-HC)₂ via a disulfide linkage to activate killer cells and T-helper 17 cells and inducing endoplasmic reticulum (ER) stress to trigger the IL-23/IL-17 axis for pro-inflammatory reactions. All these consequences lead to the pathogenesis of ankylosing spondylitis (AS). Sulfasalazine (SSA) is a common medication used for treatment of patients with AS. However, the effects of SSA treatment on (B27-HC)₂ formation and on suppression of IL-23/IL-17 axis of AS patients remain to be determined. In the current study, we examine the (B27-HC)₂ of peripheral blood mononuclear cells (PBMC), the mean grade of sarcoiliitis and lumbar spine Bath Ankylosing Spondylitis Radiology Index (BASRI) scores of 23 AS patients. The results indicated that AS patients without (B27-HC)₂ on PBMC showed the lower levels of mean grade of sarcoiliitis and the lumbar spine BASRI scores. In addition, after treatment with SSA for four months, the levels of (B27-HC)₂ on PBMCs were significantly reduced. Cytokines mRNA levels, including TNFα, IL-17A, IL-17F and IFNγ, were also significantly down-regulated in PBMCs. However, SSA treatment did not affect the levels of IL-23 and IL-23R mRNAs.

  6. Minocycline treatment suppresses juvenile development and growth by attenuating insulin/TOR signaling in Drosophila animal model

    PubMed Central

    Yun, Hyun Myoung; Noh, Sujin; Hyun, Seogang

    2017-01-01

    Minocycline is a broad spectrum, semi-synthetic tetracycline analog that is used to treat bacterial infection. Recently, this drug has been receiving increasing attention for its non-antibiotic properties, including anti-inflammatory, tumor suppressive, and neuroprotective effects. Drosophila is a useful model organism for studying human metabolism and disease. In this study, we investigated the effects of minocycline on juvenile development and growth in Drosophila. Feeding minocycline to Drosophila larvae suppresses larval body growth and delays the timing of pupation in a dose-dependent manner. We found that the drug treatment decreased the activated form of Akt and S6K in peripheral tissues, which suggested that the insulin/target of rapamycin (TOR) signaling had been attenuated. Specifically enhancing TOR activity in the prothoracic gland (PG), the ecdysone-generating organ, attenuated the drug-induced developmental delay, which is consistent with the critical role of PG’s TOR signaling in determining pupation time. Our results reveal previously unrecognized effects of minocycline and offer a new potential therapeutic opportunity for various pathological conditions associated with insulin/TOR signaling. PMID:28317899

  7. Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor.

    PubMed

    Pine, Polly R; Chang, Betty; Schoettler, Nathan; Banquerigo, Mona L; Wang, Su; Lau, Angela; Zhao, Feifei; Grossbard, Elliott B; Payan, Donald G; Brahn, Ernest

    2007-09-01

    Spleen tyrosine kinase (Syk), a key mediator of immunoreceptor signaling in inflammatory cells, is essential for immune complex-mediated signal transduction initiated by activated receptors for immunoglobulin G. In collagen-induced arthritis, R788/R406, a novel and potent small molecule Syk inhibitor suppressed clinical arthritis, bone erosions, pannus formation, and synovitis. Serum anti-collagen type II antibody levels were unaltered, while the half-life of exogenous antibody was extended when co-administered with R406. Expression of the targeted kinase (Syk) in synovial tissue correlated with the joint level of inflammatory cell infiltrates and was virtually undetectable in treated rats. Syk inhibition suppressed synovial cytokines and cartilage oligomeric matrix protein (COMP) in serum, suggesting a sensitive and reliable biomarker for R406 activity. These results highlight the role of activating Fcgamma receptors in inflammatory synovitis and suggest that interruption of the signaling cascade with a novel Syk inhibitor may be a useful addition to immunosuppressive disease-modifying anti-rheumatic drugs currently used in the treatment of human autoimmune diseases such as rheumatoid arthritis.

  8. Real-time multi-channel monitoring of burst-suppression using neural network technology during pediatric status epilepticus treatment.

    PubMed

    Papadelis, Christos; Ashkezari, Seyedeh Fatemeh Salimi; Doshi, Chiran; Thome-Souza, Sigride; Pearl, Phillip L; Grant, P Ellen; Tasker, Robert C; Loddenkemper, Tobias

    2016-08-01

    To develop a real-time monitoring system that has the potential to guide the titration of anesthetic agents in the treatment of pediatric status epilepticus (SE). We analyzed stored multichannel electroencephalographic (EEG) data collected from 12 pediatric patients with generalized SE. EEG recordings were initially segmented in 500ms time-windows. Features characterizing the power, frequency, and entropy of the signal were extracted from each segment. The segments were annotated as bursts (B), suppressions (S), or artifacts (A) by two electroencephalographers. The EEG features together with the annotations were inputted in a three-layer feed forward neural network (NN). The sensitivity and specificity of NNs with different architectures and training algorithms to classify segments into B, S, or A were estimated. The maximum sensitivity (95.96% for B, 89.25% for S, and 75% for A) and specificity (89.36 for B, 96.26% for S, and 99.8% for A) was observed for the NN with 10 nodes in the hidden layer. By using this NN, we designed a real-time system that estimates the burst-suppression index (BSI). Our system provides a reliable real-time estimate of multichannel BSI requiring minimal memory and computation time. The system has the potential to assist intensive care unit attendants in the continuous EEG monitoring. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  9. [Regulation of erythropoiesis in patients with suppressed hematopoiesis during mountain climatic treatment].

    PubMed

    Ismailova, A Z; Makeshova, A B; Eralieva, M O; Levina, A A; Makukova, Iu I; Raimzhanov, A R

    2010-01-01

    to estimate the regulation of erythropoiesis and the coagulation system in patients with suppressed hematopoiesis in a mountain hospital (3200 m above sea level). The investigation included 12 patients with aplastic anemia (AA) and 10 with idiopathic thrombocytopenic purpura (ITP). Blood was received at a Bishkek hospital, then on days 20 and 40 of stay in the mountains. The authors studied erythropoietin (EPO) by enzyme immunoassay (Protein Contour kit, Russia), serum ferritin (SF) by immunoradioassay (Immunotech kit, Czech Republic), hypoxia-inducible factor-1alpha (HIF-1alpha), homocysteine (HC), hepcidin, endothelin (ET), and thrombomodulin (TM) by sandwich enzyme immunoassay, by applying monospecific antisera and monoclonal antibodies against relevant antigens (IDG Int Inc, USA). On staying in the mountains, there was a gradual increase in the content of hemoglobin in patients with AA and ITP. On day 40, in keeping with higher hemoglobin (Hb) levels, both groups showed a decrease in HIF-1alpha concentrations to the normal values (from 8.2 to 4.5 pg/ml). Due to the anemic syndrome, baseline EPO was increased by 5-7 times in the patients from both groups. On days 20-40, the content of EPO showed a 1.3-2.5-fold increase. In AA, HC was almost 3 times greater than the normal values; in ITP, it was 1.5-fold increased. On day 20 and during the patients'stay in the mountains, the level of HC remained in the normal range in both groups. Hypoxic hypoxia positively affects a number of hematological parameters, by normalizing erythropoiesis (Hb, EPO, and HIF-1alpha), iron metabolism (SF), and the coagulation system (HC, ET, and TM).

  10. Treatment with the hyaluronic Acid synthesis inhibitor 4-methylumbelliferone suppresses LPS-induced lung inflammation.

    PubMed

    McKallip, Robert J; Ban, Hao; Uchakina, Olga N

    2015-01-01

    Exposure to bacterial endotoxins, such as lipopolysaccharide (LPS), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for LPS-induced inflammation. In the current study, we investigated the potential use of the hyaluronic acid (HA) synthesis inhibitor 4-methylumbelliferone (4-MU) on LPS-induced acute lung inflammation. Culturing LPS-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production, and an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from LPS-induced lung injury. Specifically, 4-MU treatment led to a reduction in LPS-induced hyaluronic acid synthase (HAS) messenger RNA (mRNA) levels, reduction in lung permeability, and reduction in proinflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target HA production may be an effective treatment for the inflammatory response following exposure to LPS.

  11. Conditions 10 years after sudden oak death suppression treatments in Humboldt County, California

    Treesearch

    Yana Valachovic; Richard Cobb; Brendan Twieg

    2017-01-01

    In 2006, three isolated sudden oak death- (SOD) infested locations within Humboldt County were selected for silvicultural treatments that targeted the removal and/or reduction of tanoak (Notholithocarpus densiflorus Hook. & Arn.) and California bay laurel (Umbellularia californica Hook. & Arn), the main hosts...

  12. Suppressive Effects of Resveratrol Treatment on The Intrinsic Evoked Excitability of CA1 Pyramidal Neurons

    PubMed Central

    Meftahi, Gholamhossein; Ghotbedin, Zohreh; Eslamizade, Mohammad Javad; Hosseinmardi, Narges; Janahmadi, Mahyar

    2015-01-01

    Objective Resveratrol, a phytoalexin, has a wide range of desirable biological actions. Despite a growing body of evidence indicating that resveratrol induces changes in neu- ronal function, little effort, if any, has been made to investigate the cellular effect of res- veratrol treatment on intrinsic neuronal properties. Materials and Methods This experimental study was performed to examine the acute effects of resveratrol (100 µM) on the intrinsic evoked responses of rat Cornu Ammonis (CA1) pyramidal neurons in brain slices, using whole cell patch clamp re- cording under current clamp conditions. Results Findings showed that resveratrol treatment caused dramatic changes in evoked responses of pyramidal neurons. Its treatment induced a significant (P<0.05) increase in the after hyperpolarization amplitude of the first evoked action potential. Resveratrol-treated cells displayed a significantly broader action potential (AP) when compared with either control or vehicle-treated groups. In addition, the mean instantaneous firing frequency between the first two action potentials was significantly lower in resveratrol-treated neurons. It also caused a significant reduction in the time to maximum decay of AP. The rheobase current and the utilization time were both significantly greater following resveratrol treatment. Neurons exhibited a significantly depolarized voltage threshold when exposed to resveratrol. Conclusion Results provide direct electrophysiological evidence for the inhibitory effects of resveratrol on pyramidal neurons, at least in part, by reducing the evoked neural activity. PMID:26464825

  13. Treatment with the hyaluronic acid synthesis inhibitor 4-methylumbelliferone suppresses SEB-induced lung inflammation.

    PubMed

    McKallip, Robert J; Hagele, Harriet F; Uchakina, Olga N

    2013-10-17

    Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU) on staphylococcal enterotoxin B (SEB) induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB.

  14. Treatment with the Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone Suppresses SEB-Induced Lung Inflammation

    PubMed Central

    McKallip, Robert J.; Hagele, Harriet F.; Uchakina, Olga N.

    2013-01-01

    Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU) on staphylococcal enterotoxin B (SEB) induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB. PMID:24141285

  15. Modeling fuel treatment impacts on fire suppression cost savings: A review

    Treesearch

    Matthew P. Thompson; Nathaniel M. Anderson

    2015-01-01

    High up-front costs and uncertain return on investment make it difficult for land managers to economically justify large-scale fuel treatments, which remove trees and other vegetation to improve conditions for fire control, reduce the likelihood of ignition, or reduce potential damage from wildland fire if it occurs. In the short-term, revenue from harvested...

  16. Short course acid suppressive treatment for patients with functional dyspepsia: results depend on Helicobacter pylori status

    PubMed Central

    Blum, A; Arnold, R; Stolte, M; Fischer, M; Koelz, H; the, F

    2000-01-01

    BACKGROUND AND AIMS—Treatment of functional dyspepsia with acid inhibitors is controversial and it is not known if the presence of Helicobacter pylori infection influences the response.
METHODS—After a complete diagnostic workup, 792 patients with functional dyspepsia unresponsive to one week of low dose antacid treatment were randomised to two weeks of treatment with placebo, ranitidine 150 mg, omeprazole 10 mg, or omeprazole 20 mg daily. Individual dyspeptic and other abdominal symptoms were evaluated before and after treatment according to H pylori status.
RESULTS—The proportions of patients considered to be in remission (intention to treat) at the end of treatment with placebo, ranitidine 150 mg, omeprazole 10 mg, and omeprazole 20 mg were, respectively, 42%, 50%, 48%, and 59% in the H pylori positive group and 66%, 73%, 64%, and 71% in the H pylori negative group. In H pylori positive patients, the therapeutic gain over placebo was significant for omeprazole 20 mg (17.6%, 95% confidence intervals (CI) 4.2-31.0; p<0.014 using the Bonferroni-adjusted p level of 0.017) but not for omeprazole 10 mg (6.8%, 95% CI −6.7-20.4) or ranitidine 150 mg (8.9%, 95% CI −4.2-21.9). There was no significant therapeutic gain from active treatment over placebo in H pylori negative patients. Complete disappearance of symptoms and improvement in quality of life also occurred most frequently with omeprazole 20 mg and was significant in both H pylori positive and H pylori negative groups. The six month relapse rate of symptoms requiring treatment was low (<20%) in all groups.
CONCLUSIONS—Omeprazole 20 mg per day had a small but significant favourable effect on outcome in H pylori positive patients. The differential response in these patients may be explained by an enhanced antisecretory response in the presence of H pylori. The effect of weaker acid inhibition was unsatisfactory.


Keywords: functional dyspepsia; omeprazole; ranitidine

  17. Suppression of interfacial reaction for HfO{sub 2} on silicon by pre-CF{sub 4} plasma treatment

    SciTech Connect

    Lai, C.S.; Wu, W.C.; Chao, T.S.; Chen, J.H.; Wang, J.C.; Tay, L.-L.; Rowell, Nelson

    2006-08-14

    In this letter, the effects of pre-CF{sub 4} plasma treatment on Si for sputtered HfO{sub 2} gate dielectrics are investigated. The significant fluorine was incorporated at the HfO{sub 2}/Si substrate interface for a sample with the CF{sub 4} plasma pretreatment. The Hf silicide was suppressed and Hf-F bonding was observed for the CF{sub 4} plasma pretreated sample. Compared with the as-deposited sample, the effective oxide thickness was much reduced for the pre-CF{sub 4} plasma treated sample due to the elimination of the interfacial layer between HfO{sub 2} and Si substrate. These improved characteristics of the HfO{sub 2} gate dielectrics can be explained in terms of the fluorine atoms blocking oxygen diffusion through the HfO{sub 2} film into the Si substrate.

  18. Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma.

    PubMed

    Ban, Jozef; Aryee, Dave N T; Fourtouna, Argyro; van der Ent, Wietske; Kauer, Max; Niedan, Stephan; Machado, Isidro; Rodriguez-Galindo, Carlos; Tirado, Oscar M; Schwentner, Raphaela; Picci, Piero; Flanagan, Adrienne M; Berg, Verena; Strauss, Sandra J; Scotlandi, Katia; Lawlor, Elizabeth R; Snaar-Jagalska, Ewa; Llombart-Bosch, Antonio; Kovar, Heinrich

    2014-11-15

    The developmental receptor NOTCH plays an important role in various human cancers as a consequence of oncogenic mutations. Here we describe a novel mechanism of NOTCH-induced tumor suppression involving modulation of the deacetylase SIRT1, providing a rationale for the use of SIRT1 inhibitors to treat cancers where this mechanism is inactivated because of SIRT1 overexpression. In Ewing sarcoma cells, NOTCH signaling is abrogated by the driver oncogene EWS-FLI1. Restoration of NOTCH signaling caused growth arrest due to activation of the NOTCH effector HEY1, directly suppressing SIRT1 and thereby activating p53. This mechanism of tumor suppression was validated in Ewing sarcoma cells, B-cell tumors, and human keratinocytes where NOTCH dysregulation has been implicated pathogenically. Notably, the SIRT1/2 inhibitor Tenovin-6 killed Ewing sarcoma cells in vitro and prohibited tumor growth and spread in an established xenograft model in zebrafish. Using immunohistochemistry to analyze primary tissue specimens, we found that high SIRT1 expression was associated with Ewing sarcoma metastasis and poor prognosis. Our findings suggest a mechanistic rationale for the use of SIRT1 inhibitors being developed to treat metastatic disease in patients with Ewing sarcoma. ©2014 American Association for Cancer Research.

  19. A personal light-treatment device for improving sleep quality in the elderly: dynamics of nocturnal melatonin suppression at two exposure levels.

    PubMed

    Figueiro, Mariana G; Bierman, Andrew; Bullough, John D; Rea, Mark S

    2009-05-01

    Light treatment has been used as a non-pharmacological tool to help mitigate poor sleep quality frequently found in older people. In order to increase compliance to non-pharmacological light treatments, new, more efficacious light-delivery systems need to be developed. A prototype personal light-treatment device equipped with low brightness blue light-emitting diodes (LEDs) (peak wavelength near 470 nm) was tested for its effectiveness in suppressing nocturnal melatonin, a measure of circadian stimulation. Two levels of corneal irradiance were set to deliver two prescribed doses of circadian light exposure. Eleven older subjects, between 51 and 80 yrs of age who met the selection criteria, were exposed to a high and a low level of light for 90 min on separate nights from the personal light-treatment device. Blood and saliva samples were collected at prescribed times for subsequent melatonin assay. After 1 h of light exposure, the light-induced nocturnal melatonin suppression level was about 35% for the low-light level and about 60% for the high-light level. The higher level of blue light suppressed melatonin more quickly, to a greater extent over the course of the 90 min exposure period, and maintained suppression after 60 min. The constant exposure of the low-light level resulted in a decrease in nocturnal melatonin suppression for the last sampling time, whereas for the high-light level, suppression continued throughout the entire exposure period. The present study performed with healthy adults suggests that the tested personal light-treatment device might be a practical, comfortable, and effective way to deliver light treatment to those suffering from circadian sleep disorders; however, the acceptance and effectiveness of personal light-treatment devices by older people and by other segments of the population suffering from sleep disorders in a real-life situation need to be directly tested.

  20. Lenalidomide consolidation treatment in patients with multiple myeloma suppresses myelopoieses but spares erythropoiesis.

    PubMed

    Wilk, Christian Matthias; Heinzler, Niklas; Boquoi, Amelie; Cadeddu, Ron-Patrick; Strapatsas, Tobias; Dienst, Ariane; Majidi, Fatemeh; Deenen, René; Bruns, Ingmar; Schroeder, Thomas; Köhrer, Karl; Haas, Rainer; Kobbe, Guido; Fenk, Roland

    2016-11-15

    New drugs for the treatment of multiple myeloma (MM) comprise immunomodulatory substances such as lenalidomide and related compounds. While lenalidomide has found its way into first-line treatment as well as into relapse therapy, little is known about lenalidomide effects on normal hematopoietic stem and progenitor cells (HSPCs). In this study, we investigated whether HSPCs are influenced by lenalidomide on a phenotypic, functional and gene expression level. For that purpose, samples from patients with MM were obtained who underwent equivalent first-line treatment including induction therapy, cytotoxic stem cell mobilization and high-dose melphalan therapy followed by autologous blood stem cell transplantation and a subsequent uniform lenalidomide consolidation treatment within a prospective clinical trial. We found that after six months of lenalidomide therapy, the number of CD34(+) HSPCs decreased. Additionally, lenalidomide affects the numerical composition of hematopoietic cells in the bone marrow while it does not affect long-term HSPC proliferation in vitro. We found a significant amplification of fetal hemoglobin (HbF) expression on a transcriptional level and can confirm a stimulated erythropoiesis on a phenotypic level. These effects were accompanied by silencing of the TGF-β signaling pathway on the gene expression and protein level that is known to be amplified in active MM. However, these pleiotropic effects gave no evidence for mutagenic potential. In conclusion, lenalidomide does not exert long-term effects on proliferation of HSPCs but instead promotes erythropoiesis by shifting hemoglobin expression toward HbF and by silencing the TGF-β signaling pathway.

  1. Olopatadine hydrochloride suppresses hot flashes induced by topical treatment with tacrolimus ointment in rats.

    PubMed

    Satake, Kyosuke; Ikeda, Junichi; Tamura, Tadafumi; Amano, Toru; Kobayashi, Katsuya

    2015-10-15

    Tacrolimus ointment is prescribed for patients with atopic dermatitis, although it is known to cause transient burning sensations and hot flashes in the applied skin. The aim of this study was to evaluate the effects of olopatadine hydrochloride (olopatadine), an antiallergic agent with a histamine H1 receptor (H1R) antagonistic activity, on the incidence of hot flashes induced by topical treatment with tacrolimus ointment in rats. Consequently, the skin temperature was increased by the topical application of tacrolimus ointment in rats, and the rise in skin temperature was inhibited by pretreatment with olopatadine in a dose-dependent manner. Inhibitory effect of olopatadine on tacrolimus-induced skin temperature elevation was significantly more potent than that of cetirizine hydrochloride, other antiallergic agent with H1R antagonistic activity, at doses in which both agents exhibit comparable H1R antagonistic activity in rats. These results suggest that H1R antagonistic activity-independent mechanism contribute to the inhibitory effect of olopatadine on tacrolimus-induced skin temperature elevation. Olopatadine also significantly inhibited increases in vascular permeability and nerve growth factor production in the skin induced by topical tacrolimus treatment. Thus, the onset of hot flashes in rats is quantitatively determined by measuring the skin temperature and olopatadine attenuates hot flashes induced by topical tacrolimus ointment in rats, suggesting that the combination application with olopatadine and tacrolimus ointment is useful for improving medication adherence with tacrolimus ointment treatment in patients with atopic dermatitis. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Suppression of oncoprotein Her-2 and DNA damage after treatment with Flavan-3- ol vitis labrusca extract.

    PubMed

    Scola, Gustavo; Fernandes Correia Laurino, Claudia Cilene; Menin, Eveline; Salvador, Mirian

    2013-09-01

    Hepatocellular carcinoma and breast cancer are the most prevalent cancers in the world with high morbidity and mortality. Although there are effective drugs for treating advanced stages of liver and breast cancers, the prognosis for patients with liver cancer remains poor, and patients with breast cancer show considerable mortality. Therefore, it is crucial to explore new therapeutic agents for the inhibition of carcinogenesis. This study examined the anti-carcinogenic effect of Vitis labrusca seed extract (VLE), which is a component of winery waste, on liver (HepG2) and breast cancers (MCF-7) cells. The results found in this study demonstrated VLEinduced DNA damage in liver and breast cancer cells. VLE treatment in both cell lines was accompanied by high NO production and upregulation of p53. A significant decrease in total PARP expression was also found in HepG2 cells. In the MCF-7 cell line, VLE treatment increased the expression of Bax and AIF, and decreased total PARP expression. Surprisingly, VLE suppressed Her-2 expression in HepG2 cells and caused a subtle, but significant downregulation of Her-2 in MCF-7 cells. The possible anti-carcinogenic effect of VLE reported in this study suggests the potential of this extract to be used for the development of novel therapeutic agents for the treatment of different kinds of cancers.

  3. 7,8-DHF Treatment Induces Cyr61 Expression to Suppress Hypoxia Induced ER Stress in HK-2 Cells

    PubMed Central

    Ma, Rui; Zhang, Jisheng; Liu, Xiaoyu; Yue, Shaoheng; Zhao, Qing

    2016-01-01

    Acute kidney injury (AKI) is a common syndrome which is strongly linked to high morbidity and mortality. Hypoxia is the leading cause of AKI and the proximal renal tubular cells are the most damaged part in the kidney during this period. It has been observed that 7,8-dihydroxyflavone (7,8-DHF) plays a protective role by acting on antiapoptosis and antioxidative stress. In this study we explored functions of 7,8-DHF in protecting human proximal tubular cell line HK-2 from hypoxia insults. We observed that treatment of 7,8-DHF could improve the viability of ischemic cell. Mechanistically, we found that 7,8-DHF could elevate the expression of cysteine-rich protein 61 (Cyr61), a protective immediate early gene in AKI. In addition, treatment of 7,8-DHF decreased CCAAT/enhancer-binding protein homologous protein (CHOP) expression, which is a marker protein during endoplasmic reticulum (ER) stress activation. Intriguingly, overexpression of Cyr61 significantly reduced CHOP expression. Taken together, our results provide novel insights into the possible protective role of 7,8-DHF by activating Cyr61 signaling and suppressing ER stress in hypoxic HK-2 cells which have potential clinical implications for the treatment of AKI. PMID:28116298

  4. Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide

    SciTech Connect

    Chien, Chia-Wen; Yao, Ju-Hsien; Chang, Shih-Yu; Lee, Pei-Chih; Lee, Te-Chang

    2011-11-15

    The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer. -- Highlights: Black-Right-Pointing-Pointer ATO and SAHA are therapeutic agents with different action modes. Black-Right-Pointing-Pointer Combination of ATO and SAHA synergistically inhibits tumor cell growth. Black-Right-Pointing-Pointer SAHA loosens chromatin structure resulting in increased sensitivity to DNase I. Black-Right-Pointing-Pointer ATO-induced DNA damage and apoptosis are enhanced by co-treatment with SAHA.

  5. Aerosol treatment with MNEI suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection.

    PubMed

    Woods, Donald E; Cantin, André; Cooley, Jessica; Kenney, Dianne M; Remold-O'Donnell, Eileen

    2005-02-01

    Neutrophil elastase is present at high levels in airway fluid of patients with cystic fibrosis (CF), and is responsible for considerable inflammatory damage. Human monocyte/neutrophil elastase inhibitor (MNEI), a 42-kDa serpin protein, is an effective inhibitor of neutrophil elastase, cathepsin G, and proteinase-3, related proteases released from inflammatory neutrophils. We hypothesized that recombinant MNEI would reduce inflammatory damage and enhance bacterial clearance from the lung in an animal model of chronic Pseudomonas aeruginosa infection. In vitro studies showed that MNEI causes dose-dependent inhibition of the activity of rat neutrophil elastase. Recombinant MNEI was administered daily by aerosolization to rats previously inoculated with agar beads containing P. aeruginosa to initiate chronic infection. Administered MNEI was partially recovered in lavage fluid of treated rats as a 66-kDa complex with protease indicative of in vivo inhibition of elastase or a related protease. Aerosol treatment with MNEI significantly decreased the extent of inflammatory injury, quantified as the histopathology score. MNEI, which had no bactericidal effect on P. aeruginosa in vitro, significantly enhanced clearance of bacteria from infected rat lungs. The reduction of histopathology scores and enhancement of bacterial killing were evident 6 hr after a single aerosol treatment with MNEI. These findings indicate an important function of MNEI in protecting innate antimicrobial defense. Similar results were previously obtained for aerosolized prolastin (alpha1-antitrypsin), indicating that enhanced bacterial clearance by MNEI is due to inhibition of neutrophil protease. These findings demonstrate the value of this nonantibiotic protease inhibitor as an adjunct for the treatment and prevention of the infection component of CF lung disease.

  6. Validated specific HPLC methods for determination of prazosin, terazosin and doxazosin in the presence of degradation products formed under ICH-recommended stress conditions.

    PubMed

    Bakshi, Monika; Ojha, Tina; Singh, Saranjit

    2004-01-27

    The present paper describes development of stability-indicating high-performance liquid chromatographic (HPLC) assay methods for three alpha-adrenergic-blocker drug substances, namely, prazosin, terazosin and doxazosin, in the presence of degradation products generated from forced decomposition studies. Resolution of drugs from degradation products was obtained using a reversed-phase C-18 column using water/acetonitrile/methanol/glacial acetic acid/diethylamine (25:35:40:1:0.017) as mobile phase for prazosin and terazosin and acetonitrile/water/glacial acetic acid/diethylamine (65:35:1:0.02) for doxazosin. The detection was done at 254 nm. The methods were validated with respect to linearity, precision, accuracy, specificity and robustness.

  7. Combined administration of alpha1-adrenoceptor antagonist prazosin and beta-blocker propranolol impairs spatial avoidance learning on a dry arena.

    PubMed

    Petrasek, Tomas; Doulames, Vanessa; Prokopova, Iva; Vales, Karel; Stuchlik, Ales

    2010-04-02

    Spatial learning is a widely studied type of animal behavior often considered as a model of higher human cognitive functions. Noradrenergic receptors play a modulatory role in many nerve functions, including vigilance, attention, reward, learning and memory. The present study aimed at studying the effects of separate or combined systemic administration of the alpha1-adrenergic antagonist prazosin (1 and 2 mg/kg) and beta-blocker propranolol (5 and 20 mg/kg) on the hippocampus-dependent learning in the active allothetic place avoidance (AAPA) task. Both centrally active drugs impaired spatial learning when administered together, exerting no effect in separate applications. Locomotion was impaired only in a combined application of higher doses of both drugs (2 mg/kg prazosin and 20 mg/kg propranolol). These results suggest an in vivo interaction between these two types of receptors in spatial navigation regulation.

  8. Electroconvulsive therapy suppresses the neurotoxic branch of the kynurenine pathway in treatment-resistant depressed patients.

    PubMed

    Schwieler, Lilly; Samuelsson, Martin; Frye, Mark A; Bhat, Maria; Schuppe-Koistinen, Ina; Jungholm, Oscar; Johansson, Anette G; Landén, Mikael; Sellgren, Carl M; Erhardt, Sophie

    2016-02-29

    Neuroinflammation is increasingly recognized as contributing to the pathogenesis of depression. Key inflammatory markers as well as kynurenic acid (KYNA) and quinolinic acid (QUIN), both tryptophan metabolites, have been associated with depressive symptoms and suicidality. The aim of the present study is to investigate the peripheral concentration of cytokines and tryptophan and kynurenine metabolites in patients with unipolar treatment-resistant depression before and after electroconvulsive therapy (ECT), the most effective treatment for depression. Cytokines in plasma from patients with major depressive disorder (MDD; n = 19) and healthy volunteers (n = 14) were analyzed with electrochemiluminescence detection. Tryptophan and kynurenine metabolites were detected with high-performance liquid chromatography (HPLC) and LC/MS. KYNA was analyzed in a second healthy control cohort (n = 22). Patients with MDD had increased plasma levels of interleukin (IL)-6 compared to healthy volunteers (P < 0.05). We also found an altered kynurenine metabolism in these patients displayed by decreased plasma levels of KYNA (P < 0.0001) as well as a significantly increased QUIN/KYNA ratio (P < 0.001). Plasma levels of tryptophan, kynurenine, and QUIN did not differ between patients and controls. Treatment with ECT was associated with a significant decrease in the plasma levels of tryptophan (P < 0.05), kynurenine (P < 0.01), and QUIN (P < 0.001), whereas plasma levels of KYNA did not change. The QUIN/KYNA ratio was found to significantly decrease in ECT-treated patients (P < 0.05). There was a significant inverse correlation between symptom severity and kynurenine levels at baseline (r = -0.67, P = 0.002). This study confirms an imbalanced kynurenine pathway in MDD supporting the hypothesis of a netstimulation of N-methyl-D-aspartic acid (NMDA) receptors in the disorder. Treatment with ECT profoundly decreased QUIN, an NMDA

  9. [Treatment of multiple myeloma with intravenous pamidronate. Pain prevention and suppression of hypercalcemia risk].

    PubMed

    Díaz, Carlos; Soutelo, María J; Quiroga, Luis; Palmer, Luis; Lutfi, Rubén

    2004-01-01

    In a prospective clinical study, with the patient as its own control, we selected patients with stage III multiple myeloma. We treated them monthly with intravenous (i.v.) Disodic Pamidronate: 90 mg in 2 to 21 cycles. Four patients died during the study. The remaining 13 patients presented reduced bone resorption urinary markers (D-Pyr mainly) as well as urinary calcium (bone turnover reduction). Both effects (metabolic interchange reduction and calcium variation) did not show a direct relationship, being the 1st magnitude proportional to the baseline level and the 2nd independent from it. We noted pain reduction (VAS: visual analogs scale), low analgesic consumption, and the absence of future skeletal problems. The treatment tolerance was good. All these factors contribute to justify the welfare of the patient demonstrated by ECOG (Eastern Cooperative Oncology Group), not only improving the average results but also extending this improvement to future results. Our observation suggests that under strict procedures, this treatment could be very adequate in patients with advanced multiple myeloma independent of the state of the disease at the beginning of the study.

  10. Effect of alpha(1)-adrenergic antagonist prazosin on behavioral alterations induced by MK-801 in a spatial memory task in Long-Evans rats.

    PubMed

    Stuchlík, A; Petrásek, T; Vales, K

    2009-01-01

    Animal models of neuropsychiatric disorders are current topics in behavioral neuroscience. Application of non-competitive antagonists of NMDA receptors (such as MK-801) was proposed as a model of schizophrenia, as it leads to specific behavioral alterations, which are partly analogous to human psychotic symptoms. This study examined an animal model of schizophrenia induced by a systemic application of MK-801 (0.15 and 0.20 mg/kg) into rats tested in the active allothetic place avoidance (AAPA) task. Previous studies suggested that MK-801 may interact in vivo with other neurotransmitter systems, including noradrenergic system. Our experiments therefore evaluated the hypothesis that both locomotor stimulation and deficit in avoidance behavior in AAPA task induced by this drug would be reversible by application of alpha(1)-adrenergic antagonist prazosin (1 and 2 mg/kg). The results showed that both doses of prazosin partially reversed hyperlocomotion induced by higher doses of MK-801 and an avoidance deficit measured as number of entrances into the shock sector. Interestingly, no effect of prazosin on the MK-801-induced decrease of maximum time between two entrances (another measure of cognitive performance) was observed. These results support previous data showing that prazosin can compensate for the hyperlocomotion induced by MK-801 and newly show that this partial reduction sustains even in the forced locomotor conditions, which are involved in the AAPA task. The study also shows that certain parameters of avoidance efficiency may be closely related to locomotor activity, whereas other measures of cognition may more selectively reflect cognitive changes.

  11. Rapid Suppression of Onchocerca volvulus Transmission in Two Communities of the Southern Chiapas Focus, Mexico, Achieved by Quarterly Treatments with Mectizan

    PubMed Central

    Rodríguez-Pérez, Mario A.; Lutzow-Steiner, Miguel A.; Segura-Cabrera, Aldo; Lizarazo-Ortega, Cristian; Domínguez-Vázquez, Alfredo; Sauerbrey, Mauricio; Richards, Frank; Unnasch, Thomas R.; Hassan, Hassan K.; Hernández-Hernández, Raymundo

    2008-01-01

    The impact of quarterly Mectizan (ivermectin) treatments on transmission, microfiladermia, and ocular lesions was evaluated in two formerly hyperendemic communities (Las Golondrinas and Las Nubes II) located in the main endemic focus for onchocerciasis in Southern Chiapas, Mexico. The data suggest that Onchocerca volvulus transmission has been suppressed after elimination of microfiladermia in these two communities. Increasing the frequency of Mectizan treatment to four times per year appears to have resulted in the rapid suppression of transmission in communities with residual transmission. PMID:18689630

  12. Prolonged treatment with glucocorticoid dexamethasone suppresses melatonin production by the chick pineal gland and retina.

    PubMed

    Zawilska, Jolanta B; Sadowska, Magdalena

    2002-01-01

    The chick pineal gland and retina synthesize melatonin in a circadian rhythm with high levels during the night. The rhythmic changes in the hormone production result predominantly from the fluctuation in the activity of serotonin N-acetyltransferase (AA-NAT), a penultimate and key regulatory enzyme in melatonin biosynthesis. The aim of this study was to analyze the effects of an acute and prolonged in vivo treatment with a glucocorticoid dexamethasone (4 mg/kg, ip) on the nocturnal increase in AA-NAT activity in chick pineal gland and retina. In acute experiments, dexamethasone (single dose)-injected chicks were killed after 2 h, while in prolonged experiments the glucocorticoid was given once daily for 7 days and the animals were killed 26-32 h after the last injection. Acute administration of dexamethasone did not affect AA-NAT activity in the chick pineal gland and retina. In the pineal glands and retinas of chicks that were treated with dexamethasone for one week and then killed at the end of the light phase of the 12:12 h light-dark cycle, AA-NAT activity was significantly higher than the enzyme activity found in tissues isolated from the vehicle-treated (control) animals. In addition to that, the nocturnal increase in pineal and, to a lower extent, retinal AA-NAT activity was significantly lower in dexamethasone-treated birds when compared with the respective control groups. It is suggested that prolonged treatment of animals with dexamethasone reduces the amplitude of the rhythmic melatonin production, a phenomenon which may affect chronobiological processes being under control of this hormone.

  13. Comparison of relaxation responses of cavernous and trigonal smooth muscles from rabbits by alpha1-adrenoceptor antagonists; prazosin, terazosin, doxazosin, and tamsulosin.

    PubMed Central

    Seo, K. K.; Lee, M. Y.; Lim, S. W.; Kim, S. C.

    1999-01-01

    Alpha1a-adrenergic receptor (AR) primarily mediates the contraction of the prostatic and cavernous smooth muscles. Among clinically available alpha1-AR antagonists for the medical management of benign prostatic hyperplasia (BPH), tamsulosin has a modest selectivity for alpha1A- and alpha1D- over alpha1B-ARs. To compare the effects of various alpha1-AR antagonists on relaxation responses of cavernous and trigonal smooth muscles, isometric tension studies with relatively selective (tamsulosin) and non-selective (prazosin, doxazosin, and terazosin) alpha1A-AR antagonists, were conducted in the cavernous and trigonal muscle strips of rabbits (n=10 each). Tamsulosin had the strongest inhibitory effect on contraction of trigonal smooth muscle among the various alpha1-AR antagonists, and the inhibitory activities of prazosin, doxazosin, and terazosin were not statistically different. All alpha1-AR antagonists caused concentration-dependent relaxation of the cavernous muscle strips. Tamsulosin was shown to have greater potency than prazosin (more than 100-fold), doxazosin (more than 1000-fold), and terazosin (more than 1000-fold), in relaxation of cavernous smooth muscle. In conclusion, tamsulosin might be the most effective drug among the four commonly used alpha1-AR antagonists for the medical management of BPH. Tamsulosin might be a potential substitute for phentolamine in combination with vasoactive agents as an intracavernous injection therapy for patients with erectile dysfunction. PMID:10102527

  14. Long-term effect of prazosin and losartan administration on blood pressure, heart, carotid artery, and acetylcholine induced dilation of cardiovascular system of young Wistar rats and SHR.

    PubMed

    Kristek, Frantisek; Malekova, Magdalena; Cacanyiova, Sona

    2013-06-01

    The long-term effects of prazosin and losartan administration on blood pressure, trophicity of the heart and carotid arteries, and responses of the cardiovascular system to acetylcholine, were studied in Wistar rats and spontaneously hypertensive rats (SHRs). Four-week-old rats were treated with prazosin (10 mg/kg b.w./day in tap water) or losartan (20 mg/kg b.w./day in tap water) for 5-6 weeks. BP was measured by plethysmographic method. Ten animals of each group were subjected to in vivo studies and subsequent to morphological investigations. The right jugular vein was cannulated for administration of acetylcholine (0.1, 1, and 10 µg). After perfusion with a glutaraldehyde fixative (120 mmHg), the carotid arteries were embedded in Durcupan ACM, and the inner diameter (ID), wall thickness (WT) (tunica intima and media), cross sectional area (CSA) (tunica intima and media), and WT/ID ratio were calculated. In Wistar rats and SHRs, prazosin and losartan administration produced a decrease in the blood pressure and trophicity of the heart. In Wistar rats, both drugs decreased the WT, CSA, and the WT/ID ratio. In addition, these drugs increased the circumferential stress of the artery without affecting the ID. In contrast, in the SHRs, only losartan administration produced these effects. Importantly, both the drugs improved the responses to acetylcholine in SHRs.

  15. Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression.

    PubMed

    Westerlund, Isabelle; Shi, Yao; Toskas, Konstantinos; Fell, Stuart M; Li, Shuijie; Surova, Olga; Södersten, Erik; Kogner, Per; Nyman, Ulrika; Schlisio, Susanne; Holmberg, Johan

    2017-07-25

    Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA-demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genome-wide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.

  16. Disruption of actin filaments and suppression of pancreatic cancer cell viability and migration following treatment with polyisoprenylated cysteinyl amides

    PubMed Central

    Nkembo, Augustine T; Salako, Olufisayo; Poku, Rosemary A; Amissah, Felix; Ntantie, Elizabeth; Flores-Rozas, Hernan; Lamango, Nazarius S

    2016-01-01

    Pancreatic cancer is characterized by K-Ras mutations in over 90% of the cases. The mutations make the tumors aggressive and resistant to current therapies resulting in very poor prognoses. Valiant efforts to drug mutant K-Ras and related proteins for the treatment of cancers with Ras mutations have been elusive. The need thus persists for therapies to target and suppress the hyperactive K-Ras mutant proteins to normal levels of activity. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) of polyisoprenylated methylated protein methyl esterase (PMPMEase) were designed to disrupt polyisoprenylated protein metabolism and/or functions. The potential for PCAIs to serve as targeted anticancer agents for pancreatic cancer was evaluated in pancreatic ductal adenocarcinoma (PDAC) cell lines expressing mutant (MIAPaCa-2 and Panc-1) and wild type (BxPC-3) K-Ras proteins. The PCAIs inhibited MIAPaCa-2 and BxPC-3 cell viability and induced apoptosis with EC50 values as low as 1.9 µM. The PCAIs, at 0.5 µM, inhibited MIAPaCa-2 cell migration by 50%, inhibited colony formation and disrupted F-actin filament organization. The PCAIs blocked MIAPaCa-2 cell progression at the G0/G1 phase. These results reveal that the PCAIs disrupt pertinent biological processes that lead to pancreatic cancer progression and thus have the potential to act as targeted effective treatments for pancreatic cancer. PMID:27904769

  17. Surface treatment of zinc anodes to improve discharge capacity and suppress hydrogen gas evolution

    NASA Astrophysics Data System (ADS)

    Cho, Yung-Da; Fey, George Ting-Kuo

    The shape change and redistribution of zinc anode material over the electrode during repeated cycling have been identified as the main factors that can limit the life of alkaline zinc-air batteries. Li 2O-2B 2O 3 (lithium boron oxide, LBO) glass with high Li + conductivity and stability can be coated on the surface of zinc powders. The structures of the surface-treated and pristine zinc powders were characterized by XRD, SEM, TEM, ESCA and BET analyses. XRD patterns of LBO-coated zinc powders revealed that the coating did not affect the crystal structure. TEM images of LBO-coated on the zinc particles were compact with an average passivation layer of about 250 nm. The LBO layer can prevent zinc from coming into direct contact with the KOH electrolyte and minimize the side reactions within the batteries. The 0.1 wt.% LBO-coated zinc anode material provided an initial discharge capacity of 1.70 Ah at 0.5 V, while the pristine zinc electrode delivered only 1.57 Ah. A surface-treated zinc electrode can increase discharge capacity, decrease hydrogen evolution reaction, and reduce self-discharge. The results indicated that surface treatment should be effective for improving the comprehensive properties of anode materials for zinc-air batteries.

