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By O. Alima. Coker College. 2018.

Analyses of the comparative efficacy of newer antiemetics in subpopulations were reported in only a few studies and focused on protection against postoperative and chemotherapy-related 33 sildenafil 100 mg free shipping impotence webmd, 35 purchase 50mg sildenafil visa erectile dysfunction protocol book scam, 36, 38, 40, 47, 55, 56, 58, 84 nausea, vomiting, or both. Safety comparisons in subpopulations were rarely reported. Race and ethnicity was not reported in most trials and nothing about differences in effectiveness or safety can be determined from these limited data. Comorbidities that were often excluded from these trials included obesity, gastroesophageal reflux disease, cardiovascular diseases, diabetes, and other serious conditions. Studies that did allow patients with these conditions to enroll did not analyze the effects in these subgroups. Demographics There were no differences between dolasetron, granisetron, and ondansetron in rate of complete emetic control in subpopulations based on age or gender in adult patients aged 18 to 94 years 35, 38, 40, 44, 47, 55, 56, 58 undergoing emetic chemotherapy for a variety of cancer types. These drugs Antiemetics Page 41 of 136 Final Report Update 1 Drug Effectiveness Review Project appear to work well in preventing postoperative nausea and vomiting. No differences were found in trials that included primarily women (4 of 10 studies) or in those that included more men. There were also no differences between intravenous and oral solution formulations of ondansetron in rate of complete or major control of emesis in subpopulations based on age in children 1 to 17 years undergoing moderately to highly emetic chemotherapy for treatment of 84 various cancers. In the adult populations studied for postoperative nausea and vomiting, the mean ages of patients in studies of dolasetron compared with ondansetron was 45 years and of granisetron compared with ondansetron, 42 years. In the pediatric populations, the mean ages ranged from 6 to 9. However, we found no studies that specifically evaluated the influence of age on the comparative effectiveness and harms among antiemetics for prevention of postoperative nausea and vomiting. In a pooled analysis of 2 of 6 trials in which aprepitant was added to a regimen of intravenous ondansetron 32 mg plus oral dexamethasone 12 mg on day 1 and oral dexamethasone 8 mg on days 2 through 4, aprepitant improved response rates in women (66% 193 compared with 41%) to a greater extent than in men (69% compared with 53%). Comparisons of acute and delayed periods were very similar between men and women. Because these are post hoc subgroup analyses and statistical power may be inadequate, the results should be interpreted with caution and used for design of future research. In additional subgroup analyses from trials of aprepitant submitted by the manufacturer, difference in response based on age or race is not apparent. Because these are small subgroups, statistical analysis was not undertaken. Other medications There was no difference in rate of complete emetic control between ondansetron and either dolasetron or granisetron in subpopulations based on concomitant medications including 38, 44 35 35 35, 55 35 corticosteroids, H2-receptor antagonists, opioids, benzodiazepines, or NSAIDs in patients undergoing emetic chemotherapy for a variety of cancers. Concomitant medications that were disallowed or used as part of anesthesia, preanesthesia, or postoperative pain control also varied in trials of postoperative nausea and vomiting prevention, with some excluding drugs often used as preanesthetics or anesthetics known or thought to have antiemetic properties. Overall, higher rates of complete response were seen in trials that included use of dexamethasone preoperatively, and lower rates were associated with gynecologic surgeries and lower doses of 5-HT3 antagonist. Differences between dolasetron, granisetron, and ondansetron in subpopulations based on concomitant medications were not seen in these data. Prognostic factors A post hoc subgroup analysis of a trial of patients receiving emetic chemotherapy suggested that ondansetron may be significantly better at preventing vomiting than granisetron in patients with a predisposition to nausea/vomiting (history of motion sickness, previous treatment with emetic 35 