  18. Modulation of the gut microbiota with antibiotic treatment suppresses whole body urea production in neonatal pigs.

    PubMed

    Puiman, Patrycja; Stoll, Barbara; Mølbak, Lars; de Bruijn, Adrianus; Schierbeek, Henk; Boye, Mette; Boehm, Günther; Renes, Ingrid; van Goudoever, Johannes; Burrin, Douglas

    2013-02-01

    We examined whether changes in the gut microbiota induced by clinically relevant interventions would impact the bioavailability of dietary amino acids in neonates. We tested the hypothesis that modulation of the gut microbiota in neonatal pigs receiving no treatment (control), intravenously administered antibiotics, or probiotics affects whole body nitrogen and amino acid turnover. We quantified whole body urea kinetics, threonine fluxes, and threonine disposal into protein, oxidation, and tissue protein synthesis with stable isotope techniques. Compared with controls, antibiotics reduced the number and diversity of bacterial species in the distal small intestine (SI) and colon. Antibiotics decreased plasma urea concentrations via decreased urea synthesis. Antibiotics elevated threonine plasma concentrations and turnover, as well as whole body protein synthesis and proteolysis. Antibiotics decreased protein synthesis rate in the proximal SI and liver but did not affect the distal SI, colon, or muscle. Probiotics induced a bifidogenic microbiota and decreased plasma urea concentrations but did not affect whole body threonine or protein metabolism. Probiotics decreased protein synthesis in the proximal SI but not in other tissues. In conclusion, modulation of the gut microbiota by antibiotics and probiotics reduced hepatic ureagenesis and intestinal protein synthesis, but neither altered whole body net threonine balance. These findings suggest that changes in amino acid and nitrogen metabolism resulting from antibiotic- or probiotic-induced shifts in the microbiota are localized to the gut and liver and have limited impact on whole body growth and anabolism in neonatal piglets.

  19. Experimental autoimmune anterior uveitis (EAAU): induction by melanin antigen and suppression by various treatments.

    PubMed

    Broekhuyse, R M; Kuhlmann, E D; Winkens, H J

    1993-02-01

    The uveitogenicity of melanin has been a controversial subject for a long time, presumably as a result of the use of ill-defined preparations in the experiments. We have developed procedures for the preparation of purified uveitogenic melanins from the retinal pigment epithelium and choroid that are free from pathogenic retinal photoreceptor proteins. The active melano-antigen is located at the surface of the melanin granules and is probably identical in both tissues. It retains its pathogenicity in hot polar detergent and during in vitro proteolysis, but it is inactivated by macrophage phagocytosis and hydrolysis in hot hydrochloric acid. Lewis rats immunized with microgram doses of bovine retinal pigment epithelial or choroidal melanin develop severe experimental autoimmune anterior uveitis (EAAU) about 10 days later. Retinitis and pinealitis are not observed. Skin melanin prepared in a similar way evokes EAAU as well, but it is only weakly pathogenic. EAAU cannot be transferred by serum, and its development can effectively be inhibited by antibodies to the inciting antigen and by cyclosporin. Vitamin E treatment of the animals causes a delay in its onset. The results indicate that cell-mediated immunity plays a dominant role in the pathogenesis of EAAU. This is the first time it has been shown that purified ocular and skin melanins are able to induce an autoimmune disease. The relevance of this finding for the study of melanin-related immunopathology in man is discussed.

  20. Treatment with Vitamin D/MOG Association Suppresses Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Chiuso-Minicucci, Fernanda; Ishikawa, Larissa Lumi Watanabe; Mimura, Luiza Ayumi Nishiyama; Fraga-Silva, Thais Fernanda de Campos; França, Thais Graziela Donegá; Zorzella-Pezavento, Sofia Fernanda Gonçalves; Marques, Camila; Ikoma, Maura Rosane Valerio; Sartori, Alexandrina

    2015-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model to study multiple sclerosis (MS). Considering the tolerogenic effects of active vitamin D, we evaluated the therapeutic effect of myelin oligodendrocyte glycoprotein (MOG) associated with active vitamin D in EAE development. EAE was induced in female C57BL/6 mice by immunization with MOG emulsified with Complete Freund’s Adjuvant plus Mycobacterium tuberculosis. Animals also received two intraperitoneal doses of Bordetella pertussis toxin. One day after immunization, mice were treated with 0,1μg of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) every other day during 15 days (on days 1, 3, 5, 7, 9, 11, 13 and 15). MOG (150μg) was co-administered on days 3 and 11. The administration of 1,25(OH) 2D3 or MOG determined significant reduction in EAE incidence and in clinical scores. When MOG was associated with 1,25(OH) 2D3 the animals did not develop EAE. Spleen and central nervous system (CNS) cell cultures from this group produced less IL-6 and IL-17 upon stimulation with MOG in comparison to the EAE control group. In addition, this treatment inhibited dendritic cells maturation in the spleen and reduced inflammatory infiltration in the CNS. The association of MOG with 1,25(OH) 2D3 was able to control EAE development. PMID:25965341

  1. Modulation of the gut microbiota with antibiotic treatment suppresses whole body urea production in neonatal pigs

    PubMed Central

    Puiman, Patrycja; Stoll, Barbara; Mølbak, Lars; de Bruijn, Adrianus; Schierbeek, Henk; Boye, Mette; Boehm, Günther; Renes, Ingrid; Burrin, Douglas

    2013-01-01

    We examined whether changes in the gut microbiota induced by clinically relevant interventions would impact the bioavailability of dietary amino acids in neonates. We tested the hypothesis that modulation of the gut microbiota in neonatal pigs receiving no treatment (control), intravenously administered antibiotics, or probiotics affects whole body nitrogen and amino acid turnover. We quantified whole body urea kinetics, threonine fluxes, and threonine disposal into protein, oxidation, and tissue protein synthesis with stable isotope techniques. Compared with controls, antibiotics reduced the number and diversity of bacterial species in the distal small intestine (SI) and colon. Antibiotics decreased plasma urea concentrations via decreased urea synthesis. Antibiotics elevated threonine plasma concentrations and turnover, as well as whole body protein synthesis and proteolysis. Antibiotics decreased protein synthesis rate in the proximal SI and liver but did not affect the distal SI, colon, or muscle. Probiotics induced a bifidogenic microbiota and decreased plasma urea concentrations but did not affect whole body threonine or protein metabolism. Probiotics decreased protein synthesis in the proximal SI but not in other tissues. In conclusion, modulation of the gut microbiota by antibiotics and probiotics reduced hepatic ureagenesis and intestinal protein synthesis, but neither altered whole body net threonine balance. These findings suggest that changes in amino acid and nitrogen metabolism resulting from antibiotic- or probiotic-induced shifts in the microbiota are localized to the gut and liver and have limited impact on whole body growth and anabolism in neonatal piglets. PMID:23139222

  2. Long-term effects of maternal separation on chronic stress response suppressed by amitriptyline treatment.

    PubMed

    Cotella, E M; Mestres Lascano, I; Franchioni, L; Levin, G M; Suárez, M M

    2013-07-01

    Abstract The early-life environment has many long-term effects on mammals. Maternal interaction and early stressful events may affect regulation of the HPA axis during adulthood, leading to differential glucocorticoid secretion in response to stressful situations. These adverse experiences during postnatal development may even sensitize specific neurocircuits to subsequent stressors. Later in life, the overreaction of the HPA axis to stress can constitute a risk factor for metabolic and mental diseases. As tricyclic antidepressants are known to correct glucocorticoid hypersecretion during depression, we treated maternally separated animals with amitriptyline, at a lower dose than habitually used in depression models, to prevent the response to chronic stress during adulthood. Male Wistar rats were separated from the mother for 4.5 h every day for the first 3 weeks of life. From postnatal day 50, animals were subjected to chronic variable stress during 24 d (five types of stressors at different times of day). During the stress, protocol rats were orally administered amitriptyline (5 mg/kg) daily. We observed that maternal separation caused a reduction in plasma ACTH levels (p < 0.05), but evoked hypersecretion of corticosterone (p < 0.05) when it was combined with stress in adulthood. This rise was completely prevented by antidepressant treatment with amitriptyline.

  3. Atypical antipsychotics suppress production of proinflammatory cytokines and up-regulate interleukin-10 in lipopolysaccharide-treated mice.

    PubMed

    Sugino, Haruhiko; Futamura, Takashi; Mitsumoto, Yasuhide; Maeda, Kenji; Marunaka, Yoshinori

    2009-03-17

    There is considerable evidence that schizophrenia is associated with immune system dysregulation. For example, blood and cerebrospinal fluid (CSF) levels of proinflammatory cytokines are significantly increased in schizophrenic patients, and their normalization correlates with improvement in psychotic symptoms. In fact, typical and atypical antipsychotics are reported to modulate immune function in in vitro and in vivo studies. In the present study, we examined the anti-inflammatory effect of antipsychotics, clozapine, olanzapine, risperidone and haloperidol, on serum cytokine levels in lipopolysaccharide (LPS)-treated mice. Atypical antipsychotics, such as clozapine, olanzapine and risperidone, but not haloperidol, suppressed tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and up-regulated IL-10. Moreover, only clozapine, robustly increased the serum levels of IL-10. Clozapine reproduced its anti-inflammatory feature in polyinsinic-polycytidylic acid sodium salt (Poly[I:C])-induced inflammation. Thus, the anti-inflammatory effect of clozapine would adapt to inflammation induced by some varieties of antigens. Several receptor ligands, such as 8-OH-DPAT, ketanserin, prazosin and scopolamine, were also examined as to their anti-inflammatory effects on serum cytokine levels in LPS-treated mice. Ketanserin and prazosin, but not 8-OH-DPAT nor scopolamine, behaved similarly to atypical antipsychotics. However, the remarkable increase of serum IL-10 level observed in clozapine was not detected in ketanserin and prazosin. These results suggest the unique efficacy of atypical antipsychotics in the suppression of proinflammatory cytokines, and the increase of anti-inflammatory cytokine, IL-10.

  4. Stability-Indicating RP-HPLC Method for the Simultaneous Determination of Prazosin, Terazosin, and Doxazosin in Pharmaceutical Formulations

    PubMed Central

    Shrivastava, Alankar; Gupta, Vipin B.

    2012-01-01

    The current study was carried out with an attempt to separate similarly structured title drugs by liquid chromatography. Spectrophotometric techniques were generally insufficient under these conditions because of the spectral overlapping of drugs with similar functional groups. The pharmaceutical drugs prazosin, terazosin, and doxazosin contain the same parent quinazoline nucleus, thus making it especially difficult to separate the former two drugs because of their very similar structures. A simple and sensitive method for the routine determination of these drugs in pharmaceutical formulations was attempted. We found that the mobile phase consisting of A: ACN–diethylamine (0.05 ml), B: methanol, and C: 10 mM Ammonium acetate separated these drugs effectively. Separations were carried out on a new Kromasil C18 column (250 × 4.6 mm, 5.0 μm) at 254 nm wavelength. The calibration curve was found to be linear in the range of 2–500 μg/ml. The stated method was then validated in terms of specificity, linearity, precision, and accuracy. Additionally, the proposed method reduced the duration of the analysis. PMID:23008810

  5. Stability-Indicating RP-HPLC Method for the Simultaneous Determination of Prazosin, Terazosin, and Doxazosin in Pharmaceutical Formulations.

    PubMed

    Shrivastava, Alankar; Gupta, Vipin B

    2012-01-01

    The current study was carried out with an attempt to separate similarly structured title drugs by liquid chromatography. Spectrophotometric techniques were generally insufficient under these conditions because of the spectral overlapping of drugs with similar functional groups. The pharmaceutical drugs prazosin, terazosin, and doxazosin contain the same parent quinazoline nucleus, thus making it especially difficult to separate the former two drugs because of their very similar structures. A simple and sensitive method for the routine determination of these drugs in pharmaceutical formulations was attempted. We found that the mobile phase consisting of A: ACN-diethylamine (0.05 ml), B: methanol, and C: 10 mM Ammonium acetate separated these drugs effectively. Separations were carried out on a new Kromasil C18 column (250 × 4.6 mm, 5.0 μm) at 254 nm wavelength. The calibration curve was found to be linear in the range of 2-500 μg/ml. The stated method was then validated in terms of specificity, linearity, precision, and accuracy. Additionally, the proposed method reduced the duration of the analysis.

  6. Preparation and transdermal diffusion evaluation of the prazosin hydrochloride-loaded electrospun poly(vinyl alcohol) fiber mats.

    PubMed

    Shen, Xiaobing; Xu, Qian; Xu, Shi; Li, Jie; Zhang, Niping; Zhang, Ling

    2014-07-01

    This study reports on the use of electrospun polyvinyl alcohol (PVA) nanofiber mats loaded with prazosin hydrochloride (PRH) as a transdermal drug delivery system, investigating the morphology of electrospun PVA nanofibers, the in vitro release characteristics of the drug from the as-spun fibers, and the influence of permeation enhancer (water-resoluble azone, WSA) on transdermal diffusion of PRH through a rat skin. The same was also conducted on the PRH -loaded as-cast PVA films for comparison. Results indicated that the morphology of PRH-loaded PVA fibers observed by scanning electron microscopy (SEM) relied on the electrospinning processing parameters, and the addition of WSA had obvious effects on the diameter and morphology of electrospun PVA fibers. The PRH-loaded electrospun PVA fiber mats exhibited much higher accumulated release dose and release rate of PRH than as-cast PVA films. And WAS can improve the release amount and rate of PRH from drug-loaded samples. The content of PRH in receiver was more than that in the stratum corneum and in the dermis. It was concluded that the PRH-loaded electropun PVA fiber mats as a transdermal patches can be a promising candidate for the conventional preparation.

  7. Chloroquine enhances the efficacy of cisplatin by suppressing autophagy in human adrenocortical carcinoma treatment

    PubMed Central

    Qin, Liang; Xu, Tianyuan; Xia, Leilei; Wang, Xianjin; Zhang, Xiang; Zhang, Xiaohua; Zhu, Zhaowei; Zhong, Shan; Wang, Chuandong; Shen, Zhoujun

    2016-01-01

    Background It has been demonstrated that chloroquine (CQ) enhances the efficacy of chemotherapy. However, little is known about whether CQ could enhance the efficacy of cisplatin (DDP) in the treatment of adrenocortical carcinoma (ACC). In this study, we explore the efficacy and mechanism by which CQ affects DDP sensitivity in human ACC in vitro and in vivo. Methods The autophagic gene Beclin-1 expression was detected by immunohistochemistry, and the protein levels were analyzed using immunoblotting assays of ACC tissues and normal adrenal cortex tissues. The ACC SW13 cells were treated with DDP and/or CQ. The cell viability assay was performed using the MTT method. Qualitative autophagy detection was performed by monodansylcadaverine staining of autophagic vacuoles. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to count cell apoptosis by flow cytometry. The autophagy-related protein (Beclin-1, LC3, and p62) and apoptosis relative protein (Bax and Bcl-2) levels were evaluated with Western blot analysis. Furthermore, a murine model of nude BALB/c mice bearing SW13 cell xenografts was established to evaluate the efficacy of concomitant therapy. Results The expression of the autophagic gene Beclin-1 was significantly downregulated in ACC tissues compared to normal adrenal cortex tissues. The Beclin-1 protein level in ACC tissues was lower than that in normal adrenal cortex tissues (P<0.05). In vitro concomitant therapy (DDP and CQ) was more effective in restraining SW13 cell proliferation. DDP could promote cell apoptosis and induce autophagy in SW13 cells. Concomitant therapy further promoted cell apoptosis by inhibiting autophagy. In vivo, we found that concomitant therapy was more potent than DDP monotherapy in inhibiting the growth of xenografted tumors and prolonging the survival of tumor-bearing mice. Conclusion The antitumor ability of DDP was related to autophagy activity, and the concomitant therapy (DDP and CQ) could be an

  8. A personal light-treatment device for possibly improving sleep quality in the elderly: Dynamics of nocturnal melatonin suppression at two exposure levels

    PubMed Central

    Figueiro, Mariana G.; Bierman, Andrew; Bullough, John D.; Rea, Mark S.

    2009-01-01

    Light treatment has been used as a non-pharmacological tool to help mitigate poor sleep quality frequently found in the older people. In order to increase compliance to non-pharmacological light treatments, new, more efficacious light-delivery systems need to be developed. A prototype personal light-treatment device equipped with low brightness blue light-emitting diodes (LEDs) (peak wavelength near 470 nm) was tested for its effectiveness in suppressing nocturnal melatonin, a measure of circadian stimulation. Two levels of corneal irradiance were set to deliver two prescribed doses of circadian light exposure. Eleven older subjects, between 51 and 80 yrs of age who met the selection criteria, were exposed to a high and to a low level of light for 90 min on separate nights from the personal light-treatment device. Blood and saliva samples were collected at prescribed times for subsequent melatonin assay. After 1 h of light exposure, the light-induced nocturnal melatonin suppression level was about 35% for the low light level and about 60% for the high light level. The higher level of blue light suppressed melatonin slightly faster, to a greater extent over the course of the 90 min exposure period, and was maintained after 60 min. The constant exposure of the low light level resulted in a decrease in nocturnal melatonin suppression for the last sampling time, whereas for the high light level, suppression continued throughout the entire exposure period. The present study performed with healthy adults suggests that the tested personal light-treatment device might be a practical, comfortable, and effective way to deliver light treatment to those suffering from circadian sleep disorders; however, the acceptance and effectiveness of personal light-treatment devices by older people and by other segments of the population suffering from sleep disorders in a real-life situation needs to be directly tested. PMID:19444752

  9. Retrovirus-induced oxidative stress with neuroimmunodegeneration is suppressed by antioxidant treatment with a refined monosodium alpha-luminol (Galavit).

    PubMed

    Jiang, Yuhong; Scofield, Virginia L; Yan, Mingshan; Qiang, Wenan; Liu, Na; Reid, Amy J; Lynn, William S; Wong, Paul K Y

    2006-05-01

    Oxidative stress is involved in many human neuroimmunodegenerative diseases, including human immunodeficiency virus disease/AIDS. The retrovirus ts1, a mutant of Moloney murine leukemia virus, causes oxidative stress and progressive neuro- and immunopathology in mice infected soon after birth. These pathological changes include spongiform neurodegeneration, astrogliosis, thymic atrophy, and T-cell depletion. Astrocytes and thymocytes are directly infected and killed by ts1. Neurons are not infected, but they also die, most likely as an indirect result of local glial infection. Cytopathic effects of ts1 infection in cultured astrocytes are associated with accumulation of the viral envelope precursor protein gPr80env in the endoplasmic reticulum (ER), which triggers ER stress and oxidative stress. We have reported (i) that activation of the Nrf2 transcription factor and upregulation of antioxidative defenses occurs in astrocytes infected with ts1 in vitro and (ii) that some ts1-infected astrocytes survive infection by mobilization of these pathways. Here, we show that treatment with a refined monosodium alpha-luminol (Galavit; GVT) suppresses oxidative stress and Nrf2 activation in cultured ts1-infected astrocytes. GVT treatment also inhibits the development of spongiform encephalopathy and gliosis in the central nervous system (CNS) in ts1-infected mice, preserves normal cytoarchitecture in the thymus, and delays paralysis, thymic atrophy, wasting, and death. GVT treatment of infected mice reduces ts1-induced oxidative stress, cell death, and pathogenesis in both the CNS and thymus of treated animals. These studies suggest that oxidative stress mediates ts1-induced neurodegeneration and T-cell loss.

  10. Retrovirus-Induced Oxidative Stress with Neuroimmunodegeneration Is Suppressed by Antioxidant Treatment with a Refined Monosodium α-Luminol (Galavit)

    PubMed Central

    Jiang, Yuhong; Scofield, Virginia L.; Yan, Mingshan; Qiang, Wenan; Liu, Na; Reid, Amy J.; Lynn, William S.; Wong, Paul K. Y.

    2006-01-01

    Oxidative stress is involved in many human neuroimmunodegenerative diseases, including human immunodeficiency virus disease/AIDS. The retrovirus ts1, a mutant of Moloney murine leukemia virus, causes oxidative stress and progressive neuro- and immunopathology in mice infected soon after birth. These pathological changes include spongiform neurodegeneration, astrogliosis, thymic atrophy, and T-cell depletion. Astrocytes and thymocytes are directly infected and killed by ts1. Neurons are not infected, but they also die, most likely as an indirect result of local glial infection. Cytopathic effects of ts1 infection in cultured astrocytes are associated with accumulation of the viral envelope precursor protein gPr80env in the endoplasmic reticulum (ER), which triggers ER stress and oxidative stress. We have reported (i) that activation of the Nrf2 transcription factor and upregulation of antioxidative defenses occurs in astrocytes infected with ts1 in vitro and (ii) that some ts1-infected astrocytes survive infection by mobilization of these pathways. Here, we show that treatment with a refined monosodium α-luminol (Galavit; GVT) suppresses oxidative stress and Nrf2 activation in cultured ts1-infected astrocytes. GVT treatment also inhibits the development of spongiform encephalopathy and gliosis in the central nervous system (CNS) in ts1-infected mice, preserves normal cytoarchitecture in the thymus, and delays paralysis, thymic atrophy, wasting, and death. GVT treatment of infected mice reduces ts1-induced oxidative stress, cell death, and pathogenesis in both the CNS and thymus of treated animals. These studies suggest that oxidative stress mediates ts1-induced neurodegeneration and T-cell loss. PMID:16611916

  11. IVIg immune reconstitution treatment alleviates the state of persistent immune activation and suppressed CD4 T cell counts in CVID.

    PubMed

    Paquin-Proulx, Dominic; Santos, Bianca A N; Carvalho, Karina I; Toledo-Barros, Myrthes; Barreto de Oliveira, Ana Karolina; Kokron, Cristina M; Kalil, Jorge; Moll, Markus; Kallas, Esper G; Sandberg, Johan K

    2013-01-01

    Common variable immunodeficiency (CVID) is characterized by defective B cell function, impaired antibody production, and increased susceptibility to bacterial infections. Here, we addressed the hypothesis that poor antibody-mediated immune control of infections may result in substantial perturbations in the T cell compartment. Newly diagnosed CVID patients were sampled before, and 6-12 months after, initiation of intravenous immunoglobulin (IVIg) therapy. Treatment-naïve CVID patients displayed suppressed CD4 T cell counts and myeloid dendritic cell (mDC) levels, as well as high levels of immune activation in CD8 T cells, CD4 T cells, and invariant natural killer T (iNKT) cells. Expression of co-stimulatory receptors CD80 and CD83 was elevated in mDCs and correlated with T cell activation. Levels of both FoxP3+ T regulatory (Treg) cells and iNKT cells were low, whereas soluble CD14 (sCD14), indicative of monocyte activation, was elevated. Importantly, immune reconstitution treatment with IVIg partially restored the CD4 T cell and mDC compartments. Treatment furthermore reduced the levels of CD8 T cell activation and mDC activation, whereas levels of Treg cells and iNKT cells remained low. Thus, primary deficiency in humoral immunity with impaired control of microbial infections is associated with significant pathological changes in cell-mediated immunity. Furthermore, therapeutic enhancement of humoral immunity with IVIg infusions alleviates several of these defects, indicating a relationship between poor antibody-mediated immune control of infections and the occurrence of abnormalities in the T cell and mDC compartments. These findings help our understanding of the immunopathogenesis of primary immunodeficiency, as well as acquired immunodeficiency caused by HIV-1 infection.

  12. IVIg Immune Reconstitution Treatment Alleviates the State of Persistent Immune Activation and Suppressed CD4 T Cell Counts in CVID

    PubMed Central

    Carvalho, Karina I.; Toledo-Barros, Myrthes; Barreto de Oliveira, Ana Karolina; Kokron, Cristina M.; Kalil, Jorge; Moll, Markus; Kallas, Esper G.; Sandberg, Johan K.

    2013-01-01

    Common variable immunodeficiency (CVID) is characterized by defective B cell function, impaired antibody production, and increased susceptibility to bacterial infections. Here, we addressed the hypothesis that poor antibody-mediated immune control of infections may result in substantial perturbations in the T cell compartment. Newly diagnosed CVID patients were sampled before, and 6–12 months after, initiation of intravenous immunoglobulin (IVIg) therapy. Treatment-naïve CVID patients displayed suppressed CD4 T cell counts and myeloid dendritic cell (mDC) levels, as well as high levels of immune activation in CD8 T cells, CD4 T cells, and invariant natural killer T (iNKT) cells. Expression of co-stimulatory receptors CD80 and CD83 was elevated in mDCs and correlated with T cell activation. Levels of both FoxP3+ T regulatory (Treg) cells and iNKT cells were low, whereas soluble CD14 (sCD14), indicative of monocyte activation, was elevated. Importantly, immune reconstitution treatment with IVIg partially restored the CD4 T cell and mDC compartments. Treatment furthermore reduced the levels of CD8 T cell activation and mDC activation, whereas levels of Treg cells and iNKT cells remained low. Thus, primary deficiency in humoral immunity with impaired control of microbial infections is associated with significant pathological changes in cell-mediated immunity. Furthermore, therapeutic enhancement of humoral immunity with IVIg infusions alleviates several of these defects, indicating a relationship between poor antibody-mediated immune control of infections and the occurrence of abnormalities in the T cell and mDC compartments. These findings help our understanding of the immunopathogenesis of primary immunodeficiency, as well as acquired immunodeficiency caused by HIV-1 infection. PMID:24130688

  13. Treatment options for parasomnias.

    PubMed

    Attarian, Hrayr

    2010-11-01

    Parasomnias are undesirable physical or experiential events that occur in and around sleep. Treatments include reassurance in some cases, various forms of cognitive-behavioral therapy (CBT), and pharmacologic agents. Cognitive restructuring, imagery rehearsal, relaxation, hypnosis, desensitization, and anticipatory awakenings are some of the common CBT and nonpharmacologic interventions. Medications that are used belong to a wide variety of pharmacologic classes, such as alpha-blockers (prazosin), tricyclic antidepressants (imipramine and clomipramine), selective serotonin reuptake inhibitors, benzodiazepines (diazepam and clonazepam), anticonvulsants (topiramate and gabapentin), desmopressin acetate, and anticholinergic agents (oxybutynin and tolterodine). Data on efficacy are only available from randomized trials on CBT and prazosin for nightmares and on pharmacologic and alarm therapy for enuresis. No large-scale randomized trials are available to assess the efficacy of the other treatments, and most data come from anecdotal case reports, case series, or small open-label trials.

  14. Resveratrol Treatment after Status Epilepticus Restrains Neurodegeneration and Abnormal Neurogenesis with Suppression of Oxidative Stress and Inflammation

    PubMed Central

    Mishra, Vikas; Shuai, Bing; Kodali, Maheedhar; Shetty, Geetha A.; Hattiangady, Bharathi; Rao, Xiaolan; Shetty, Ashok K.

    2015-01-01

    Antiepileptic drug therapy, though beneficial for restraining seizures, cannot thwart status epilepticus (SE) induced neurodegeneration or down-stream detrimental changes. We investigated the efficacy of resveratrol (RESV) for preventing SE-induced neurodegeneration, abnormal neurogenesis, oxidative stress and inflammation in the hippocampus. We induced SE in young rats and treated with either vehicle or RESV, commencing an hour after SE induction and continuing every hour for three-hours on SE day and twice daily thereafter for 3 days. Seizures were terminated in both groups two-hours after SE with a diazepam injection. In contrast to the vehicle-treated group, the hippocampus of animals receiving RESV during and after SE presented no loss of glutamatergic neurons in hippocampal cell layers, diminished loss of inhibitory interneurons expressing parvalbumin, somatostatin and neuropeptide Y in the dentate gyrus, reduced aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidative stress byproduct malondialdehyde and pro-inflammatory cytokine tumor necrosis factor-alpha, normalized expression of oxidative stress responsive genes and diminished numbers of activated microglia. Thus, 4 days of RESV treatment after SE is efficacious for thwarting glutamatergic neuron degeneration, alleviating interneuron loss and abnormal neurogenesis, and suppressing oxidative stress and inflammation. These results have implications for restraining SE-induced chronic temporal lobe epilepsy. PMID:26639668

  15. Simulating Patterns of Patient Engagement, Treatment Adherence, and Viral Suppression: A System Dynamics Approach to Evaluating HIV Care Management

    PubMed Central

    Schwartz, Brian; Palma, Anton

    2015-01-01

    Abstract System dynamics (SD) modeling belongs to the rapidly evolving, interdisciplinary field of system science research. This field adds value to more traditional health research by contributing to the design and testing of complex integrated models of change, to examine health system performance and patient outcomes. Using selected milestones in HIV care management to frame our simulation research, we created a SD model to examine three patient subgroups of women of color (WOC) represented in our multi-site cohort, classified by their health care seeking status at baseline. Asked to reflect on their circumstance 6 months prior to enrollment in the MSE cohort, 53% noted they were receiving some care (In Care, n=341), 31% that they had been seeking care (Seeking Care, n=201), and 16% that they were undecided about seeking care (i.e., answered that they may or may not look for care) for treatment of their HIV (May or May Not Seek Care, n=103). Our SD model compared simulated patterns of patient retention over 24 months in relation to: (1) access to antiretroviral therapy (ART), (2) adherence to ART, and (3) viral suppression. Assessed patterns yielded insights about system capacities and constraints in the context of the SPNS initiative under evaluation. PMID:25561309

  16. Fire behavior, fuel treatments, and fire suppression on the Hayman Fire - Part 4: Relation of roads to burn severity

    Treesearch

    Charles W. McHugh; Mark A. Finney

    2003-01-01

    Effects of roads on fire behavior intensity and severity can be studied directly or indirectly. A direct study of road effects would include uses by fire suppression, burnout operations, and delay of fire progress at the roadside. Interpretations after the fire burns are easily confounded by the unknown nature of suppression activities and fire arrival time, and fire...

  17. Telmisartan treatment targets inflammatory cytokines to suppress the pathogenesis of acute colitis induced by dextran sulphate sodium.

    PubMed

    Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Giridharan, Vijayasree V; Karuppagounder, Vengadeshprabhu; Pitchaimani, Vigneshwaran; Afrin, Mst Rejina; Miyashita, Shizuka; Nomoto, Mayumi; Harima, Meilei; Suzuki, Hiroshi; Nakamura, Takashi; Nakamura, Masahiko; Suzuki, Kenji; Watanabe, Kenichi

    2015-08-01

    The renin angiotensin system (RAS) is essential for the regulation of cardiovascular and renal functions to maintain the fluid and electrolyte homeostasis. Recent studies have demonstrated a locally expressed RAS in various tissues of mammals, which is having pathophysiological roles in those organ system. Interestingly, local RAS has important role during the inflammatory bowel disease pathogenesis. Further to delineate its role and also to identify the potential effects of telmisartan, an angiotensin receptor blocker, we have used a mouse model of acute colitis induced by dextran sulphate sodium. We have used 0.01 and 5mg/kg body weight doses of telmisartan and administered as enema to facilitate the on-site action and to reduce the systemic adverse effects. Telmisartan high dose treatment significantly reduced the disease activity index score when compared with the colitis control mice. In addition, oxidative stress and endoplasmic reticulum stress markers expression were also significantly reduced when compared with the colitis control mice. Subsequent experiments were carried out to investigate some of the mechanisms underlying its anti-inflammatory effects and identified that the mRNA levels of pro-inflammatory cytokines such as tumour necrosis factor α, interleukin 1β, interleukin 6 and monocyte chemoattractant protein 1 as well as cellular DNA damage were significantly suppressed when compared with the colitis control mice. Similarly the apoptosis marker proteins such as cleaved caspase 3 and 7 levels were down-regulated and anti-apoptotic protein Bcl2 level was significantly upregulated by telmisartan treatment. These results indicate that blockade of RAS by telmisartan can be an effective therapeutic option against acute colitis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. [Actuals of the treatment for gender identity disorder at puberty: introducing the suppression of secondary sexual characteristics from psychotherapy].

    PubMed

    Koh, Jun

    2013-01-01

    We have treated young patients who feel gender dysphoria to help them accept their feelings of disconnection. We tell them that such feelings of disconnection are never strange, so they do not have to be suppressed, and can be expressed. To do that, the most important thing is that their parents firmly accept the situation, whereas they are the ones who also feel the most anxious. We need to provide psychological support carefully. The first major hurdle for children who have gender dysphoria is elementary school, even if parents are accepting. In elementary school, even children can distinguish beween male and female, and there are many situations where there is separation by gender in school events, so it is difficult to realize the expression of disconnection without school support. Therefore, understanding by school teachers is needed. When a school shows understanding, parental anxiety is alleviated. When a teacher provides firm support, children around them are more likely to accept the situation. Accordingly, support for children who have gender dysphoria consists of three pillars. The first of these is to help children accept their feelings of gender dysphoria and feel that they can be expressed. The second is to help their parents accept gender dysphoria and create an environment where it can be expressed. The third is to encourage schools to actively create such an environment. To deal with concrete problems which children face by providing these approaches promptly assists in promoting the social growth of children. Even if children feeling gender dysphoria have active school lives with such support, they face the following major hurdle : the secondary sexual characteristics. It has been reported in not only foreign countries but also Japan that there are many children who become mentally unbalanced and enter a maladaptive state, such as truancy and self-injury, on secondary sexual development. In the West, it has been reported that suppressive therapy

  19. Efficacy of alginate-based reflux suppressant and magnesium-aluminium antacid gel for treatment of heartburn in pregnancy: a randomized double-blind controlled trial

    PubMed Central

    Meteerattanapipat, Pontip; Phupong, Vorapong

    2017-01-01

    The aim of this study was to compare the therapeutic efficacy of alginate-based reflux suppressant and magnesium-aluminium antacid gel for treatment of heartburn in pregnancy. A double-blinded, randomized, controlled trial was conducted. One hundred pregnant women at less than 36 weeks gestation with heartburn at least twice per week were randomized to either alginate-based reflux suppressant or to magnesium-aluminium antacid gel. Details of heartburn were recorded before beginning the treatment and the second week of study. Primary outcome measure was the improvement of heartburn frequency after treatment and secondary outcome were the improvement of heartburn intensity, quality of life, maternal satisfaction, maternal side effects, pregnancy and neonatal outcomes. There was no difference between treatment and control groups in improvement of heartburn frequency (80% vs 88%, p = 0.275), 50% reduction of frequency of heartburn (56% vs 52%, p = 0.688), improvement of heartburn intensity (92% vs 92%, p = 1.000) and 50% reduction of heartburn intensity (68% vs 80% cases, p = 0.075). There were also no significant differences in quality of life, maternal satisfaction, maternal side effects, pregnancy and neonatal outcomes. Alginate-based reflux suppressant was not different from magnesium-aluminium antacid gel in the treatment of heartburn in pregnancy. PMID:28317885

  20. Prazosin Augmentation of Outpatient Treatment of Alcohol Use Disorders in Active Duty Soldiers with and without PTSD

    DTIC Science & Technology

    2016-10-01

    and Substance Abuse Program (ASAP) at Madigan Health Care System/Joint Base Lewis McChord. The aims of this trial are 1) to determine prazosin’s...OIF/OEF soldiers both with and without comorbid PTSD enrolled in the Alcohol and Substance Abuse Program (ASAP) at Madigan Health Care System/Joint

  1. Improving ART programme retention and viral suppression are key to maximising impact of treatment as prevention - a modelling study.

    PubMed

    McCreesh, Nicky; Andrianakis, Ioannis; Nsubuga, Rebecca N; Strong, Mark; Vernon, Ian; McKinley, Trevelyan J; Oakley, Jeremy E; Goldstein, Michael; Hayes, Richard; White, Richard G

    2017-08-09

    UNAIDS calls for fewer than 500,000 new HIV infections/year by 2020, with treatment-as-prevention being a key part of their strategy for achieving the target. A better understanding of the contribution to transmission of people at different stages of the care pathway can help focus intervention services at populations where they may have the greatest effect. We investigate this using Uganda as a case study. An individual-based HIV/ART model was fitted using history matching. 100 model fits were generated to account for uncertainties in sexual behaviour, HIV epidemiology, and ART coverage up to 2015 in Uganda. A number of different ART scale-up intervention scenarios were simulated between 2016 and 2030. The incidence and proportion of transmission over time from people with primary infection, post-primary ART-naïve infection, and people currently or previously on ART was calculated. In all scenarios, the proportion of transmission by ART-naïve people decreases, from 70% (61%-79%) in 2015 to between 23% (15%-40%) and 47% (35%-61%) in 2030. The proportion of transmission by people on ART increases from 7.8% (3.5%-13%) to between 14% (7.0%-24%) and 38% (21%-55%). The proportion of transmission by ART dropouts increases from 22% (15%-33%) to between 31% (23%-43%) and 56% (43%-70%). People who are currently or previously on ART are likely to play an increasingly large role in transmission as ART coverage increases in Uganda. Improving retention on ART, and ensuring that people on ART remain virally suppressed, will be key in reducing HIV incidence in Uganda.

  2. Oral delivery of Acid Alpha Glucosidase epitopes expressed in plant chloroplasts suppresses antibody formation in treatment of Pompe mice

    PubMed Central

    Su, Jin; Sherman, Alexandra; Doerfler, Phillip A.; Byrne, Barry J.; Herzog, Roland W.; Daniell, Henry

    2015-01-01

    Summary Deficiency of acid alpha glucosidase (GAA) causes Pompe disease in which the patients systemically accumulate lysosomal glycogen in muscles and nervous systems, often resulting in infant mortality. Although enzyme replacement therapy (ERT) is effective in treating patients with Pompe disease, formation of antibodies against rhGAA complicates treatment. In this report, we investigated induction of tolerance by oral administration of GAA expressed in chloroplasts. Because full-length GAA could not be expressed, N-terminal 410-amino acids of GAA (as determined by T-cell epitope mapping) were fused with the transmucosal carrier CTB. Tobacco transplastomic lines expressing CTB-GAA were generated through site-specific integration of transgenes into the chloroplast genome. Homoplasmic lines were confirmed by Southern blot analysis. Despite low-level expression of CTB-GAA in chloroplasts, yellow or albino phenotype of transplastomic lines was observed due to binding of GAA to a chloroplast protein that has homology to mannose-6 phosphate receptor. Oral administration of the plant-made CTB-GAA fusion protein even at 330-fold lower dose (1.5 μg) significantly suppressed immunoglobulin formation against GAA in Pompe mice injected with 500 μg rhGAA per dose, with several-fold lower titre of GAA-specific IgG1 and IgG2a. Lyophilization increased CTB-GAA concentration by 30-fold (up to 190 μg per g of freeze-dried leaf material), facilitating long-term storage at room temperature and higher dosage in future investigations. This study provides the first evidence that oral delivery of plant cells is effective in reducing antibody responses in ERT for lysosomal storage disorders facilitating further advances in clinical investigations using plant cell culture system or in vitro propagation. PMID:26053072

  3. Trends and disparities in antiretroviral therapy initiation and virologic suppression among newly treatment-eligible HIV-infected individuals in North America, 2001-2009.

    PubMed

    Hanna, David B; Buchacz, Kate; Gebo, Kelly A; Hessol, Nancy A; Horberg, Michael A; Jacobson, Lisa P; Kirk, Gregory D; Kitahata, Mari M; Korthuis, P Todd; Moore, Richard D; Napravnik, Sonia; Patel, Pragna; Silverberg, Michael J; Sterling, Timothy R; Willig, James H; Lau, Bryan; Althoff, Keri N; Crane, Heidi M; Collier, Ann C; Samji, Hasina; Thorne, Jennifer E; Gill, M John; Klein, Marina B; Martin, Jeffrey N; Rodriguez, Benigno; Rourke, Sean B; Gange, Stephen J

    2013-04-01

    Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count<350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non-injection drug abuse, alcohol abuse, and mental illness. Among 10,692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend<.001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend<.001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P<.001). In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide.

  4. Trends and Disparities in Antiretroviral Therapy Initiation and Virologic Suppression Among Newly Treatment-Eligible HIV-Infected Individuals in North America, 2001–2009

    PubMed Central

    Hanna, David B.; Buchacz, Kate; Gebo, Kelly A.; Hessol, Nancy A.; Horberg, Michael A.; Jacobson, Lisa P.; Kirk, Gregory D.; Kitahata, Mari M.; Korthuis, P. Todd; Moore, Richard D.; Napravnik, Sonia; Patel, Pragna; Silverberg, Michael J.; Sterling, Timothy R.; Willig, James H.; Lau, Bryan; Althoff, Keri N.; Crane, Heidi M.; Collier, Ann C.; Samji, Hasina; Thorne, Jennifer E.; Gill, M. John; Klein, Marina B.; Martin, Jeffrey N.; Rodriguez, Benigno; Rourke, Sean B.; Gange, Stephen J.; Benson, A.; Bosch, Ronald J.; Collier, Ann C.; Boswell, Stephen; Grasso, Chris; Mayer, Ken; Hogg, Robert S.; Harrigan, Richard; Montaner, Julio; Cescon, Angela; Brooks, John T.; Buchacz, Kate; Gebo, Kelly A.; Moore, Richard D.; Rodriguez, Benigno; Horberg, Michael A.; Silverberg, Michael J.; Thorne, Jennifer E.; Goedert, James J.; Jacobson, Lisa P.; Klein, Marina B.; Rourke, Sean B.; Burchell, Ann; Rachlis, Anita R.; Hunter-Mellado, Robert F.; Mayor, Angel M.; Gill, M. John; Deeks, Steven G.; Martin, Jeffrey N.; Saag, Michael S.; Mugavero, Michael J.; Willig, James; Eron, Joseph J.; Napravnik, Sonia; Kitahata, Mari M.; Crane, Heidi M.; Justice, Amy C.; Dubrow, Robert; Fiellin, David; Sterling, Timothy R.; Haas, David; Bebawy, Sally; Turner, Megan; Gange, Stephen J.; Anastos, Kathryn; Moore, Richard D.; Saag, Michael S.; Gange, Stephen J.; Kitahata, Mari M.; McKaig, Rosemary G.; Justice, Amy C.; Freeman, Aimee M.; Moore, Richard D.; Freeman, Aimee M.; Lent, Carol; Platt, Aaron; Kitahata, Mari M.; Van Rompaey, Stephen E.; Crane, Heidi M.; Webster, Eric; Morton, Liz; Simon, Brenda; Gange, Stephen J.; Abraham, Alison G.; Lau, Bryan; Althoff, Keri N.; Zhang, Jinbing; Jing, Jerry; Golub, Elizabeth; Modur, Shari; Hanna, David B.; Rebeiro, Peter; Wong, Cherise; Mendes, Adell

    2013-01-01

    Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes. Methods. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count <350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non–injection drug abuse, alcohol abuse, and mental illness. Results. Among 10 692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend < .001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend < .001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P < .001). Conclusions. In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide. PMID:23315317

  5. Prazosin blocks the glutamatergic effects of N-methyl-D-aspartic acid on lordosis behavior and luteinizing hormone secretion in the estrogen-primed female rat.

    PubMed

    Landa, A I; Cabrera, R J; Gargiulo, P A

    2006-03-01

    We have observed that intracerebroventricular (icv) injection of selective N-methyl-D-aspartic acid (NMDA)-type glutamatergic receptor antagonists inhibits lordosis in ovariectomized (OVX), estrogen-primed rats receiving progesterone or luteinizing hormone-releasing hormone (LHRH). When NMDA was injected into OVX estrogen-primed rats, it induced a significant increase in lordosis. The interaction between LHRH and glutamate was previously explored by us and another groups. The noradrenergic systems have a functional role in the regulation of LHRH release. The purpose of the present study was to explore the interaction between glutamatergic and noradrenergic transmission. The action of prazosin, an alpha1- and alpha2b-noradrenergic antagonist, was studied here by injecting it icv (1.75 and 3.5 microg/6 microL) prior to NMDA administration (1 microg/2 microL) in OVX estrogen-primed Sprague-Dawley rats (240-270 g). Rats manually restrained were injected over a period of 2 min, and tested 1.5 h later. The enhancing effect induced by NMDA on the lordosis/mount ratio at high doses (67.06 +/- 3.28, N = 28) when compared to saline controls (6 and 2 microL, 16.59 +/- 3.20, N = 27) was abolished by prazosin administration (17.04 +/- 5.52, N = 17, and 9.33 +/- 3.21, N = 20, P < 0.001 for both doses). Plasma LH levels decreased significantly only with the higher dose of prazosin (1.99 +/- 0.24 ng/mL, N = 18, compared to saline-NMDA effect, 5.96 +/- 2.01 ng/mL, N = 13, P < 0.05). Behavioral effects seem to be more sensitive to the alpha-blockade than hormonal effects. These findings strongly suggest that the facilitatory effects of NMDA on both lordosis and LH secretion in this model are mediated by alpha-noradrenergic transmission.

  6. Long-Term Continuous Suppression With Once-Yearly Histrelin Subcutaneous Implants for the Treatment of Central Precocious Puberty: A Final Report of a Phase 3 Multicenter Trial

    PubMed Central

    Neely, E. Kirk; Kletter, Gad B.; Lewis, Katherine; Chitra, Surya; Terleckyj, Oksana; Eugster, Erica A.

    2015-01-01

    Context and Objective: The histrelin implant has proven to be an effective method of delivering GnRH analog (GnRHa) therapy to children with central precocious puberty (CPP), yet there are limited data available regarding hormonal suppression and auxological changes during an extended course of therapy. Design: This was a phase 3, prospective, open-label study. Setting and Participants: Thirty-six children with CPP who participated in a phase 3, open-label study and required further GnRHa therapy were eligible to continue treatment receiving a new implant upon removal of the prior 12-month histrelin implant during a long-term extension phase. Outcome Measures: Hormone levels and auxologic parameters were measured periodically for up to 6 years of treatment and up to 1 year of posttreatment follow-up. Results: Hormonal suppression was maintained throughout the study in patients who had prior GnRHa therapy (n = 16) and in treatment-naive patients (n = 20). Bone age to chronological age ratio decreased from 1.417 (n = 20) at baseline to 1.18 (n = 8) at 48 months in treatment-naive children (P < .01). Predicted adult height in girls increased from 151.9 cm at baseline to 166.5 cm at month 60 (n = 6; P < .05), with a 10.7-cm height gain observed among treatment-naive children (n = 5). No adverse effect on growth or recovery of the hypothalamic-pituitary-gonadal axis was observed with hormonal suppression. The histrelin implant was generally well tolerated during long-term therapy. Conclusions: Long-term histrelin implant therapy provided sustained gonadotropin suppression safely and effectively and improved predicted adult height in children with CPP. PMID:25803268

  7. Pumpkin seed oil and phytosterol-F can block testosterone/prazosin-induced prostate growth in rats.

    PubMed

    Tsai, Yuh-Shyan; Tong, Yat-Ching; Cheng, Juei-Tang; Lee, Chung-Ho; Yang, Fu-Shan; Lee, Hua-Yang

    2006-01-01

    This study was undertaken to investigate the effects of pumpkin seed oil alone or combined with Phytosterol-F on testosterone/prazosin-induced (T-P) prostate growth in rats. Forty adult Wistar rats were divided into five groups, including: one control group, rats treated with vehicle only, one group treated with T-P, and two groups of T-P-treated rats, one receiving orally pumpkin seed oil alone and one group receiving orally pumpkin seed oil combined with Phytosterol-F. Two weeks later, the prostatic weight-to-body weight ratio was determined after sacrifice. The total protein concentration was measured by using a protein assay. Some ventral prostatic tissues were histologically examined after hematoxylin-eosin staining. Histological sections of the ventral prostate showed that the architecture of the prostate glands became hyperplastic in the T-P rats, but not in the control or vehicle-treated animals. As compared with the control or vehicle group, T-P rats had a significantly higher prostatic weight-to-body weight ratio for the ventral prostate (p=0.05 and p=0.007, respectively), but not for the dorsolateral prostate (p=0.53 and p=0.73, respectively). The T-P rats had significantly higher protein levels within both lobes (ventral lobe, p=0.02 and p<0.0001, respectively; dorsolateral lobe, p=0.06 and p=0.005, respectively). As compared with the T-P-alone rats, the TP rats treated with pumpkin seed oil alone or pumpkin seed oil combined with Phytosterol-F had a significantly lower weight ratio for the ventral prostate (p=0.01 and p=0.004, respectively) and significantly lower protein levels within both lobes (p=0.03 and p=0.003, respectively; p=0.007 and p=0.002, respectively). In addition, Phytosterol-F had some additive effect on the total protein synthesis within the ventral prostate (p=0.02). Pumpkin seed oil alone or combined with Phytosterol-F can block the T-P-induced increases in prostatic weight-to-body weight ratio and protein synthesis. Copyright (c

  8. Association of Implementation of a Universal Testing and Treatment Intervention With HIV Diagnosis, Receipt of Antiretroviral Therapy, and Viral Suppression in East Africa.

    PubMed

    Petersen, Maya; Balzer, Laura; Kwarsiima, Dalsone; Sang, Norton; Chamie, Gabriel; Ayieko, James; Kabami, Jane; Owaraganise, Asiphas; Liegler, Teri; Mwangwa, Florence; Kadede, Kevin; Jain, Vivek; Plenty, Albert; Brown, Lillian; Lavoy, Geoff; Schwab, Joshua; Black, Douglas; van der Laan, Mark; Bukusi, Elizabeth A; Cohen, Craig R; Clark, Tamara D; Charlebois, Edwin; Kamya, Moses; Havlir, Diane

    2017-06-06

    Antiretroviral treatment (ART) is now recommended for all HIV-positive persons. UNAIDS has set global targets to diagnose 90% of HIV-positive individuals, treat 90% of diagnosed individuals with ART, and suppress viral replication among 90% of treated individuals, for a population-level target of 73% of all HIV-positive persons with HIV viral suppression. To describe changes in the proportions of HIV-positive individuals with HIV viral suppression, HIV-positive individuals who had received a diagnosis, diagnosed individuals treated with ART, and treated individuals with HIV viral suppression, following implementation of a community-based testing and treatment program in rural East Africa. Observational analysis based on interim data from 16 rural Kenyan (n = 6) and Ugandan (n = 10) intervention communities in the SEARCH Study, an ongoing cluster randomized trial. Community residents who were 15 years or older (N = 77 774) were followed up for 2 years (2013-2014 to 2015-2016). HIV serostatus and plasma HIV RNA level were measured annually at multidisease health campaigns followed by home-based testing for nonattendees. All HIV-positive individuals were offered ART using a streamlined delivery model designed to reduce structural barriers, improve patient-clinician relationships, and enhance patient knowledge and attitudes about HIV. Primary outcome was viral suppression (plasma HIV RNA<500 copies/mL) among all HIV-positive individuals, assessed at baseline and after 1 and 2 years. Secondary outcomes included HIV diagnosis, ART among previously diagnosed individuals, and viral suppression among those who had initiated ART. Among 77 774 residents (male, 45.3%; age 15-24 years, 35.1%), baseline HIV prevalence was 10.3% (7108 of 69 283 residents). The proportion of HIV-positive individuals with HIV viral suppression at baseline was 44.7% (95% CI, 43.5%-45.9%; 3464 of 7745 residents) and after 2 years of intervention was 80.2% (95% CI, 79.1%-81.2%; 5666

  9. Suppression of pokeweed mitogen-stimulated immunoglobulin production in patients with rheumatoid arthritis after treatment with total lymphoid irradiation

    SciTech Connect

    Kotzin, B.L.; Strober, S.; Kansas, G.S.; Terrell, C.P.; Engleman, E.G.

    1984-02-01

    Patients with intractable rheumatoid arthritis (RA) were treated with total lymphoid irradiation (TLI, 200 rad). The authors previously reported long-lasting clinical improvement in this group associated with a persistent decrease in circulating Leu-3 (helper subset) T cells and marked impairment of in vitro lymphocyte function. In the present experiments, they studied the mechanisms underlying the decrease in pokeweed mitogen stimulated immunoglobulin (Ig) secretion observed after TLI. Peripheral blood mononuclear cells (PBL) from TLI-treated patients produced 10-fold less Ig (both IgM and IgG) in response to pokeweed mitogen than before radiotherapy. This decrease in Ig production was associated with the presence of suppressor cells in co-culture studies. By using responder cells obtained from normal individuals (allogeneic system), PBL from eight of 12 patients after TLI suppressed Ig synthesis by more than 50%. In contrast, PBL from the same patients before TLI failed to suppress Ig synthesis. PBL with suppressive activity contained suppressor T cells, and the latter cells bore the Leu-2 surface antigen. In 50% of the patients studied suppressor cells were also found in the non-T fraction and were adherent to plastic. Interestingly, the Leu-2/sup +/ cells from TLI-treated patients were no more potent on a cell per cell basis than purified Leu-2/sup +/ cells obtained before TLI. Additional experiments suggested that the suppression mediated by T cells after TLI is related to the increased ratio of Leu-2 to Leu-3 cells observed after radiotherapy.

  10. Predominant Suppression of FSHβ-immunoreactivity after Long-Term Treatment of Intact and Castrate Adult Male Rats with the GnRH Agonist Deslorelin

    PubMed Central

    Smith, Arik W.; Asa, Cheryl S.; Edwards, Brian S.; Murdoch, William J.; Skinner, Donal C.

    2017-01-01

    GnRH agonists are used to treat gonadal steroid-dependent disorders in humans and contracept animals. These agonists are thought to work by desensitizing gonadotropes to GnRH, thereby suppressing FSH and LH secretion. It is not known whether changes occur in the cellular composition of the pituitary gland following chronic GnRH agonist exposure. Adult male Sprague-Dawley rats were treated with a sham, deslorelin, or deslorelin plus testosterone implant for 41.0±0.6 days. In a second experiment, rats were castrated and treated with deslorelin and/or testosterone. Pituitary sections were labeled immunocytochemically for FSHβ and LHβ, or αGSU. Deslorelin suppressed testis weight by two thirds and reduced plasma FSH and LH in intact rats. Deslorelin decreased the percentage of gonadotropes but the effect was specific to the FSHβ-ir cells. Testosterone did not reverse the deslorelin-induced reduction in the overall gonadotrope population. However, in the presence of testosterone, the proportion of gonadotropes that was FSHβ-ir increased in the remaining gonadotropes. There was no effect of treatment on the total LHβ-ir cell population although the loss of FSHβ in bi-hormonal cells increased the proportion of mono-hormonal LHβ-ir gonadotropes. The castration-induced plasma LH and FSH increases were suppressed by deslorelin, testosterone or both. Castration increased both LH-ir and FSH-ir without increasing the overall gonadotrope population; thus increasing the proportion of bi-hormonal cells. Deslorelin suppressed these increases. Testosterone increased FSH-ir in deslorelin-treated castrate rats. Deslorelin did not affect αGSU immunoreactivity, suggesting that the gonadotrope population per se is not eliminated by deslorelin but the ability of gonadotropes to synthesize FSHβ is compromised. We hypothesize that the FSH dominant suppression may be central to the long-term contraceptive efficacy of deslorelin in the male. PMID:22172059

  11. Full Viral Suppression, Low-Level Viremia, and Quantifiable Plasma HIV-RNA at the End of Pregnancy in HIV-Infected Women on Antiretroviral Treatment

    PubMed Central

    Baroncelli, Silvia; Pirillo, Maria F.; Tamburrini, Enrica; Guaraldi, Giovanni; Pinnetti, Carmela; Antoni, Anna Degli; Galluzzo, Clementina M.; Stentarelli, Chiara; Amici, Roberta

    2015-01-01

    Abstract There is limited information on full viral suppression and low-level HIV-RNA viremia in HIV-infected women at the end of pregnancy. We investigated HIV-RNA levels close to delivery in women on antiretroviral treatment in order to define rates of complete suppression, low-level viremia, and quantifiable HIV-RNA, exploring as potential determinants some clinical and viroimmunological variables. Plasma samples from a national study in Italy, collected between 2003 and 2012, were used. According to plasma HIV-RNA levels, three groups were defined: full suppression (target not detected), low-level viremia (target detected but <37 copies/ml), and quantifiable HIV-RNA (≥37 copies/ml). Multivariable logistic regression was used to define determinants of full viral suppression and of quantifiable HIV-RNA. Among 107 women evaluated at a median gestational age of 35 weeks, 90 (84.1%) had HIV-RNA <37 copies/ml. Most of them (59/90, 65.6%) had full suppression, with the remaining (31/90, 34.4%) showing low-level viremia (median: 11.9 copies/ml; IQR 7.4–16.3). Among the 17 women with quantifiable viral load, median HIV-RNA was 109 copies/ml (IQR 46–251), with only one case showing resistance (mutation M184V; rate: 9.1%). In multivariable analyses, women with higher baseline HIV-RNA levels and with hepatitis C virus (HCV) coinfection were significantly more likely to have quantifiable HIV-RNA in late pregnancy. Full viral suppression was significantly more likely with nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens and significantly less likely with higher HIV-RNA in early pregnancy. No cases of HIV transmission occurred. In conclusion, HIV-infected pregnant women showed a high rate of viral suppression and a low resistance rate before delivery. In most cases no target HIV-RNA was detected in plasma, suggesting a low risk of subsequent virological rebound and development of resistance. Women with high levels of HIV-RNA in early pregnancy and

  12. Informal HIV Caregiver Proxy Reports of Care Recipients' Treatment Adherence: Relationship Factors Associated with Concordance with Recipients' Viral Suppression.

    PubMed

    Knowlton, Amy R; Mitchell, Mary M; Robinson, Allysha C; Nguyen, Trang Q; Isenberg, Sarina; Denison, Julie

    2015-11-01

    To explore the role of informal caregivers in adherence, we compared adherence reports by caregivers to those of care recipients. We identified individual-level and relationship factors associated with agreement between caregivers' reports of recipients' adherence and assessed viral suppression. Participants were care recipients, who were on ART and had ever injected drugs, and their caregivers (N = 258 dyads). Nearly three-fourths of caregivers' reports of recipients' ART adherence agreed with recipients' viral suppression status. Agreement was associated with recipient age and expressing affection or gratitude to the caregiver, caregiver's having been close to someone who died of HIV/AIDS, and caregiver's fear of caregiving-related HIV (re)infection, while it was negatively associated with recipient's limited physical functioning. Our findings support the utility of caregiver proxy reports of care recipients' ART adherence and suggest ways to identify and promote HIV caregiver attention to and support of this vulnerable population's ART adherence.

  13. Oral treatment with the herbal formula B307 alleviates cardiac toxicity in doxorubicin-treated mice via suppressing oxidative stress, inflammation, and apoptosis.

    PubMed

    Lien, Chia-Ying; Chuang, Tai-Yuan; Hsu, Chih-Hsiang; Lin, Ching-Lung; Wang, Sheue-Er; Sheu, Shuenn-Jyi; Chien, Chiang-Ting; Wu, Chung-Hsin

    2015-01-01

    This study aimed to investigate whether the herbal formula B307 could alleviate doxorubicin (DOX)-induced acute cardiotoxicity. If so, we further unraveled possible molecular mechanisms of cardiac protection under treatment with the herbal formula B307. Before the animal experiment, we examined relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307. To test whether oral treatment with the herbal formula B307 could alleviate cardiotoxicity, equal volumes of B307 (50 mg/kg) or saline (sham treatment) were administered to 20-week-old male mice once daily for 14 consecutive days. Then, DOX (10 mg/kg; ip) was administered to male mice under B307 and sham treatments at 22-23 weeks of age. Cardiac functions in these mice were assessed via echocardiography at 23-24 weeks of age. Then, expressions of oxidative stress, inflammation, and apoptosis-related proteins were examined in the heart tissue by immunohistochemistry and Western blotting at 24-25 weeks of age. Apart from this, mortality rate and body weight were measured during the experiment. In vitro, the relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307 had shown no obvious change at doses of 10-160 ng/mL. Furthermore, the relative viabilities of Huh7 cancer cells were significantly reduced under DOX treatment but showed no significant change under DOX only and DOX plus B307 treatment. In vivo, the mortality rate, body weight, and cardiac function of DOX-treated mice were obviously improved under oral treatment with the herbal formula B307. Furthermore, cardiac expressions of endothelial nitric oxide synthase, superoxide dismutase 2, and B-cell lymphoma 2 were significantly enhanced, but tumor necrosis factor alpha, NFKB1 (p50 and its precursor, p105), neurotrophin-3, Bcl-2-associated X protein, calpain, caspase 12, caspase 9, and caspase 3 were significantly suppressed in DOX-treated mice under oral treatment with the herbal formula B307. Our results

  14. Oral treatment with the herbal formula B307 alleviates cardiac toxicity in doxorubicin-treated mice via suppressing oxidative stress, inflammation, and apoptosis

    PubMed Central

    Lien, Chia-Ying; Chuang, Tai-Yuan; Hsu, Chih-Hsiang; Lin, Ching-Lung; Wang, Sheue-Er; Sheu, Shuenn-Jyi; Chien, Chiang-Ting; Wu, Chung-Hsin

    2015-01-01

    Objective This study aimed to investigate whether the herbal formula B307 could alleviate doxorubicin (DOX)-induced acute cardiotoxicity. If so, we further unraveled possible molecular mechanisms of cardiac protection under treatment with the herbal formula B307. Methods Before the animal experiment, we examined relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307. To test whether oral treatment with the herbal formula B307 could alleviate cardiotoxicity, equal volumes of B307 (50 mg/kg) or saline (sham treatment) were administered to 20-week-old male mice once daily for 14 consecutive days. Then, DOX (10 mg/kg; ip) was administered to male mice under B307 and sham treatments at 22–23 weeks of age. Cardiac functions in these mice were assessed via echocardiography at 23–24 weeks of age. Then, expressions of oxidative stress, inflammation, and apoptosis-related proteins were examined in the heart tissue by immunohistochemistry and Western blotting at 24–25 weeks of age. Apart from this, mortality rate and body weight were measured during the experiment. Results In vitro, the relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307 had shown no obvious change at doses of 10–160 ng/mL. Furthermore, the relative viabilities of Huh7 cancer cells were significantly reduced under DOX treatment but showed no significant change under DOX only and DOX plus B307 treatment. In vivo, the mortality rate, body weight, and cardiac function of DOX-treated mice were obviously improved under oral treatment with the herbal formula B307. Furthermore, cardiac expressions of endothelial nitric oxide synthase, superoxide dismutase 2, and B-cell lymphoma 2 were significantly enhanced, but tumor necrosis factor alpha, NFKB1 (p50 and its precursor, p105), neurotrophin-3, Bcl-2-associated X protein, calpain, caspase 12, caspase 9, and caspase 3 were significantly suppressed in DOX-treated mice under oral treatment with

  15. The irrationality of continued fire suppression: A partial analysis of the costs and benefits of restoration-based fuel reduction treatments vs. no treatment

    Treesearch

    G. B. Snider; P. J. Daugherty

    2008-01-01

    (Please note, this is an abstract only) In 1905, the Bureau of Forestry became the U.S. Forest Service and was given responsibility for protecting newly designated forest reserves. A critical part of its charge was the prevention and control of fires. In 1908 Congress set up a unique system, like an open checkbook, that assured payment for fire suppression as needed....

  16. A fuel treatment reduces potential fire severity and increases suppression efficiency in a Sierran mixed conifer forest

    Treesearch

    Jason J. Moghaddas

    2006-01-01

    Fuel treatments are being widely implemented on public and private lands across the western U.S. While scientists and managers have an understanding of how fuel treatments can modify potential fire behavior under modeled conditions, there is limited information on how treatments perform under real wildfire conditions in Sierran mixed conifer forests. The Bell Fire...

  17. Informal HIV caregiver proxy reports of care recipients’ treatment adherence: Relationship factors associated with concordance with recipients’ viral suppression

    PubMed Central

    Knowlton, Amy R.; Mitchell, Mary M.; Robinson, Allysha C.; Nguyen, Trang Q.; Isenberg, Sarina; Denison, Julie

    2015-01-01

    Objective To explore the role of informal caregivers in adherence, we compared adherence reports by caregivers to those of care recipients. We identified individual-level and relationship factors associated with agreement between caregivers’ reports of recipients’ adherence and assessed viral suppression. Methods Participants were care recipients, who were on ART and had ever injected drugs, and their caregivers (N=258 dyads). Results Nearly three-fourths of caregivers’ reports of recipients’ ART adherence agreed with recipients’ viral suppression status. Agreement was associated with recipient age and expressing affection or gratitude to the caregiver, caregiver’s having been close to someone who died of HIV/AIDS, and caregiver’s fear of caregiving-related HIV (re)infection, while it was negatively associated with recipient’s limited physical functioning. Conclusions Our findings support the utility of caregiver proxy reports of care recipients’ ART adherence and suggest ways to identify and promote HIV caregiver attention to and support of this vulnerable population’s ART adherence. PMID:26036463

  18. Adrenergic receptor and catecholamine distribution in rat cerebral cortex: binding studies with [3H]prazosin, [3H]idazoxan and [3H]dihydroalprenolol.

    PubMed

    Diop, L; Brière, R; Grondin, L; Reader, T A

    1987-02-03

    The tritiated adrenergic antagonists [3H]dihydroalprenolol ([3H]DHA; beta-receptors), [3H]prazosin ([3H]PRZ; alpha 1-receptors), and [3H]idazoxan ([3H]IDA; alpha 2-receptors) were used to determine the distribution of these sites in 5 defined areas of the adult rat cerebral cortex. The highest density of [3H]PRZ binding was found in the prefrontal cortex, with a lower and homogeneous distribution for the frontal, parietal, occipital and temporal areas. The [3H]IDA binding sites were fairly uniform for all areas, except for the temporal cortex where it was very dense. In contrast, beta-adrenoceptors labelled by [3H]DHA were very homogeneous for all the regions examined. The functional significance of the distribution of alpha 1, alpha 2 and beta-adrenoceptors is discussed in relation to the catecholamine innervation and monoamine contents measured by high performance liquid chromatography.

  19. Dasatinib suppression of medulloblastoma survival and migration is markedly enhanced by combining treatment with the aurora kinase inhibitor AT9283.

    PubMed

    Petersen, William; Liu, Jingbo; Yuan, Liangping; Zhang, Hongying; Schneiderjan, Matthew; Cho, Yoon-Jae; MacDonald, Tobey J

    2014-11-01

    Medulloblastoma (MB) expresses Src kinase, while aurora kinase A overexpression correlates with poor survival. We thus investigated novel combination treatment with dasatinib and AT9283, inhibitors of Src and aurora kinase, respectively, on MB growth in vitro and in vivo. Treatment with each drug significantly reduced cell viability and combined treatment markedly potentiated this response. AT9283 induced p53 expression, autophagy, and G2/M cell-cycle arrest, while combined treatment induced S phase arrest. Dasatinib treatment caused tumor regression in vivo. Activated Src was detected in 44% MB analyzed. We conclude that further evaluation of this combination therapy for MB is highly warranted.

  20. VDR in Osteoblast-Lineage Cells Primarily Mediates Vitamin D Treatment-Induced Increase in Bone Mass by Suppressing Bone Resorptiontdg%ang*tok.

    PubMed

    Nakamichi, Yuko; Udagawa, Nobuyuki; Horibe, Kanji; Mizoguchi, Toshihide; Yamamoto, Yoko; Nakamura, Takashi; Hosoya, Akihiro; Kato, Shigeaki; Suda, Tatsuo; Takahashi, Naoyuki

    2017-02-08

    Long-term treatment with active vitamin D [1α,25(OH)2 D3 ] and its derivatives is effective for increasing bone mass in patients with primary and secondary osteoporosis. Derivatives of 1α,25(OH)2 D3 , including eldecalcitol (ELD), exert their actions through the vitamin D receptor (VDR). ELD is more resistant to metabolic degradation than 1α,25(OH)2 D3 . It is reported that ELD treatment causes a net increase in bone mass by suppressing bone resorption rather than by increasing bone formation in animals and humans. VDR in bone and extraskeletal tissues regulates bone mass and secretion of osteotropic hormones. Therefore, it is unclear what types of cells expressing VDR preferentially regulate the vitamin D-induced increase in bone mass. Here, we examined the effects of 4-week treatment with ELD (50 ng/kg/day) on bone using osteoblast lineage-specific VDR conditional knockout (Ob-VDR-cKO) and osteoclast-specific VDR cKO (Ocl-VDR-cKO) male mice aged 10 weeks. Immunohistochemically, VDR in bone was detected preferentially in osteoblasts and osteocytes. Ob-VDR-cKO mice showed normal bone phenotypes, despite no appreciable immunostaining of VDR in bone. Ob-VDR-cKO mice failed to increase bone mass in response to ELD treatment. Ocl-VDR-cKO mice also exhibited normal bone phenotypes, but normally responded to ELD. ELD-induced FGF23 production in bone was regulated by VDR in osteoblast-lineage cells. These findings suggest that the vitamin D treatment-induced increase in bone mass is mediated by suppressing bone resorption through VDR in osteoblast-lineage cells. © 2017 American Society for Bone and Mineral Research.

  1. Treatment Combining X-Irradiation and a Ribonucleoside Anticancer Drug, TAS106, Effectively Suppresses the Growth of Tumor Cells Transplanted in Mice

    SciTech Connect

    Yasui, Hironobu; Inanami, Osamu; Asanuma, Taketoshi; Iizuka, Daisuke; Nakajima, Takayuki; Kon, Yasuhiro; Matsuda, Akira; Kuwabara, Mikinori . E-mail: kuwabara@vetmed.hokudai.ac.jp

    2007-05-01

    Purpose: To examine the in vivo antitumor efficacy of X-irradiation combined with administration of a ribonucleoside anticancer drug, 1-(3-C-ethynyl-{beta}-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd), to tumor cell-transplanted mice. Methods and Materials: Colon26 murine rectum adenocarcinoma cells and MKN45 human gastric adenocarcinoma cells were inoculated into the footpad in BALB/c mice and severe combined immunodeficient mice, respectively. They were treated with a relatively low dose of X-irradiation (2 Gy) and low amounts of TAS106 (0.1 mg/kg and 0.5 mg/kg). The tumor growth was monitored by measuring the tumor volume from Day 5 to Day 16 for Colon26 and from Day 7 to Day 20 for MKN45. Histologic analyses for proliferative and apoptotic cells in the tumors were performed using Ki-67 immunohistochemical and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. The expression of survivin, a key molecule related to tumor survival, was assessed by quantitative polymerase chain reaction and immunohistochemical analysis. Results: When X-irradiation and TAS106 treatment were combined, significant inhibition of tumor growth was observed in both types of tumors compared with mice treated with X-irradiation or TAS106 alone. Marked inhibition of tumor growth was observed in half of the mice that received the combined treatment three times at 2-day intervals. Parallel to these phenomena, the suppression of survivin expression and appearance of Ki-67-negative and apoptotic cells were observed. Conclusions: X-irradiation and TAS106 effectively suppress tumor growth in mice. The inhibition of survivin expression by TAS106 is thought to mainly contribute to the suppression of the tumor growth.

  2. Fetal pancreas transplantation in miniature swine. IV. Suppression of DTH and MLR responses by treatment with ultraviolet light-irradiated peripheral blood lymphocytes

    SciTech Connect

    Taura, Y.; Stein, E.; Miyazawa, K.; Mullen, Y. )

    1990-07-01

    Irradiation of peripheral blood lymphocytes of miniature swine with ultraviolet light prevented them from initiating proliferative responses in allogeneic mixed lymphocyte reactions and also reduced IL-2 production in these MLRs. When pigs were injected in a series of 4-5 weekly transfusions with UV-irradiated allogeneic PBL differing at the MHC, PBL of recipient pigs progressively responded less strongly to donor PBL in MLRs over the treatment period. These pigs also gave negligible delayed-type hypersensitivity responses to donor PBL at the end of the treatment period. Of the seven UV-irradiated PBL-treated pigs, four produced no antidonor PBL antibody and three produced antibody. Serum from the three antibody-producing pigs also suppressed MLRs of unrelated PBL. By contrast, pigs that received a series of injections of untreated allogeneic PBL gave strong DTH responses to donor PBL and heightened proliferation in MLRs with donor PBL, and all produced antidonor PBL antibody.

  3. Review article: novel methods for the treatment of non-alcoholic steatohepatitis - targeting the gut immune system to decrease the systemic inflammatory response without immune suppression.

    PubMed

    Ilan, Y

    2016-12-01

    The systemic immune system plays a role in inflammation and fibrogenesis associated with non-alcoholic steatohepatitis (NASH) and has become a potential target for drug development. In particular, the gut immune system has been suggested as a means for generating signals that can target the systemic immune system. To describe seven novel methods being developed for the treatment of NASH that target the gut immune system for alleviation of the systemic inflammatory response, including oral administration of fatty-liver-derived proteins, anti-CD3 antibodies, tumour necrosis factor fusion protein, anti-lipopolysaccharide antibodies, glucosylceramide, delayed-release mercaptopurine, and soy-derived extracts. A search for these methods for oral immunotherapy for NASH was conducted. Oral administration of these compounds provides an opportunity for immune modulation without immune suppression, with the advantage of being independent of a single molecular/inflammatory pathway. These modes of oral immune therapy demonstrate superior safety profiles, such that the patient is not exposed to general immune suppression. Moreover, these approaches target the whole spectrum of the disease and may serve as adjuvants to other therapies, such that they provide a platform for treatment of concomitant disorders in patients with NASH, including diabetes and hyperlipidaemia. Most of the compounds reviewed are currently in phase II trials, and it is anticipated that the acquisition of more clinical data in the next few years will enable the use of this new class of drugs for the treatment of NASH. Oral immunotherapy may provide a novel platform for the treatment of NASH. © 2016 The Author. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

  4. Effects of Treatment with Suppressive Combination Antiretroviral Drug Therapy and the Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid; (SAHA) on SIV-Infected Chinese Rhesus Macaques

    PubMed Central

    Ling, Binhua; Piatak, Michael; Rogers, Linda; Johnson, Ann-Marie; Russell-Lodrigue, Kasi; Hazuda, Daria J.; Lifson, Jeffrey D.; Veazey, Ronald S.

    2014-01-01

    Objectives Viral reservoirs–persistent residual virus despite combination antiretroviral therapy (cART)–remain an obstacle to cure of HIV-1 infection. Difficulty studying reservoirs in patients underscores the need for animal models that mimics HIV infected humans on cART. We studied SIV-infected Chinese-origin rhesus macaques (Ch-RM) treated with intensive combination antiretroviral therapy (cART) and 3 weeks of treatment with the histone deacetyalse inhibitor, suberoylanilide hydroxamic acid (SAHA). Methods SIVmac251 infected Ch-RM received reverse transcriptase inhibitors PMPA and FTC and integrase inhibitor L-870812 beginning 7 weeks post infection. Integrase inhibitor L-900564 and boosted protease inhibitor treatment with Darunavir and Ritonavir were added later. cART was continued for 45 weeks, with daily SAHA administered for the last 3 weeks, followed by euthanasia/necropsy. Plasma viral RNA and cell/tissue-associated SIV gag RNA and DNA were quantified by qRT-PCR/qPCR, with flow cytometry monitoring changes in immune cell populations. Results Upon cART initiation, plasma viremia declined, remaining <30 SIV RNA copy Eq/ml during cART, with occasional blips. Decreased viral replication was associated with decreased immune activation and partial restoration of intestinal CD4+ T cells. SAHA was well tolerated but did not result in demonstrable treatment-associated changes in plasma or cell associated viral parameters. Conclusions The ability to achieve and sustain virological suppression makes cART-suppressed, SIV-infected Ch-RM a potentially useful model to evaluate interventions targeting residual virus. However, despite intensive cART over one year, persistent viral DNA and RNA remained in tissues of all three animals. While well tolerated, three weeks of SAHA treatment did not demonstrably impact viral RNA levels in plasma or tissues; perhaps reflecting dosing, sampling and assay limitations. PMID:25033210

  5. A Traditional Chinese Medicine Xiao-Ai-Tong Suppresses Pain through Modulation of Cytokines and Prevents Adverse Reactions of Morphine Treatment in Bone Cancer Pain Patients

    PubMed Central

    Cong, Yan; Sun, Kefu; He, Xueming; Li, Jinxuan; Dong, Yanbin; Zheng, Bin; Tan, Xiao; Song, Xue-Jun

    2015-01-01

    Treating cancer pain continues to possess a major challenge. Here, we report that a traditional Chinese medicine Xiao-Ai-Tong (XAT) can effectively suppress pain and adverse reactions following morphine treatment in patients with bone cancer pain. Visual Analogue Scale (VAS) and Quality of Life Questionnaire (EORTC QLQ-C30) were used for patient's self-evaluation of pain intensity and evaluating changes of adverse reactions including constipation, nausea, fatigue, and anorexia, respectively, before and after treatment prescriptions. The clinical trials showed that repetitive oral administration of XAT (200 mL, bid, for 7 consecutive days) alone greatly reduced cancer pain. Repetitive treatment with a combination of XAT and morphine (20 mg and 30 mg, resp.) produced significant synergistic analgesic effects. Meanwhile, XAT greatly reduced the adverse reactions associated with cancer and/or morphine treatment. In addition, XAT treatment significantly reduced the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α and increased the endogenous anti-inflammatory cytokine interleukin-10 in blood. These findings demonstrate that XAT can effectively reduce bone cancer pain probably mediated by the cytokine mechanisms, facilitate analgesic effect of morphine, and prevent or reduce the associated adverse reactions, supporting a use of XAT, alone or with morphine, in treating bone cancer pain in clinic. PMID:26617438

  6. A Traditional Chinese Medicine Xiao-Ai-Tong Suppresses Pain through Modulation of Cytokines and Prevents Adverse Reactions of Morphine Treatment in Bone Cancer Pain Patients.

    PubMed

    Cong, Yan; Sun, Kefu; He, Xueming; Li, Jinxuan; Dong, Yanbin; Zheng, Bin; Tan, Xiao; Song, Xue-Jun

    2015-01-01

    Treating cancer pain continues to possess a major challenge. Here, we report that a traditional Chinese medicine Xiao-Ai-Tong (XAT) can effectively suppress pain and adverse reactions following morphine treatment in patients with bone cancer pain. Visual Analogue Scale (VAS) and Quality of Life Questionnaire (EORTC QLQ-C30) were used for patient's self-evaluation of pain intensity and evaluating changes of adverse reactions including constipation, nausea, fatigue, and anorexia, respectively, before and after treatment prescriptions. The clinical trials showed that repetitive oral administration of XAT (200 mL, bid, for 7 consecutive days) alone greatly reduced cancer pain. Repetitive treatment with a combination of XAT and morphine (20 mg and 30 mg, resp.) produced significant synergistic analgesic effects. Meanwhile, XAT greatly reduced the adverse reactions associated with cancer and/or morphine treatment. In addition, XAT treatment significantly reduced the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α and increased the endogenous anti-inflammatory cytokine interleukin-10 in blood. These findings demonstrate that XAT can effectively reduce bone cancer pain probably mediated by the cytokine mechanisms, facilitate analgesic effect of morphine, and prevent or reduce the associated adverse reactions, supporting a use of XAT, alone or with morphine, in treating bone cancer pain in clinic.

  7. The role of clinical pharmacists in treatment adherence: fast impact in suppression of chronic myeloid leukemia development and symptoms.

    PubMed

    Moulin, Silmara Mendes Martins; Eutrópio, Frederico Jacob; Souza, Jessica de Oliveira; Busato, Fernanda de Oliveira; Olivieri, David N; Tadokoro, Carlos Eduardo

    2017-03-01

    Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease, accounting for 15 to 20% of leukemias, with an incidence of one to two cases/100,000 inhabitants. In Brazil, the estimated incidence of leukemia is six cases/100,000 men and 4.28 cases/100,000 women. CML is characterized by the presence of the Philadelphia chromosome. At present, three types of tyrosine kinase inhibitors (TKI) are administered to treat CML patients in the Brazilian public national health system (NHS), called the Unified Health System (in Portuguese, "Sistema Único de Saúde", SUS). Such treatments are only effective if patients adhere to strict dosage regimens; protocol improvements that increase patient adherence to treatment would have economic and health benefits for overburdened health care systems. Here, pharmacist-monitored treatment is assessed. In our study, we applied two questionnaires, one to assess the adherence to pharmacological treatment and another to assess the quality of life. All patients studied (n = 23) were diagnosed with CML at a local hospital in "Espírito Santo" State, the "Hospital Evangélico Vila Velha" (HEVV). Treatment adherence was significantly higher in pharmacist-monitored patients than in nonmonitored patients (p = 0.0135). The quality of life of CML patients was also analyzed, indicating that monitored patients had a lower number of symptoms/complaints during treatment periods than nonmonitored patients. Finally, improved treatment adherence also translated into better clinical conditions, particularly during the early stage of treatment (e.g., the first 4 months). The intervention of a clinical pharmacist is significant to obtain positive clinical results. Therefore, it is recommended that this protocol be included in the standard NHS treatment protocol CML patient outcomes to reduce the indirect and recurring costs to the health care system caused by nonadherence.

  8. Pharmacological and non-pharmacological treatments for nightmare disorder.

    PubMed

    Nadorff, Michael R; Lambdin, Karen K; Germain, Anne

    2014-04-01

    Interest in the treatment of nightmares has greatly increased over the last several years as research has demonstrated the clinical significance of nightmare disorder. This paper provides an overview of nightmare disorder, its clinical relevance, and the leading treatments that are available. In particular, the paper defines nightmare disorder and then summarize the recent literature examining the clinical relevance of nightmare disorder, including its relation to post-traumatic stress disorder and other psychiatric conditions. The relation between nightmares and suicidality is also discussed. Recent findings on the treatment of nightmare with imagery rehearsal therapy and prazosin are then summarized. Lastly, the paper comments on potential future uses of nightmare treatment including using imagery rehearsal therapy or prazosin as a first-line intervention for post-traumatic stress disorder and using these treatments as an adjunctive therapy to reduce suicide risk in those at risk of suicide with nightmares.

  9. Hypofractionated passively scattered proton radiotherapy for low- and intermediate-risk prostate cancer is not associated with post-treatment testosterone suppression.

    PubMed

    Kil, Whoon Jong; Nichols, Romaine C; Hoppe, Bradford S; Morris, Christopher G; Marcus, Robert B; Mendenhall, William; Mendenhall, Nancy P; Li, Zuofeng; Costa, Joseph A; Williams, Christopher R; Henderson, Randal H

    2013-04-01

    To investigate post-treatment changes in serum testosterone in low- and intermediate-risk prostate cancer patients treated with hypofractionated passively scattered proton radiotherapy. Between April 2008 and October 2011, 228 patients with low- and intermediate-risk prostate cancer were enrolled into an institutional review board-approved prospective protocol. Patients received doses ranging from 70 Cobalt Gray Equivalent (CGE) to 72.5 CGE at 2.5 CGE per fraction using passively scattered protons. Three patients were excluded for receiving androgen deprivation therapy (n = 2) or testosterone supplementation (n = 1) before radiation. Of the remaining 226 patients, pretreatment serum testosterone levels were available for 217. Of these patients, post-treatment serum testosterone levels were available for 207 in the final week of treatment, 165 at the six-month follow-up, and 116 at the 12-month follow-up. The post-treatment testosterone levels were compared with the pretreatment levels using Wilcoxon's signed-rank test for matched pairs. The median pretreatment serum testosterone level was 367.7 ng/dl (12.8 nmol/l). The median changes in post-treatment testosterone value were as follows: +3.0 ng/dl (+0.1 nmol/l) at treatment completion; +6.0 ng/dl (+0.2 nmol/l) at six months after treatment; and +5.0 ng/dl (0.2 nmol/l) at 12 months after treatment. None of these changes were statistically significant. Patients with low- and intermediate-risk prostate cancer treated with hypofractionated passively scattered proton radiotherapy do not experience testosterone suppression. Our findings are consistent with physical measurements demonstrating that proton radiotherapy is associated with less scatter radiation exposure to tissues beyond the beam paths compared with intensity-modulated photon radiotherapy.

  10. Hypofractionated passively scattered proton radiotherapy for low- and intermediate-risk prostate cancer is not associated with post-treatment testosterone suppression

    PubMed Central

    2013-01-01

    Background. To investigate post-treatment changes in serum testosterone in low- and intermediate-risk prostate cancer patients treated with hypofractionated passively scattered proton radiotherapy. Material and methods. Between April 2008 and October 2011, 228 patients with low- and intermediate-risk prostate cancer were enrolled into an institutional review board-approved prospective protocol. Patients received doses ranging from 70 Cobalt Gray Equivalent (CGE) to 72.5 CGE at 2.5 CGE per fraction using passively scattered protons. Three patients were excluded for receiving androgen deprivation therapy (n = 2) or testosterone supplementation (n = 1) before radiation. Of the remaining 226 patients, pretreatment serum testosterone levels were available for 217. Of these patients, post-treatment serum testosterone levels were available for 207 in the final week of treatment, 165 at the six-month follow-up, and 116 at the 12-month follow-up. The post-treatment testosterone levels were compared with the pretreatment levels using Wilcoxon's signed-rank test for matched pairs. Results. The median pretreatment serum testosterone level was 367.7 ng/dl (12.8 nmol/l). The median changes in post-treatment testosterone value were as follows: +3.0 ng/dl (+0.1 nmol/l) at treatment completion; +6.0 ng/dl (+0.2 nmol/l) at six months after treatment; and +5.0 ng/dl (0.2 nmol/l) at 12 months after treatment. None of these changes were statistically significant. Conclusion. Patients with low- and intermediate-risk prostate cancer treated with hypofractionated passively scattered proton radiotherapy do not experience testosterone suppression. Our findings are consistent with physical measurements demonstrating that proton radiotherapy is associated with less scatter radiation exposure to tissues beyond the beam paths compared with intensity-modulated photon radiotherapy. PMID:23477360

  11. [Effects of alpha-1-blocking agent in the treatment of detrusor sphincter dyssynergia].