chemotherapy). Intravenous granisetron 3 mg was associated with a lower rate of complete protection from emesis in patients with a history of motion sickness than in those without motion sickness (17% compared with 43%; P<0. Intravenous ondansetron 24 mg was associated with a similar rate of complete protection regardless of the history of motion sickness (20% 35 compared with 30%, not significant). Intravenous granisetron was also associated with Antiemetics Page 42 of 136 Final Report Update 1 Drug Effectiveness Review Project significantly lower rates of protection from emesis than intravenous ondansetron in a subgroup 35 of patients treated with emetic chemotherapy. Authors note that these outcomes may be due to chance, given that the numbers of patients in these subgroups were small. Antiemetics Page 43 of 136 Final Report Update 1 Drug Effectiveness Review Project SUMMARY Table 9 summarizes the results of this review. Summary of the evidence by key question Key Question 1. What is the comparative effectiveness/efficacy of newer antiemetics in treating or preventing nausea and/or vomiting? What are the comparative safety and tolerability of newer antiemetics in treating or preventing nausea and/or vomiting? Comparison Population Quality Conclusion Good for dolasetron, granisetron, Aprepitant, No consistent significant and dolasetron, Mainly postoperative differences in overall ondansetron. Are there subgroups of patients based on demographics (age, race, gender), pregnancy, other medications, or comorbidities for which one newer antiemetic is more effective or associated with fewer adverse events Comparison Population Quality Conclusion No consistent differences in Demographics and other comparisons of 5-HT3 Fair medications antagonists in different Dolasetron, patient subgroups granisetron, Ondansetron superior to ondansetron Prognostic risk factors: Patients granisetron in preventing with a predisposition to Poor vomiting in a subgroup nausea/vomiting analysis of a single trial Inconclusive based on mixed findings across pooled subgroup analysis from 2 of 6 placebo- Aprepitant Gender, race Poor controlled trials and small subgroup analyses from trials of aprepitant compared with ondansetron submitted by manufacturer Abbreviations: 5-HT3, type 3 serotonin; NNT, number needed to treat. Antiemetics Page 45 of 136 Final Report Update 1 Drug Effectiveness Review Project REFERENCES 1. On the receiving end--patient perception of the side-effects of cancer chemotherapy. Efficacy of an ondansetron orally disintegrating tablet: A novel oral formulation of this 5-HT3 receptor antagonist in the treatment of fractionated radiotherapy-induced nausea and emesis. Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting.

Comparison of a new multidose powder 6-POWDER inhaler with a pressurized aerosol in children with asthma generic 50 mg sildenafil visa erectile dysfunction statistics singapore. The effect of metaproterenol 6 in chronic asthmatic children receiving therapeutic doses of theophylline buy discount sildenafil 100 mg erectile dysfunction (ed) - causes symptoms and treatment modalities. The severity of asthma in relation to beta agonist 6-DESIGN prescribing. A dose-ranging trial of nebulized 5 (R)-albuterol (Levalbuterol) with racemic albuterol in pediatric patients with asthma. Comparative study of a new beta- 6 adrenergic stimulant in asthma: salbutamol. Gent PN, Hughes DT, Nisbet IG, Pearson SB, Sturgeon JG. Double- 5 blind comparative trial of two metered bronchodilator aerosols. Clinical comparability of 6-POWDER albuterol delivered by the breath-actuated inhaler (Spiros) and albuterol by MDI in patients with asthma. Bronchodilator effect of a new 3 oral beta adrenoreceptor stimulant, Th1165a. Quick-relief medications for asthma Page 90 of 113 Final Report Update 1 Drug Effectiveness Review Project Citation Exclusion Code Gibson GJ, Greenacre JK, Konig P, Conolly ME, Pride NB. Use of 6 exercise challenge to investigate possible tolerance to beta- adrenoceptor stimulation in asthma. Gilmartin JJ, Veale D, Murray A, Adams PC, Gibson GJ. Cardiac effects 6 of salbutamol given by air driven nebuliser at home. The salmeterol multicenter asthma research trial 5 (SMART). The use of Fenoterol (Berotec) respirator solution 0. Terbutaline: an effective bronchodilator by inhalation. SHORT pulmonary effects of high-dose formoterol in COPD: a comparison with