    PubMed

    Gotoh, M; Yoshikawa, Y; Otani, T; Kato, T; Kobayashi, M; Kato, K; Saito, M; Kondo, A; Miyake, K

    1990-12-01

    Effects of adrenergic alpha-1-blocking agent, prazosin, in the treatment of detrusor external-sphincter dyssynergia (DSD) were evaluated in both experimental and clinical aspects. Experimentally, in the urethral pressure profile in dogs, the maximum urethral closing pressure was depressed after intravenous injection of 1 mg prazosin. When experimental DSD was obtained in dogs by stimulating electrically the unilateral 2nd sacral root, intra-venous injection of 1 mg prazosin inhibited contraction of the external urethral sphincter. Clinically, 74 patients with DSD based on neurogenic bladder from cerebral vascular attack (CVA) (13 cases) and spinal cord injury (61 cases) were retrospectively surveyed in terms of therapeutical effects of prazosin for DSD. Spinal cord injury was subdivided to 4 groups for clinical evaluation; cervical cord injury (C) with complete paralysis, thoracic cord injury (Th) with complete paralysis, lumbar cord injury (L) with complete paralysis and spinal cord injury with incomplete paralysis. Patients with CVA and spinal cord injury with incomplete paralysis showed good response rates in subjective improvement, 69% and 60% respectively. However, those with spinal cord injury with complete paralysis showed a poor response (28% for C, 23% for Th and 14% for L). The amount of residual urine significantly decreased after treatment, in all the groups except that of lumbar cord injury with complete paralysis. In all the groups, however, even after the drug treatment the amount of residual urine ranged from 80 to 170 ml and the rates of needing clean intermittent catheterization unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Viral suppression rates in salvage treatment with raltegravir improved with the administration of genotypic partially active or inactive nucleoside/tide reverse transcriptase inhibitors.

    PubMed

    Scherrer, Alexandra U; von Wyl, Viktor; Böni, Jürg; Yerly, Sabine; Klimkait, Thomas; Bürgisser, Philippe; Garzoni, Christian; Hirschel, Bernard; Cavassini, Matthias; Battegay, Manuel; Vernazza, Pietro L; Bernasconi, Enos; Ledergerber, Bruno; Günthard, Huldrych F

    2011-05-01

    Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs. The effect of <2 compared with 2 NRTIs on viral suppression (HIV-1 RNA < 50 copies/mL) at week 24 was studied in salvage patients receiving raltegravir. Intent-to-treat and per-protocol analyses were performed; last observation carried forward imputation was used to deal with missing information. Logistic regressions were weighted to create a pseudopopulation in which the probability of receiving <2 and 2 NRTIs was unrelated to baseline factors predicting treatment response. One-hundred thirty patients were included, of whom 58.5% (n = 76) received <2 NRTIs. NRTIs were often replaced by other drug classes. Patients with 2 NRTIs received less additional drug classes compared with patients with <2 NRTIs [median (IQR): 1 (1-2) compared with 2 (1-2), P Wilcoxon < 0.001]. The activity of non-NRTI treatment components was lower in the 2 NRTIs group compared with the <2 NRTIs group [median (IQR) genotypic sensitivity score: 2 (1.5-2.5) compared with 2.5 (2-3), P Wilcoxon < 0.001]. The administration of <2 NRTIs was associated with a worse viral suppression rate at week 24. The odds ratios were 0.34 (95% confidence interval: 0.13 to 0.89, P = 0.027) and 0.19 (95% confidence interval: 0.05 to 0.79, P = 0.023) when performing the last observation carried forward and the per-protocol approach, respectively. Our findings showed that partially active or inactive NRTIs contribute to treatment response, and thus the use of 2 NRTIs in salvage regimens that include raltegravir seems warranted.

  13. Effects of desipramine on prazosin potency at α1A- and α1D-adrenoceptors in rat vas deferens: implications for the α1L-adrenoceptor subclassification.

    PubMed

    Docherty, J R

    2014-12-05

    This study investigates the interaction between cocaine, desipramine and prazosin at α1-adrenoceptor subtypes mediating contractions to noradrenaline in epididymal portions of rat vas deferens. Noradrenaline potency was not significantly affected by desipramine (0.1-1.0 μM) and reduced by desipramine (10 μM), but was increased by the presence of cocaine (3.0-30 μM), particularly in terms of phasic contractions to low concentrations of noradrenaline. In vehicle experiments, prazosin exhibited relatively low potency as an antagonist against the predominantly α1A-adrenoceptor mediated response (pKB 8.50). In the presence of cocaine, prazosin exhibited higher potency against the revealed α1D-adrenoceptor mediated component (e.g. pKB 9.12). In the presence of desipramine, the potency of prazosin was either unchanged or indeed decreased. Cocaine (0.3-30 μM) significantly increased the single pulse nerve-stimulation-evoked contraction, with a maximum increase to 156±12% of control (n=9). In contrast, desipramine in low concentrations (0.1-0.3 μM) produced a small but significant increase to 126.6±5.5% (n=11), but higher concentrations failed to increase the response. In conclusion, desipramine fails to produce sufficient noradrenaline transporter block in low concentrations (0.1 μM) and produces α1-adrenoceptor antagonism in slightly higher concentrations (0.3-1 μM), and so is unsuitable for use in α1-adrenoceptor subclassification studies. Contractions of rat vas deferens are mediated by α1A- and α1D-adrenoceptors, and prazosin has selectivity for α1D- over α1A-adrenoceptors. The α1L-adrenoceptor previously identified in rat vas deferens is the native α1A-adrenoceptor. The range of prazosin potencies and receptor subtypes previously reported in rat vas deferens may be explained by the choice of cocaine or desipramine as noradrenaline transporter blocker.

  14. Embryologic development of the prostate. Insights into the etiology and treatment of benign prostatic hyperplasia.

    PubMed

    Shapiro, E

    1990-08-01

    Pharmacologic strategies for the treatment of BPH are at present directed toward relaxing prostate smooth muscle and reducing prostate volume. Historically, the primary limitation of pharmacotherapy for BPH has been that the symptomatic improvement achieved was overshadowed by the morbidity of treatment. However, the morbidity has been markedly diminished based on a more precise understanding of the embryology, physiology, and pharmacology of the prostate. The origins and pharmacologic properties of the smooth musculature of the prostate and bladder are unique. Therefore, drugs such as alpha blockers may relax the prostate selectively without altering bladder function. Although phenoxybenzamine, a nonselective alpha blocker, relieves infravesical obstruction secondary to BPH, the severity of the adverse reactions limits the use of this drug. The contractile properties of the prostate smooth muscle are mediated by alpha-1 adrenoceptors. The effectiveness of phenoxybenzamine and selective alpha-1 blockers such as prazosin and terazosin are similar. The side effects of the selective alpha-1 blockers are negligible. Androgen suppression, which lowers testosterone, produces intolerable side effects such as gynecomastia, erectile dysfunction, and impaired libido. The androgen dependency of the prostate provides the rationale for using 5 alpha-reductase inhibitors for the treatment of BPH. Reduction of prostate volume can be achieved by blocking the action or synthesis of dihydrotestosterone without impotence, gynecomastia, and hot flashes. These recent advances in pharmacotherapy for BPH are based on understanding of the fundamental developmental properties of the prostate.

  15. Capparis ovata treatment suppresses inflammatory cytokine expression and ameliorates experimental allergic encephalomyelitis model of multiple sclerosis in C57BL/6 mice.

    PubMed

    Ozgun-Acar, Ozden; Celik-Turgut, Gurbet; Gazioglu, Isil; Kolak, Ufuk; Ozbal, Seda; Ergur, Bekir U; Arslan, Sevki; Sen, Alaattin; Topcu, Gulacti

    2016-09-15

    Since ancient times, Capparis species have been widely used in traditional medicine to treat various diseases. Our recent investigations have suggested Capparis ovata's potential anti-neuroinflammatory application for the treatment of multiple sclerosis (MS). The present study was designed to precisely determine the underlying mechanism of its anti-neuroinflammatory effect in a mouse model of MS. C. ovata water extract (COWE) was prepared using the plant's fruit, buds, and flower parts (Turkish Patent Institute, PT 2012/04,093). We immunized female C57BL/6J mice with MOG35-55/CFA. COWE was administered at a daily dose of 500mg/kg by oral gavage either from the day of immunization (T1) or at disease onset (T2) for 21days. Gene expression analysis was performed using a Mouse Multiple Sclerosis RT² Profiler PCR Array, and further determinations and validations of the identified genes were performed using qPCR. Whole-genome transcriptome profiling was analyzed using Agilent SurePrint G3 Mouse GE 8X60K microarrays. Immunohistochemical staining was applied to brain sections of the control and treated mice to examine the degree of degeneration. COWE was further fractionated and analyzed phytochemically using the Zivak Tandem Gold Triple Quadrupole LC/MS-MS system. COWE remarkably suppressed the development of EAE in T1, and the disease activity was completely inhibited. In the T2 group, the maximal score was significantly reduced compared with that of the parallel EAE group. The COWE suppression of EAE was associated with a significantly decreased expression of genes that are important in inflammatory signaling, such as TNFα, IL6, NF-κB, CCL5, CXCL9, and CXCK10. On the other hand, the expression of genes involved in myelination/remyelination was significantly increased. Immunohistochemical analysis further supported these effects, showing that the number of infiltrating immune cells was decreased in the brains of COWE-treated animals. In addition, differential

  16. Combinatorial treatment with polyI:C and anti-IL6 enhances apoptosis and suppresses metastasis of lung cancer cells

    PubMed Central

    Lau, Wai Hoe; Zhu, Xiphias Ge; Ho, Shamaine Wei Ting; Chang, Shu Chun; Ding, Jeak Ling

    2017-01-01

    Activation of TLR3 stimulates cancer cell apoptosis and triggers secretion of inflammatory cytokines. PolyI:C, a TLR3 agonist, activates immune cells and regresses metastatic lung cancer in vivo. Although polyI:C reportedly kills lung carcinomas, the mechanism remains elusive. Here, we demonstrated that polyI:C suppressed the proliferation and survival of metastatic (NCI-H358 and NCI-H292) and non-metastatic (A549) lung cancer cells. Notably, A549, NCI-H292 and NCI-H358 which are inducible by polyI:C, expressed low-to-medium level of TLR3 protein, and were susceptible to polyI:C treatment. By contrast, NCI-H1299, which endogenously expresses high level of TLR3 protein, was insensitive to polyI:C. We showed that polyI:C stimulated pro-inflammatory cytokines associated with survival and metastasis in a cell type-specific manner. While A549 and NCI-H292 released high levels of IL6, IL8 and GRO, the NCI-H358 cells endogenously secretes abundant levels of these cytokines, and was not further induced by polyI:C. Thus, NCI-H358 was resistant to the inhibition of cytokine-dependent metastasis. NCI-H1299, which was unresponsive to polyI:C, did not produce any of the pro-inflammatory cytokines. Treatment of A549 with a combination of polyI:C and anti-IL6 antibody significantly decreased IL6 production, and enhanced polyI:C-mediated killing and suppression of oncogenicity and metastasis. While polyI:C stimulated the phosphorylation of STAT3 and JAK2, blockade of these proteins enhanced polyI:C-mediated suppression of survival and metastasis. Taken together, polyI:C alone provoked apoptosis of lung cancer cells that express low-to-medium levels of functional TLR3 protein. The combinatorial treatment with polyI:C and anti-IL6 enhanced polyI:C-mediated anticancer activities through IL6/JAK2/STAT3 signalling, and apoptosis via TLR3-mediated caspase 3/8 pathway. PMID:28427199

  17. Violacein Treatment Modulates Acute and Chronic Inflammation through the Suppression of Cytokine Production and Induction of Regulatory T Cells.

    PubMed

    Verinaud, Liana; Lopes, Stefanie Costa Pinto; Prado, Isabel Cristina Naranjo; Zanucoli, Fábio; Alves da Costa, Thiago; Di Gangi, Rosária; Issayama, Luidy Kazuo; Carvalho, Ana Carolina; Bonfanti, Amanda Pires; Niederauer, Guilherme Francio; Duran, Nelson; Costa, Fábio Trindade Maranhão; Oliveira, Alexandre Leite Rodrigues; Höfling, Maria Alice da Cruz; Machado, Dagmar Ruth Stach; Thomé, Rodolfo

    2015-01-01

    Inflammation is a necessary process to control infection. However, exacerbated inflammation, acute or chronic, promotes deleterious effects in the organism. Violacein (viola), a quorum sensing metabolite from the Gram-negative bacterium Chromobacterium violaceum, has been shown to protect mice from malaria and to have beneficial effects on tumors. However, it is not known whether this drug possesses anti-inflammatory activity. In this study, we investigated whether viola administration is able to reduce acute and chronic autoimmune inflammation. For that purpose, C57BL/6 mice were intraperitoneally injected with 1 μg of LPS and were treated with viola (3.5mg/kg) via i.p. at the same time-point. Three hours later, the levels of inflammatory cytokines in the sera and phenotypical characterization of leukocytes were determined. Mice treated with viola presented a significant reduction in the production of inflammatory cytokines compared with untreated mice. Interestingly, although viola is a compound derived from bacteria, it did not induce inflammation upon administration to naïve mice. To test whether viola would protect mice from an autoimmune inflammation, Experimental Autoimmune Encephalomyelitis (EAE)-inflicted mice were given viola i.p. at disease onset, at the 10th day from immunization. Viola-treated mice developed mild EAE disease in contrast with placebo-treated mice. The frequencies of dendritic cells and macrophages were unaltered in EAE mice treated with viola. However, the sole administration of viola augmented the levels of splenic regulatory T cells (CD4+Foxp3+). We also found that adoptive transfer of viola-elicited regulatory T cells significantly reduced EAE. Our study shows, for the first time, that violacein is able to modulate acute and chronic inflammation. Amelioration relied in suppression of cytokine production (in acute inflammation) and stimulation of regulatory T cells (in chronic inflammation). New studies must be conducted in order to

  18. Violacein Treatment Modulates Acute and Chronic Inflammation through the Suppression of Cytokine Production and Induction of Regulatory T Cells

    PubMed Central

    Verinaud, Liana; Lopes, Stefanie Costa Pinto; Prado, Isabel Cristina Naranjo; Zanucoli, Fábio; Alves da Costa, Thiago; Di Gangi, Rosária; Issayama, Luidy Kazuo; Carvalho, Ana Carolina; Bonfanti, Amanda Pires; Niederauer, Guilherme Francio; Duran, Nelson; Costa, Fábio Trindade Maranhão; Oliveira, Alexandre Leite Rodrigues; Höfling, Maria Alice da Cruz; Machado, Dagmar Ruth Stach; Thomé, Rodolfo

    2015-01-01

    Inflammation is a necessary process to control infection. However, exacerbated inflammation, acute or chronic, promotes deleterious effects in the organism. Violacein (viola), a quorum sensing metabolite from the Gram-negative bacterium Chromobacterium violaceum, has been shown to protect mice from malaria and to have beneficial effects on tumors. However, it is not known whether this drug possesses anti-inflammatory activity. In this study, we investigated whether viola administration is able to reduce acute and chronic autoimmune inflammation. For that purpose, C57BL/6 mice were intraperitoneally injected with 1 μg of LPS and were treated with viola (3.5mg/kg) via i.p. at the same time-point. Three hours later, the levels of inflammatory cytokines in the sera and phenotypical characterization of leukocytes were determined. Mice treated with viola presented a significant reduction in the production of inflammatory cytokines compared with untreated mice. Interestingly, although viola is a compound derived from bacteria, it did not induce inflammation upon administration to naïve mice. To test whether viola would protect mice from an autoimmune inflammation, Experimental Autoimmune Encephalomyelitis (EAE)-inflicted mice were given viola i.p. at disease onset, at the 10th day from immunization. Viola-treated mice developed mild EAE disease in contrast with placebo-treated mice. The frequencies of dendritic cells and macrophages were unaltered in EAE mice treated with viola. However, the sole administration of viola augmented the levels of splenic regulatory T cells (CD4+Foxp3+). We also found that adoptive transfer of viola-elicited regulatory T cells significantly reduced EAE. Our study shows, for the first time, that violacein is able to modulate acute and chronic inflammation. Amelioration relied in suppression of cytokine production (in acute inflammation) and stimulation of regulatory T cells (in chronic inflammation). New studies must be conducted in order to

  19. Transitory FGF treatment results in the long-lasting suppression of the proliferative response to repeated FGF stimulation.

    PubMed

    Poole, Ashleigh; Knowland, Nicholas; Cooper, Emily; Cole, Rebecca; Wang, Hongchuan; Booth, Lucas; Kacer, Doreen; Tarantini, Francesca; Friesel, Robert; Prudovsky, Igor

    2014-05-01

    FGF applied as a single growth factor to quiescent mouse fibroblasts induces a round of DNA replication, however continuous stimulation results in arrest in the G1 phase of the next cell cycle. We hypothesized that FGF stimulation induces the establishment of cell memory, which prevents the proliferative response to repeated or continuous FGF application. When a 2-5 days quiescence period was introduced between primary and repeated FGF treatments, fibroblasts failed to efficiently replicate in response to secondary FGF application. The establishment of "FGF memory" during the first FGF stimulation did not require DNA synthesis, but was dependent on the activity of FGF receptors, MEK, p38 MAPK and NFκB signaling, and protein synthesis. While secondary stimulation resulted in strongly decreased replication rate, we did not observe any attenuation of morphological changes, Erk1/2 phosphorylation and cyclin D1 induction. However, secondary FGF stimulation failed to induce the expression of cyclin A, which is critical for the progression from G1 to S phase. Treatment of cells with a broad range histone deacetylase inhibitor during the primary FGF stimulation rescued the proliferative response to the secondary FGF treatment suggesting that the establishment of "FGF memory" may be based on epigenetic changes. We suggest that "FGF memory" can prevent the hyperplastic response to cell damage and inflammation, which are associated with an enhanced FGF production and secretion. "FGF memory" may present a natural obstacle to the efficient application of recombinant FGFs for the treatment of ulcers, ischemias, and wounds.

  20. Differential suppression of ethylene biosynthesis and receptor genes in 'Golden Delicious' apple by preharvest and postharvest 1-MCP treatments

    USDA-ARS?s Scientific Manuscript database

    Harvista™, a spraying formulation of 1-MCP, is a recently available tool for managing preharvest on-tree fruit maturation whereas SmartFresh™ is the widely-used treatment for postharvest handling and storage. In the current study, the timing of pre-harvest application and its effects on fruit ripeni...

  1. Chronic fluoxetine treatment suppresses plasticity (long-term potentiation) in the mature rodent primary auditory cortex in vivo.

    PubMed

    Dringenberg, Hans C; Branfield Day, Leora R; Choi, Deanna H

    2014-01-01

    Several recent studies have provided evidence that chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine can facilitate synaptic plasticity (e.g., ocular dominance shifts) in the adult central nervous system. Here, we assessed whether fluoxetine enhances long-term potentiation (LTP) in the thalamocortical auditory system of mature rats, a developmentally regulated form of plasticity that shows a characteristic decline during postnatal life. Adult rats were chronically treated with fluoxetine (administered in the drinking water, 0.2 mg/mL, four weeks of treatment). Electrophysiological assessments were conducted using an anesthetized (urethane) in vivo preparation, with LTP of field potentials in the primary auditory cortex (A1) induced by theta-burst stimulation of the medial geniculate nucleus. We find that, compared to water-treated control animals, fluoxetine-treated rats did not express higher levels of LTP and, in fact, exhibited reduced levels of potentiation at presumed intracortical A1 synapses. Bioactivity of fluoxetine was confirmed by a reduction of weight gain and fluid intake during the four-week treatment period. We conclude that chronic fluoxetine treatment fails to enhance LTP in the mature rodent thalamocortical auditory system, results that bring into question the notion that SSRIs act as general facilitators of synaptic plasticity in the mammalian forebrain.

  2. An open-label, multicentre study to assess the safety and efficacy of a novel reflux suppressant (Gaviscon Advance) in the treatment of heartburn during pregnancy.

    PubMed

    Lindow, S W; Regnéll, P; Sykes, J; Little, S

    2003-04-01

    This study investigated the efficacy and safety of a novel reflux suppressant, Gaviscon Advance, in the treatment of heartburn during pregnancy. The study was an open-label, multicentre, phase IV study in general practice and antenatal clinics in the UK and Republic of South Africa. Pregnant women (< or = 38 weeks gestation; n=150) aged 18-40 years suffering from heartburn were instructed to take Gaviscon Advance 5-10 ml, as required, to relieve symptoms. The main outcome measures were the efficacy rating of the study medication by the investigator and women after four weeks using a five-point efficacy scale. After four weeks the investigators' and women's rating of efficacy was 'very good' or 'good' in 88% and 90% of women, respectively. Most women (57%, n=83) reported symptom relief within 10 minutes. Thus Gaviscon Advance effectively and rapidly treats heartburn during pregnancy. Its use during pregnancy presents no known significant safety concerns for mother or child.

  3. Energy controllable steep pulse (ECSP) treatment suppresses tumor growth in rats implanted with Walker 256 carcinosarcoma cells through apoptosis and an antitumor immune response.

    PubMed

    Luo, Xiao-Dong; Sun, Jiang-chuan; Liu, Feng; Hu, Li-Na; Dong, Xiao-Jing; Sun, Di-Na; Xiao, Jin

    2012-01-01

    Electrochemotherapy has been widely used for the treatment of solid tumors, although the underlying mechanism remains unclear. We aimed to investigate the effects of energy controllable steep pulse (ECSP) on the regulation of tumor growth and apoptosis in rats implanted with Walker 256 carcinosarcoma cells. A rat tumor model was established by injection of Walker 256 carcinosarcoma cells into the inguinal area. H&E staining, transmission electron microscopy, and the TUNEL assay were used to detect apoptosis. Concanavalin A-induced lymphocyte transformation and MTT assays were used to assess lymphocyte proliferation. ELISA was used to determine serum cytokine levels. After 2 weeks of ECSP treatment, tumor growth in rats was effectively suppressed, while tumor cell apoptosis was significantly induced compared to the control tumor group. Moreover, ECSP treatment enhanced proliferation and activation of lymphocytes and natural killer (NK) cells. Serum IL-2 and IFN-gamma levels were significantly decreased, and IL-4 and 1-10 levels dramatically increased in rats with control tumors compared to rats without tumors and lacking treatment (p < 0.05). In contrast, ECSP treatment increased IL-2 and IFN-gamma levels, but reduced IL-4 and IL-10 levels to normal values. Moreover, ECSP also increased TNF-alpha production, possibly from peritoneal microphages. Our current study demonstrates that ECSP treatment is able to effectively reduce tumors in rats via induction of apoptosis and activation of the rat antitumor immune response. These data provide insightful information for the future application of ECSP-based electrochemotherapy in clinical trials against solid tumors.

  4. The role of an acute pasireotide suppression test in predicting response to treatment in patients with Cushing's disease: findings from a pilot study.

    PubMed

    Trementino, L; Zilio, M; Marcelli, G; Michetti, G; Barbot, M; Ceccato, F; Boscaro, M; Scaroni, C; Arnaldi, G

    2015-09-01

    Pasireotide is a multireceptor-targeted somatostatin analog effective in the treatment of Cushing's disease (CD). We evaluate the value of an acute pasireotide suppression test (PST) in predicting response to medium/long-term treatment in CD. Nineteen patients with active CD were prospectively investigated at two referral centers from May 2013 to August 2014. Follow-up data (median 6 months; range 1-9 months) were available for sixteen patients. All patients received at 09:00 h a single subcutaneous (sc) injection of 600 μg pasireotide. Serum cortisol and plasma ACTH were assessed before, and every 2 h for 8 h after, drug administration. Late-night salivary cortisol (LNSC) was assessed before and after pasireotide administration. After acute PST, all patients were continued on pasireotide 600 μg sc twice a day. During PST, cortisol and ACTH levels quickly decreased in all patients except one with a mean percentage fall, respectively, of 48.9 ± 24.3 and 48.1 ± 25.4 % compared to baseline. LNSC decreased in about 82 % of patients (14/17) achieving a normalization in five of them. Pasireotide treatment was associated with a normalization of 24-h urinary-free cortisol at last follow-up in about 68 % of patients. A fall >27 % of LNSC during PST calculated by ROC curve was the best parameter in predicting a positive response to treatment with pasireotide (sensitivity 91 %; specificity 100 %; positive predictive value 100 %; negative predictive value 75 %). Acute PST may be useful to identify CD patients who will benefit from pasireotide treatment. A LNSC fall >27 % as well as a LNSC normalization during PST is associated with a probability of 100 % of achieving a favorable response to pasireotide treatment in the medium/long term.

  5. Cellular induction of chronic allotype suppression of IgG2a in Ighb/b homozygous mice and its abrogation by in vivo treatment with anti-CD8 monoclonal antibody

    PubMed Central

    1988-01-01

    We report here the successful induction of allotype suppression in homozygous Ighb/b mice (CB20 or C57BL/6) by neonatal injection of T splenocytes from Igha congenic sensitized mice (BALB/c or BC8, respectively). The sensitization of the T cell donors was achieved by two intravenous injections of B splenocytes from Ighb congenic mice. Treated homozygous Ighb/b mice developed, as of 16-24 wk of age, a chronic suppression of Igh-1b expression (IgG2a of Ighb haplotype). The other productions tested (IgM, IgD, and IgA) of Ighb haplotype were unaffected. In vivo treatment with cytotoxic anti-CD4 or anti-CD8 mAb of mice subjected to chronic Igh-1b suppression clearly showed that CD8+ lymphocytes (suppressor or cytotoxic cell) were essential for the maintenance of the suppression. The suppression was indeed abrogated after a 1-wk treatment with anti-CD8 mAb containing culture supernatant, whereas, the anti-CD4-treated mice continued to be subjected to suppression. This anti-CD8 in vivo treatment was shown to have no effect on thymus but to severely reduce the percentages of CD8+ cells in spleen and in peripheral blood without affecting the percentages of CD4+ cells, leading to a large and rapid Igh-1b expression (up to 0.5 mg per ml of serum, the day after the end of the treatment). This suppression abrogation, and thus the Igh-1b expression, was either transient or permanent. When it was transient, a second 1-wk treatment with anti-CD8 mAb containing culture supernatant induced once again a rapid and significant production of Igh-1b (up to 0.3 mg of Igh-1b per ml of serum). PMID:2902183

  6. Olopatadine hydrochloride suppresses the rebound phenomenon after discontinuation of treatment with a topical steroid in mice with chronic contact hypersensitivity.

    PubMed

    Tamura, T; Matsubara, M; Hasegawa, K; Ohmori, K; Karasawa, A

    2005-01-01

    Olopatadine hydrochloride (olopatadine; Allelock) is one of the second-generation antihistamines that are treated for allergic disorders such as rhinitis, urticaria and eczema dermatitis. Olopatadine has recently been shown to have inhibitory effects on the chronic contact hypersensitivity induced by repeated application of oxazolone in mice. Although topical steroids have widely been prescribed for atopic dermatitis, a relapse often occurs within several days after discontinuation of their prolonged use. We investigated the possible efficacy of olopatadine against the relapse after discontinuation of prolonged use of topical prednisolone in the Balb/c mice with oxazolone-induced chronic contact hypersensitivity. Mice with the chronic contact hypersensitivity induced by repeated application of oxazolone were treated with olopatadine as a sequential therapeutic agent. The effects of olopatadine were quantified by measurements of ear-swelling, and levels of cytokines and histamine in the lesioned ear. Results Topical prednisolone (0.05 mg/ear/day) significantly inhibited the increases in ear swelling and production of IL-1beta, IL-4, IL-18, granulocyte-macrophage colony-stimulating factor (GM-CSF) and histamine. However, after discontinuation of the treatment with topical prednisolone, the inflammation relapsed and the IL-4 level exceeded the control one. The sequential treatment with olopatadine (10 mg/kg/day) after discontinuation of the treatment with topical prednisolone alone, or topical prednisolone with olopatadine, significantly inhibited the increases in ear swelling and levels of IL-1beta, IL-4, IL-18, GM-CSF, nerve growth factor and histamine. These results indicate that olopatadine is an antihistamine agent having inhibitory activities against the rebound phenomenon following the discontinuation of topical steroid therapy. Olopatadine is thus expected to be a sequential therapeutic agent after discontinuation of the chronic treatment with a topical

  7. Combination treatment with eldecalcitol (ED-71) and raloxifene improves bone mechanical strength by suppressing bone turnover and increasing bone mineral density in ovariectomized rats.

    PubMed

    Takeda, Satoshi; Sakai, Sadaoki; Shiraishi, Ayako; Koike, Nobuo; Mihara, Masahiko; Endo, Koichi

    2013-03-01

    levels of the sham-operated control, suggesting that the combination therapy with ELD and RAL may not cause oversuppression of bone turnover. These results indicated that the combination treatment with ELD and RAL might be a beneficial therapy with respect to their combined effects of enhancing the mechanical properties of trabecular and cortical bone by suppressing bone turnover and increasing BMD more than either monotherapy. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Lactobacillus farciminis treatment suppresses stress induced visceral hypersensitivity: a possible action through interaction with epithelial cell cytoskeleton contraction

    PubMed Central

    Ait‐Belgnaoui, A; Han, W; Lamine, F; Eutamene, H; Fioramonti, J; Bueno, L; Theodorou, V

    2006-01-01

    Background Stress induced increase in colonic paracellular permeability results from epithelial cell cytoskeleton contraction and is responsible for stress induced hypersensitivity to colorectal distension (CRD). The probiotic Lactobacillus farciminis releases spontaneously nitric oxide (NO) in the colonic lumen in vivo and exerts anti‐inflammatory effects. This study aimed: (i) to evaluate the effects of L farciminis on stress induced hypersensitivity to CRD and increase in colonic paracellular permeability; and (ii) to ascertain whether these effects are NO mediated and related to changes in colonocyte myosin light chain phosphorylation (p‐MLC). Methods Female Wistar rats received either 1011 CFU/day of L farciminis or saline orally over 15 days before partial restraint stress (PRS) or sham‐PRS application. Visceral sensitivity to CRD and colonic paracellular permeability was assessed after PRS or sham‐PRS. Haemoglobin was used as an NO scavenger. Western blotting for MLC kinase, MLC, and p‐MLC were performed in colonic mucosa from L farciminis treated and control rats after PRS or sham‐PRS. Results PRS significantly increased the number of spike bursts for CRD pressures of 30–60 mm Hg as well as colonic paracellular permeability. L farciminis treatment prevented both effects, while haemoglobin reversed the protective effects of L farciminis. p‐MLC expression increased significantly from 15 to 45 minutes after PRS, and L farciminis treatment prevented this increase. Conclusion L farciminis treatment prevents stress induced hypersensitivity, increase in colonic paracellular permeability, and colonocyte MLC phosphorylation. This antinociceptive effect occurs via inhibition of contraction of colonic epithelial cell cytoskeleton and the subsequent tight junction opening, and may also involve direct or indirect effects of NO produced by this probiotic. PMID:16507583

  9. Randomized Controlled Study Investigating Viral Suppression and Serological Response following Pre-S1/Pre-S2/S Vaccine Therapy Combined with Lamivudine Treatment in HBeAg-Positive Patients with Chronic Hepatitis B▿

    PubMed Central

    Hoa, Pham Thi Le; Huy, Nguyen Tien; Thu, Le The; Nga, Cao Ngoc; Nakao, Kazuhiko; Eguchi, Katsumi; Chi, Nguyen Huu; Hoang, Bui Huu; Hirayama, Kenji

    2009-01-01

    The aim of the current study was to evaluate viral suppression following combined treatment with an S/pre-S1/pre-S2 vaccine and lamivudine in patients with chronic hepatitis B. We established a randomized, controlled clinical trial to compare the responses of three different treatment groups: those receiving vaccine monotherapy, lamivudine monotherapy, or combination treatment. Viral response was evaluated via hepatitis B virus (HBV) DNA suppression using different levels of classification. Seroconversion was evaluated via HBeAg loss, HBeAg seroconversion, HBsAg loss, and anti-HBs response. We found that the group receiving combination treatment demonstrated a significant increase in viral suppression over that for the lamivudine or vaccine monotherapy group, although the HBeAg seroconversion rate was not different. This enhanced suppression effect in the combination group was reversed after the discontinuation of vaccine treatment, suggesting that booster doses are required for a sustained viral response. Anti-HBs was detected in 55/120 vaccine recipients, but only 3 patients demonstrated HBsAg loss, indicating that the vaccine-induced anti-HBs was unable to completely neutralize HBsAg in the serum. At the study end point, anti-HBs responders showed significantly higher HBeAg seroconversion rates, greater suppression of HBV DNA levels, and a lower median reduction in HBV DNA levels than those of anti-HBs nonresponders. Our results suggest that combined treatment with the vaccine and lamivudine was significantly more effective than lamivudine monotherapy in the short term and was especially successful in producing viral suppression and an enhanced anti-HBs antibody response. PMID:19770281

  10. Serpin treatment suppresses inflammatory vascular lesions in temporal artery implants (TAI) from patients with giant cell arteritis.

    PubMed

    Chen, Hao; Zheng, Donghang; Ambadapadi, Sriram; Davids, Jennifer; Ryden, Sally; Samy, Hazem; Bartee, Mee; Sobel, Eric; Dai, Erbin; Liu, Liying; Macaulay, Colin; Yachnis, Anthony; Weyand, Cornelia; Thoburn, Robert; Lucas, Alexandra

    2015-01-01

    Giant cell arteritis (GCA) and Takayasu's disease are inflammatory vasculitic syndromes (IVS) causing sudden blindness and widespread arterial obstruction and aneurysm formation. Glucocorticoids and aspirin are mainstays of treatment, predominantly targeting T cells. Serp-1, a Myxomavirus-derived serpin, blocks macrophage and T cells in a wide range of animal models. Serp-1 also reduced markers of myocardial injury in a Phase IIa clinical trial for unstable coronary disease. In recent work, we detected improved survival and decreased arterial inflammation in a mouse Herpesvirus model of IVS. Here we examine Serp-1 treatment of human temporal artery (TA) biopsies from patients with suspected TA GCA arteritis after implant (TAI) into the aorta of immunodeficient SCID (severe combined immunodeficiency) mice. TAI positive for arteritis (GCApos) had significantly increased inflammation and plaque when compared to negative TAI (GCAneg). Serp-1 significantly reduced intimal inflammation and CD11b+ cell infiltrates in TAI, with reduced splenocyte Th1, Th17, and Treg. Splenocytes from mice with GCApos grafts had increased gene expression for interleukin-1 beta (IL-1β), IL-17, and CD25 and decreased Factor II. Serp-1 decreased IL-1β expression. In conclusion, GCApos TAI xenografts in mice provide a viable disease model and have increased intimal inflammation as expected and Serp-1 significantly reduces vascular inflammatory lesions with reduced IL-1β.

  11. Tumor growth accelerated by chemotherapy-induced senescent cells is suppressed by treatment with IL-12 producing cellular vaccines

    PubMed Central

    Simova, Jana; Sapega, Olena; Imrichova, Terezie; Stepanek, Ivan; Kyjacova, Lenka; Mikyskova, Romana; Indrova, Marie; Bieblova, Jana; Bubenik, Jan; Bartek, Jiri; Hodny, Zdenek; Reinis, Milan

    2016-01-01

    Standard-of-care chemo- or radio-therapy can induce, besides tumor cell death, also tumor cell senescence. While senescence is considered to be a principal barrier against tumorigenesis, senescent cells can survive in the organism for protracted periods of time and they can promote tumor development. Based on this emerging concept, we hypothesized that elimination of such potentially cancer-promoting senescent cells could offer a therapeutic benefit. To assess this possibility, here we first show that tumor growth of proliferating mouse TC-1 HPV-16-associated cancer cells in syngeneic mice becomes accelerated by co-administration of TC-1 or TRAMP-C2 prostate cancer cells made senescent by pre-treatment with the anti-cancer drug docetaxel, or lethally irradiated. Phenotypic analyses of tumor-explanted cells indicated that the observed acceleration of tumor growth was attributable to a protumorigenic environment created by the co-injected senescent and proliferating cancer cells rather than to escape of the docetaxel-treated cells from senescence. Notably, accelerated tumor growth was effectively inhibited by cell immunotherapy using irradiated TC-1 cells engineered to produce interleukin IL-12. Collectively, our data document that immunotherapy, such as the IL-12 treatment, can provide an effective strategy for elimination of the detrimental effects caused by bystander senescent tumor cells in vivo. PMID:27448982

  12. [Intravenous nitroglycerin infusion suppresses exercise-induced arrhythmia in patients with ischemic cardiopathy: indications for chronic treatment ].

    PubMed

    Bonetti, F; Margonato, A; Mailhac, A; Vicedomini, G; Cianflone, D; Scarpazza, P; Chierchia, S L

    1990-05-01

    In patients with ischemic heart disease and arrhythmias, selection of antiarrhythmic treatment is often difficult as it is hard to separate "primary" from ischemic arrhythmias. We studied 20 patients with ischemic heart disease, who developed ventricular arrhythmias consistently during exercise test. Exercise test was performed twice during infusion of placebo and then during intravenous administration of nitroglycerin, titrated to reduce systolic blood pressure by 10 mmHg. Exercise duration was 7.8 +/- 1.7 and 7.9 +/- 1.5 min, in the 2 placebo tests (NS). Angina developed in 5 patients and ischemic ST changes in 10. With nitroglycerin exercise duration increased to 8.4 +/- 20 min (p less than 0.05), diagnostic ST segment depression was observed in 2 patients and only 1 had angina. In all 20 patients, ventricular arrhythmias were consistently present during both tests on placebo, that were markedly reduced by nitroglycerin. In fact, ventricular ectopic beats were 455 (mean 35.8 +/- 16.8) and 418 (mean 34.4 +/- 11.1) in the 2 exercise tests with placebo, and 11 during nitroglycerin infusion (mean 0.6 +/- 0.1; p less than 0.001). Couplets were 28 and 29 during placebo (NS) and 0 during nitroglycerin (p less than 0.001). Ventricular tachycardia was present in 6 and 8 patients during placebo but in none during nitroglycerin (p less than 0.001). Reduction of exercise-induced arrhythmias was maintained during chronic treatment with oral vasodilators. Prevention of exercise-related arrhythmias by nitroglycerin infusion appears a good indicator of their ischemic origin and may provide valuable information for long-term profilaxis with oral vasodilators, then avoiding the use of antiarrhythmic agents and their potential side effects.

  13. Repeated landscape-scale treatments following fire suppress a non-native annual grass and promote recovery of native perennial vegetation

    USGS Publications Warehouse

    Munson, Seth M.; Long, A. Lexine; Decker, Cheryl E.; Johnson, Katie A.; Walsh, Kathleen; Miller, Mark E.

    2015-01-01

    Invasive non-native species pose a large threat to restoration efforts following large-scale disturbances. Bromus tectorum (cheatgrass) is a non-native annual grass in the western U.S. that both spreads quickly following fire and accelerates the fire cycle. Herbicide and seeding applications are common restoration practices to break the positive fire-invasion feedback loop and recover native perennial species, but their interactive effects have infrequently been tested at the landscape-scale and repeated in time to encourage long-lasting effects. We determined the efficacy of repeated post-fire application of the herbicide imazapic and seeding treatments to suppressBromus abundance and promote perennial vegetation recovery. We found that the selective herbicide reduced Bromus cover by ~30 % and density by >50 % across our study sites, but had a strong initial negative effect on seeded species. The most effective treatment to promote perennial seeded species cover was seeding them alone followed by herbicide application 3 years later when the seeded species had established. The efficacy of the treatments was strongly influenced by water availability, as precipitation positively affected the density and cover of Bromus; soil texture and aspect secondarily influenced Bromus abundance and seeded species cover by modifying water retention in this semi-arid region. Warmer temperatures positively affected the non-native annual grass in the cool-season, but negatively affected seeded perennial species in the warm-season, suggesting an important role of seasonality in a region projected to experience large increases in warming in the future. Our results highlight the importance of environmental interactions and repeated treatments in influencing restoration outcomes at the landscape-scale.

  14. Short-term treatment with metformin suppresses toll like receptors (TLRs) activity in isoproterenol-induced myocardial infarction in rat: are AMPK and TLRs connected?

    PubMed

    Soraya, Hamid; Farajnia, Safar; Khani, Sajjad; Rameshrad, Maryam; Khorrami, Arash; Banani, Armita; Maleki-Dizaji, Nasrin; Garjani, Alireza

    2012-12-01

    AMP-activated protein kinase (AMPK) is a key sensor of cellular energy. The activation of AMPK by metformin prevents cardiac remodeling after myocardial infarction (MI). Besides, the innate immune response through TLRs is activated during MI. In the present study, the effects of short-term treatment with metformin on TLRs activity and its relation with AMPK in isoproterenol-induced MI were assessed in rats. To induce MI, a subcutaneous injection of isoproterenol was given to Wistar rats for two consecutive days. Metformin (25, 50, and 100mg/kg) was orally administered to rats twice daily for two days. Interstitial fibrosis was dose-dependently attenuated in the treated groups in comparison to the MI group (score: 1.25 ± 0.28 with 100 mg/kg metformin versus 3.5 ± 0.28; P<0.001). Further, metformin reduced TLR-dependent inflammatory cytokines as indexed by reduced myocardial levels of TNFα (maximum 68%; P<0.001) and IL6 (maximum 84%; P<0.001) as well as by reduced myocardial MPO activity (25%; P<0.01). It was found that the level of phosphorylated AMPK was significantly upregulated by 165% (P<0.001) when treated with 100 mg/kg of metformin, but not with 25 and 50mg/kg. This was associated with a remarkable suppression of TLR4 expression and reduction of protein level of TLRs adapter protein, MyD88 (P<0.01) in the infarcted myocardium. These results suggest that AMPK activation by metformin and the subsequent suppression of TLRs activity could be considered as a target in protecting the infarcted heart, which may indicate a link between AMPK and TLRs.

  15. Young adult outcomes in the follow-up of the multimodal treatment study of attention-deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression.

    PubMed

    Swanson, James M; Arnold, L Eugene; Molina, Brooke S G; Sibley, Margaret H; Hechtman, Lily T; Hinshaw, Stephen P; Abikoff, Howard B; Stehli, Annamarie; Owens, Elizabeth B; Mitchell, John T; Nichols, Quyen; Howard, Andrea; Greenhill, Laurence L; Hoza, Betsy; Newcorn, Jeffrey H; Jensen, Peter S; Vitiello, Benedetto; Wigal, Timothy; Epstein, Jeffery N; Tamm, Leanne; Lakes, Kimberly D; Waxmonsky, James; Lerner, Marc; Etcovitch, Joy; Murray, Desiree W; Muenke, Maximilian; Acosta, Maria T; Arcos-Burgos, Mauricio; Pelham, William E; Kraemer, Helena C

    2017-06-01

    The Multimodal Treatment Study (MTA) began as a 14-month randomized clinical trial of behavioral and pharmacological treatments of 579 children (7-10 years of age) diagnosed with attention-deficit/hyperactivity disorder (ADHD)-combined type. It transitioned into an observational long-term follow-up of 515 cases consented for continuation and 289 classmates (258 without ADHD) added as a local normative comparison group (LNCG), with assessments 2-16 years after baseline. Primary (symptom severity) and secondary (adult height) outcomes in adulthood were specified. Treatment was monitored to age 18, and naturalistic subgroups were formed based on three patterns of long-term use of stimulant medication (Consistent, Inconsistent, and Negligible). For the follow-up, hypothesis-generating analyses were performed on outcomes in early adulthood (at 25 years of age). Planned comparisons were used to estimate ADHD-LNCG differences reflecting persistence of symptoms and naturalistic subgroup differences reflecting benefit (symptom reduction) and cost (height suppression) associated with extended use of medication. For ratings of symptom severity, the ADHD-LNCG comparison was statistically significant for the parent/self-report average (0.51 ± 0.04, p < .0001, d = 1.11), documenting symptom persistence, and for the parent/self-report difference (0.21 ± 0.04, p < .0001, d = .60), documenting source discrepancy, but the comparisons of naturalistic subgroups reflecting medication effects were not significant. For adult height, the ADHD group was 1.29 ± 0.55 cm shorter than the LNCG (p < .01, d = .21), and the comparisons of the naturalistic subgroups were significant: the treated group with the Consistent or Inconsistent pattern was 2.55 ± 0.73 cm shorter than the subgroup with the Negligible pattern (p < .0005, d = .42), and within the treated group, the subgroup with the Consistent pattern was 2.36 ± 1.13 cm shorter than the subgroup with the

  16. Structural equation modelling of viral tropism reveals its impact on achieving viral suppression within 6 months in treatment-naive HIV-1-infected patients after combination antiretroviral therapy.

    PubMed

    Mengoli, Carlo; Andreis, Samantha; Scaggiante, Renzo; Cruciani, Mario; Bosco, Oliviero; Ferretto, Roberto; Leoni, Davide; Maffongelli, Gaetano; Basso, Monica; Torti, Carlo; Sarmati, Loredana; Andreoni, Massimo; Palù, Giorgio; Parisi, Saverio Giuseppe

    2017-01-01

    To evaluate the role of pre-treatment co-receptor tropism of plasma HIV on the achievement of viral suppression (plasma HIV RNA 1.69 log10 copies/mL) at the sixth month of combination antiretroviral therapy (cART) in a cohort of naive patients using, for the first time in this context, a path analysis (PA) approach. Adult patients with chronic infection by subtype B HIV-1 were consecutively enrolled from the start of first-line cART (T0). Genotypic analysis of viral tropism was performed on plasma and interpreted using the bioinformatic tool Geno2pheno, with a false positive rate of 10%. A Bayesian network starting from the viro-immunological data at T0 and at the sixth month of treatment (T1) was set up and this model was evaluated using a PA approach. A total of 262 patients (22.1% bearing an X4 virus) were included; 178 subjects (67.9%) achieved viral suppression. A significant positive indirect effect of bearing X4 virus in plasma at T0 on log10 HIV RNA at T1 was detected (P = 0.009), the magnitude of this effect was, however, over 10-fold lower than the direct effect of log10 HIV RNA at T0 on log10 HIV RNA at T1 (P = 0.000). Moreover, a significant positive indirect effect of bearing an X4 virus on log10 HIV RNA at T0 (P = 0.003) was apparent. PA overcame the limitations implicit in common multiple regression analysis and showed the possible role of pre-treatment viral tropism at the recommended threshold on the outcome of plasma viraemia in naive patients after 6 months of therapy. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  17. Treatment of tumors with vitamin E suppresses myeloid derived suppressor cells and enhances CD8+ T cell-mediated antitumor effects.

    PubMed

    Kang, Tae Heung; Knoff, Jayne; Yeh, Wei-Hsi; Yang, Benjamin; Wang, Chenguang; Kim, Young Seob; Kim, Tae Woo; Wu, Tzyy-Choou; Hung, Chien-Fu

    2014-01-01

    Vitamin E has been shown to have strong anticarcinogenic properties, including antioxidant characteristics, making it an ideal candidate for use in combination with immunotherapies that modify the tumor microenvironment. The tumor microenvironment contains immunosuppressive components, which can be diminished, and immunogenic components, which can be augmented by immunotherapies in order to generate a productive immune response. In the current study, we employ the α-tocopherol succinate isomer of vitamin E to reduce immunosuppression by myeloid derived suppressor cells (MDSCs) as well as adoptive transfer of antigen-specific CD8+ T cells to generate potent antitumor effects against the HPV16 E7-expressing TC-1 tumor model. We show that vitamin E alone induces necrosis of TC-1 cells and elicits antitumor effects in TC-1 tumor-bearing mice. We further demonstrate that vitamin E reverses the suppression of T cell activation by MDSCs and that this effect is mediated in part by a nitric oxide-dependent mechanism. Additionally, treatment with vitamin E reduces the percentage of MDSCs in tumor loci, and induces a higher percentage of T cells, following T cell adoptive transfer. Finally, we demonstrate that treatment with vitamin E followed by E7-specific T cell adoptive transfer experience elicits potent antitumor effects in tumor-bearing mice. Our data provide additional evidence that vitamin E has anticancer properties and that it has promise for use as an adjuvant in combination with a variety of cancer therapies.

  18. ROS-induced nanotherapeutic approach for ovarian cancer treatment based on the combinatorial effect of photodynamic therapy and DJ-1 gene suppression.

    PubMed

    Schumann, Canan; Taratula, Olena; Khalimonchuk, Oleh; Palmer, Amy L; Cronk, Lauren M; Jones, Carson V; Escalante, Cesar A; Taratula, Oleh

    2015-11-01

    This study represents a novel approach for intraoperative ovarian cancer treatment based on the combinatorial effect of a targeted photodynamic therapy (PDT) associated with suppression of the DJ-1 protein, one of the key players in the ROS defense of cancer cells. To assess the potential of the developed therapy, dendrimer-based nanoplatforms for cancer-targeted delivery of near-infrared photosensitizer, phthalocyanine, and DJ-1 siRNA have been constructed. In vitro studies revealed that therapeutic efficacy of the combinatorial approach was enhanced when compared to PDT alone and this enhancement was more pronounced in ovarian carcinoma cells, which are characterized by higher basal levels of DJ-1 protein. Moreover, the ovarian cancer tumors exposed to a single dose of combinatorial therapy were completely eradicated from the mice and the treated animals showed no evidence of cancer recurrence. Thus, the developed therapeutic approach can be potentially employed intraoperatively to eradicate unresactable cancer cells. The complete clearance of microscopic residual tumor cells during excision surgery is important to improve survival of the patient. In this interesting paper, the authors developed a novel approach using targeted photodynamic therapy (PDT), combining a photosensitizer, phthalocyanine, and DJ-1 siRNA for the treatment of ovarian cancer. The data showed that this approach increased cancer cell killing and may pave way for future clinical studies. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Antiviral drug valacyclovir treatment combined with a clean feeding system enhances the suppression of salivary gland hypertrophy in laboratory colonies of Glossina pallidipes.

    PubMed

    Abd-Alla, Adly Mm; Marin, Carmen; Parker, Andrew G; Vreysen, Marc Jb

    2014-05-08

    Hytrosaviridae cause salivary gland hypertrophy (SGH) syndrome in some infected tsetse flies (Diptera: Glossinidae). Infected male and female G. pallidipes with SGH have a reduced fecundity and fertility. Due to the deleterious impact of the virus on G. pallidipes colonies, adding the antiviral drug valacyclovir to the blood diet and changing the feeding regime to a clean feeding system (each fly receives for each feeding a fresh clean blood meal) have been investigated to develop virus management strategies. Although both approaches used alone successfully reduced the virus load and the SGH prevalence in small experimental groups, considerable time was needed to obtain the desired SGH reduction and both systems were only demonstrated with colonies that had a low initial virus prevalence (SGH ≤ 10%). As problems with SGH are often only recognized once the incidence is already high, it was necessary to demonstrate that this combination would also work for high prevalence colonies. Combining both methods at colony level successfully suppressed the SGH in G. pallidipes colonies that had a high initial virus prevalence (average SGH of 24%). Six months after starting the combined treatment SGH symptoms were eliminated from the treated colony, in contrast to 28 months required to obtain the same results using clean feeding alone and 21 months using antiviral drug alone. Combining valacyclovir treatment with the clean feeding system provides faster control of SGH in tsetse than either method alone and is effective even when the initial SGH prevalence is high.

  20. Effect of combined treatment with salvage radiotherapy plus androgen suppression on quality of life in patients with recurrent prostate cancer after radical prostatectomy

    SciTech Connect

    Pearce, Andrew; Choo, Richard . E-mail: choo.c@mayo.edu; Danjoux, Cyril; Morton, Gerard; Loblaw, D. Andrew; Szumacher, Ewa; Cheung, Patrick; Deboer, Gerrit; Chander, Sarat

    2006-05-01

    Purpose: To examine the effect of salvage radiotherapy (RT) plus 2-year androgen suppression (AS) on quality of life (QOL). Methods and Materials: A total of 74 patients with biopsy-proven local recurrence or PSA relapse after radical prostatectomy were treated with salvage RT plus 2-year AS, as per a phase II study. Quality of life was prospectively assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-Item Version 3.0 with the added prostate cancer-specific module at baseline and predefined follow-up visits. Results: Patients experienced a significant increase in bowel dysfunction (23%) by the end of RT (p < 0.0001). This bowel dysfunction improved after RT but remained slightly elevated (5-10%) throughout the 2-year AS period. This extent of residual bowel dysfunction would be considered of minimal clinical importance. A similar, but less pronounced, pattern of change did occur for urinary dysfunction. Erectile function showed no change during RT, but had an abrupt decline (10%) with initiation of AS that was of moderate clinical significance (p < 0.01). None of the other QOL domains demonstrated a persistent, significant change from baseline that would be considered of major clinical significance. Conclusion: The combined treatment with salvage RT plus 2-year AS had relatively minor long-term effects on QOL.

  1. Antiviral drug valacyclovir treatment combined with a clean feeding system enhances the suppression of salivary gland hypertrophy in laboratory colonies of Glossina pallidipes

    PubMed Central

    2014-01-01

    Background Hytrosaviridae cause salivary gland hypertrophy (SGH) syndrome in some infected tsetse flies (Diptera: Glossinidae). Infected male and female G. pallidipes with SGH have a reduced fecundity and fertility. Due to the deleterious impact of the virus on G. pallidipes colonies, adding the antiviral drug valacyclovir to the blood diet and changing the feeding regime to a clean feeding system (each fly receives for each feeding a fresh clean blood meal) have been investigated to develop virus management strategies. Although both approaches used alone successfully reduced the virus load and the SGH prevalence in small experimental groups, considerable time was needed to obtain the desired SGH reduction and both systems were only demonstrated with colonies that had a low initial virus prevalence (SGH ≤ 10%). As problems with SGH are often only recognized once the incidence is already high, it was necessary to demonstrate that this combination would also work for high prevalence colonies. Findings Combining both methods at colony level successfully suppressed the SGH in G. pallidipes colonies that had a high initial virus prevalence (average SGH of 24%). Six months after starting the combined treatment SGH symptoms were eliminated from the treated colony, in contrast to 28 months required to obtain the same results using clean feeding alone and 21 months using antiviral drug alone. Conclusions Combining valacyclovir treatment with the clean feeding system provides faster control of SGH in tsetse than either method alone and is effective even when the initial SGH prevalence is high. PMID:24886248

  2. Treatment of platelets with riboflavin and ultraviolet light mediates complement activation and suppresses monocyte interleukin-12 production in whole blood.

    PubMed

    Loh, Y S; Dean, M M; Johnson, L; Marks, D C

    2015-11-01

    Pathogen inactivation (PI) and storage may alter the immunomodulatory capacity of platelets (PLTs). The aim of this study was to examine the effect of PI (Riboflavin and ultraviolet light treatment) and storage on the capacity of PLTs to induce cytokine responses in recipient inflammatory cells. A pool and split design was used to prepare untreated and PI-treated buffy coat-derived platelet concentrates (PCs). Samples were taken on days 2 and 7 postcollection and incubated with ABO/RhD-matched fresh whole blood for 6 h with or without lipopolysaccharide (LPS). The intracellular production of IP-10, MCP-1, MIP-1α, IL-8, IL-6, IL-10, IL-12, TNF-α and MIP-1β in monocytes and neutrophils was assessed using flow cytometry. Complement proteins in PLT supernatants were measured using a cytometric bead array. PLTs and PLT supernatant (both untreated and PI-treated) resulted in modulation of intracellular MIP-1β and IL-12 production in monocytes. Compared to untreated PLTs, PI-treated PLTs resulted in significantly lower LPS-induced monocyte IL-12 production (day 7). The concentration of C3a and C5a (and their desArg forms) was significantly increased in PLT supernatants following PI. PI results in decreased LPS-induced monocyte IL-12 production and increased complement activation. The association between platelet-induced complement activation and IL-12 production warrants further investigation. © 2015 International Society of Blood Transfusion.

  3. Improved Antisense Oligonucleotide Design to Suppress Aberrant SMN2 Gene Transcript Processing: Towards a Treatment for Spinal Muscular Atrophy

    PubMed Central

    Mitrpant, Chalermchai; Porensky, Paul; Zhou, Haiyan; Price, Loren; Muntoni, Francesco; Fletcher, Sue; Wilton, Steve D.; Burghes, Arthur H. M.

    2013-01-01

    Spinal muscular atrophy (SMA) is caused by loss of the Survival Motor Neuron 1 (SMN1) gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene (or genes) that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMNΔ7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides (PMO) that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV. PMID:23630626

  4. Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparins.

    PubMed Central

    Lider, O; Baharav, E; Mekori, Y A; Miller, T; Naparstek, Y; Vlodavsky, I; Cohen, I R

    1989-01-01

    The ability of activated T lymphocytes to penetrate the extracellular matrix and migrate to target tissues was found to be related to expression of a heparanase enzyme (Naparstek, Y., I. R. Cohen, Z. Fuks, and I. Vlodavsky. 1984. Nature (Lond.). 310:241-243; Savion, N., Z. Fuks, and I. Vlodavsky. 1984. J. Cell. Physiol. 118:169-176; Fridman, R., O. Lider, Y. Naparstek, Z. Fuks, I. Vlodavsky, and I. R. Cohen. 1987. J. Cell. Physiol. 130:85-92; Lider, O., J. Mekori, I. Vlodavsky, E. Baharav, Y. Naparstek, and I. R. Cohen, manuscript submitted for publication). We found previously that heparin molecules inhibited expression of T lymphocyte heparanase activity in vitro and in vivo, and administration of a low dose of heparin in mice inhibited lymphocyte traffic and delayed-type hypersensitivity reactions (Lider, O., J. Mekori, I. Vlodavsky, E. Baharav, Y. Naparstek, and I. R. Cohen, manuscript submitted for publication). We now report that treatment with commercial or chemically modified heparins at relatively low doses once daily (5 micrograms for mice and 20 micrograms for rats) led to inhibition of allograft rejection and the experimental autoimmune diseases adjuvant arthritis and experimental autoimmune encephalomyelitis. Higher doses of the heparins were less effective. The ability of chemically modified heparins to inhibit these immune reactions was associated with their ability to inhibit expression of T lymphocyte heparanase. There was no relationship to anticoagulant activity. Thus heparins devoid of anticoagulant activity can be effective in regulating immune reactions when used at appropriate doses. PMID:2493485

  5. Oral treatment with herbal formula B307 alleviates cardiac failure in aging R6/2 mice with Huntington's disease via suppressing oxidative stress, inflammation, and apoptosis.

    PubMed

    Lin, Ching-Lung; Wang, Sheue-Er; Hsu, Chih-Hsiang; Sheu, Shuenn-Jyi; Wu, Chung-Hsin

    2015-01-01

    Cardiac failure is often observed in aging patients with Huntington's disease (HD). However, conventional pharmacological treatments for cardiac failure in HD patients have rarely been studied. Chinese herbal medicines, especially combined herbal formulas, have been widely used to treat cardiac dysfunctions over the centuries. Thus, we assess whether oral treatment with herbal formula B307 can alleviate cardiac failure in transgenic mice with HD. After oral B307 or vehicle treatment for 2 weeks, cardiac function and cardiomyocytes in 12-week-old male R6/2 HD mice and their wild-type littermate controls (WT) were examined and then compared via echocardiography, immunohistochemistry, and Western blotting. We found that cardiac performance in aging R6/2 HD mice had significantly deteriorated in comparison with their WT (P<0.01). Cardiac expressions of superoxide dismutase 2 (SOD2) and B-cell lymphoma 2 (Bcl-2) in aging R6/2 HD mice were significantly lower than their WT (P<0.01), but cardiac expressions of tumor necrosis factor alpha (TNF-α), neurotrophin-3 (3-NT), 4-hydroxynonenal (4-HNE), Bcl-2-associated X protein (Bax), calpain, caspase 12, caspase 9, and caspase 3 of aging R6/2 HD mice were significantly higher than their WT (P<0.05). Furthermore, we found that cardiac performance in aging R6/2 HD mice had significantly improved under oral B307 treatment (P<0.05). Cardiac expressions of SOD2 and Bcl-2 of aging R6/2 HD mice were significantly higher under oral B307 treatment (P<0.01), but cardiac expressions of TNF-α, 3-NT, 4-HNE, Bax, calpain, caspase 12, caspase 9, and caspase 3 of aging R6/2 HD mice were significantly reduced under oral B307 treatment (P<0.05). Oral B307 treatment may briefly alleviate cardiac failure in aging HD R6/2 mice via suppressing cardiac oxidative stress, inflammation, and apoptosis. We suggested that the herbal formula B307 may be further developed as a potential health supplement for ameliorating cardiac failure associated with

  6. Suppression of rat and human androgen biosynthetic enzymes by apigenin: Possible use for the treatment of prostate cancer.

    PubMed

    Wang, Xiudi; Wang, Guimin; Li, Xiaoheng; Liu, Jianpeng; Hong, Tingting; Zhu, Qiqi; Huang, Ping; Ge, Ren-Shan

    2016-06-01

    Apigenin is a natural flavone. It has recently been used as a chemopreventive agent. It may also have some beneficial effects to treat prostate cancer by inhibiting androgen production. The objective of the present study was to investigate the effects of apigenin on the steroidogenesis of rat immature Leydig cells and some human testosterone biosynthetic enzyme activities. Rat immature Leydig cells were incubated for 3h with 100μM apigenin without (basal) or with 1ng/ml luteinizing hormone (LH), 10mM 8-bromoadenosine 3',5'-cyclic monophosphate (8BR), and 20μM of the following steroid substrates: 22R-hydroxychloesterol (22R), pregnenolone (P5), progesterone (P4), and androstenedione (D4). The medium levels of 5α-androstane-3α, 17β-diol (DIOL), the primary androgen produced by rat immature Leydig cells, were measured. Apigenin significantly inhibited basal, 8BR, 22R, PREG, P4, and D4 stimulated DIOL production in rat immature Leydig cells. Further study showed that apigenin inhibited rat 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase/17, 20-lyase, and 17β-hydroxysteroid dehydrogenase 3 with IC50 values of 11.41±0.7, 8.98±0.10, and 9.37±0.07μM, respectively. Apigenin inhibited human 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 with IC50 values of 2.17±0.04 and 1.31±0.09μM, respectively. Apigenin is a potent inhibitor of rat and human steroidogenic enzymes, being possible use for the treatment of prostate cancer.

  7. PEDF expression is inhibited by insulin treatment in adipose tissue via suppressing 11β-HSD1.

    PubMed

    Zhou, Yinli; Xu, Fen; Deng, Hongrong; Bi, Yan; Sun, Weiping; Zhao, Yi; Chen, Zonglan; Weng, Jianping

    2013-01-01

    Early intensive insulin therapy improves insulin sensitivity in type 2 diabetic patients; while the underlying mechanism remains largely unknown. Pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, is believed to be involved in the pathogenesis of insulin resistance. Here, we hypothesize that PEDF might be down regulated by insulin and then lead to the improved insulin resistance in type 2 diabetic patients during insulin therapy. We addressed this issue by investigating insulin regulation of PEDF expression in diabetic conditions. The results showed that serum PEDF was reduced by 15% in newly diagnosed type 2 diabetic patients after insulin therapy. In adipose tissue of diabetic Sprague-Dawley rats, PEDF expression was associated with TNF-α elevation and it could be decreased both in serum and in adipose tissue by insulin treatment. In adipocytes, PEDF was induced by TNF-α through activation of NF-κB. The response was inhibited by knockdown and enhanced by over expression of NF-κB p65. However, PEDF expression was indirectly, not directly, induced by NF-κB which promoted 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) expression in adipocytes. 11β-HSD1 is likely to stimulate PEDF expression through production of active form of glucocorticoids as dexamethasone induced PEDF expression in adipose tissue. Insulin inhibited PEDF by down-regulating 11β-HSD1 expression. The results suggest that PEDF activity is induced by inflammation and decreased by insulin through targeting 11β-HSD1/glucocorticoid pathway in adipose tissue of diabetic patients.

  8. Tamoxifen with ovarian function suppression versus tamoxifen alone as an adjuvant treatment for premenopausal breast cancer: a meta-analysis of published randomized controlled trials

    PubMed Central

    Yan, Shunchao; Li, Kai; Jiao, Xin; Zou, Huawei

    2015-01-01

    Background Ovarian function suppression (OFS) significantly downregulates the concentration of plasma estrogens. However, it is unclear whether it offers any survival benefits if combined with adjuvant tamoxifen treatment in premenopausal women. This meta-analysis was designed to assess data from previous studies involving adjuvant tamoxifen treatment plus OFS in premenopausal breast cancer. Methods Electronic literature databases (PubMed, Embase, the Web of Science, and the Cochrane Library) were searched for relevant randomized controlled trials published prior to February 1, 2015. Only randomized controlled trials that compared tamoxifen alone with tamoxifen plus OFS for premenopausal women with breast cancer were selected. The evaluated endpoints were disease-free survival and overall survival. Results Four randomized controlled trials comprising 6,279 patients (OFS combination, n=3,133; tamoxifen alone, n=3,146) were included in the meta-analysis. There was no significant improvement in disease-free survival or overall survival with addition of OFS in either the whole population or the hormone receptor-positive subgroup. The risk of distant recurrence was not reduced with the addition of OFS in the whole population. A subgroup analysis showed that addition of OFS significantly improved overall survival in patients who were administered chemotherapy. Conclusion Based on the available studies, concurrent administration of OFS and adjuvant tamoxifen treatment for premenopausal women with breast cancer has no effect on prolonging disease-free survival and overall survival, excluding patients who were administered chemotherapy. It should not be widely recommended, except perhaps for women who were hormone-receptor positive and who were also administered adjuvant chemotherapy. PMID:26109867

  9. Treatment of steroid-induced osteonecrosis of the femoral head using porous Se@SiO2 nanocomposites to suppress reactive oxygen species

    NASA Astrophysics Data System (ADS)

    Deng, Guoying; Niu, Kerun; Zhou, Feng; Li, Buxiao; Kang, Yingjie; Liu, Xijian; Hu, Junqing; Li, Bo; Wang, Qiugen; Yi, Chengqing; Wang, Qian

    2017-03-01

    Reducing oxidative stress (ROS) have been demonstrated effective for steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH). Selenium (Se) plays an important role in suppressing oxidative stress and has huge potential in ONFH treatments. However the Se has a narrow margin between beneficial and toxic effects which make it hard for therapy use in vivo. In order to make the deficiency up, a control release of Se (Se@SiO2) were realized by nanotechnology modification. Porous Se@SiO2 nanocomposites have favorable biocompatibility and can reduced the ROS damage effectively. In vitro, the cck-8 analysis, terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) stain and flow cytometry analysis showed rare negative influence by porous Se@SiO2 nanocomposites but significantly protective effect against H2O2 by reducing ROS level (detected by DCFH-DA). In vivo, the biosafety of porous Se@SiO2 nanocomposites were confirmed by the serum biochemistry, the ROS level in serum were significantly reduced and the curative effect were confirmed by Micro CT scan, serum Elisa assay (inflammatory factors), Western blotting (quantitative measurement of ONFH) and HE staining. It is expected that the porous Se@SiO2 nanocomposites may prevent steroid-induced ONFH by reducing oxidative stress.

  10. Treatment of steroid-induced osteonecrosis of the femoral head using porous Se@SiO2 nanocomposites to suppress reactive oxygen species

    PubMed Central

    Deng, Guoying; Niu, Kerun; Zhou, Feng; Li, Buxiao; Kang, Yingjie; Liu, Xijian; Hu, Junqing; Li, Bo; Wang, Qiugen; Yi, Chengqing; Wang, Qian

    2017-01-01

    Reducing oxidative stress (ROS) have been demonstrated effective for steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH). Selenium (Se) plays an important role in suppressing oxidative stress and has huge potential in ONFH treatments. However the Se has a narrow margin between beneficial and toxic effects which make it hard for therapy use in vivo. In order to make the deficiency up, a control release of Se (Se@SiO2) were realized by nanotechnology modification. Porous Se@SiO2 nanocomposites have favorable biocompatibility and can reduced the ROS damage effectively. In vitro, the cck-8 analysis, terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) stain and flow cytometry analysis showed rare negative influence by porous Se@SiO2 nanocomposites but significantly protective effect against H2O2 by reducing ROS level (detected by DCFH-DA). In vivo, the biosafety of porous Se@SiO2 nanocomposites were confirmed by the serum biochemistry, the ROS level in serum were significantly reduced and the curative effect were confirmed by Micro CT scan, serum Elisa assay (inflammatory factors), Western blotting (quantitative measurement of ONFH) and HE staining. It is expected that the porous Se@SiO2 nanocomposites may prevent steroid-induced ONFH by reducing oxidative stress. PMID:28256626

  11. Bcl-2 anti-apoptotic oncoprotein suppresses angiogenesis in non-small cell lung cancer: implications in resistance to photodynamic treatment?

    NASA Astrophysics Data System (ADS)

    Koukourakis, M. I.; Giatromanolaki, A.; Skarlatos, J.; Kosma, L.; Apostolikas, N.; Beroukas, K.

    1998-07-01

    PDT cytotoxicity is likely to occur through photooxidative reactions. In that way mechanisms that define poor oxygenation should be involved in defining resistance to photo-dynamic treatment (PDT). On the other hand bcl-2 anti- apoptotic protein has been shown to delay cell death and protect cells from toxic oxidative products. We examined 134 specimens from T1,2-NO,1 staged patients treated with surgery alone. Specimens were immunohistochemically examined for vascular grade using the JC70 MoAb, and bcl-2 oncoprotein expression. Bcl-2 expression correlated with low vascular grade. Only 3/27 of bcl2+ case had high angiogenesis vs. 34/107 of cases without bcl-2 expression. In the present study we provide evidence that bcl-2 overexpression directly suppresses angiogenesis in non-small cell lung cancer, which obviously results in decreased blood supply and oxygenation. This finding implies that reduced intratumoral angiogenesis and immortalizing oncoprotein overexpression are linked to each other and may have a role in defining tumors resistant to PDT.

  12. Treatment of steroid-induced osteonecrosis of the femoral head using porous Se@SiO2 nanocomposites to suppress reactive oxygen species.

    PubMed

    Deng, Guoying; Niu, Kerun; Zhou, Feng; Li, Buxiao; Kang, Yingjie; Liu, Xijian; Hu, Junqing; Li, Bo; Wang, Qiugen; Yi, Chengqing; Wang, Qian

    2017-03-03

    Reducing oxidative stress (ROS) have been demonstrated effective for steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH). Selenium (Se) plays an important role in suppressing oxidative stress and has huge potential in ONFH treatments. However the Se has a narrow margin between beneficial and toxic effects which make it hard for therapy use in vivo. In order to make the deficiency up, a control release of Se (Se@SiO2) were realized by nanotechnology modification. Porous Se@SiO2 nanocomposites have favorable biocompatibility and can reduced the ROS damage effectively. In vitro, the cck-8 analysis, terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) stain and flow cytometry analysis showed rare negative influence by porous Se@SiO2 nanocomposites but significantly protective effect against H2O2 by reducing ROS level (detected by DCFH-DA). In vivo, the biosafety of porous Se@SiO2 nanocomposites were confirmed by the serum biochemistry, the ROS level in serum were significantly reduced and the curative effect were confirmed by Micro CT scan, serum Elisa assay (inflammatory factors), Western blotting (quantitative measurement of ONFH) and HE staining. It is expected that the porous Se@SiO2 nanocomposites may prevent steroid-induced ONFH by reducing oxidative stress.

  13. Topical glucocorticoid or pimecrolimus treatment suppresses thymic stromal lymphopoietin-related allergic inflammatory mechanism in an oxazolone-induced atopic dermatitis murine model.

    PubMed

    Yoon, Na Young; Jung, Min young; Kim, Dong Hye; Lee, Hae Jin; Choi, Eung Ho

    2015-09-01

    Congenitally or early impaired skin barrier as the first event starting the 'atopic march' in atopic dermatitis (AD) patients can increase allergen penetration that results in sensitization, even in the airways, followed by asthma and allergic rhinitis. Thymic stromal lymphopoietin (TSLP) is a cytokine existing in high levels in AD skin and is considered as a novel therapeutic target for atopic disease. We generated oxazolone (Ox)-induced AD-like (Ox-AD) hairless mice and divided them into four groups according to the therapeutic challenges: topical glucocorticoid, pimecrolimus, emollient, and control (acetone-only treated). We assessed the functional studies of skin barrier, epidermal expressions of differentiation markers, IL-1α, TNF-α, proteinase-activated receptor-2 (PAR-2), TSLP and antimicrobial peptides (AMP), and serum IgE in each group. Topical glucocorticoid or pimecrolimus treatment improved AD-like skin lesions and barrier functions, and restored the epidermal expression of differentiation markers, IL-1α, TNF-α, PAR-2, and TSLP, in Ox-AD mice. The improvement was relatively better with the glucocorticoid than pimecrolimus. Epidermal AMP expression was restored by topical glucocorticoid, but not pimecrolimus. Our result showed that topical glucocorticoid or pimecrolimus improved the AD-like skin lesions and barrier impairment by suppressing TSLP-related allergic inflammation.

  14. Early antiretroviral treatment (eART) limits viral diversity over time in a long-term HIV viral suppressed perinatally infected child.

    PubMed

    Palma, Paolo; Zangari, Paola; Alteri, Claudia; Tchidjou, Hyppolite K; Manno, Emma Concetta; Liuzzi, Giuseppina; Perno, Carlo Federico; Rossi, Paolo; Bertoli, Ada; Bernardi, Stefania

    2016-12-09

    HIV genetic diversity implicates major challenges for the control of viral infection by the immune system and for the identification of an effective immunotherapeutic strategy. With the present case report we underline as HIV evolution could be effectively halted by early antiretroviral treatment (eART). Few cases supported this evidence due to the difficulty of performing amplification and sequencing analysis in long-term viral suppressed patients. Here, we reported the case of limited HIV-1 viral evolution over time in a successful early treated child. A perinatally HIV-1 infected infant was treated within 7 weeks of age with zidovudine, lamivudine, nevirapine and lopinavir/ritonavir. At antiretroviral treatment (ART) initiation HIV-1 viral load (VL) and CD4 percentage were >500,000 copies/ml and 35%, respectively. Plasma genotypic resistance test showed a wild-type virus. The child reached VL undetectability after 33 weeks of combination antiretroviral therapy (cART) since he maintained a stable VL <40copies/ml. After 116 weeks on ART we were able to perform amplification and sequencing assay on the plasma virus. At this time VL was <40 copies/ml and CD4 percentage was 40%. Again the genotypic resistance test revealed a wild-type virus. The phylogenetic analysis performed on the HIV-1 pol sequences of the mother and the child revealed that sequences clustered with C subtype reference strains and formed a monophyletic cluster distinct from the other C sequences included in the analysis (bootstrap value >90%). Any major evolutionary divergence was detected. eART limits the viral evolution avoiding the emergence of new viral variants. This result may have important implications in host immune control and may sustain the challenge search of new personalized immunotherapeutic approaches to achieve a prolonged viral remission.

  15. Economic implications of entecavir treatment in suppressing viral replication in chronic hepatitis B (CHB) patients in China from a perspective of the Chinese Social Security program.

    PubMed

    Yuan, Yong; Iloeje, Uchenna; Li, Hong; Hay, Joel; Yao, Guang B

    2008-03-01

    Of estimated 112 million persons infected with chronic hepatitis B (CHB) in China, 15% to 40% will eventually develop liver complications. Most patients do not actively seek antiviral agents for treatment due in part to lack of good understanding of the disease. Entecavir is a new therapeutic option for CHB patients and the purpose of this study was to evaluate the cost-effectiveness of entecavir treatment in China, based on projected clinical benefits from its superior viral suppression efficacy. The analysis was based on the perspective of the Chinese Social Security program. Adjusted relative risks on the association between viral load (VL) and clinical end points (liver cirrhosis/hepatocellular carcinoma) were derived from a publication of a Taiwan CHB prospective cohort with 42,115 person-years of follow-up, and applied to patients enrolled in a randomized phase III trial in China. In this trial, hepatitis B virus (HBV) DNA (by polymerase chain reaction assay) was the key efficacy end point after 48 weeks of treatment with either entecavir or lamivudine monotherapy. Entecavir and lamivudine daily prices were assumed to be Renminbi Yuan (RMB) 40 and 16.71, respectively. Life expectancy tables were based on China vital statistics. Direct medical cost and utility scores for different phases of CHB were estimated from published China specific data, and costs were adjusted to 2006 values using the Chinese Consumer Price Index. Probabilistic sensitivity analyses were conducted to evaluate parameter uncertainty on event distribution and treatment failure rates beyond the trial period. A total of 519 subjects were enrolled in the study, comprising of 82% males, 87% HBeAg+, and a mean age of 30 years. Based on the efficacy measurement of the percentage of patients achieving HBV DNA <300 copies/ml at week 48, entecavir was superior to lamivudine (78.7% vs. 46.7%, respectively [P < 0.05]). In the base case, compared with lamivudine, 1 year of entecavir therapy gained 0

  16. Prazosin-related compounds. Effect of transforming the piperazinylquinazoline moiety into an aminomethyltetrahydroacridine system on the affinity for alpha1-adrenoreceptors.

    PubMed

    Rosini, Michela; Antonello, Alessandra; Cavalli, Andrea; Bolognesi, Maria L; Minarini, Anna; Marucci, Gabriella; Poggesi, Elena; Leonardi, Amedeo; Melchiorre, Carlo

    2003-11-06

    In a search for structurally new alpha(1)-adrenoreceptor (alpha(1)-AR) antagonists, prazosin (1)-related compounds 2-11 were synthesized and their affinity profiles were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO cells expressing human cloned alpha(1)-AR subtypes. Transformation of the piperazinylquinazoline moiety of 1 into an aminomethyltetrahydroacridine system afforded compound 2, endowed with reduced affinity, in particular for the alpha(1A)-AR subtype. Then, to investigate the optimal features of the tricyclic moiety, the aliphatic ring of 2 was modified by synthesizing the lower and higher homologues 3 and 4. An analysis of the pharmacological profile, together with a molecular modeling study, indicated the tetrahydroacridine moiety as the most promising skeleton for alpha(1)-antagonism. Compounds 5-8, where the replacement of the furoyl group of 2 with a benzoyl moiety afforded the possibility to evaluate the effect of the substituent trifluoromethyl on receptor binding, resulted, except for 7, in a rather surprising selectivity toward alpha(1B)-AR, in particular vs the alpha(1A) subtype. Also the insertion of the 2,6-dimethoxyphenoxyethyl function of WB 4101 on the tetrahydroacridine skeleton of 2, and/or the replacement of the aromatic amino function with a hydroxy group, affording derivatives 9-11, resulted in alpha(1B)-AR selectivity also vs the alpha(1D) subtype. On the basis of these results, the tetrahydroacridine moiety emerged as a promising tool for the characterization of the alpha(1)-AR, owing to the receptor subtype selectivity achieved by an appropriate modification of the lateral substituents.

  17. Randomised clinical trial: mucosal protection combined with acid suppression in the treatment of non-erosive reflux disease - efficacy of Esoxx, a hyaluronic acid-chondroitin sulphate based bioadhesive formulation.

    PubMed

    Savarino, V; Pace, F; Scarpignato, C

    2017-03-01

    Several studies have shown that patients with non-erosive reflux disease (NERD) are less responsive to proton pump inhibitors (PPIs) than those with erosive disease as they belong to different subgroups, in whom factors other than acid can trigger symptoms. To evaluate whether combined therapy (mucosal protection plus acid suppression) would improve symptom relief compared to PPI treatment alone. In a multicenter, randomised, double-blind trial, 154 patients with NERD were randomised to receive Esoxx (Alfa Wassermann, Bologna, Italy), a hyaluronic acid-chondroitin sulphate based bioadhesive formulation, or placebo, in addition to acid suppression with standard dose PPIs for 2 weeks. Symptoms (heartburn, acid regurgitation, retrosternal pain and acid taste in the mouth) and health-related quality of life (HRQL) were evaluated before and after treatment. The primary endpoint was the proportion of patients with at least a 3-point reduction in the total symptom score. At the end of treatment, the primary endpoint was reached by 52.6% of patients taking Esoxx compared to 32.1% of those given placebo (P < 0.01). The same was true also for HRQL, evaluated by means of the Short Form-36 questionnaire, which improved with both treatments, but some items were significantly better after Esoxx plus PPI therapy. The synergistic effect of Essox with PPI treatment suggests that mucosal protection added to acid suppression could improve symptoms and HRQL in NERD patients. © 2017 The Authors. Alimentary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.

  18. Evaluation of the clinical efficacy of Gonazon implants in the treatment of reproductive pathologies, behavioral problems, and suppression of reproductive function in the male dog.

    PubMed

    Goericke-Pesch, S; Wilhelm, E; Ludwig, C; Desmoulins, P O; Driancourt, M A; Hoffmann, B

    2010-04-15

    Efficacy of a slow-release gonadotropin-releasing hormone (GnRH)-agonist implant (Gonazon) was assessed in 53 male dogs presented with benign prostatic hyperplasia (BPH), hypersexuality, aggressive behavior (either alone or in combination), excessive micturition, or to suppress fertility. Changes in testosterone (T) and estradiol (E2) concentrations and size of testes and prostate were monitored on Weeks 0, +8, and +26 after implantation. Additional measurements during and after this period were performed in 35 dogs. Clinical signs were assessed by the owners. All implants except one were retained throughout the study. Full downregulation of testicular function (T<0.35 nmol/L) was achieved in 46 dogs, five dogs showed partial downregulation (T = 0.36 to 0.47 nmol/L), one dog did not respond, and another one displayed a transient downregulation on Week +18. On Week +8, mean T and E2 levels were reduced by 96% and 62%, respectively, and did not further decrease. Full downregulation (T<0.35 nmol/L) lasted between 6 to >22 mo in most dogs except two. Compared with pretreatment values, mean testicular and prostatic size was reduced (P<0.00001) by 54% and 52%, respectively, on Week +8 and by 68% and 64%, respectively, on Week +26. Relative reduction of prostatic size was more marked in dogs with BPH than in healthy ones on Week +8 (P<0.05) and Week +26 (P<0.02), and clinical signs of BPH disappeared rapidly after implantation. Dogs affected with BPH were significantly older (P<0.001) than nonaffected ones (9.7 vs. 2.5 yr). Hypersexuality was more common in dogs<3 yr of age, and treatment clearly improved clinical signs. Age significantly affected the response to treatment in aggressive dogs; 75% of the cases responded with an improvement. The only minor and possibly treatment-related events observed were a short-lasting exacerbation of clinical signs of BPH (two dogs), increased weight gain (three dogs), and anxiety (three dogs) with one of these dogs developing a blunt

  19. Disparities in Initiation of Combination Antiretroviral Treatment and in Virologic Suppression Among Patients in the HIV Outpatient Study, 2000-2013.

    PubMed

    Novak, Richard M; Hart, Rachel L D; Chmiel, Joan S; Brooks, John T; Buchacz, Kate

    2015-09-01

    The National HIV/AIDS Strategy emphasizes virologic suppression (VS) to reduce HIV incidence in the United States. We assessed temporal trends of and disparities in time to combination antiretroviral therapy (cART) initiation and HIV VS in a large demographically diverse cohort of HIV-infected patients. We included antiretroviral-naive HIV Outpatient Study participants from 2000 to 2013 enrolled within 6 months of their HIV diagnosis who attended ≥2 HIV care-related visits. We evaluated time from HIV diagnosis to first use of cART, time from HIV diagnosis to VS, and time from first use of cART to VS. Kaplan-Meier time-to-event curves and Cox proportional hazards models were used to assess temporal trends and correlates of initiating cART and achieving HIV VS (<500 copies per milliliter). Among 1156 HIV Outpatient Study patients [median age, 37 years; 43.2% non-Hispanic/Latino black (NHB), 14.1% Hispanic/Latino], estimated median times from HIV diagnosis to cART initiation and from HIV diagnosis to VS both shortened by >40% during the 13.5-year study period, reaching, respectively, 2.5 and 5.4 months. In multivariable analyses, NHB patients (as compared with non-Hispanic/Latino white) and those who had injected drugs (as compared with those who did not) initiated cART in a less timely fashion. After adjusting for CD4 cell count and viral load at cART initiation, NHB patients and those aged <30 years (compared with ≥40 years) had lower rates of VS. Despite improvements in HIV treatment over time, patients who were NHB, younger, or used injection drugs had less favorable outcomes.

  20. Combination External Beam Radiation and Brachytherapy Boost With Androgen Suppression for Treatment of Intermediate-Risk Prostate Cancer: An Initial Report of CALGB 99809

    SciTech Connect

    Hurwitz, Mark D.; McGinnis, Lamar S.; Keuttel, Michael R.; DiBiase, Steven J.; Small, Eric J.

    2008-11-01

    Purpose: Transperineal prostate brachytherapy (TPPB) can be used with external beam radiation therapy (EBRT) to provide a high-dose conformal boost to the prostate. The results of a multicenter Phase II trial assessing safety of combination of EBRT and TPPB boost with androgen suppression (AST) in treatment of intermediate-risk prostate cancer are present here. Materials and Methods: Patients had intermediate-risk prostate cancer. Six months of AST was administered. EBRT to the prostate and seminal vesicles was administered to 45Gy followed by TPPB using either {sup 125}I or {sup 103}Pd to deliver an additional 100Gy or 90Gy. Toxicity was graded using the National Cancer Institute CTC version 2 and the Radiation Therapy Oncology Group late radiation morbidity scoring systems. Results: Sixty-three patients were enrolled. Median follow-up was 38 months. Side effects of AST including sexual dysfunction and vasomotor symptoms were commonly observed. Apart from erectile dysfunction, short-term Grade 2 and 3 toxicity was noted in 21% and 7%, primarily genitourinary related. Long-term Grade 2 and 3 toxicities were noted in 13% and 3%. Two patients had Grade 3 dysuria that resolved with longer follow-up. The most common Grade 2 long-term toxicity was urinary frequency (5%). No biochemical or clinical evidence of progression was noted for the entire cohort. Conclusions: In a cooperative group setting, combination EBRT and TPPB boost with 6 months of AST was generally well tolerated with expected genitourinary and gastrointestinal toxicities. Further follow-up will be required to fully assess long-term toxicity and cancer control.