salbutamol. SHORT of inhaled albuterol and two formulations of salmeterol on airway reactivity in asthmatic subjects. SHORT inhaled formoterol in children with asthma: a double-blind cross-over study versus salbutamol. Bronchodilator effects of 6 clemastine, ipratropium, bromide, and salbutamol in preschool children with asthma. SHORT Turbuhaler gave better protection than terbutaline against repeated exercise challenge for up to 12 hours in children and adolescents. Effects of an anticholinergic bronchodilator on 6 arterial blood gases of hypoxemic patients with chronic obstructive pulmonary disease. Grossman J, Geoffroy P, Hill MR, Vaughan LM, Nichols K. Comparison 5 of efficacy and safety of single and double doses of albuterol sulfate via Spiros? The Diskus/Accuhaler multi- 6-DELIVERY dose powder inhaler for the delivery of salmeterol in adult asthmatics. Comparison of the 6-POWDER bronchodilator response to salbutamol delivered by the Clickhaler and by Ventodisk. A comparison of 6-POWDER efficacy and patient compliance between inhaled aerosol and powder forms of salbutamol in asthma. Quick-relief medications for asthma Page 91 of 113 Final Report Update 1 Drug Effectiveness Review Project Citation Exclusion Code Gupta SC, Mathur RN, Swaroop AK, Goyal RK. Metabolic effects of 4 salbutamol in bronchial asthma. A double-blind comparison of the bronchodilatory effect 6-DELIVERY of cumulative doses of salbutamol from Diskus (Accuhaler) and Turbuhaler. Salmeterol 50 [micro]g twice 6-DELIVERY daily in the treatment of mild-to-moderate asthma in childhood - a comparison of two inhalation devices. Effects of airway function, exercise capacity, and quality of life. Haahtela T, Vidgren M, Nyberg A, Korhonen P, Laurikainen K, Silvasti 6-DELIVERY M. Salbutamol powder and aerosol give equal bronchodilatation with equal doses. The administration of beta -agonists2 6 for paediatric asthma and its adverse reaction in Australian and New Zealand emergency departments: a cross-sectional survey. Bronchodilator therapy 6 and hyperactivity in preschool children. Levalbuterol affords superior health and cost benefit over 5 racemic albuterol in the emergency department.

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Immediate-release dextroamphetamine was associated with a significantly lower mean weight gain (kg) than 259 methylphenidate after 9 months in 1 study generic 50 mg sildenafil with amex erectile dysfunction medicine names, significantly greater declines in weight percentiles 258 265 after the first of 5 years another study discount 100 mg sildenafil free shipping erectile dysfunction use it or lose it, and at end of treatment (≥ 2 years) in yet another. In the 5-year, partly retrospective and partly prospective study that involved 84 children (mean age at initiation of drug therapy, 9 years; 82% male), however, differences in decreased weight percentiles between immediate-release dextroamphetamine and methylphenidate resolved by the second year and resulted in significantly greater than expected mean increases in weight 258 percentiles at final follow-up (+10. The first suggests that comparison of mean weight gain between immediate-release dextroamphetamine and methylphenidate may have been confounded by dosage disparities. Apparently, the difference between immediate- release dextroamphetamine and methylphenidate resolved when 4 patients taking lower-dose methylphenidate (20 mg daily) were removed from the analysis (0. Weight gain in children who continued medication over the summer compared with those who discontinued medication during the summer was also reported. In patients taking immediate-release dextroamphetamine, medication continuation was associated with significantly lower mean weight gain than in children who discontinued medication (0. Medication continuation status did not have an effect on weight gain in the group of patients taking methylphenidate. Attention deficit hyperactivity disorder 90 of 200 Final Update 4 Report Drug Effectiveness Review Project Comparative studies: Immediate-release methylphenidate and mixed amphetamine salts. A study of methylphenidate compared with mixed amphetamine salts (any formulation) found no statistically significant differences in z-scores for weight change over a 3 year period between the 2 drugs, but did find a significant negative association of duration of treatment with mixed 270 amphetamine salts and z-score (P=0. Overall, the children in the study were heavier than average, such that the mean final weights were not below average for age. Noncomparative studies 260, 263 provide mixed evidence about the association between immediate-release methylphenidate and suppression of weight gain in school-aged children. In the earliest study (1977), only 2 of 36 boys with minimal brain dysfunction (5. The next study, published in 1979, involved 72 boys (age range 6-12) with hyperactivity that were taking 260 methylphenidate for up to 2 years. The growth weight deficit associated with methylphenidate 0. Results of a subgroup analysis suggest that the deficit in weight gain was only significant in patients that continue to use medication over the summer months compared with those who did not. The third study, published in 1983, involved relatively higher mean dosages of methylphenidate (39. Methylphenidate was associated with significant declines in weight percentiles in all 4 years of the study (Year 1 [–9. The final study, published in 1999, found an insignificant difference (0. In a study following children taking stimulants for 5 years, described above, stimulant dose ≥2. Comparing the models for height and weight, the authors find that the impact of increased dose is greater on weight than height. Using the change in z-score based on dose, the estimated difference in weight gain in a 10 year old boy using a stimulant for more than 1 year was found to be 1. Again, these results are based on small numbers of children and could be subject to change in a larger sample were used. A 3-year randomized controlled trial (N=62) of withdrawing immediate-release methylphenidate during summer months compared with not withdrawing found that after summer 1, the immediate-release methylphenidate ON group gained significantly less (0. However, in summer 2 the 289 difference was non-significant (0. Serious limitations of this study, in design and conduct, limited the likelihood that the findings were valid. Overall, 42% of those randomized withdrew, with data available for 58 children at the end of summer 1 (ON, n=32; OFF, n=26); and 34 at the end of summer 2 (ON, n=20; OFF, n=14). Weight and height were collected by unblinded secretaries, but not for the purposes of this study. Results were mixed across 2 studies that compared children taking methylphenidate to 255, 266 unmedicated hyperactive children, however. In 1 study, methylphenidate was associated Attention deficit hyperactivity disorder 91 of 200 Final Update 4 Report Drug Effectiveness Review Project with significantly greater declines in weight percentiles than in the unmedicated children after 1 255 year. The differences between the methylphenidate groups and the unmedicated group increased numerically along with the dosages (<20 mg, –6. In the other study, the methylphenidate group and the unmedicated group 266 demonstrated similar absolute weight gain (kg) after 364 days. Based on data from the Preschool ADHD Treatment Study, preschool-aged children were 290 heavier than age-based norms by 1. After a year of treatment, those who stayed on immediate-release methylphenidate experienced less weight gain than those who did not complete by 1. In the before-after study of 407 children (above), absolute weight increased a mean of 6.

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The investigators also assessed the relation- relapsed/refractory DLBCL buy 75 mg sildenafil otc impotence in women. Tumor tissue was analyzed to identify ship between mutations and overall response rate (Figure 4) order 25mg sildenafil with visa erectile dysfunction laser treatment. Patients with ABC DLBCL had a were documented in 71% (5/7) of patients with mutant CD79B and significantly higher response (83% vs 13%; P. Interestingly, 80% (4/5) of patients GCB DLBCL (Figure 2). These results provide a rational therapeu- with both mutant CD79B and MYD88 responded, whereas patients tic approach based on genetically distinct DLBCL subtypes. Several with wild-type CD79B and mutant MYD88 did not respond, suggest- randomized studies of R-CHOP with or without bortezomib in ing a MYD88-independent pathway for NF- B activation. Patients untreated DLBCL patients have been initiated. As a single agent, lenalidomide demonstrated a PKC is a serine/threonine kinase amplified through the BCR response rate of 55% in patients with ABC DLBCL compared with signaling pathway