  1. Tamsulosin: assessment of affinity of 3H-prazosin bindings to two alpha1-adrenoceptor subtypes (alpha1H and alpha1L) in bovine prostate and rat heart and brain.

    PubMed

    Maruyama, K; Nakamura, T; Yoshihara, T; Fukutomi, J; Sugiyama, K; Hattorim, K; Ohnuki, T; Watanabe, K; Nagatomo, T

    1998-10-01

    1. The present study was designed to assess the displacement potencies of tamsulosin to 3H-prazosin bindings in two alpha1-adrenoceptor (AR) subtypes (alpha1H and alpha1L) in bovine prostate, rat heart and brain compared with those of amosulalol, labetalol, ketanserin, clonidine and propranolol. 2. The pKi values of tamsulosin to alpha1H and alpha1L subtypes in bovine prostate were 9.13 and 8.99 and these values were almost the same as those of prazosin. On the other hand, low pKi binding values of amosulalol, labetalol, ketanserin, clonidine and propranolol to these subtypes were observed. 3. Low pKi values of tamsulosin to alpha2- and beta-ARs and muscarinic and 5HT2 receptors in the rat brain were observed. 4. These results suggest that tamsulosin has high affinities to alpha1L-AR subtypes in bovine prostate and rat hearts as well as alpha1H-AR subtypes, implying an inhibitory effect of this drug on the contraction of the prostate.

  2. Experimental evaluation of a spinning-mode acoustic-treatment design concept for aircraft inlets. [suppression of YF-102 engine fan noise

    NASA Technical Reports Server (NTRS)

    Heidelberg, L. J.; Rice, E. J.; Homyak, L.

    1980-01-01

    An aircraft-inlet noise suppressor method based on mode cutoff ratio was qualitatively checked by testing a series of liners on a YF-102 turbofan engine. Far-field directivity of the blade passing frequency was used extensively to evaluate the results. The trends and observations of the test data lend much qualitative support to the design method. The best of the BPF liners attained a suppression at design frequency of 19 dB per unit length-diameter ratio. The best multiple-pure-tone linear attained a remarkable suppression of 65.6 bB per unit length-diameter ratio.

  3. Menstrual suppression in special circumstances.

    PubMed

    Kirkham, Yolanda A; Ornstein, Melanie P; Aggarwal, Anjali; McQuillan, Sarah

    2014-10-01

    To provide a Canadian consensus document for health care providers with recommendations for menstrual suppression in patients with physical and/or cognitive challenges or those who are undergoing cancer treatment in whom menstruation may have a deleterious effect on their health. This document reviews the options available for menstrual suppression, its specific indications, contraindications, and side effects, both immediate and long-term, and the investigations and monitoring necessary throughout suppression. Clinicians will be better informed about the options and indications for menstrual suppression in patients with cognitive and/or physical disabilities and patients undergoing chemotherapy, radiation, or other treatments for cancer. Published literature was retrieved through searches of Medline, EMBASE, OVID, and the Cochrane Library using appropriate controlled vocabulary and key words (heavy menstrual bleeding, menstrual suppression, chemotherapy/radiation, cognitive disability, physical disability, learning disability). Results were restricted to systematic reviews, randomized controlled trials, observation studies, and pilot studies. There were no language or date restrictions. Searches were updated on a regular basis and new material was incorporated into the guideline until September 2013. Grey (unpublished) literature was identified through searching websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). There is a need for specific guidelines on menstrual suppression in at-risk populations for health care providers. Recommendations 1. Menstrual suppression and therapeutic amenorrhea should be considered safe and viable options for women who need or want to have

  4. Lifestyle/dietary supplement partial androgen suppression and/or estrogen manipulation. A novel PSA reducer and preventive/treatment option for prostate cancer?

    PubMed

    Moyad, Mark A

    2002-02-01

    There is a large interest in prostate cancer prevention and/or slowing the progression of this disease via dietary/lifestyle/supplement interventions. Numerous mechanisms have been suggested as to how these interventions may lower PSA levels. However, it is possible that the primary mechanism of action is partial androgen suppression and/or estrogen manipulation.

  5. Evaluation of early-season baculovirus treatment for suppression of Heliothis virescens and Helicouverpa zea (Lepidoptera: Noctuidae) over a wide area

    Treesearch

    Jane Leslie Hayes; Marion Bell

    1994-01-01

    Pheromone trap counts of F1 male cotton bollworm, Helicoverpa zea (Bodie), and tobacco budworm, Heliothis virescens (F1) were used to assess the effect of areawide suppression achieved by early-season application of a Heliocoverpa/Heliothis specific nuclear...

  6. Growth suppression caused by corticosteroid eye drops.

    PubMed

    Wolthers, Ole D

    2011-01-01

    Scarce data on systemic activity of corticosteroid eye drops are available in children. Two weeks treatment with fluorometholone eye drops in a case series of five children caused growth suppression detected by knemometry. The suppression had no impact on height growth during the following year.

  7. Suppression subtractive hybridization.

    PubMed

    Ghorbel, Mohamed T; Murphy, David

    2011-01-01

    Comparing two RNA populations that differ from the effects of a single independent variable, such as a drug treatment or a specific genetic defect, can establish differences in the abundance of specific transcripts that vary in a population dependent manner. There are different methods for identifying differentially expressed genes. These methods include microarray, Serial Analysis of Gene Expression (SAGE), and quantitative Reverse-Transcriptase Polymerase Chain Reaction (qRT-PCR). Herein, the protocol describes an easy and cost-effective alternative that does not require prior knowledge of the transcriptomes under examination. It is specifically relevant when low levels of RNA starting material are available. This protocol describes the use of Switching Mechanism At RNA Termini Polymerase Chain Reaction (SMART-PCR) to amplify cDNA from small amounts of RNA. The amplified cDNA populations under comparison are then subjected to Suppression Subtractive Hybridization (SSH-PCR). SSH-PCR is a technique that couples subtractive hybridization with suppression PCR to selectively amplify fragments of differentially expressed genes. The resulting products are cDNA populations enriched for significantly overrepresented transcripts in either of the two input RNAs. These cDNA populations can then be cloned to generate subtracted cDNA library. Microarrays made with clones from the subtracted forward and reverse cDNA libraries are then screened for differentially expressed genes using targets generated from tester and driver total RNAs.

  8. Ammonium treatments to suppress toxic blooms of Prymnesium parvum in a subtropical lake of semi-arid climate: results from in situ mesocosm experiments.

    PubMed

    Grover, James P; Roelke, Daniel L; Brooks, Bryan W; Gable, George M; Neisch, Michael T; Hayden, Natanya J; Valenti, Theodore W; Prosser, Krista N; Umphres, George D; Hewitt, Natalie C

    2013-09-01

    Prymnesium parvum is a haptophyte alga that forms toxic, fish-killing blooms in a variety of brackish coastal and inland waters. Its abundance and toxicity are suppressed by ammonium additions in laboratory cultures and aquaculture ponds. In a cove of a large reservoir (Lake Granbury, Texas, USA) with recurring, seasonal blooms of P. parvum, ammonium additions were tested in mesocosm enclosures for their ability to suppress blooms and their effects on non-target planktonic organisms. One experiment occurred prior to the peak abundance of a P. parvum bloom in the cove, and one encompassed the peak abundance and decline of the bloom. During 21-day experiments, weekly doses raised ammonium concentrations by either 10 or 40 μM. The added ammonium accumulated in experimental mesocosms, with little uptake by biota or other losses. Effects of ammonium additions generally increased over the course of the experiments. The higher ammonium dose suppressed the abundance and toxicity of P. parvum. The biomass of non-haptophyte algae was stimulated by ammonium additions, while positive, negative and neutral effects on zooplankton taxa were observed. Low ammonium additions insufficient to control P. parvum exacerbated its harmful effects. Our results indicate a potential for mitigating blooms of P. parvum with sufficient additions of ammonium to coves of larger lakes. However, factors excluded from mesocosms, such as dilution of ammonium by water exchange and sediment ammonium uptake, could reduce the effectiveness of such additions, and they would entail a risk of eutrophication from the added nitrogen.

  9. Dexamethasone suppression test

    MedlinePlus

    DST; ACTH suppression test; Cortisol suppression test ... During this test, you will receive dexamethasone. This is a strong man-made (synthetic) glucocorticoid medication. Afterward, your blood is drawn ...

  10. Health information technology interventions enhance care completion, engagement in HIV care and treatment, and viral suppression among HIV-infected patients in publicly funded settings.

    PubMed

    Shade, Starley B; Steward, Wayne T; Koester, Kimberly A; Chakravarty, Deepalika; Myers, Janet J

    2015-04-01

    The National HIV/AIDS Strategy (NHAS) emphasizes the use of technology to facilitate coordination of comprehensive care for people with HIV. We examined the effect of six health information technology (HIT) interventions in a Ryan White-funded Special Projects of National Significance (SPNS) on care completion services, engagement in HIV care, and viral suppression. Interventions included use of surveillance data to identify out-of-care individuals, extending access to electronic health records to support service providers, use of electronic laboratory ordering and prescribing, and development of a patient portal. Data from a sample of electronic patient records from each site were analyzed to assess changes in utilization of comprehensive care (prevention screening, support service utilization), engagement in primary HIV medical care (receipt of services and use of antiretroviral therapy), and viral suppression. We used weighted generalized estimating equations to estimate outcomes while accounting for the unequal contribution of data and differences in the distribution of patient characteristics across sites and over time. We observed statistically significant changes in the desired direction in comprehensive care utilization and engagement in primary care outcomes targeted by each site. Five of six sites experienced statistically significant increases in viral suppression. These results provide additional support for the use of HIT as a valuable tool for achieving the NHAS goal of providing comprehensive care for all people living with HIV. HIT has the potential to increase utilization of services, improve health outcomes for people with HIV, and reduce community viral load and subsequent transmission of HIV. © The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com For affiliation see end of article.

  11. BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells

    PubMed Central

    Horiuchi, Akiko; Wang, Cuiju; Kikuchi, Norihiko; Osada, Ryosuke; Nikaido, Toshio; Konishi, Ikuo

    2006-01-01

    BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA double-strand breaks, and its abnormality is responsible for hereditary ovarian cancer syndrome. It has recently been reported that reduced expression of BRCA1 is also common in sporadic ovarian carcinoma via its promoter hypermethylation, and that ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Specific siRNA for BRCA1 gene was transfected into 3 ovarian cancer cell lines with various p53 status. Reduced expression of BRCA1 by transfection of BRCA1-siRNA resulted in a 5.3-fold increase in sensitivity to cisplatin in p53-wild A2780 cells, but not in p53-mutated A2780/CDDP and p53-deleted SKOV3 cells. Regarding the sensitivity to paclitaxel, BRCA1 suppression caused no significant changes in all the 3 cell lines. For ionizing radiation sensitivity, BRCA1 suppression also showed a significant higher sensitivity in A2780 cells. Growth curve and cell cycle analyses showed no significant differences between BRCA1-siRNA-transfected A2780 cells and control cells. However, cisplatin treatment under suppression of BRCA1 showed a significantly increased apoptosis along with up-regulation of p53 and p21 in A2780 cells. Accordingly, reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis via up-regulation of p53 and p21, but does not affect the paclitaxel sensitivity. Expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma. PMID:19690636

  12. Effects of tic suppression: ability to suppress, rebound, negative reinforcement, and habituation to the premonitory urge.

    PubMed

    Specht, Matt W; Woods, Douglas W; Nicotra, Cassandra M; Kelly, Laura M; Ricketts, Emily J; Conelea, Christine A; Grados, Marco A; Ostrander, Rick S; Walkup, John T

    2013-01-01

    The comprehensive behavioral intervention for tics (CBIT) represents a safe, effective non-pharmacological treatment for Tourette's disorder that remains underutilized as a treatment option. Contributing factors include the perceived negative consequences of tic suppression and the lack of a means through which suppression results in symptom improvement. Participants (n = 12) included youth ages 10-17 years with moderate-to-marked tic severity and noticeable premonitory urges who met Tourette's or chronic tic disorder criteria. Tic frequency and urge rating data were collected during an alternating sequence of tic freely or reinforced tic suppression periods. Even without specific instructions regarding how to suppress tics, youth experienced a significant, robust (72%), stable reduction in tic frequency under extended periods (40 min) of contingently reinforced tic suppression in contrast to periods of time when tics were ignored. Following periods of prolonged suppression, tic frequency returned to pre-suppression levels. Urge ratings did not show the expected increase during the initial periods of tic suppression, nor a subsequent decline in urge ratings during prolonged, effective tic suppression. Results suggest that environments conducive to tic suppression result in reduced tic frequency without adverse consequences. Additionally, premonitory urges, underrepresented in the literature, may represent an important enduring etiological consideration in the development and maintenance of tic disorders.

  13. Fire Suppression and Response

    NASA Technical Reports Server (NTRS)

    Ruff, Gary A.

    2004-01-01

    This report is concerned with the following topics regarding fire suppression:What is the relative effectiveness of candidate suppressants to extinguish a representative fire in reduced gravity, including high-O2 mole fraction, low -pressure environments? What are the relative advantages and disadvantages of physically acting and chemically-acting agents in spacecraft fire suppression? What are the O2 mole fraction and absolute pressure below which a fire cannot exist? What effect does gas-phase radiation play in the overall fire and post-fire environments? Are the candidate suppressants effective to extinguish fires on practical solid fuels? What is required to suppress non-flaming fires (smoldering and deep seated fires) in reduced gravity? How can idealized space experiment results be applied to a practical fire scenario? What is the optimal agent deployment strategy for space fire suppression?

  14. Fire Suppression, District 5

    Treesearch

    Roy Headley

    1916-01-01

    The increasing effectiveness of suppression practice is shown by the fact that in 1915 fire suppression cost one-third as much as in 1914, and damage to Government property was kept down to one-fourth the 1914 figure. The seasons were approximately equal in danger. Is further progress to be expected?

  15. Androgen deprivation by adrenal suppression using low-dose hydrocortisone for the treatment of breast carcinoma with apocrine features: a case report illustrating this new paradigm.

    PubMed

    Jongen, Lynn; Paridaens, Robert; Floris, Giuseppe; Wildiers, Hans; Neven, Patrick

    2016-02-01

    We report on a postmenopausal patient with a secondary metastatic apocrine breast cancer successfully treated with low-dose hydrocortisone only following several lines of chemotherapy. The tumor cells in the primary and metastatic lesion exhibited a 'triple-negative' status (estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-negative); the androgen receptor (AR) was strongly expressed. Twenty milligrams of hydrocortisone, a low substitution dose known to suppress adrenal steroid production, twice daily led to a clinical benefit lasting for one year, with symptom control, radiologically stable disease, and steady decrease in CA15.3. Our observation demonstrates that an AR-expressing apocrine breast cancer may respond to androgen deprivation, as an ER-positive breast cancer may benefit from estrogen deprivation. It highlights the importance of further research targeting the AR pathway in apocrine carcinoma, for which androgens represent the sole (known) steroid hormone stimulating tumor growth. Future clinical trials should not only focus on AR inhibitors like enzalutamide, but also on ablative modalities like low-dose hydrocortisone aiming at medical adrenalectomy. This method of androgen deprivation is largely available, cheap, and nearly devoid of toxicity.

  16. Yeast-derived Particulate β-Glucan Treatment Subverts the Suppression of Myeloid-derived Suppressor Cells by Inducing PMN-MDSC Apoptosis and M-MDSC Differentiation to APC in Cancer

    PubMed Central

    Albeituni, Sabrin H.; Ding, Chuanlin; Liu, Min; Hu, Xiaoling; Luo, Fengling; Kloecker, Goetz; Bousamra, Micahel; Zhang, Huang-ge; Yan, Jun

    2016-01-01

    Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. Herein, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole β-glucan particles (WGP), a ligand to engage and activate dectin-1, oral treatment in vivo significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of PMN-MDSC but not M-MDSC, and decreased PMN-MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80+CD11c+ cells in vitro that served as potent antigen-presenting cells (APC) to induce Ag-specific CD4+ and CD8+ T cell responses in a dectin-1 dependent manner. In addition, ERK1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c+ cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated subcutaneously with LLC cells. This effect was dependent of the dectin-1 receptor. Strikingly, patients with non-small cell lung cancer (NSCLC) that had received WGP treatment for 10–14 days prior to any other treatment had a decreased frequency of CD14−HLA-DR−CD11b+CD33+ MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer. PMID:26810222

  17. Yeast-Derived Particulate β-Glucan Treatment Subverts the Suppression of Myeloid-Derived Suppressor Cells (MDSC) by Inducing Polymorphonuclear MDSC Apoptosis and Monocytic MDSC Differentiation to APC in Cancer.

    PubMed

    Albeituni, Sabrin H; Ding, Chuanlin; Liu, Min; Hu, Xiaoling; Luo, Fengling; Kloecker, Goetz; Bousamra, Michael; Zhang, Huang-ge; Yan, Jun

    2016-03-01

    Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. In this study, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole β-glucan particles (WGP; a ligand to engage and activate dectin-1, oral treatment in vivo) significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of polymorphonuclear MDSC but not monocytic MDSC (M-MDSC), and decreased polymorphonuclear MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80(+)CD11c(+) cells in vitro that served as potent APC to induce Ag-specific CD4(+) and CD8(+) T cell responses in a dectin-1-dependent manner. Additionally, Erk1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c(+) cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated s.c. with Lewis lung carcinoma cells. This effect was dependent on the dectin-1 receptor. Strikingly, patients with non-small cell lung carcinoma that had received WGP treatment for 10-14 d prior to any other treatment had a decreased frequency of CD14(-)HLA-DR(-)CD11b(+)CD33(+) MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer.

  18. Repeated 100 Hz TENS for the Treatment of Chronic Inflammatory Hyperalgesia and Suppression of Spinal Release of Substance P in Monoarthritic Rats

    PubMed Central

    Liu, Hong-Xiang; Tian, Jin-Bin; Luo, Fei; Jiang, Yu-Hui; Deng, Zu-Guo; Xiong, Liang; Liu, Cheng; Wang, Jin-Shu

    2007-01-01

    Transcutaneous electrical nerve stimulation (TENS) has been shown to be an effective measure for pain relief. The aim of the present study was to determine the optimal intensity and interval of repeated 100 Hz TENS for the treatment of chronic inflammatory hyperalgesia in a monoarthritic pain model of the rat, and to assess the changes of the spinal substance P (SP) release in response to TENS treatment. A reliable, reproducible chronic monoarthritic pain model was produced by intra-articular injection of complete Freund's adjuvant (CFA) at single ankle joint. The efficacy of 100 Hz TENS treatments with different frequencies and intensities was compared. In the acute period (within 3 weeks) of monoarthritis, twice-a-week schedule of TENS reduced the swelling of the inflamed ankle significantly. In the stable period (4–9 weeks), however, once-a-week schedule produced a significantly better therapeutic effect on both inflammation and arthritic hyperalgesia than that of twice- or five-times-a-week schedule. Using three levels of intensity of TENS, we found that the weaker (1-1-2 mA) stimulation produced significantly better therapeutic effects. Repeated TENS produced a reduction of SP content in spinal perfusate in parallel with the progressive reduction of the arthritic pain scores. Our results suggest that (i) consecutive TENS treatments produced cumulative effect for chronic hyperalgesia, (ii) for chronic inflammatory hyperalgesia, a weaker intensity and more sparsely arranged treatment schedule may produce better therapeutic effect and (iii) a decrease in SP release may serve as one of the possible neurochemical mechanisms underlying the therapeutic effects of multiple TENS treatments on chronic inflammatory hyperalgesia. PMID:17342243

  19. Fenofibrate pre-treatment suppressed inflammation by activating phosphoinositide 3 kinase/protein kinase B (PI3K/Akt) signaling in renal ischemia-reperfusion injury.

    PubMed

    Yang, Feng-jie; He, Yong-hua; Zhou, Jian-hua

    2015-02-01

    The aim of this study was to investigate the possible beneficial effects of Fenofibrate on renal ischemia-reperfusion injury (IRI) in mice and its potential mechanism. IRI was induced by bilateral renal ischemia for 60 min followed by reperfusion for 24 h. Eighteen male C57BL/6 mice were randomly divided into three groups: sham-operated group (sham), IRI+saline group (IRI group), IRI+Fenofibrate (FEN) group. Normal saline or Fenofibrate (3 mg/kg) was intravenously injected 60 min before renal ischemia in IRI group and FEN group, respectively. Blood samples and renal tissues were collected at the end of reperfusion. The renal function, histopathologic changes, and the expression levels of pro-inflammatory cytokines [interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α) and IL-6] in serum and renal tissue homogenate were assessed. Moreover, the effects of Fenofibrate on activating phosphoinositide 3 kinase/protein kinase B (PI3K/Akt) signaling and peroxisome proliferator-activated receptor-α (PPAR-α) were also measured in renal IRI. The results showed that plasma levels of blood urea nitrogen and creatinine, histopathologic scores and the expression levels of TNF-α, IL-8 and IL-6 were significantly lower in FEN group than in IRI group. Moreover, Fenofibrate pretreatment could further induce PI3K/Akt signal pathway and PPAR-α activation following renal IRI. These findings indicated PPAR-α activation by Fenofibrate exerts protective effects on renal IRI in mice by suppressing inflammation via PI3K/Akt activation. Thus, Fenofibrate could be a novel therapeutic alternative in renal IRI.

  20. Suppression of volatile production in tomato fruit exposed to chilling temperature and alleviation of chilling injury by a pre-chilling heat treatment

    USDA-ARS?s Scientific Manuscript database

    Chilling exposure of tomato fruit to 5 °C for less than 5 days at mature green stage does not cause visual symptom of chilling injury (CI), however, it is unknown whether such conditions would impact flavor quality (internal CI) after ripening, and if a pre-chilling heat treatment could alleviate in...

  1. Long-term nicotine treatment suppresses IL-1β release and attenuates substance P- and 5-HT-evoked Ca²⁺ responses in astrocytes.

    PubMed

    Westerlund, Anna; Björklund, Ulrika; Rönnbäck, Lars; Hansson, Elisabeth

    2013-10-11

    The aim of this study was to investigate whether short- or long-term nicotine treatment, had an influence on Ca(2+)-induced intracellular Ca(2+) release in astrocytes co-cultured with microvascular endothelial cells, and if the release of interleukin-1β (IL-1β) changed during this treatment. We found that nicotine-evoked Ca(2+) transients were not attenuated up to 10d of incubation with nicotine, neither was the α7-nicotine acetylcholine receptor (α7-nAChR) protein. After 10d the IL-1β release was decreased. Furthermore, substance P- and 5-hydroxytryptamine (5-HT)-evoked Ca(2+) transients were attenuated after 10d of nicotine treatment, but glial cell line-derived neurotrophic factor (GDNF) had no effect on these transients. The results show that long-term nicotine treatment had no influence on nicotine-evoked Ca(2+) transients or protein expression of the α7-nAChR, but had with a decreased IL-1β release. The Gq protein and inositoltrisphosphate system seems to be influenced by the attenuation of Ca(2+)-evoked intracellular Ca(2+) release after stimulation with substance P and 5-HT.

  2. Assessment of the Safety and Efficacy of a Raft-Forming Alginate Reflux Suppressant (Liquid Gaviscon) for the Treatment of Heartburn during Pregnancy

    PubMed Central

    Strugala, Vicki; Bassin, Julian; Swales, Valerie S.; Lindow, Stephen W.; Dettmar, Peter W.; Thomas, Edward C. M.

    2012-01-01

    Gastro-oesophageal reflux (GER) and the symptoms of heartburn and regurgitation are common in pregnancy. These symptoms are transient and mostly resolve postpartum but have a negative impact on quality of life. Here, we present a prospective clinical evaluation of the safety and efficacy of an alginate raft-forming oral suspension that is licensed for use in pregnancy. The study was a multicentre, prospective, open-label, and baseline-controlled study of Liquid Gaviscon (LG) in the treatment of heartburn in pregnant women with current symptoms of heartburn and/or reflux requiring treatment (recruited 144). The efficacy of the study medication was rated by the investigator (primary endpoint) and patient. Treatment was deemed to be a success in 91% of patients as judged by the investigator (95% CI 85.0–95.3) and 90% (95% CI 84.1–94.8) when assessed by the patient themselves. Very few adverse events or serious adverse events were reported that were considered to be related to the study medication, and these were consistent with the normal population incidences. Serum sodium levels remained unchanged. This prospective open-label study in a large number of pregnant women has shown that LG is both safe and highly efficacious in the treatment of heartburn and GER symptoms in pregnancy. PMID:23209926

  3. Assessment of the Safety and Efficacy of a Raft-Forming Alginate Reflux Suppressant (Liquid Gaviscon) for the Treatment of Heartburn during Pregnancy.

    PubMed

    Strugala, Vicki; Bassin, Julian; Swales, Valerie S; Lindow, Stephen W; Dettmar, Peter W; Thomas, Edward C M

    2012-01-01

    Gastro-oesophageal reflux (GER) and the symptoms of heartburn and regurgitation are common in pregnancy. These symptoms are transient and mostly resolve postpartum but have a negative impact on quality of life. Here, we present a prospective clinical evaluation of the safety and efficacy of an alginate raft-forming oral suspension that is licensed for use in pregnancy. The study was a multicentre, prospective, open-label, and baseline-controlled study of Liquid Gaviscon (LG) in the treatment of heartburn in pregnant women with current symptoms of heartburn and/or reflux requiring treatment (recruited 144). The efficacy of the study medication was rated by the investigator (primary endpoint) and patient. Treatment was deemed to be a success in 91% of patients as judged by the investigator (95% CI 85.0-95.3) and 90% (95% CI 84.1-94.8) when assessed by the patient themselves. Very few adverse events or serious adverse events were reported that were considered to be related to the study medication, and these were consistent with the normal population incidences. Serum sodium levels remained unchanged. This prospective open-label study in a large number of pregnant women has shown that LG is both safe and highly efficacious in the treatment of heartburn and GER symptoms in pregnancy.

  4. Fuel treatments, fire suppression, and their interaction with wildfire and its impacts: the Warm Lake experience during the Cascade Complex of wildfires in central Idaho, 2007

    Treesearch

    Russell T. Graham; Theresa B. Jain; Mark Loseke

    2009-01-01

    Wildfires during the summer of 2007 burned over 500,000 acres within central Idaho. These fires burned around and through over 8,000 acres of fuel treatments designed to offer protection from wildfire to over 70 summer homes and other buildings located near Warm Lake. This area east of Cascade, Idaho, exemplifies the difficulty of designing and implementing fuel...

  5. Dual Therapy Treatment Strategies for the Management of Patients Infected with HIV: A Systematic Review of Current Evidence in ARV-Naive or ARV-Experienced, Virologically Suppressed Patients.

    PubMed

    Baril, Jean-Guy; Angel, Jonathan B; Gill, M John; Gathe, Joseph; Cahn, Pedro; van Wyk, Jean; Walmsley, Sharon

    2016-01-01

    We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection. A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations. Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels. The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here provide valuable insights into the

  6. Suppression of alveolar bone resorption by etidronate treatment for periodontal disease: 4- to 5-year follow-up of four patients.

    PubMed

    Takaishi, Y; Ikeo, T; Miki, T; Nishizawa, Y; Morii, H

    2003-01-01

    Four women with periodontitis received intermittent cyclical etidronate (etidronate administered orally at a dose of 200 mg/day for 2 weeks, at intervals of 10-12 weeks or 6 months) for 4-5 years in addition to ordinary dental therapy. Alveolar bone density was measured using a new method comparing the percentage increase in density. Mean alveolar bone density increased significantly during intermittent cyclical etidronate treatment. Significant reductions were observed in the mobility of the teeth and the depth of periodontal pockets. There were significant correlations between alveolar bone density and both mobility of the teeth and the depth of the alveolar pockets. It is concluded that increases in alveolar bone density are associated with the clinical benefits of etidronate in the treatment of periodontitis.

  7. Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial.

    PubMed

    Arribas, José R; Girard, Pierre-Marie; Landman, Roland; Pich, Judit; Mallolas, Josep; Martínez-Rebollar, María; Zamora, Francisco X; Estrada, Vicente; Crespo, Manuel; Podzamczer, Daniel; Portilla, Joaquín; Dronda, Fernando; Iribarren, José A; Domingo, Pere; Pulido, Federico; Montero, Marta; Knobel, Hernando; Cabié, André; Weiss, Laurence; Gatell, José M

    2015-07-01

    Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression. In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir-ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821. Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group (difference -1·2% [95% CI -9·6 to 7·3]; p=0·92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0·515), and study drug discontinuations due to adverse events occurred in

  8. Minimal dose interferon suppository treatment suppresses viral replication with platelet counts and serum albumin levels increased in chronically hepatitis C virus-infected patients: a phase 1b, placebo-controlled, randomized study.

    PubMed

    Haruna, Yoshimichi; Inoue, Atsuo

    2014-02-01

    Animal studies have shown that rectally administrated interferon (IFN) is transferred into the lymphatic system via the rectal mucous membrane, suggesting that an IFN suppository could serve as another drug delivery method. We developed an IFN suppository and administered it to patients with chronic hepatitis C to evaluate its efficacy and safety. Twenty-eight patients with chronic hepatitis C participated in the study. The low-dose IFN suppository containing 1,000 international units (IU) of lymphoblastoid IFNα was administered to 14 patients daily for 24 weeks. Others had a placebo dosing. In 13 of the 14 IFN suppository-treated patients, viral load decreased at week 4. The serum hepatitis C virus (HCV) RNA levels (Log IU/mL, mean±standard error) were 5.65±0.18 before the treatment and 5.17±0.27 at week 4 (P=0.01). The 2'-5' oligoadenylate synthetase activity increased, while the CD4/CD8 ratio decreased significantly. Interestingly, platelet counts and serum albumin levels were significantly increased during and after the treatment. No serious adverse events were observed. The low-dose IFN suppository treatment suppressed HCV replication, modifying host immunity, with increased platelet counts and serum albumin levels. The IFN suppository could be considered a new drug delivery method to preserve the quality of life of patients.

  9. Growth hormone suppression test

    MedlinePlus

    GH suppression test; Glucose loading test; Acromegaly - blood test; Gigantism - blood test ... drink anything. You then drink a solution containing glucose (sugar). You may be told to drink slowly ...

  10. Jet noise suppression

    NASA Astrophysics Data System (ADS)

    Gliebe, P. R.; Brausch, J. F.; Majjigi, R. K.; Lee, R.

    1991-08-01

    The objectives of this chapter are to review and summarize the jet noise suppression technology, to provide a physical and theoretical model to explain the measured jet noise suppression characteristics of different concepts, and to provide a set of guidelines for evolving jet noise suppression designs. The underlying principle for all jet noise suppression devices is to enhance rapid mixing (i.e., diffusion) of the jet plume by geometric and aerothermodynamic means. In the case of supersonic jets, the shock-cell broadband noise reduction is effectively accomplished by the elimination or mitigation of the shock-cell structure. So far, the diffusion concepts have predominantly concentrated on jet momentum and energy (kinetic and thermal) diffusion, in that order, and have yielded better noise reduction than the simple conical nozzles. A critical technology issue that needs resolution is the effect of flight on the noise suppression potential of mechanical suppressor nozzles. A more thorough investigation of this mechanism is necessary for the successful development and design of an acceptable noise suppression device for future high-speed civil transports.

  11. Jet Noise Suppression

    NASA Technical Reports Server (NTRS)

    Gliebe, P. R.; Brausch, J. F.; Majjigi, R. K.; Lee, R.

    1991-01-01

    The objectives of this chapter are to review and summarize the jet noise suppression technology, to provide a physical and theoretical model to explain the measured jet noise suppression characteristics of different concepts, and to provide a set of guidelines for evolving jet noise suppression designs. The underlying principle for all jet noise suppression devices is to enhance rapid mixing (i.e., diffusion) of the jet plume by geometric and aerothermodynamic means. In the case of supersonic jets, the shock-cell broadband noise reduction is effectively accomplished by the elimination or mitigation of the shock-cell structure. So far, the diffusion concepts have predominantly concentrated on jet momentum and energy (kinetic and thermal) diffusion, in that order, and have yielded better noise reduction than the simple conical nozzles. A critical technology issue that needs resolution is the effect of flight on the noise suppression potential of mechanical suppressor nozzles. A more thorough investigation of this mechanism is necessary for the successful development and design of an acceptable noise suppression device for future high-speed civil transports.

  12. Trap-State Suppression and Improved Charge Transport in PbS Quantum Dot Solar Cells with Synergistic Mixed-Ligand Treatments.

    PubMed

    Pradhan, Santanu; Stavrinadis, Alexandros; Gupta, Shuchi; Bi, Yu; Di Stasio, Francesco; Konstantatos, Gerasimos

    2017-06-01

    The power conversion efficiency of colloidal PbS-quantum-dot (QD)-based solar cells is significantly hampered by lower-than-expected open circuit voltage (VOC ). The VOC deficit is considerably higher in QD-based solar cells compared to other types of existing solar cells due to in-gap trap-induced bulk recombination of photogenerated carriers. Here, this study reports a ligand exchange procedure based on a mixture of zinc iodide and 3-mercaptopropyonic acid to reduce the VOC deficit without compromising the high current density. This layer-by-layer solid state ligand exchange treatment enhances the photovoltaic performance from 6.62 to 9.92% with a significant improvement in VOC from 0.58 to 0.66 V. This study further employs optoelectronic characterization, X-ray photoelectron spectroscopy, and photoluminescence spectroscopy to understand the origin of VOC improvement. The mixed-ligand treatment reduces the sub-bandgap traps and significantly reduces bulk recombination in the devices. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Repeated Baclofen treatment ameliorates motor dysfunction, suppresses reflex activity and decreases the expression of signaling proteins in reticular nuclei and lumbar motoneurons after spinal trauma in rats.

    PubMed

    Kucharíková, Andrea; Schreiberová, Andrea; Závodská, Monika; Gedrová, Štefánia; Hricová, Ľudmila; Pavel, Jaroslav; Gálik, Ján; Maršala, Martin; Lukáčová, Nadežda

    2014-03-01

    The interruption of supraspinal input to the spinal cord leads to motor dysfunction and the development of spasticity. Clinical studies have shown that Baclofen (a GABAB agonist), while effective in modulating spasticity is associated with side-effects and the development of tolerance. The aim of the present study was to assess if discontinued Baclofen treatment and its repeated application leads antispasticity effects, and whether such changes affect neuronal nitric oxide synthase (nNOS) in the brainstem, nNOS and parvalbumin (PV) in lumbar α-motoneurons and glial fibrillary acidic protein in the ventral horn of the spinal cord. Adult male Wistar rats were exposed to Th9 spinal cord transection. Baclofen (30mg/b.w.) diluted in drinking water, was administered for 6 days, starting at week 1 after injury and then repeated till week 4 after injury. The behavior of the animals was tested (tail-flick test, BBB locomotor score) from 1 to 8 weeks. Our results clearly indicate the role of nitric oxide, produced by nNOS in the initiation and the maintenance of spasticity states 1, 6 and 8 weeks after spinal trauma. A considerable decrease of nNOS staining after Baclofen treatment correlates with improvement of motor dysfunction. The findings also show that parvalbumin and astrocytes participate in the regulation of ion concentrations in the sub-acute phase after the injury.

  14. Oral Treatment with Extract of Agaricus blazei Murill Enhanced Th1 Response through Intestinal Epithelial Cells and Suppressed OVA-Sensitized Allergy in Mice

    PubMed Central

    Bouike, Go; Nishitani, Yosuke; Shiomi, Hideyuki; Yoshida, Masaru; Azuma, Takeshi; Hashimoto, Takashi; Kanazawa, Kazuki; Mizuno, Masashi

    2011-01-01

    To clarify the mechanism of the antiallergic activity of Agaricus blazei Murill extract (ABME), the present paper used an in vivo allergy model and an in vitro intestinal gut model. During OVA sensitization, the serum IgE levels decreased significantly in ABME group. Interleukin (IL)-4 and -5 produced from OVA-restimulated splenocytes was significantly decreased, and anti-CD3ε/CD28 antibody treatment also reduced IL-10, -4, and -5 production and increased IFN-γ production in ABME group. These results suggest that oral administration of ABME improves Th1/Th2 balance. Moreover, a coculture system constructed of Caco-2 cells and splenocytes from OT-II mice or RAW 264.7 cells indicated that the significant increases in IFN-γ production by ABME treatment. Therefore, it was concluded that the antiallergic activity of ABME was due to the activation of macrophages by epithelial cells and the promotion of the differentiation of naïve T cells into Th1 cells in the immune. PMID:20953432

  15. Combined treatment of curcumin and small molecule inhibitors suppresses proliferation of A549 and H1299 human non-small-cell lung cancer cells.

    PubMed

    Lin, Hui-Ping; Kuo, Li-Kuo; Chuu, Chih-Pin

    2012-01-01

    Curcumin (diferuloylmethane) is a phenolic compound present in turmeric and is ingested daily in many parts of the world. Curcumin has been reported to cause inhibition on proliferation and induction of apoptosis in many human cancer cell lines, including non-small cell lung cancer cells (NSCLC). However, the clinical application of curcumin is restricted by its low bioavailability. In this report, it was observed that combined treatment of a low dosage of curcumin (5-10 µM) with a low concentration (0.1-2.5 µM) of small molecule inhibitors, including AG1478, AG1024, PD173074, LY294002 and caffeic acid phenethyl ester (CAPE) increased the growth inhibition in two human NSCLC cell lines: A549 and H1299 cells. The observation suggested that combined treatment of a low dosage of curcumin with inhibitors against epidermal growth factor receptor (EGFR), insulin-like growth factor 1 (IGF-1R), fibroblast growth factors receptor (FGFR), phosphatidylinositol 3-kinases (PI3K) or NF-κB signaling pathway may be a potential adjuvant therapy beneficial to NSCLC patients.

  16. Detection and description of soils with specific nematode suppressiveness.

    PubMed

    Westphal, Andreas

    2005-03-01

    Soils with specific suppressiveness to plant-parasitic nematodes are of interest to define the mechanisms that regulate population density. Suppressive soils prevent nematodes from establishing and from causing disease, and they diminish disease severity after initial nematode damage in continuous culturing of a host. A range of non-specific and specific soil treatments, followed by infestation with a target nematode, have been employed to identify nematode-suppressive soils. Biocidal treatments, soil transfer tests, and baiting approaches together with observations of the plant-parasitic nematode in the root zone of susceptible host plants have improved the understanding of nematode-suppressive soils. Techniques to demonstrate specific soil suppressiveness against plant-parasitic nematodes are compared in this review. The overlap of studies on soil suppressiveness with recent advances in soil health and quality is briefly discussed. The emphasis is on methods (or criteria) used to detect and identify soils that maintain specific soil suppressiveness to plant-parasitic nematodes. While biocidal treatments can detect general and specific soil suppressiveness, soil transfer studies, by definition, apply only to specific soil suppressiveness. Finally, potential strategies to exploit suppressive soils are presented.

  17. Detection and Description of Soils with Specific Nematode Suppressiveness

    PubMed Central

    Westphal, Andreas

    2005-01-01

    Soils with specific suppressiveness to plant-parasitic nematodes are of interest to define the mechanisms that regulate population density. Suppressive soils prevent nematodes from establishing and from causing disease, and they diminish disease severity after initial nematode damage in continuous culturing of a host. A range of non-specific and specific soil treatments, followed by infestation with a target nematode, have been employed to identify nematode-suppressive soils. Biocidal treatments, soil transfer tests, and baiting approaches together with observations of the plant-parasitic nematode in the root zone of susceptible host plants have improved the understanding of nematode-suppressive soils. Techniques to demonstrate specific soil suppressiveness against plant-parasitic nematodes are compared in this review. The overlap of studies on soil suppressiveness with recent advances in soil health and quality is briefly discussed. The emphasis is on methods (or criteria) used to detect and identify soils that maintain specific soil suppressiveness to plant-parasitic nematodes. While biocidal treatments can detect general and specific soil suppressiveness, soil transfer studies, by definition, apply only to specific soil suppressiveness. Finally, potential strategies to exploit suppressive soils are presented. PMID:19262851

  18. Iodine-131 treatment of thyroid cancer cells leads to suppression of cell proliferation followed by induction of cell apoptosis and cell cycle arrest by regulation of B-cell translocation gene 2-mediated JNK/NF-κB pathways.

    PubMed

    Zhao, L M; Pang, A X

    2017-01-16

    Iodine-131 (131I) is widely used for the treatment of thyroid-related diseases. This study aimed to investigate the expression of p53 and BTG2 genes following 131I therapy in thyroid cancer cell line SW579 and the possible underlying mechanism. SW579 human thyroid squamous carcinoma cells were cultured and treated with 131I. They were then assessed for 131I uptake, cell viability, apoptosis, cell cycle arrest, p53 expression, and BTG2 gene expression. SW579 cells were transfected with BTG2 siRNA, p53 siRNA and siNC and were then examined for the same aforementioned parameters. When treated with a JNK inhibitor of SP600125 and 131I or with a NF-κB inhibitor of BMS-345541 and 131I, non-transfected SW579 cells were assessed in JNK/NFκB pathways. It was observed that 131I significantly inhibited cell proliferation, promoted cell apoptosis and cell cycle arrest. Both BTG2 and p53 expression were enhanced in a dose-dependent manner. An increase in cell viability by up-regulation in Bcl2 gene, a decrease in apoptosis by enhanced CDK2 gene expression and a decrease in cell cycle arrest at G0/G1 phase were also observed in SW579 cell lines transfected with silenced BTG2 gene. When treated with SP600125 and 131I, the non-transfected SW579 cell lines significantly inhibited JNK pathway, NF-κB pathway and the expression of BTG2. However, when treated with BMS-345541 and 131I, only the NF-κB pathway was suppressed. 131I suppressed cell proliferation, induced cell apoptosis, and promoted cell cycle arrest of thyroid cancer cells by up-regulating B-cell translocation gene 2-mediated activation of JNK/NF-κB pathways.

  19. Iodine-131 treatment of thyroid cancer cells leads to suppression of cell proliferation followed by induction of cell apoptosis and cell cycle arrest by regulation of B-cell translocation gene 2-mediated JNK/NF-κB pathways

    PubMed Central

    Zhao, L.M.; Pang, A.X.

    2017-01-01

    Iodine-131 (131I) is widely used for the treatment of thyroid-related diseases. This study aimed to investigate the expression of p53 and BTG2 genes following 131I therapy in thyroid cancer cell line SW579 and the possible underlying mechanism. SW579 human thyroid squamous carcinoma cells were cultured and treated with 131I. They were then assessed for 131I uptake, cell viability, apoptosis, cell cycle arrest, p53 expression, and BTG2 gene expression. SW579 cells were transfected with BTG2 siRNA, p53 siRNA and siNC and were then examined for the same aforementioned parameters. When treated with a JNK inhibitor of SP600125 and 131I or with a NF-κB inhibitor of BMS-345541 and 131I, non-transfected SW579 cells were assessed in JNK/NFκB pathways. It was observed that 131I significantly inhibited cell proliferation, promoted cell apoptosis and cell cycle arrest. Both BTG2 and p53 expression were enhanced in a dose-dependent manner. An increase in cell viability by up-regulation in Bcl2 gene, a decrease in apoptosis by enhanced CDK2 gene expression and a decrease in cell cycle arrest at G0/G1 phase were also observed in SW579 cell lines transfected with silenced BTG2 gene. When treated with SP600125 and 131I, the non-transfected SW579 cell lines significantly inhibited JNK pathway, NF-κB pathway and the expression of BTG2. However, when treated with BMS-345541 and 131I, only the NF-κB pathway was suppressed. 131I suppressed cell proliferation, induced cell apoptosis, and promoted cell cycle arrest of thyroid cancer cells by up-regulating B-cell translocation gene 2-mediated activation of JNK/NF-κB pathways. PMID:28099584

  20. Pharmacological suppression of the Ras/MAPK pathway in thyroid carcinoma cells can provoke opposite effects on cell migration and proliferation: The appearance of yin-yang effects and the need of combinatorial treatments.

    PubMed

    Glassmann, Alexander; Winter, Jochen; Kraus, Dominik; Veit, Nadine; Probstmeier, Rainer

    2014-12-01

    A major challenge in tumor therapy is the decrease or even the halting of cell proliferation and migration of cancerous cells. In the present study, we have analyzed the impact of a pharmacological blockade of the PI3K/Akt and MAPK/ERK1/2 signaling pathways on cell migration, proliferation and cell death in three human thyroid tumor cell lines that represent the main types of malignant thyroid carcinomas (B-CPAP, follicular; Cal-62, anaplastic; FTC-133, papillary thyroid carcinoma cells) and in which these pathways are constitutively activated. In general, pharmacological perturbation of PI3/Akt (application of MK-2206) and MEK/ERK1/2 (application of PD0325901 or U0126) signaling led to a cell line and drug-specific decrease in the proliferation and migration potential of thyroid carcinoma cells, although to a varying extent. However, one exception became apparent: in Cal-62 cells inhibition of the MEK/ERK1/2 module increased the migration rate up to 50%. This effect could be prevented by a simultaneous suppression of the PI3/Akt pathway, but also by application of the multiple kinase inhibitor sorafenib, a treatment that did not change the activation state of Akt. Thus, a pharmacological perturbation of canonical signaling pathways in thyroid carcinoma may induce drug-dependent yin-yang effects that are characterized by a simultaneous suppression of one (i.e., proliferation) and the activation of another (i.e., migration) cellular process. The appearance of such phenomena should be taken into account when therapy plans are established.

  1. Oral treatment with herbal formula B307 alleviates cardiac failure in aging R6/2 mice with Huntington’s disease via suppressing oxidative stress, inflammation, and apoptosis

    PubMed Central

    Lin, Ching-Lung; Wang, Sheue-Er; Hsu, Chih-Hsiang; Sheu, Shuenn-Jyi; Wu, Chung-Hsin

    2015-01-01

    Cardiac failure is often observed in aging patients with Huntington’s disease (HD). However, conventional pharmacological treatments for cardiac failure in HD patients have rarely been studied. Chinese herbal medicines, especially combined herbal formulas, have been widely used to treat cardiac dysfunctions over the centuries. Thus, we assess whether oral treatment with herbal formula B307 can alleviate cardiac failure in transgenic mice with HD. After oral B307 or vehicle treatment for 2 weeks, cardiac function and cardiomyocytes in 12-week-old male R6/2 HD mice and their wild-type littermate controls (WT) were examined and then compared via echocardiography, immunohistochemistry, and Western blotting. We found that cardiac performance in aging R6/2 HD mice had significantly deteriorated in comparison with their WT (P<0.01). Cardiac expressions of superoxide dismutase 2 (SOD2) and B-cell lymphoma 2 (Bcl-2) in aging R6/2 HD mice were significantly lower than their WT (P<0.01), but cardiac expressions of tumor necrosis factor alpha (TNF-α), neurotrophin-3 (3-NT), 4-hydroxynonenal (4-HNE), Bcl-2-associated X protein (Bax), calpain, caspase 12, caspase 9, and caspase 3 of aging R6/2 HD mice were significantly higher than their WT (P<0.05). Furthermore, we found that cardiac performance in aging R6/2 HD mice had significantly improved under oral B307 treatment (P<0.05). Cardiac expressions of SOD2 and Bcl-2 of aging R6/2 HD mice were significantly higher under oral B307 treatment (P<0.01), but cardiac expressions of TNF-α, 3-NT, 4-HNE, Bax, calpain, caspase 12, caspase 9, and caspase 3 of aging R6/2 HD mice were significantly reduced under oral B307 treatment (P<0.05). Oral B307 treatment may briefly alleviate cardiac failure in aging HD R6/2 mice via suppressing cardiac oxidative stress, inflammation, and apoptosis. We suggested that the herbal formula B307 may be further developed as a potential health supplement for ameliorating cardiac failure associated with

  2. Systemic Treatment with a miR-146a Mimic Suppresses Endotoxin Sensitivity and Partially Protects Mice from the Progression of Acute Graft-versus-Host Disease.

    PubMed

    Gartner, John G; Durston, Melanie M; Booth, Stephanie A; Ellison, Cynthia A

    2017-08-29

    Acute GVHD (aGVHD) is driven by interactions between the allogenic T cell response, inflammation, tissue injury and microbial products that enter the circulation when protective barriers such as the intestinal epithelium become compromised. Mice with aGVHD become hypersensitive to LPS, secreting large quantities of inflammatory mediators that exacerbate tissue injury. We hypothesized that microRNA (miR) modulators could be used in vivo to mitigate LPS hypersensitivity, altering the course of aGVHD. Using the C57BL/6 → (C57BL/6 x DBA/2)F1-hybrid model of aGVHD, we measured intestinal permeability over time and used a qPCR array to detect concomitant changes in the expression levels of certain microRNAs (miRs) in the intestine. Large increases in permeability were seen on day 15, when endotoxemia becomes detectable and GVHD associated histopathological lesions develop. Amongst the miRs with altered expression levels were some that regulate sensitivity to endotoxin. We chose to focus on miR-146a and treated recipient mice systemically with a miR-146a mimic early in the GVH reaction. This led to a reduction in the burst of IFNγ that likely plays a priming role in the mechanism underlying heightened sensitivity to endotoxin. LPS-induced TNFα release and GVHD-associated weight loss were also diminished and survival was prolonged. In summary, systemic treatment with a miR-146a mimic dampens the heightened sensitivity to LPS that occurs concomitantly with increased intestinal permeability and provides partial protection from the progression of acute GVHD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  3. Treatment with the PI3K inhibitor buparlisib (NVP-BKM120) suppresses the growth of established patient-derived GBM xenografts and prolongs survival in nude rats.

    PubMed

    Netland, I A; Førde, H E; Sleire, L; Leiss, L; Rahman, M A; Skeie, B S; Miletic, H; Enger, P Ø; Goplen, D

    2016-08-01

    Glioblastomas (GBMs) are aggressive brain tumours with a dismal prognosis, despite combined surgery, radio- and chemotherapy. Close to 90 % of all GBMs harbour a deregulated PI3K pathway, which is essential in regulating central cellular functions such as proliferation, cell growth, motility and survival. Thus, PI3K represents a potential target for molecular therapy in GBM. We investigated the anti-tumour efficacy of the PI3K inhibitor buparlisib (NVP-BKM120) in GBM cell lines in vitro and in vivo, when treatment was initiated after MRI-confirmed tumour engraftment. We found that buparlisib inhibited glioma cell proliferation in a dose dependent manner, demonstrated by MTS assay, manual cell count and BrdU incorporation. A dose dependent increase in apoptosis was observed through flow cytometric analysis. Furthermore, by immunocytochemistry and western blot, we found a dose dependent inhibition of Akt phosphorylation. Moreover, buparlisib prolonged survival of nude rats harboring human GBM xenografts in three independent studies and reduced the tumours' volumetric increase, as determined by MRI. In addition, histological analyses of xenograft rat brains showed necrotic areas and change in tumour cell nuclei in buparlisib-treated animals. The rats receiving buparlisib maintained their weight, activity level and food- and water intake. In conclusion, buparlisib effectively inhibits glioma cell proliferation in vitro and growth of human GBM xenografts in nude rats. Moreover, the compound is well tolerated when administered at doses providing anti-tumour efficacy. Thus, buparlisib may have a future role in glioma therapy, and further studies are warranted to validate this compound for human use.

  4. PACAP intraperitoneal treatment suppresses appetite and food intake via PAC1 receptor in mice by inhibiting ghrelin and increasing GLP-1 and leptin.

    PubMed

    Vu, John P; Goyal, Deepinder; Luong, Leon; Oh, Suwan; Sandhu, Ravneet; Norris, Joshua; Parsons, William; Pisegna, Joseph R; Germano, Patrizia M

    2015-11-15

    Pituitary adenylate cyclase-activating peptide (PACAP) is expressed within the gastroenteric system, where it has profound physiological effects. PACAP was shown to regulate food intake and thermogenesis centrally; however, PACAP peripheral regulation of appetite and feeding behavior is unknown. Therefore, we studied PACAP's effect on appetite and food intake control by analyzing feeding behavior and metabolic hormones in PAC1-deficient (PAC1-/-) and age-matched wild-type (WT) mice intraperitoneally injected with PACAP1-38 or PACAP1-27 before the dark phase of feeding. Food intake and feeding behavior were analyzed using the BioDAQ system. Active ghrelin, glucagon-like peptide-1 (GLP-1), leptin, peptide YY, pancreatic polypeptide, and insulin were measured following PACAP1-38 administration in fasted WT mice. PACAP1-38/PACAP1-27 injected into WT mice significantly decreased in a dose-dependent manner cumulative food intake and reduced bout and meal feeding parameters. Conversely, PACAP1-38 injected into PAC1-/- mice failed to significantly change food intake. Importantly, PACAP1-38 reduced plasma levels of active ghrelin compared with vehicle in WT mice. In PAC1-/- mice, fasting levels of active ghrelin, GLP-1, insulin, and leptin and postprandial levels of active ghrelin and insulin were significantly altered compared with levels in WT mice. Therefore, PAC1 is a novel regulator of appetite/satiety. PACAP1-38/PACAP1-27 significantly reduced appetite and food intake through PAC1. In PAC1-/- mice, the regulation of anorexigenic/orexigenic hormones was abolished, whereas active ghrelin remained elevated even postprandially. PACAP significantly reduced active ghrelin in fasting conditions. These results establish a role for PACAP via PAC1 in the peripheral regulation of appetite/satiety and suggest future studies to explore a therapeutic use of PACAP or PAC1 agonists for obesity treatment.

  5. Cadmium treatment suppresses DNA polymerase δ catalytic subunit gene expression by acting on the p53 and Sp1 regulatory axis.

    PubMed

    Antoniali, Giulia; Marcuzzi, Federica; Casarano, Elena; Tell, Gianluca

    2015-11-01

    Cadmium (Cd) is a carcinogenic and neurotoxic environmental pollutant. Among the proposed mechanisms for Cd toxic effects, its ability to promote oxidative stress and to inhibit, in vitro, the activities of some Base Excision DNA Repair (BER) enzymes, such as hOGG1, XRCC1 and APE1, have been already established. However, the molecular mechanisms at the basis of these processes are largely unknown especially at sub-lethal doses of Cd and no information is available on the effect of Cd on the expression levels of BER enzymes. Here, we show that non-toxic treatment of neuronal cell lines, with pro-mitogenic doses of Cd, promotes a significant time- and dose-dependent down-regulation of DNA polymerase δ (POLD1) expression through a transcriptional mechanism with a modest effect on Polβ, XRCC1 and APE1. We further elucidated that the observed transcriptional repression on Polδ is acted by through competition by activated p53 on Sp1 at POLD1 promoter and by a squelching effect. We further proved the positive effect of Sp1 not only on POLD1 expression but also on Polβ, XRCC1 and APE1 expression, suggesting that Sp1 has pleiotropic effects on the whole BER pathway. Our results indicated that Cd-mediated impairment of BER pathway, besides acting on the enzymatic functions of some key proteins, is also exerted at the gene expression level of Polδ by acting on the p53-Sp1 regulatory axis. These data may explain not only the Cd-induced neurotoxic effects but also the potential carcinogenicity of this heavy metal.

  6. Explosion suppression system

    DOEpatents

    Sapko, Michael J.; Cortese, Robert A.

    1992-01-01

    An explosion suppression system and triggering apparatus therefor are provided for quenching gas and dust explosions. An electrically actuated suppression mechanism which dispenses an extinguishing agent into the path ahead of the propagating flame is actuated by a triggering device which is light powered. This triggering device is located upstream of the propagating flame and converts light from the flame to an electrical actuation signal. A pressure arming device electrically connects the triggering device to the suppression device only when the explosion is sensed by a further characteristic thereof beside the flame such as the pioneer pressure wave. The light powered triggering device includes a solar panel which is disposed in the path of the explosion and oriented between horizontally downward and vertical. Testing mechanisms are also preferably provided to test the operation of the solar panel and detonator as well as the pressure arming mechanism.

  7. Sensory suppression during feeding

    PubMed Central

    Foo, H.; Mason, Peggy

    2005-01-01

    Feeding is essential for survival, whereas withdrawal and escape reactions are fundamentally protective. These critical behaviors can compete for an animal's resources when an acutely painful stimulus affects the animal during feeding. One solution to the feeding-withdrawal conflict is to optimize feeding by suppressing pain. We examined whether rats continue to feed when challenged with a painful stimulus. During feeding, motor withdrawal responses to noxious paw heat either did not occur or were greatly delayed. To investigate the neural basis of sensory suppression accompanying feeding, we recorded from brainstem pain-modulatory neurons involved in the descending control of pain transmission. During feeding, pain-facilitatory ON cells were inhibited and pain-inhibitory OFF cells were excited. When a nonpainful somatosensory stimulus preactivated ON cells and preinhibited OFF cells, rats interrupted eating to react to painful stimuli. Inactivation of the brainstem region containing ON and OFF cells also blocked pain suppression during eating, demonstrating that brainstem pain-modulatory neurons suppress motor reactions to external stimulation during homeostatic behaviors. PMID:16275919

  8. Adjuvant ovarian suppression in premenopausal breast cancer.

    PubMed

    Francis, Prudence A; Regan, Meredith M; Fleming, Gini F; Láng, István; Ciruelos, Eva; Bellet, Meritxell; Bonnefoi, Hervé R; Climent, Miguel A; Da Prada, Gian Antonio; Burstein, Harold J; Martino, Silvana; Davidson, Nancy E; Geyer, Charles E; Walley, Barbara A; Coleman, Robert; Kerbrat, Pierre; Buchholz, Stefan; Ingle, James N; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Colleoni, Marco; Viale, Giuseppe; Coates, Alan S; Goldhirsch, Aron; Gelber, Richard D

    2015-01-29

    Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain. We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal. After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87). Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further

  9. Reversible Suppression of Menstruction with Antiprogestins

    DTIC Science & Technology

    1997-10-01

    reversible method of menstrual suppression through use of antiprogestins. These compounds, which include mifepristone (RU 486), onapristone (ZK 98 299...through competitive binding at the receptor level. Hodgen’s laboratory was the first to report that treatment of cynomolgus monkeys with mifepristone on...cycle. Moreover, long term mifepristone treatment in women with endometriosis blocked ovarian cyclicity and caused amenorrhea (3). Such effects were

  10. Effect of Prazosin and Naltrexone on Script Induced Alcohol Craving in Veterans with Alcohol Use Disorders with and without Co-Occurring PTSD

    DTIC Science & Technology

    2016-01-01

    with and without Co-occurring PTSD PRINCIPAL INVESTIGATOR: Tracy Simpson, PhD CONTRACTING ORGANIZATION: Seattle Institute for Biomedical and Clinical ...ORGANIZATION NAME(S) AND ADDRESS(ES) Seattle Institute for Biomedical and Clinical Research 1660 S Columbia Way, S-151F, Seattle, WA 98108-1532 8...period we plan to hone recruitment strategies by  strategically recruiting likely eligible vets through our addiction treatment  clinic , through

  11. Plasmacytoid dendritic cell and functional HIV Gag p55-specific T cells before treatment interruption can inform set-point plasma HIV viral load after treatment interruption in chronically suppressed HIV-1+ patients

    PubMed Central

    Papasavvas, Emmanouil; Foulkes, Andrea; Yin, Xiangfan; Joseph, Jocelin; Ross, Brian; Azzoni, Livio; Kostman, Jay R; Mounzer, Karam; Shull, Jane; Montaner, Luis J

    2015-01-01

    The identification of immune correlates of HIV control is important for the design of immunotherapies that could support cure or antiretroviral therapy (ART) intensification-related strategies. ART interruptions may facilitate this task through exposure of an ART partially reconstituted immune system to endogenous virus. We investigated the relationship between set-point plasma HIV viral load (VL) during an ART interruption and innate/adaptive parameters before or after interruption. Dendritic cell (DC), natural killer (NK) cell and HIV Gag p55-specific T-cell functional responses were measured in paired cryopreserved peripheral blood mononuclear cells obtained at the beginning (on ART) and at set-point of an open-ended interruption from 31 ART-suppressed chronically HIV-1+ patients. Spearman correlation and linear regression modeling were used. Frequencies of plasmacytoid DC (pDC), and HIV Gag p55-specific CD3+ CD4− perforin+ IFN-γ+ cells at the beginning of interruption associated negatively with set-point plasma VL. Inclusion of both variables with interaction into a model resulted in the best fit (adjusted R2 = 0·6874). Frequencies of pDC or HIV Gag p55-specific CD3+ CD4− CSFElo CD107a+ cells at set-point associated negatively with set-point plasma VL. The dual contribution of pDC and anti-HIV T-cell responses to viral control, supported by our models, suggests that these variables may serve as immune correlates of viral control and could be integrated in cure or ART-intensification strategies. PMID:25684333

  12. Corticosteroids and Immune Suppressive Therapies in Horses.

    PubMed

    Leclere, Mathilde

    2017-04-01

    Immune suppressive therapies target exaggerated and deleterious responses of the immune system. Triggered by exogenous or endogenous factors, these improper responses can lead to immune or inflammatory manifestations, such as urticaria, equine asthma, or autoimmune and immune-mediated diseases. Glucocorticoids are the most commonly used immune suppressive drugs and the only ones supported by robust evidence of clinical efficacy in equine medicine. In some conditions, combining glucocorticoids with other pharmacologic and nonpharmacologic treatments, such as azathioprine, antihistamine, bronchodilators, environmental management, or desensitization, can help to decrease dosages and associated side effects.

  13. Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone.

    PubMed

    Hughes, Sam; Hickey, Louise; Donaldson, Lucy F; Lumb, Bridget M; Pickering, Anthony E

    2015-02-01

    The descending noradrenergic (NAergic) projection to the spinal cord forms part of an endogenous analgesic system. After nerve injury, a localised failure in this compensatory system has been implicated as a permissive factor in the development of neuropathic sensitisation. We investigated whether restoring descending NAergic tone with intrathecal reboxetine can oppose the development of the neuropathic pain phenotype after tibial nerve transection (TNT). Rats had a lumbar intrathecal catheter implanted at the time of nerve injury for administration of reboxetine (10 μg) in both acute and chronic dosing experiments. In acute dosing experiments, both intrathecal and systemic (30 mg/kg) reboxetine partially reversed mechanical allodynia. This antiallodynic effect of intrathecal reboxetine was blocked by prior administration of yohimbine (α2-adrenoceptor antagonist, 30 μg) but not by prazosin (α1-adrenoceptor antagonist, 30 μg) or propranolol (β-adrenoceptor antagonist, 100 μg). Chronic intrathecal reboxetine (10 μg, intrathecally, twice daily for 2 weeks) suppressed the development of cold and mechanical allodynia. Nerve-injured animals demonstrated a place preference for intrathecal reboxetine, suggesting that it also reduced spontaneous pain. In contrast, an equivalent antiallodynic dose of systemic reboxetine (30 mg/kg) was aversive in both naive and TNT rats. On cessation of chronic intrathecal reboxetine, there was a gradual development of allodynic sensitisation that was indistinguishable from control TNT animals by 7 days after the end of dosing. Our results suggest that pharmacological restoration of spinal NAergic tone with intrathecal reboxetine can suppress both allodynia and spontaneous pain in the TNT model.

  14. Pressure suppression containment system

    DOEpatents

    Gluntz, D.M.; Townsend, H.E.

    1994-03-15

    A pressure suppression containment system includes a containment vessel surrounding a reactor pressure vessel and defining a drywell therein containing a non-condensable gas. An enclosed wetwell pool is disposed inside the containment vessel, and a gravity driven cooling system (GDCS) pool is disposed above the wetwell pool in the containment vessel. The wetwell pool includes a plenum for receiving the non-condensable gas carried with steam from the drywell following a loss-of-coolant-accident (LOCA). The wetwell plenum is vented to a plenum above the GDCS pool following the LOCA for suppressing pressure rise within the containment vessel. A method of operation includes channeling steam released into the drywell following the LOCA into the wetwell pool for cooling along with the non-condensable gas carried therewith. The GDCS pool is then drained by gravity, and the wetwell plenum is vented into the GDCS plenum for channeling the non-condensable gas thereto. 6 figures.

  15. Pressure suppression containment system

    DOEpatents

    Gluntz, Douglas M.; Townsend, Harold E.

    1994-03-15

    A pressure suppression containment system includes a containment vessel surrounding a reactor pressure vessel and defining a drywell therein containing a non-condensable gas. An enclosed wetwell pool is disposed inside the containment vessel, and a gravity driven cooling system (GDCS) pool is disposed above the wetwell pool in the containment vessel. The wetwell pool includes a plenum for receiving the non-condensable gas carried with steam from the drywell following a loss-of coolant-accident (LOCA). The wetwell plenum is vented to a plenum above the GDCS pool following the LOCA for suppressing pressure rise within the containment vessel. A method of operation includes channeling steam released into the drywell following the LOCA into the wetwell pool for cooling along with the non-condensable gas carried therewith. The GDCS pool is then drained by gravity, and the wetwell plenum is vented into the GDCS plenum for channeling the non-condensable gas thereto.

  16. Drug Insight: appetite suppressants.

    PubMed

    Bray, George A

    2005-02-01

    The term 'appetite suppressant' is used to denote drugs that act primarily on the neurochemical transmitters of the central nervous system to reduce food intake. In addition to drugs that release or mimic the effect of norepinephrine (noradrenaline), this could include drugs that inhibit: reuptake of norepinephrine or 5-hydroxytryptamine (also known as serotonin); bind to the gamma-aminobutyric acid receptors or the cannabinoid receptors; and some peptides that reduce food intake. The sympathomimetic drugs phentermine, diethylpropion, benzphetamine, and phendimetrazine--so named because they mimic many effects of norepinephrine--are only approved in a few countries, and then only for short-term use. Sibutramine, a norepinephrine-5-hydroxytryptamine reuptake inhibitor, is approved for long-term use. Several new mechanisms for drug action are under investigation. Appetite suppressants should be viewed as useful adjuncts to diet and physical activity and might help selected patients to achieve and maintain weight loss.

  17. Learning motion discrimination with suppressed and un-suppressed MT.

    PubMed

    Thompson, Benjamin; Liu, Zili

    2006-06-01

    Perceptual learning of motion direction discrimination is generally thought to rely on the middle temporal area of the brain (MT/V5). A recent study investigating learning of motion discrimination when MT was psychophysically suppressed found that learning was possible with suppressed MT, but only when the task was sufficiently easy [Lu, H., Qian, N., Liu, Z. (2004). Learning motion discrimination with suppressed MT. Vision Research 44, 1817-1825]. We investigated whether this effect was indeed due to MT suppression or whether it could be explained by task difficulty alone. By comparing learning of motion discrimination when MT was suppressed vs. un-suppressed, at different task difficulties, we found that task difficulty alone could not explain the effects. At the highest difficulty, learning was not possible with suppressed MT, confirming [Lu, H., Qian, N., Liu, Z. (2004). Learning motion discrimination with suppressed MT. Vision Research 44, 1817-1825]. In comparison, learning was possible with un-suppressed MT at the same difficulty level. At the intermediate task difficulty, there was a clear learning disadvantage when MT was suppressed. Only for the easiest level of difficulty, did learning become equally possible for both suppressed and un-suppressed conditions. These findings suggest that MT plays an important role in learning to discriminate relatively fine differences in motion direction.

  18. Suppression Workshop Summary

    DTIC Science & Technology

    1987-04-07

    the sodium is just about as effective as potassium in accelerating the OH decay rates . These results can be used to validate the kinetic suppression... rate of reaction of the combustibles. It represents the proportion of combustibles in the breech. It was found that a very strong effect on the blast...accelerating the CH decay rate decreased with continued potassium addition. They also found that, for a Fg c amount of potassium added to the flames, the

  19. Tremor suppression in ECG

    PubMed Central

    Dotsinsky, Ivan A; Mihov, Georgy S

    2008-01-01

    Background Electrocardiogram recordings are very often contaminated by high-frequency noise usually power-line interference and EMG disturbances (tremor). Specific method for interference cancellation without affecting the proper ECG components, called subtraction procedure, was developed some two decades ago. Filtering out the tremor remains a priori partially successful since it has a relatively wide spectrum, which overlaps the useful ECG frequency band. Method The proposed method for tremor suppression implements the following three procedures. Contaminated ECG signals are subjected to moving averaging (comb filter with linear phase characteristic) with first zero set at 50 Hz to suppress tremor and PL interference simultaneously. The reduced peaks of QRS complexes and other relatively high and steep ECG waves are then restored by an introduced by us procedure called linearly-angular, so that the useful high frequency components are preserved in the range specified by the embedded in the ECG instrument filter, usually up to 125 Hz. Finally, a Savitzky-Golay smoothing filter is applied for supplementary tremor suppression outside the QRS complexes. Results The results obtained show a low level of the residual EMG disturbances together with negligible distortion of the wave shapes regardless of rhythm and morphology changes. PMID:19019218

  20. Abnormal Grain Growth Suppression in Aluminum Alloys

    NASA Technical Reports Server (NTRS)

    Hales, Stephen J. (Inventor); Claytor, Harold Dale (Inventor); Alexa, Joel A. (Inventor)

    2015-01-01

    The present invention provides a process for suppressing abnormal grain growth in friction stir welded aluminum alloys by inserting an intermediate annealing treatment ("IAT") after the welding step on the article. The IAT may be followed by a solution heat treatment (SHT) on the article under effectively high solution heat treatment conditions. In at least some embodiments, a deformation step is conducted on the article under effective spin-forming deformation conditions or under effective superplastic deformation conditions. The invention further provides a welded article having suppressed abnormal grain growth, prepared by the process above. Preferably the article is characterized with greater than about 90% reduction in area fraction abnormal grain growth in any friction-stir-welded nugget.

  1. MEK5 suppresses osteoblastic differentiation

    SciTech Connect

    Kaneshiro, Shoichi; Otsuki, Dai; Yoshida, Kiyoshi; Yoshikawa, Hideki; Higuchi, Chikahisa

    2015-07-31

    Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family and is activated by its upstream kinase, MAPK kinase 5 (MEK5), which is a member of the MEK family. Although the role of MEK5 has been investigated in several fields, little is known about its role in osteoblastic differentiation. In this study, we have demonstrated the role of MEK5 in osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells and bone marrow stromal ST2 cells. We found that treatment with BIX02189, an inhibitor of MEK5, increased alkaline phosphatase (ALP) activity and the gene expression of ALP, osteocalcin (OCN) and osterix, as well as it enhanced the calcification of the extracellular matrix. Moreover, osteoblastic cell proliferation decreased at a concentration of greater than 0.5 μM. In addition, knockdown of MEK5 using siRNA induced an increase in ALP activity and in the gene expression of ALP, OCN, and osterix. In contrast, overexpression of wild-type MEK5 decreased ALP activity and attenuated osteoblastic differentiation markers including ALP, OCN and osterix, but promoted cell proliferation. In summary, our results indicated that MEK5 suppressed the osteoblastic differentiation, but promoted osteoblastic cell proliferation. These results implied that MEK5 may play a pivotal role in cell signaling to modulate the differentiation and proliferation of osteoblasts. Thus, inhibition of MEK5 signaling in osteoblasts may be of potential use in the treatment of osteoporosis. - Highlights: • MEK5 inhibitor BIX02189 suppresses proliferation of osteoblasts. • MEK5 knockdown and MEK5 inhibitor promote differentiation of osteoblasts. • MEK5 overexpression inhibits differentiation of osteoblasts.

  2. Interocular suppression in children with deprivation amblyopia.

    PubMed

    Hamm, Lisa; Chen, Zidong; Li, Jinrong; Black, Joanna; Dai, Shuan; Yuan, Junpeng; Yu, Minbin; Thompson, Benjamin

    2017-04-01

    In patients with anisometropic or strabismic amblyopia, interocular suppression can be minimized by presenting high contrast stimulus elements to the amblyopic eye and lower contrast elements to the fellow eye. This suggests a structurally intact binocular visual system that is functionally suppressed. We investigated whether suppression can also be overcome by contrast balancing in children with deprivation amblyopia due to childhood cataracts. To quantify interocular contrast balance, contrast interference thresholds were measured using an established dichoptic global motion technique for 21 children with deprivation amblyopia, 14 with anisometropic or mixed strabismic/anisometropic amblyopia and 10 visually normal children (mean age mean=9.9years, range 5-16years). We found that interocular suppression could be overcome by contrast balancing in most children with deprivation amblyopia, at least intermittently, and all children with anisometropic or mixed anisometropic/strabismic amblyopia. However, children with deprivation amblyopia due to early unilateral or bilateral cataracts could tolerate only very low contrast levels to the stronger eye indicating strong suppression. Our results suggest that treatment options reliant on contrast balanced dichoptic presentation could be attempted in a subset of children with deprivation amblyopia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Safety and feasibility of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients on stable treatment with two nucleos(t)ide reverse transcriptase inhibitors + atazanavir/ritonavir with virological suppression (Atazanavir and Lamivudine for treatment Simplification, AtLaS pilot study).

    PubMed

    Di Giambenedetto, Simona; Fabbiani, Massimiliano; Colafigli, Manuela; Ciccarelli, Nicoletta; Farina, Salvatore; Sidella, Letizia; D'Avino, Alessandro; Mondi, Annalisa; Cingolani, Antonella; Tamburrini, Enrica; Murri, Rita; Navarra, Pierluigi; Cauda, Roberto; De Luca, Andrea

    2013-06-01

    To explore 48 week safety and efficacy of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression on a stable atazanavir/ritonavir-based standard triple regimen. This was a single-arm pilot study, enrolling 40 patients on atazanavir/ritonavir + two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), without previous treatment failure, with HIV-RNA <50 copies/mL for >3 months and CD4 >200 cells/mm(3). At baseline, patients were switched to 300/100 mg of atazanavir/ritonavir + 300 mg of lamivudine once daily. Laboratory parameters, atazanavir plasma levels, self-reported adherence, quality of life, neurocognitive performance, bone composition and body fat distribution were monitored. Virological failure was defined as HIV-RNA >50 copies/mL on two consecutive determinations or a single level >1000 copies/mL. After 48 weeks, 4/40 (10%) regimen discontinuations occurred: 1 death (brain haemorrhage), 1 study withdrawal (inadequate atazanavir plasma levels), 1 re-induction with two NRTIs due to pregnancy and 1 virological failure without development of resistance. Seven moderate to severe adverse events were recorded (including four renal colics, possibly treatment-related) in six patients. At week 48, increases in total (mean change +17 mg/dL, P = 0.001), high-density lipoprotein (+6 mg/dL, P < 0.001) and low-density lipoprotein (+8 mg/dL, P = 0.052) cholesterol were observed. The glomerular filtration rate improved (+7 mL/min/1.73 m(2), P < 0.001), as did scores exploring self-reported physical and mental health (+11, P = 0.009 and +13, P < 0.001 on a 0-100 scale), neuropsychological performance (-1 pathological task, P = 0.002) and total bone mineral density (+0.03 g/cm(2), P = 0.026). There were no significant changes in CD4 cell count, bilirubin, atazanavir plasma levels, adherence and body fat distribution over time. Simplification to atazanavir

  4. Therapeutic Treatment of Arthritic Mice with 15-Deoxy Δ(12,14)-Prostaglandin J2 (15d-PGJ2) Ameliorates Disease through the Suppression of Th17 Cells and the Induction of CD4(+)CD25(-)FOXP3(+) Cells.

    PubMed

    Carregaro, Vanessa; Napimoga, Marcelo H; Peres, Raphael S; Benevides, Luciana; Sacramento, Laís Amorim; Pinto, Larissa G; Grespan, Renata; Cunha, Thiago M; da Silva, João Santana; Cunha, Fernando Q

    2016-01-01

    The prostaglandin, 15-deoxy Δ(12,14)-prostaglandin J2 (15d-PGJ2), is a lipid mediator that plays an important role in the control of chronic inflammatory disease. However, the role of prostanoid in rheumatoid arthritis (RA) is not well determined. We demonstrated the therapeutic effect of 15d-PGJ2 in an experimental model of arthritis. Daily administration of 15d-PGJ2 attenuated the severity of CIA, reducing the clinical score, pain, and edema. 15d-PGJ2 treatment was associated with a marked reduction in joint levels of proinflammatory cytokines. Although the mRNA expression of ROR-γt was profoundly reduced, FOXP3 was enhanced in draining lymph node cells from 15d-PGJ2-treated arthritic mice. The specific and polyclonal CD4(+) Th17 cell responses were limited during the addition of prostaglandin to cell culture. Moreover, in vitro 15d-PGJ2 increased the expression of FOXP3, GITR, and CTLA-4 in the CD4(+)CD25(-) population, suggesting the induction of Tregs on conventional T cells. Prostanoid addition to CD4(+)CD25(-) cells selectively suppressed Th17 differentiation and promoted the enhancement of FOXP3 under polarization conditions. Thus, 15d-PGJ2 ameliorated symptoms of collagen-induced arthritis by regulating Th17 differentiation, concomitant with the induction of Tregs, and, consequently, protected mice from diseases aggravation. Altogether, these results indicate that 15d-PGJ2 may represent a potential therapeutic strategy in RA.

  5. Next generation fire suppressants

    NASA Technical Reports Server (NTRS)

    Brown, Jerry A.

    1995-01-01

    Spectrex, Inc., located in Cedar Grove, NJ is a manufacturer of fire detection and suppression equipment. Spectrex is one of the original pioneers in high speed fire detection and suppression systems for combat vehicles. Spectrex has installed fire suppressions systems in thousands of combat vehicles and ships throughout the world. Additionally, they manufacture flame explosion detectors, ship damage control systems, and optical gas and vapor detectors. The culmination of several years of research and development has recently produced an innovative electro-optical continuous monitoring systems called SharpEye 20/20I IR(sup 3) and SAFEYE that provide fast and reliable gas, vapor, aerosol, flame, and explosion detection. SharpEye 20/20I IR(sup 3) is a self-contained triple spectrum flame detector which scans for oscillating IR radiation (1 to 10 Hz) in the spectral bands ranging from 4.0 to 5.0 microns and uses programmed algorithms to check the ratio and correlation of data received by the three sensors to make the system highly immune to false alarms. It is extremely sensitive as it can detect a 1 x 1 square foot gasoline pan fire at 200 feet in less than 3 seconds. The sensitivity is user programmable, offering 4 ranges of detection. SAFEYE is comprised of a selected number of multispectral ban microprocessors controlled detectors which are in communication with one or more radiation sources that is projected along a 600 feet optical path. The signals from the selected narrow bands are processed and analyzed by highly sophisticated algorithms. It is ideal for high risk, remote, large areas such as petroleum and chemical manufacturing sites, waste dumps, aircraft cargo bays, and ship compartments. The SAFEYE will perform direct readings of the presence or rate of rise of concentrations of gases, vapors, or aerosols at the range of parts per million and provide alarms at various set points at different levels of concentrations.

  6. Enhancing thought suppression with hypnosis.

    PubMed

    Bryant, Richard A; Wimalaweera, Subodha

    2006-10-01

    Much research indicates that attempts to suppress thoughts lead to increased accessibility of those thoughts, especially when additional cognitive load is present. On the premise that hypnosis may permit more effective management of cognitive load, it was hypothesized that hypnosis may enhance more effective thought suppression. The present research examined whether the obstacle of cognitive load could be bypassed using hypnosis to facilitate successful thought suppression. Thirty-nine high and 40 low hypnotizable participants were hypnotized and received either a suppression instruction or no instruction for a memory of an embarrassing experience and subsequently completed a sentence-unscrambling task that indexed accessibility of embarrassing thoughts. Whereas lows instructed to suppress displayed a delayed increase in suppressed thoughts, highs did not. These findings support the proposition that hypnosis facilitates thought suppression.

  7. Planck-suppressed operators

    SciTech Connect

    Assassi, Valentin; Baumann, Daniel; Green, Daniel; McAllister, Liam E-mail: dbaumann@damtp.cam.ac.uk E-mail: mcallister@cornell.edu

    2014-01-01

    We show that the recent Planck limits on primordial non-Gaussianity impose strong constraints on light hidden sector fields coupled to the inflaton via operators suppressed by a high mass scale Λ. We study a simple effective field theory in which a hidden sector field is coupled to a shift-symmetric inflaton via arbitrary operators up to dimension five. Self-interactions in the hidden sector lead to non-Gaussianity in the curvature perturbations. To be consistent with the Planck limit on local non-Gaussianity, the coupling to any hidden sector with light fields and natural cubic couplings must be suppressed by a very high scale Λ > 10{sup 5}H. Even if the hidden sector has Gaussian correlations, nonlinearities in the mixing with the inflaton still lead to non-Gaussian curvature perturbations. In this case, the non-Gaussianity is of the equilateral or orthogonal type, and the Planck data requires Λ > 10{sup 2}H.

  8. Pharmacology of appetite suppression.

    PubMed

    Halford, J C; Blundell, J E

    2000-01-01

    Despite a rising worldwide epidemic of obesity there is currently only a very small number of anti-obesity drugs available to manage the problem. Large numbers of differing pharmacological agents reliably produce a reduction in food intake when administered acutely to animals, and when administered chronically they result in a significant decrease in body mass. Behavioural analysis of drug-induced anorexia in animals demonstrates that various compounds profoundly effect feeding behaviour in differing ways. This indicates the variety of mechanisms by which pharmacological agents can induce changes in food intake, body weight and eventually body composition. Some of the same drugs produce decreases in food intake and weight loss in humans. Some of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). Such drugs can be considered as "appetite suppressants" with clinical potential as anti-obesity agents. Other drugs induce changes in food intake and body weight through various physiological mechanisms inducing feelings of nausea or even by side effect related malaise. Of the drugs considered suitable candidates for appetite suppressants are agents which act via peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), or alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin and Melanocortins) or levels of the key CNS appetite monoamine neurotransmitters such as serotonin (5-HT) and noradrenaline (NA). Recently, the hormone leptin has been regarded as a hormonal signal linking adipose tissue status with a number of key central nervous system circuits. The peptide itself stimulates leptin receptors and it links with POMC and MC-4 receptors. These receptors may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i

  9. Allowing a wildfire to burn: estimating the effect on future fire suppression costs

    Treesearch

    Rachel M. Houtman; Claire A. Montgomery; Aaron R. Gagnon; David E. Calkin; Thomas G. Dietterich; Sean McGregor; Mark Crowley

    2013-01-01

    Where a legacy of aggressive wildland fire suppression has left forests in need of fuel reduction, allowing wildland fire to burn may provide fuel treatment benefits, thereby reducing suppression costs from subsequent fires. The least-cost-plus-net-value-change model of wildland fire economics includes benefits of wildfire in a framework for evaluating suppression...

  10. Ultrasonic Frost Suppression

    NASA Astrophysics Data System (ADS)

    Adachi, Kazunari; Saiki, Kazushi; Sato, Hiroki; Ito, Takahiro

    2003-02-01

    The authors have observed the accumulation of frost on the surface of a rectangular aluminum alloy (duralumin) plate flexurally vibrating at approximately 37 kHz in an atmosphere of almost 100% relative humidity at 2°C. The plate surface, which had been prepolished with abrasive slurry for maintaining its average surface roughness of about 100 nm, was refrigerated at a temperature of -20°C with cold carbon-dioxide gas as coolant. Experiments have been conducted with and without fine silver oxide powder spread on the plate surface so as to examine the effect of artificial ice crystal nuclei. Ultrasonic vibrations with an amplitude of 3.4 μm (rms) are found to suppress frost accumulation by approximately 60%. The phenomenon cannot be ascribed directly to the heat generation caused by high-amplitude vibration, but may have a complex mechanical and/or acoustical effect on small ice crystals.

  11. Pressure suppression system

    DOEpatents

    Gluntz, D.M.

    1994-10-04

    A pressure suppression system includes a containment vessel surrounding a reactor pressure vessel and defining a drywell therein containing a non-condensable gas. An enclosed wetwell pool is disposed inside the containment vessel, and an enclosed gravity driven cooling system (GDCS) pool is disposed above the wetwell pool in the containment vessel. The GDCS pool includes a plenum for receiving through an inlet the non-condensable gas carried with steam from the drywell following a loss-of-coolant accident (LOCA). A condenser is disposed in the GDCS plenum for condensing the steam channeled therein and to trap the non-condensable gas therein. A method of operation includes draining the GDCS pool following the LOCA and channeling steam released into the drywell following the LOCA into the GDCS plenum for cooling along with the non-condensable gas carried therewith for trapping the gas therein. 3 figs.

  12. Pressure suppression system

    DOEpatents

    Gluntz, Douglas M.

    1994-01-01

    A pressure suppression system includes a containment vessel surrounding a reactor pressure vessel and defining a drywell therein containing a non-condensable gas. An enclosed wetwell pool is disposed inside the containment vessel, and an enclosed gravity driven cooling system (GDCS) pool is disposed above the wetwell pool in the containment vessel. The GDCS pool includes a plenum for receiving through an inlet the non-condensable gas carried with steam from the drywell following a loss-of-coolant accident (LOCA). A condenser is disposed in the GDCS plenum for condensing the steam channeled therein and to trap the non-condensable gas therein. A method of operation includes draining the GDCS pool following the LOCA and channeling steam released into the drywell following the LOCA into the GDCS plenum for cooling along with the non-condensable gas carried therewith for trapping the gas therein.