that may also play an essential role in the only 9% in patients with GCB DLBCL, suggesting differential activation of the NF- B pathway in B cells (Figure 4). Enzastaurin is a potent oral inhibitor of PKC that has been IRF4, which requires the expression of the E3 ubiquitin ligase studied in relapsed/refractory DLBCL and in combination with complex coreceptor protein cereblon. R-CHOP in patients with intermediate- and high-risk DLBCL. It is also important to understand and target upstream targets involved in NF- B activation (Figure 3). Chronic BCR signaling and activating Studies have also targeted the PI3K/AKT/mTOR signaling pathway mutations of CARD11 and MYD88 promote NF- B activation, using mTOR inhibitors. Although the patients have been heteroge- suggesting several targets. One potential target is Bruton tyrosine neous, mTOR inhibitors (temsirolimus and everolimus) have in- kinase (Btk), in which the selective inhibitor ibrutinib is selectively duced complete remissions across lymphoma subtypes. BCR and MYD88 signaling pathways and potential targets. Signaling also activates the AKT/MTOR and MAP kinase pathways. Constitutive MYD88 signaling is an alternative pathway leading to NF- B activation. Although GCB DLBCL has a better prognosis than ABC DLBCL, Although the ideal target for the PI3K/AKT/mTOR pathway is upwards of 30% of patients are not cured with R-CHOP–based unknown, investigators are targeting upstream molecules such as treatment (Figure 1A). Bcl-6 is a key transcription factor expressed AKT and PI3K. GS 1101 is a potent small-molecule inhibitor of by GCBs, including GCB DLBCL, that regulates cell growth and PI3K p110 that blocks constitutive PI3K signaling in vitro. Bcl-6 suppresses genes that are involved in lymphocyte 1101 was studied in 9 patients with DLBCL and was well tolerated, activation, differentiation, and cell cycle arrest and the DNA but did not result in clinical responses. In GCB DLBCL, chromo- somal translocations affecting the Bcl-6 locus juxtapose heterolo- Alternative activation of the classical NF- B signaling pathway gous promoters from the partner chromosome with intact Bcl-6 occurs through stimulation of MYD88 (Figure 3). MYD88 muta- coding sequences, leading to deregulated expression of Bcl-6; in tions are present in 30% of ABC DLBCL cases and promote NF- B addition, Bcl-6 can be altered by multiple somatic mutations. These activation through this pathway via the kinase activity of IRAK1 mutations/translocations in Bcl-6 enhance its inhibitory effect on and IRAK4. In ABC DLBCL cell lines, it is the activity of IRAK4 the apoptotic stress response and promote proliferation, both of but not IRAK1 that is required for the oncogenic effect of MYD88. These results suggest Small-molecule inhibitors of IRAK4 have demonstrated selective that BCL6 is an important target for GCB DLBCL. BCL6 is difficult toxicity for ABC DLBCL cell lines and represent another potential to target directly. Recently, a small molecule known as the 79-6 therapeutic target in ABC DLBCL. A potentially important observation is the effect of topoisomerase II inhibition on Bcl-6 expression. Inhibition of topoisomerase II by etoposide leads to the down-regulation of Bcl-6 expression through ubiquitin-mediated protein degradation and possibly transcriptional inhibition. This raises the possibility that inhibition of topoisomerase II may be important in GCB DLBCL and may partially explain the finding by the German cooperative group (DSHNHL) that the addition of etoposide to CHOP (CHOEP) Figure 4. Blockade of BCR signaling in ABC DLBCL with ibrutinib, improved the event-free survival (EFS) of younger patients, who an irreversible inhibitor of BTK. Shown is the pilot analysis of ABC have a higher incidence of GCB DLBCL compared with older DLBCL gene mutations and response to ibrutinib. In GCB DLBCL, bcl-2 expression is associated with suggest that topoisomerase inhibition is important. In this regard, the recently, Gascoyne et al published a study showing that the con- DA-EPOCH-R regimen inhibits topoisomerase II through several current protein expression of MYC and BCL-2 had an adverse strategies: (1) it incorporates 2 topoisomerase II inhibitors, etopo- outcome, whereas expression of either alone did not portend a worse side and doxorubicin; (2) it optimizes topoisomerase II inhibition outcome with R-CHOP.

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