  13. ZERO SUPPRESSION FOR RECORDERS

    DOEpatents

    Fort, W.G.S.

    1958-12-30

    A zero-suppression circuit for self-balancing recorder instruments is presented. The essential elements of the circuit include a converter-amplifier having two inputs, one for a reference voltage and the other for the signal voltage under analysis, and a servomotor with two control windings, one coupled to the a-c output of the converter-amplifier and the other receiving a reference input. Each input circuit to the converter-amplifier has a variable potentiometer and the sliders of the potentiometer are ganged together for movement by the servoinotor. The particular noveity of the circuit resides in the selection of resistance values for the potentiometer and a resistor in series with the potentiometer of the signal circuit to ensure the full value of signal voltage variation is impressed on a recorder mechanism driven by servomotor.

  14. Factors influencing dust suppressant effectiveness

    SciTech Connect

    Copeland, C.R.; Eisele, T.C.; Chesney, D.J.; Kawatra, S.K.

    2008-11-15

    Water sprays are a common method used to reduce particulate matter (PM) emissions. Various factors such as wettability, surface area coverage, fine particle engulfment rates, interparticle adhesion forces, suppressant penetration and suppressant longevity have all been suggested as critical factors in achieving effective PM control. However, it has not been established which of these factors are the most important. Experimental work indicated that suppressant penetration is the most critical of these factors. The length of time after application that suppressants were effective was also improved by using hygroscopic reagents that retained moisture to prevent evaporation. Maximizing suppressant penetration and improving suppressant longevity led to an average 86% reduction in PM10 concentrations in laboratory dust tower tests.

  15. Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction

    PubMed Central

    Forget, Benoit; Wertheim, Carrie; Mascia, Paola; Pushparaj, Abhiram; Goldberg, Steven R; Le Foll, Bernard

    2010-01-01

    Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic α1 receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic α1 receptor antagonist prazosin (0.25–1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic α1 receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to α1 adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans. PMID:20357760

  16. The site of saccadic suppression.

    PubMed

    Thilo, Kai V; Santoro, Loredana; Walsh, Vincent; Blakemore, Colin

    2004-01-01

    During rapid eye movements, or saccades, stable vision is maintained by active reduction of visual sensitivity. The site of this saccadic suppression remains uncertain. Here we show that phosphenes--small illusory visual perceptions--induced by transcranial magnetic stimulation (TMS) to the human occipital cortex are immune to saccadic suppression, whereas phosphenes induced by retinal stimulation are not, thus providing direct physiological evidence that saccadic suppression occurs between the retina and the occipital visual cortex.

  17. CBMG, a novel derivative of mansonone G suppresses adipocyte differentiation via suppression of PPARγ activity.

    PubMed

    Kim, Hyo Kyeong; Hairani, Rita; Jeong, Hana; Jeong, Mi Gyeong; Chavasiri, Warinthorn; Hwang, Eun Sook

    2017-08-01

    Mansorins and mansonones have been isolated from Mansonia gagei heartwoods, a traditional herbal medicine used to treat heart failure, and characterized to have anti-oxidant, anti-bacterial, anti-tumor, and anti-estrogenic activities. However, there is as yet no information on their effects on adipogenesis and lipid storage associated with heart disease. In this study, we investigated the effects of naturally occurring compounds on adipogenic differentiation and sought to develop more potent anti-adipogenic compound. We found that mansonone G (MG) suppressed adipocyte differentiation of 3T3-L1 cells, with a 40% decrease in lipid accumulation at 10 μM. MG derivatives including ether and ester analogues were then synthesized and assayed for their ability to suppress adipogenesis. A novel MG derivative, chlorobenzoyl MG (CBMG) most potently suppressed adipocyte differentiation with the decreased level of aP2 and adiponectin. Interestingly, CBMG treatment decreased the expression of CCAAT enhancer binding protein-α (C/EBPα) and peroxisome proliferator-activated receptor-γ (PPARγ). Further analysis confirmed that CBMG suppressed both the expression and activity of PPARγ, a master regulator of adipogenesis, and subsequently led to decreases in transcription of C/EBPα, aP2, and adiponectin in adipogenesis, thereby attenuating adipocyte differentiation. Our results suggest that a novel MG derivative, CBMG may have beneficial applications in the control of obesity through the suppression of PPARγ-induced adipocyte differentiation and lipid accumulation. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. STRV Cryocooler Tip Motion Suppression

    NASA Technical Reports Server (NTRS)

    Glaser, R.; Ross, R. G., Jr.; Johnson, D. L.

    1994-01-01

    The Space Technology Research Vehicle (STRV-1b) scheduled to fly at the beginning of June 1994, has a cryocooler vibration suppression experiment aboard doing motion suppression of the tip of the coldfinger. STRV-1b is a bread box sized satellite to be launched on the next flight of the Ariane-4.

  19. An Alternative to Thought Suppression?

    ERIC Educational Resources Information Center

    Boice, Robert

    2012-01-01

    Comments on the original article, "Setting free the bears: Escape from thought suppression," by D. M. Wegner (see record 2011-25622-008). While Wegner supposed that we might have to learn to live with bad thoughts, the present author discusses the use of imagination and guided imagery as an alternative to forced thought suppression.

  20. An Alternative to Thought Suppression?

    ERIC Educational Resources Information Center

    Boice, Robert

    2012-01-01

    Comments on the original article, "Setting free the bears: Escape from thought suppression," by D. M. Wegner (see record 2011-25622-008). While Wegner supposed that we might have to learn to live with bad thoughts, the present author discusses the use of imagination and guided imagery as an alternative to forced thought suppression.

  1. STRV Cryocooler Tip Motion Suppression

    NASA Technical Reports Server (NTRS)

    Glaser, R.; Ross, R. G., Jr.; Johnson, D. L.

    1994-01-01

    The Space Technology Research Vehicle (STRV-1b) scheduled to fly at the beginning of June 1994, has a cryocooler vibration suppression experiment aboard doing motion suppression of the tip of the coldfinger. STRV-1b is a bread box sized satellite to be launched on the next flight of the Ariane-4.

  2. Suppressing Display Cockpit Reflections

    NASA Astrophysics Data System (ADS)

    Hartmann, Rudolf

    1987-09-01

    Modern aircraft displays with relatively high visual brightness levels present day and night sensor images (generated by electro-optical systems) to crew members for navigation and fire control purposes. A heads out display (HOD) on a cathode ray tube (CRT) screen, while effective for one crew member, may distract or irritate another crew member if the image is reflected off a canopy panel into his eyes, particularly at night. This paper presents one solution applied to canopy reflection suppression encountered in the U.S. Army's APACHE Advanced Attack Helicopter where the co-pilot's HOD reflections interfered with the pilot's vision. When the co-pilot would move his head away from the screen, the reflected image path to the pilot, sitting above and behind the co-pilot, would no longer be blocked and distract him. A variety of polarizers were studied and the problem was solved by placing a linear polarizer over the CRT with its axis crossed relative to the skipping vector of the reflection, letting the canopy panel act as an analyzer. Reflected luminance was reduced by more than 25 times.

  3. Painful consequences of anger suppression.

    PubMed

    Quartana, Phillip J; Burns, John W

    2007-05-01

    The authors experimentally examined the effects of anger suppression on pain perception. On the basis of ironic process theory, they proposed that efforts to suppress experiential or expressive components of anger may paradoxically enhance cognitive accessibility of anger-related thoughts and feelings, thereby contaminating perception of succeeding pain in an anger-congruent manner. Participants were randomly assigned to nonsuppression or experiential or expressive suppression conditions during mental arithmetic with or without harassment. A cold-pressor task followed. Results revealed that participants instructed to suppress experiential or expressive components of emotion during harassment not only reported the greatest pain levels, but also rated the anger-specific dimensions of pain uniquely strong. Results suggest that attempts to suppress anger may amplify pain sensitivity by ironically augmenting perception of the irritating and frustrating qualities of pain.

  4. Inducing amnesia through systemic suppression

    PubMed Central

    Hulbert, Justin C.; Henson, Richard N.; Anderson, Michael C.

    2016-01-01

    Hippocampal damage profoundly disrupts the ability to store new memories of life events. Amnesic windows might also occur in healthy people due to disturbed hippocampal function arising during mental processes that systemically reduce hippocampal activity. Intentionally suppressing memory retrieval (retrieval stopping) reduces hippocampal activity via control mechanisms mediated by the lateral prefrontal cortex. Here we show that when people suppress retrieval given a reminder of an unwanted memory, they are considerably more likely to forget unrelated experiences from periods surrounding suppression. This amnesic shadow follows a dose-response function, becomes more pronounced after practice suppressing retrieval, exhibits characteristics indicating disturbed hippocampal function, and is predicted by reduced hippocampal activity. These findings indicate that stopping retrieval engages a suppression mechanism that broadly compromises hippocampal processes and that hippocampal stabilization processes can be interrupted strategically. Cognitively triggered amnesia constitutes an unrecognized forgetting process that may account for otherwise unexplained memory lapses following trauma. PMID:26977589

  5. Suppression of Eimeria tenella sporulation by disinfectants.

    PubMed

    You, Myung-Jo

    2014-08-01

    The disinfectant effects (DEs) of 10 types of chemicals, defined by their ability to destroy or inhibit oocysts and consequently prevent sporulation of Eimeria tenella field isolate, were evaluated in vitro. Correct species assignments and sample purities were confirmed by the singular internal transcribed spacer (ITS)-PCR analysis. A total of 18 treatments were performed, and the disinfection suppression levels were 75.9% for 39% benzene + 22% xylene (1:10 dilution), 85.5% for 30% cresol soup (1:1 dilution), and 91.7% for 99.9% acetic acid (1:2 dilution) group. The results indicate that acetic acid, cresol soup, and benzene+xylene are good candidates for suppression of E. tenella oocyst sporulation.

  6. Appetite suppressants and valvular heart disease.

    PubMed

    Seghatol, Frank F; Rigolin, Vera H

    2002-09-01

    Appetite suppressants fenfluramine, dexfenfluramine, and phentermine have been used alone or in combination as an alternative to diet and surgery in the management of obesity. This therapy was halted in 1997 after reports of valvular lesions affecting almost one third of patients treated with these drugs. Fortunately, most cases of appetite suppressant-related valve disease are mild or moderate and rarely required valve repair or replacement. Follow-up studies have suggested improvement in valvulopathy after discontinuation of the treatment. The mechanism of valve disease induced by these drugs is speculative and may be related to their serotonergic effects. Echocardiographic features are similar to carcinoid heart disease and valvulopathy associated with ergot use. Most cases require only follow-up and endocarditis prophylaxis; surgery is rarely needed.

  7. Glucose Suppresses Biological Ferroelectricity in Aortic Elastin

    NASA Astrophysics Data System (ADS)

    Liu, Yuanming; Wang, Yunjie; Chow, Ming-Jay; Chen, Nataly Q.; Ma, Feiyue; Zhang, Yanhang; Li, Jiangyu

    2013-04-01

    Elastin is an intriguing extracellular matrix protein present in all connective tissues of vertebrates, rendering essential elasticity to connective tissues subjected to repeated physiological stresses. Using piezoresponse force microscopy, we show that the polarity of aortic elastin is switchable by an electrical field, which may be associated with the recently discovered biological ferroelectricity in the aorta. More interestingly, it is discovered that the switching in aortic elastin is largely suppressed by glucose treatment, which appears to freeze the internal asymmetric polar structures of elastin, making it much harder to switch, or suppressing the switching completely. Such loss of ferroelectricity could have important physiological and pathological implications from aging to arteriosclerosis that are closely related to glycation of elastin.

  8. HIV-1 Reservoirs During Suppressive Therapy

    PubMed Central

    Barton, Kirston; Winckelmann, Anni; Palmer, Sarah

    2016-01-01

    The introduction of antiretroviral therapy (ART) 20 years ago has dramatically reduced morbidity and mortality associated with HIV-1. Initially there was hope that ART would be curative, but it quickly became clear that even though ART was able to restore CD4+ T cell counts and suppress viral loads below levels of detection, discontinuation of treatment resulted in a rapid rebound of infection. This is due to persistence of a small reservoir of latently infected cells with a long half-life, which necessitates life-long ART. Over the past few years, significant progress has been made in defining and characterizing the latent reservoir of HIV-1, and here we review how understanding the latent reservoir during suppressive therapy will lead to significant advances in curative approaches for HIV-1. PMID:26875617

  9. Currently available cough suppressants for chronic cough.

    PubMed

    Chung, Kian Fan

    2008-01-01

    Chronic cough is a common symptom but only a fraction of patients seek medical attention. Addressing the causes of chronic cough may lead to control of cough; however, this approach is not always successful since there is a certain degree of failure even when the cause(s) of cough are adequately treated; in idiopathic cough, there is no cause to treat. Persistent cough may be associated with deterioration of quality of life, and treatment with cough suppressants is indicated. Currently available cough suppressants include the centrally acting opioids such as morphine, codeine, and dextromethorphan. Peripherally acting antitussives include moguisteine and levodropropizine. Early studies report success in reducing cough in patients with chronic bronchitis or COPD; however, a carefully conducted study showed no effect of codeine on cough of COPD. Success with these cough suppressants can be achieved at high doses that are associated with side effects. Slow-release morphine has been reported to be useful in controlling intractable cough with good tolerance to constipation and drowsiness. There have been case reports of the success of centrally acting drugs such as amitryptiline, paroxetine, gabapentin, and carbamezepine in chronic cough. New opioids such as nociceptin or antagonists of TRPV1 may turn out to be more effective. Efficacy of cough suppressants must be tested in double-blind randomised trials using validated measures of cough in patients with chronic cough not responding to specific treatments. Patients with chronic cough are in desperate need of effective antitussives that can be used either on demand or on a long-term basis.

  10. Ovarian follicular growth suppression by long-term treatment with a GnRH agonist and impact on small follicle number, oocyte yield, and in vitro embryo production in Zebu beef cows.

    PubMed

    Batista, E O S; Vieira, L M; Sá Filho, M F; Dias, E A R; Bayeux, B M; Accorsi, M F; Monteiro, F M; Souza, A H; Baruselli, P S; D'Occhio, M J

    2016-06-01

    The aim of the present study was to evaluate small follicle number, oocyte yield, and in vitro embryo production (IVEP) in Zebu beef cows treated long term with a GnRH agonist to suppress ovarian follicular growth. Nelore (Bos indicus) cows (n = 20) showing regular estrous cycles were randomly assigned to one of two groups: control (n = 10, placebo ear implant without a GnRH agonist); GnRH agonist (n = 10, GnRH agonist ear implant containing 9.4-mg deslorelin). All cows underwent an ovum pick-up (OPU) session 14 days (Day 14) before the start of treatments (Day 0) followed by seven OPU-IVEP procedures at 30-day intervals (Days 0, 30, 60, 90, 120, 150, and 180). Semen from a single batch of a previously tested bull was used for all the IVEP. Cows treated with agonist reported a decrease over time in the proportion of animals with a (CL; P ≤ 0.05) and large follicles (>10 mm, P ≤ 0.05). These cows had a lesser number of medium + large follicles (>5 mm; 1.74 ± 0.5 vs. 4.13 ± 0.5; P ≤ 0.05), greater number of small follicles (2-5 mm; 44.3 ± 2.8 vs. 30.8 ± 1.8; P ≤ 0.05), greater yield of cumulus-oocyte complexes (COCs; 21.0 ± 2.3 vs. 15.6 ± 1.9; P ≤ 0.05), greater proportion of COCs cultured (79.2 vs. 73.9%; P ≤ 0.05), COCs cleaved (10.6 ± 1.5 vs. 6.8 ± 1.1, P ≤ 0.05), and cleaved rate (52.8 vs. 44.3%; P ≤ 0.05) compared with control cows. The number (3.4 ± 0.7 vs. 3.0 ± 0.6; P > 0.05) and proportion (16.5 vs. 19.1%; P > 0.05) of blastocysts produced were similar between agonist and control cows, respectively. The study has shown that Zebu beef cows treated long term with a GnRH agonist had follicular growth restricted to small follicles. This did not compromise the ability of oocytes to undergo IVF and embryonic development.

  11. Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases.

    PubMed

    Keeling, Kim M; Bedwell, David M

    2011-01-01

    Suppression therapy is a treatment strategy for genetic diseases caused by nonsense mutations. This therapeutic approach utilizes pharmacological agents that suppress translation termination at in-frame premature termination codons (PTCs) to restore translation of a full-length, functional polypeptide. The efficiency of various classes of compounds to suppress PTCs in mammalian cells is discussed along with the current limitations of this therapy. We also elaborate on approaches to improve the efficiency of suppression that include methods to enhance the effectiveness of current suppression drugs and the design or discovery of new, more effective suppression agents. Finally, we discuss the role of nonsense-mediated mRNA decay (NMD) in limiting the effectiveness of suppression therapy, and describe tactics that may allow the efficiency of NMD to be modulated in order to enhance suppression therapy.

  12. Androgen synthesis in the gonadotropin-suppressed human testes can be markedly suppressed by ketoconazole.

    PubMed

    Roth, M Y; Nya-Ngatchou, J J S; Lin, K; Page, S T; Anawalt, B D; Matsumoto, A M; Marck, B T; Bremner, W J; Amory, J K

    2013-03-01

    The concentration of intratesticular testosterone (IT-T) required for human spermatogenesis is unknown because spermatogenesis can persist despite the markedly reduced IT-T concentrations observed with LH suppression. Methods to lower IT-T further are needed to determine the relationship between IT-T and spermatogenesis. The objective of the study was to determine the effect of inhibiting the synthesis and metabolism of testosterone (T) on IT-T in gonadotropin-suppressed human testes. Forty normal men participated in a blinded, placebo-controlled, randomized trial at an academic center. INTERVENTION/OUTCOME MEASURES: All men were first administered the GnRH antagonist acyline to suppress LH. Forty-eight hours after acyline administration, subjects were randomly assigned to placebo, ketoconazole (to inhibit T synthesis) at 400 or 800 mg, dutasteride (to inhibit T metabolism) 2.5 mg, or anastrazole (to inhibit T metabolism) 1 mg, daily for 7 days (n = 8/group). Intratesticular steroid concentrations were measured 48 hours after acyline administration alone and again after 7 days of combination treatment. After 7 days of combination treatment, the median IT-T (25th, 75th percentile) in the placebo group was 14 (8.0, 21.2) ng/mL. IT-T was reduced to 3.7 (2.5, 7.1) ng/mL in the ketoconazole 400 mg group and 1.7 (0.8, 4.0) ng/mL in the ketoconazole 800 mg group (P < .001 vs placebo for both comparisons). IT-T concentrations in the dutasteride and anastrazole groups were similar to placebo. Combining inhibition of steroidogenesis with gonadotropin suppression lowers IT-T more than gonadotropin suppression alone. This combination might be useful to determine the minimum IT-T concentration necessary for human spermatogenesis, information essential for developing male hormonal contraceptives.

  13. In Vivo Treg Suppression Assays

    PubMed Central

    Workman, Creg J.; Collison, Lauren W.; Bettini, Maria; Pillai, Meenu R.; Rehg, Jerold E.; Vignali, Dario A.A.

    2011-01-01

    To fully examine the functionality of a regulatory T cell (Treg) population, one needs to assess their ability to suppress in a variety of in vivo models. We describe five in vivo models that examine the suppressive capacity of Tregs upon different target cell types. The advantages and disadvantages of each model includ ing resources, time, and technical expertise required to execute each model are also described. PMID:21287333

  14. Suppressing bullfrog larvae with carbon dioxide

    USGS Publications Warehouse

    Gross, Jackson A.; Ray, Andrew; Sepulveda, Adam J.; Watten, Barnaby J.; Densmore, Christine L.; Layhee, Megan J.; Mark Abbey-Lambert,; ,

    2014-01-01

    Current management strategies for the control and suppression of the American Bullfrog (Lithobates catesbeianus = Rana catesbeiana Shaw) and other invasive amphibians have had minimal effect on their abundance and distribution. This study evaluates the effects of carbon dioxide (CO2) on pre- and prometamorphic Bullfrog larvae. Bullfrogs are a model organism for evaluating potential suppression agents because they are a successful invader worldwide. From experimental trials we estimated that the 24-h 50% and 99% lethal concentration (LC50 and LC99) values for Bullfrog larvae were 371 and 549 mg CO2/L, respectively. Overall, larvae that succumbed to experimental conditions had a lower body condition index than those that survived. We also documented sublethal changes in blood chemistry during prolonged exposure to elevated CO2. Specifically, blood pH decreased by more than 0.5 pH units after 9 h of exposure and both blood partial pressure of CO2 (pCO2) and blood glucose increased. These findings suggest that CO2 treatments can be lethal to Bullfrog larvae under controlled laboratory conditions. We believe this work represents the necessary foundation for further consideration of CO2 as a potential suppression agent for one of the most harmful invaders to freshwater ecosystems.

  15. Suppressed Charmed B Decay

    SciTech Connect

    Snoek, Hella Leonie

    2009-06-02

    This thesis describes the measurement of the branching fractions of the suppressed charmed B0 → D*- a0+ decays and the non-resonant B0 → D*- ηπ+ decays in approximately 230 million Υ(4S) → B$\\bar{B}$ events. The data have been collected with the BABAR detector at the PEP-II B factory at the Stanford Linear Accelerator Center in California. Theoretical predictions of the branching fraction of the B0 → D*- a{sub 0}+ decays show large QCD model dependent uncertainties. Non-factorizing terms, in the naive factorization model, that can be calculated by QCD factorizing models have a large impact on the branching fraction of these decay modes. The predictions of the branching fractions are of the order of 10-6. The measurement of the branching fraction gives more insight into the theoretical models. In general a better understanding of QCD models will be necessary to conduct weak interaction physics at the next level. The presence of CP violation in electroweak interactions allows the differentiation between matter and antimatter in the laws of physics. In the Standard Model, CP violation is incorporated in the CKM matrix that describes the weak interaction between quarks. Relations amongst the CKM matrix elements are used to present the two relevant parameters as the apex of a triangle (Unitarity Triangle) in a complex plane. The over-constraining of the CKM triangle by experimental measurements is an important test of the Standard Model. At this moment no stringent direct measurements of the CKM angle γ, one of the interior angles of the Unitarity Triangle, are available. The measurement of the angle γ can be performed using the decays of neutral B mesons. The B0 → D*- a0+ decay is sensitive to the angle γ and, in comparison to the current decays that are being employed, could significantly

  16. Curcumin suppresses ovalbumin-induced allergic conjunctivitis

    PubMed Central

    Chung, So-Hyang; Choi, Seong Hyun; Choi, Jin A.; Chuck, Roy S.

    2012-01-01

    Purpose Allergic conjunctivitis (AC) from an allergen-driven T helper 2 (Th2) response is characterized by conjunctival eosinophilic infiltration. Because curcumin has shown anti-allergic activity in an asthma and contact dermatitis laboratory models, we examined whether administration of curcumin could affect the severity of AC and modify the immune response to ovalbumin (OVA) allergen in an experimental AC model. Methods Mice were challenged with two doses of topical OVA via the conjunctival sac after systemic sensitization with OVA in aluminum hydroxide (ALUM). Curcumin was administered 1 h before OVA challenge. Several indicators for allergy such as serum immunoglubulin E (IgE) antibodies production, eosinophil infiltration into the conjunctiva and Th2 cytokine production were evaluated in mice with or without curcumin treatment. Results Mice challenged with OVA via the conjunctival sac following systemic sensitization with OVA in ALUM had severe AC. Curcumin administration markedly suppressed IgE-mediated and eosinophil-dependent conjunctival inflammation. In addition, mice administered curcumin had less interleukin-4 (IL-4) and interleukin-5 (IL-5) (Th2 type cytokine) production in conjunctiva, spleen, and cervical lymph nodes than mice in the non-curcumin-administered group. OVA challenge resulted in activation of the production of inducible nitric oxide (iNOS), and curcumin treatment inhibited iNOS production in the conjunctiva. Conclusions We believe our findings are the first to demonstrate that curcumin treatment suppresses allergic conjunctival inflammation in an experimental AC model. PMID:22876123

  17. Reduction of CpG-induced arthritis by suppressive oligodeoxynucleotides.

    PubMed

    Zeuner, Rainald A; Ishii, Ken J; Lizak, Martin J; Gursel, Ihsan; Yamada, Hiroshi; Klinman, Dennis M; Verthelyi, Daniela

    2002-08-01

    Bacterial DNA contains immunostimulatory CpG motifs that cause inflammation when injected into the knee joints of normal mice. We examined whether synthetic oligodeoxynucleotides (ODN) that suppress CpG-induced immune responses prevent CpG-induced arthritis. CpG, suppressive, and/or control ODN were injected into the knees of BALB/c mice. Joint swelling and inflammation were evaluated by physical measurement, by histologic analysis of joint tissue, and by magnetic resonance imaging. Immunostimulatory CpG DNA induced local arthritis, characterized by swelling of the knee joints, the presence of inflammatory cell infiltrates, the perivascular accumulation of mononuclear cells, and hyperplasia of the synovial lining. Administering suppressive (but not control) ODN reduced the manifestations and severity of arthritis up to 80%. Suppressive ODN may be useful for the prevention or treatment of arthritis induced by bacterial DNA.

  18. Exploring dielectric elastomers as actuators for hand tremor suppression

    NASA Astrophysics Data System (ADS)

    Kelley, Christopher R.; Kauffman, Jeffrey L.

    2017-04-01

    Pathological tremor results in undesired motion of body parts, with the greatest effect typically occurring in the hands. Since common treatment methods are ineffective in some patients or have risks associated with surgery or side effects, researchers are investigating mechanical means of tremor suppression. This work explores the viability of dielectric elastomers as the actuators in a tremor suppression control system. Dielectric elastomers have many properties similar to human muscle, making them a natural fit for integration into the human biomechanical system. This investigation develops a model of the integrated wrist-actuator system to determine actuator parameters that produce the necessary control authority without significantly affecting voluntary motion. Furthermore, this paper develops a control law for the actuator voltage to increase the effective viscous damping of the system. Simulations show excellent theoretical tremor suppression, demonstrating the potential for dielectric elastomers to suppress tremor while maximizing compatibility between the actuator and the human body.

  19. Pharmacological studies on androgen suppression in therapy of prostate carcinoma.

    PubMed

    Sandow, J; von Rechenberg, W; Engelbart, K

    1988-01-01

    In hormone-dependent prostate carcinoma, androgens can be suppressed into the castrate range by LHRH agonists. Testosterone secretion is blocked at two levels: testicular androgens and adrenal androgens. In humans, the contribution of testicular androgens is about 95%, whereas in the rat, the adrenal androgen secretion is negligible. Pharmacological studies were performed on the suppressive effect of the LHRH agonist, buserelin on androgen-dependent organs in adult rats. The reduction in pituitary and testicular binding capacity was monitored during treatment by injection, or by long-term infusion. Marked differences in suppressive mechanisms activated by the different regimens were observed. Changes in testicular steroid biosynthesis were analysed by incubation of testes after treatment with HCG, measuring the spectrum of C21/C19-steroids in incubation media. In particular, the levels of intraprostatic androgens were determined during treatment with daily buserelin injections, or with sustained release formulations of buserelin. The tissue content of testosterone and 5-alpha-dihydrotestosterone (DHT) were both markedly lowered. In castrate rats, stimulation of adrenal function by ACTH infusion had no effect on the prostate weight or intratesticular T/DHT content. Combination therapy during the initial phase of treatment by an androgen receptor blocker (cyproterone acetate) and buserelin (infusion or implants) was more effective to suppress prostate weight and intra-prostatic T/DHT content than therapy with the single compounds alone. Spermatogenesis and fertility were suppressed after prolonged treatment periods of 6-12 months; the testicular atrophy was not reversible in these long-term injection studies. Similar studies in dogs and monkeys have shown a different result: inhibition of spermatogenesis was fully reversible. It is concluded that studies on the mechanism of androgen suppression by LHRH agonists and the effects on androgen dependent organs provide

  20. Neurotropin suppresses inflammatory cytokine expression and cell death through suppression of NF-κB and JNK in hepatocytes.

    PubMed

    Zhang, Bi; Roh, Yoon Seok; Liang, Shuang; Liu, Cheng; Naiki, Mitsuru; Masuda, Koichi; Seki, Ekihiro

    2014-01-01

    Inflammatory response and cell death in hepatocytes are hallmarks of chronic liver disease, and, therefore, can be effective therapeutic targets. Neurotropin® (NTP) is a drug widely used in Japan and China to treat chronic pain. Although NTP has been demonstrated to suppress chronic pain through the descending pain inhibitory system, the action mechanism of NTP remains elusive. We hypothesize that NTP functions to suppress inflammatory pathways, thereby attenuating disease progression. In the present study, we investigated whether NTP suppresses inflammatory signaling and cell death pathways induced by interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) in hepatocytes. NTP suppressed nuclear factor-κB (NF-κB) activation induced by IL-1β and TNFα assessed by using hepatocytes isolated from NF-κB-green fluorescent protein (GFP) reporter mice and an NF-κB-luciferase reporter system. The expression of NF-κB target genes, Il6, Nos2, Cxcl1, ccl5 and Cxcl2 induced by IL-1β and TNFα was suppressed after NTP treatment. We also found that NTP suppressed the JNK phosphorylation induced by IL-1β and TNFα. Because JNK activation contributes to hepatocyte death, we determined that NTP treatment suppressed hepatocyte death induced by IL-1β and TNFα in combination with actinomycin D. Taken together, our data demonstrate that NTP attenuates IL-1β and TNFα-mediated inflammatory cytokine expression and cell death in hepatocytes through the suppression of NF-κB and JNK. The results from the present study suggest that NTP may become a preventive or therapeutic strategy for alcoholic and non-alcoholic fatty liver disease in which NF-κB and JNK are thought to take part.

  1. Parathyroid growth and suppression in renal failure.

    PubMed

    Lewin, Ewa; Huan, Jinxing; Olgaard, Klaus

    2006-01-01

    In advanced uremia, parathyroid hormone (PTH) levels should be controlled at a moderately elevated level in order to promote normal bone turnover. As such, a certain degree of parathyroid hyperplasia has to be accepted. Uremia is associated with parathyroid growth. In experimental studies, proliferation of the parathyroid cells is induced by uremia and further promoted by hypocalcemia, phosphorus retention, and vitamin D deficiency. On the other hand, parathyroid cell proliferation might be arrested by treatment with a low-phosphate diet, vitamin D analogs, or calcimimetics. When established, parathyroid hyperplasia is poorly reversible. There exists no convincing evidence of programmed parathyroid cell death or apoptosis in hyperplastic parathyroid tissue or of involution of parathyroid hyperplasia. However, even considerable parathyroid hyperplasia can be controlled when the functional demand for increased PTH levels is removed by normalization of kidney function. Today, secondary hyperparathyroidism can be controlled in patients with long-term uremia in whom considerable parathyroid hyperplasia is to be expected. PTH levels can be suppressed in most uremic patients and this suppression can be maintained by continuous treatment with phosphate binders, vitamin D analogs, or calcimimetics. Thus modern therapy permits controlled development of parathyroid growth. When nonsuppressible secondary hyperparathyroidism is present, nodular hyperplasia with suppressed expression of the calcium-sensing receptor (CaR) and vitamin D receptor (VDR) has been found in most cases. An altered expression of some autocrine/paracrine factors has been demonstrated in the nodules. The altered quality of the parathyroid mass, and not only the increased parathyroid mass per se, might be responsible for uncontrollable hyperparathyroidism in uremia and after kidney transplantation.

  2. Efficacy and safety of emtricitabine/tenofovir alafenamide (FTC/TAF) vs. emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as a backbone for treatment of HIV-1 infection in virologically suppressed adults: subgroup analysis by third agent of a randomized, double-blind, active-controlled phase 3 trial().

    PubMed

    Post, Frank A; Yazdanpanah, Yazdan; Schembri, Gabriel; Lazzarin, Adriano; Reynes, Jacques; Maggiolo, Franco; Yan, Mingjin; Abram, Michael E; Tran-Muchowski, Cecilia; Cheng, Andrew; Rhee, Martin S

    2017-05-01

    FTC/TAF was shown to be noninferior to FTC/TDF with advantages in markers of renal and bone safety. To evaluate the efficacy and safety of switching to FTC/TAF from FTC/TDF by third agent (boosted protease inhibitor [PI] vs. unboosted third agent). We conducted a 48-week subgroup analysis based on third agent from a randomized, double blind study in virologically suppressed adults on a FTC/TDF-containing regimen who switched to FTC/TAF vs. continued FTC/TDF while remaining on the same third agent. We randomized (1:1) 663 participants to either switch to FTC/TAF (N = 333) or continue FTC/TDF (N = 330), each with baseline third agent stratifying by class of third agent in the prior treatment regimen (boosted PI 46%, unboosted third agent 54%). At week 48, significant differences in renal biomarkers and bone mineral density were observed favoring FTC/TAF over FTC/TDF (p < 0.05 for all), with similar improvements in the FTC/TAF arm in those who received boosted PI vs. unboosted third agents. At week 48, virologic success rates were similar between treatment groups for those who received a boosted PI (FTC/TAF 92%, FTC/TDF 93%) and for those who received an unboosted third agent (97% vs. 93%). In virologically suppressed patients switching to FTC/TAF from FTC/TDF, high rates of virologic suppression were maintained, while renal and bone safety parameters improved, regardless of whether participants were receiving a boosted PI or an unboosted third agent. FTC/TAF offers safety advantages over FTC/TDF and can be an important option as an NRTI backbone given with a variety of third agents.

  3. Suppression of fertility in adult dogs.

    PubMed

    Maenhoudt, C; Santos, N R; Fontbonne, A

    2014-06-01

    Unfortunately, the overpopulation of dogs is still a problem in the majority of countries and even though surgical methods of sterilization, the most traditional and commonly used technique, have been intensively performed, the impact on the dog population is negligible. The neutering of companion animals as ovariohysterectomy (spaying) or orchidectomy (castration) has its limitations because of the cost, the need of a surgical environment and the risk of surgical and/or anaesthetical complications (ACCD 2009). In fact, surgical castration has been banished in some northern European countries and has limited acceptance in other countries. In a survey performed in Sao Paulo, Brazil, 56.5% of the owners of adopted shelter dogs were against the surgical procedure for different reasons (Soto et al. 2005). Currently, the options for contraception, defined as suppression of fertility are based on hormonal treatment. The treatments can be divided into analogues of gonadotropin releasing hormone (GnRH), progestins and androgens. Other possibilities of contraception are via the immunological system with vaccinations against GnRH, the luteinizing hormone (LH) receptor and the zona pellucida proteins. Finally, there is also the intra-epididymal or intratesticular injection of sclerosing substances in dogs. Mechanical devices to disrupt fertility are not used anymore due to the side effects. Suppression of fertility in adult dogs will be reviewed in order of use and possible impact on the dog population. © 2014 Blackwell Verlag GmbH.

  4. Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long-term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and alpha 1-adrenoceptors.

    PubMed

    Tachibana, Kaori; Matsumoto, Machiko; Togashi, Hiroko; Kojima, Taku; Morimoto, Yuji; Kemmotsu, Osamu; Yoshioka, Mitsuhiro

    2004-03-04

    Pharmacological characteristics of a serotonin (5-HT) and noradrenaline reuptake inhibitor (SNRI), milnacipran, in modulation of the synaptic plasticity were investigated. Milnacipran (30 mg/kg, i.p.) suppressed the long-term potentiation (LTP) in the hippocampal CA1 field of anesthetized rats. Milnacipran-induced suppression was reversed by pretreatment with the selective 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg, i.v.) or the alpha1-adrenoceptor antagonist prazosin (1 and 10 microg/rat, i.c.v.). The alpha2-adrenoceptor antagonist idazoxan (5 mg/kg, i.p.) did not influence the milnacipran-induced synaptic responses. These data suggest that the inhibitory effects of milnacipran on LTP induction are mediated via both 5-HT1A receptors and alpha1-adrenoceptors. In other words, functional interaction between the serotonergic and noradrenergic neuronal systems is involved in alteration of the hippocampal synaptic plasticity, which may be implicated in the SNRI-induced therapeutic effect on psychiatric disorders.

  5. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer

    PubMed Central

    Pagani, Olivia; Regan, Meredith M.; Walley, Barbara A.; Fleming, Gini F.; Colleoni, Marco; Láng, István; Gomez, Henry L.; Tondini, Carlo; Burstein, Harold J.; Perez, Edith A.; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R.; Martino, Silvana; Geyer, Charles E.; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P.; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N.; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S.; Gelber, Richard D.; Goldhirsch, Aron; Francis, Prudence A.

    2014-01-01

    BACKGROUND Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor–positive breast cancer. METHODS In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor–positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. RESULTS After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane–ovarian suppression group and 87.3% in the tamoxifen–ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane–ovarian suppression group, as compared with 88.8% in the tamoxifen–ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane–ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane–ovarian suppression group and 29.4% of those in the tamoxifen–ovarian suppression group, with profiles similar to those for postmenopausal women. CONCLUSIONS In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT Clinical

  6. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.

    PubMed

    Pagani, Olivia; Regan, Meredith M; Walley, Barbara A; Fleming, Gini F; Colleoni, Marco; Láng, István; Gomez, Henry L; Tondini, Carlo; Burstein, Harold J; Perez, Edith A; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R; Martino, Silvana; Geyer, Charles E; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S; Gelber, Richard D; Goldhirsch, Aron; Francis, Prudence A

    2014-07-10

    Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

  7. Local cortical dynamics of burst suppression in the anaesthetized brain.

    PubMed

    Lewis, Laura D; Ching, Shinung; Weiner, Veronica S; Peterfreund, Robert A; Eskandar, Emad N; Cash, Sydney S; Brown, Emery N; Purdon, Patrick L

    2013-09-01

    , subcortical circuits express seemingly different sensitivities to high doses of anaesthetics that suggest a hierarchy governing how the brain enters burst suppression, and emphasize the role of local dynamics in what has previously been regarded as a global state. These findings suggest a conceptual shift in how neurologists could assess the brain function of patients undergoing burst suppression. First, analysing spatial variation in burst suppression could provide insight into the circuit dysfunction underlying a given pathology, and could improve monitoring of medically-induced coma. Second, analysing the temporal dynamics within a burst could help assess the underlying brain state. This approach could be explored as a prognostic tool for recovery from coma, and for guiding treatment of status epilepticus. Overall, these results suggest new research directions and methods that could improve patient monitoring in clinical practice.

  8. Bacterial rRNA genes associated with soil suppressiveness against the plant-parasitic nematode Heterodera schachtii.

    PubMed

    Yin, Bei; Valinsky, Lea; Gao, Xuebiao; Becker, J Ole; Borneman, James

    2003-03-01

    The goal of this study was to identify bacteria involved in soil suppressiveness against the plant-parasitic nematode Heterodera schachtii. Since H. schachtii cysts isolated from the suppressive soil can transfer this beneficial property to nonsuppressive soils, analysis of the cyst-associated microorganisms should lead to the identification of the causal organisms. Our experimental approach was to identify bacterial rRNA genes (rDNA) associated with H. schachtii cysts obtained from soil mixtures with various levels of suppressiveness. We hypothesized that we would be able to identify bacteria involved in the suppressiveness by correlating population shifts with differing levels of suppressiveness. Soil treatments containing different amounts of suppressive and fumigation-induced nonsuppressive soils exhibited various levels of suppressiveness after two nematode generations. The 10%-suppressive-soil treatment contained numbers of eggs per gram of soil similar to those of the 100%-suppressive-soil treatment, indicating that the suppressive factor(s) had been transferred. Bacterial rDNA associated with H. schachtii cysts were identified using a culture-independent method termed oligonucleotide fingerprinting of rRNA genes. Bacteria from five major taxonomic groups (Actinobacteria, Cytophaga-Flexibacter-Bacteroides, alpha-Proteobacteria, beta-Proteobacteria, and gamma-Proteobacteria) were identified. Three bacterial rDNA groups contained clones that were more prevalent in the highly suppressive soil treatments than in the less suppressive treatments, indicating a potential involvement in the H. schachtii suppressiveness. When these three groups were examined with specific PCR analyses performed on H. schachtii cysts that developed in soils treated with three biocidal compounds, only one bacterial rDNA group with moderate to high sequence identity to rDNA from several Rhizobium species and uncultured alpha-proteobacterial clones was consistently associated with the

  9. Bacterial rRNA Genes Associated with Soil Suppressiveness against the Plant-Parasitic Nematode Heterodera schachtii

    PubMed Central

    Yin, Bei; Valinsky, Lea; Gao, Xuebiao; Becker, J. Ole; Borneman, James

    2003-01-01

    The goal of this study was to identify bacteria involved in soil suppressiveness against the plant-parasitic nematode Heterodera schachtii. Since H. schachtii cysts isolated from the suppressive soil can transfer this beneficial property to nonsuppressive soils, analysis of the cyst-associated microorganisms should lead to the identification of the causal organisms. Our experimental approach was to identify bacterial rRNA genes (rDNA) associated with H. schachtii cysts obtained from soil mixtures with various levels of suppressiveness. We hypothesized that we would be able to identify bacteria involved in the suppressiveness by correlating population shifts with differing levels of suppressiveness. Soil treatments containing different amounts of suppressive and fumigation-induced nonsuppressive soils exhibited various levels of suppressiveness after two nematode generations. The 10%-suppressive-soil treatment contained numbers of eggs per gram of soil similar to those of the 100%-suppressive-soil treatment, indicating that the suppressive factor(s) had been transferred. Bacterial rDNA associated with H. schachtii cysts were identified using a culture-independent method termed oligonucleotide fingerprinting of rRNA genes. Bacteria from five major taxonomic groups (Actinobacteria, Cytophaga-Flexibacter-Bacteroides, α-Proteobacteria, β-Proteobacteria, and γ-Proteobacteria) were identified. Three bacterial rDNA groups contained clones that were more prevalent in the highly suppressive soil treatments than in the less suppressive treatments, indicating a potential involvement in the H. schachtii suppressiveness. When these three groups were examined with specific PCR analyses performed on H. schachtii cysts that developed in soils treated with three biocidal compounds, only one bacterial rDNA group with moderate to high sequence identity to rDNA from several Rhizobium species and uncultured α-proteobacterial clones was consistently associated with the highly

  10. Visual Surround Suppression in Schizophrenia

    PubMed Central

    Tibber, Marc S.; Anderson, Elaine J.; Bobin, Tracy; Antonova, Elena; Seabright, Alice; Wright, Bernice; Carlin, Patricia; Shergill, Sukhwinder S.; Dakin, Steven C.