Celebrex

By E. Garik. Elizabeth City State University. 2018.

Efficacy and harms • Pramlintide 90 mcg or 120 mcg added to fixed- or stable doses of insulin decreased A1c by 0 generic 100 mg celebrex. Rates of hypoglycemia after 4 weeks were similar among treatment groups buy 100mg celebrex overnight delivery. Diabetes Page 15 of 99 Final Report Drug Effectiveness Review Project Table3. Characteristics of pram lintideplacebo-controlledtrials inadults with type1diabetes Baselinevalues: a A1c (%)(SD) a a Age(years)(SD) W eight(kg) a 2 a Sam ple % M ale BM I (kg/m ) a Author, size(N ) % W hite Totaldailyinsulin a a year F ollow- % Hispanic dose(units) a Country up Diabetes duration Glycem ic goals Com bination Q uality (weeks) (years) prespecified? Interventions therapy Treatm entarm s receivedthe 40. Abbreviations:CSII,Continuoussubcutaneousinsulininfusion;M DI,M ultipledailyinjections;N R ,notreported;SD, standarddeviation;TID,threetim esdaily;Q ID,fourtim esdaily. Diabetes Page 16 of 99 Final Report Drug Effectiveness Review Project Detailed Assessment of Pramlintide in Type 1 Diabetes Key Question 1. For children and adults with type 1 diabetes, does pramlintide differ in efficacy, effectiveness, or harms in achieving glycemic control when added to prandial insulin compared with conventional insulin therapy? Details of the three included placebo-controlled trials are presented in Table 3 and glycemic control results are presented in Table 4. None of these trials were similar enough for efficacy data to be pooled. This section reports key details of individual studies. Flexible-dose insulin In a fair-quality trial the addition of pramlintide 30 mcg or 60 mcg 3 or 4 times a day with meals to a flexible-dose insulin regimen did not significantly improve A1c (-0. The comparison group was patients receiving a combination of short- and long-acting insulin 13 plus placebo adjusted to achieve specified glycemic targets over 29 weeks. According to the study investigators, a greater percentage of pramlintide-treated patients who self-monitored blood glucose concentrations achieved post-prandial glucoses below the American Diabetes Association targets for all three meals compared with those on insulin plus placebo (breakfast: 68% compared with 51%; lunch: 71% compared with 61%; dinner: 70% compared with 58%, P<0. Pramlintide-treated patients lost slightly more weight than insulin-only patients (-1. Pramlintide-treated patients also exhibited slightly larger reductions in total daily insulin doses (-12% of total daily dose from baseline) than patients using insulin plus placebo (+1% of total daily dose from baseline) by the end of 29 weeks. In the initial 4 weeks of treatment however, more pramlintide-treated patients decreased their prandial insulin doses than compared with patients on insulin plus placebo (-28% of prandial insulin dose vs. During the remainder of the trial, patients in both treatment arms required dose increases to their basal insulin regimen (pramlintide, +3% of basal insulin dose vs. All patients received stable doses (±10% change from baseline) of intensive insulin therapy using multiple daily injections or continuous insulin infusion before enrolling in the study. Patients were mainly middle-aged and white and had long-standing type 1 diabetes. A 30%-50% reduction in mealtime insulin was recommended before starting pramlintide to avoid hypoglycemic events. A patient survey examined whether subjects in this study believed that pramlintide added 19 to insulin provided marked benefits compared with placebo plus insulin. A significantly greater proportion of subjects receiving pramlintide believed their study medication provided them with more control over their blood sugar, weight, appetite, and ability to function than compared with those in the insulin plus placebo arm. However, more pramlintide-treated patients believed their study medication “had side effects that would keep me from using it on a long-term basis” relative to those randomized to the placebo plus insulin arm. The authors of this study stratified the results by insulin delivery method (multiple injections or continuous infusion). Patients using placebo plus continuously infused insulin were more likely to have lower satisfaction than patients on pramlintide plus insulin delivered by either modality. Because baseline treatment satisfaction data were not presented, this study could not be used to determine whether significant changes in satisfaction occurred over the duration of Diabetes Page 17 of 99 Final Report Drug Effectiveness Review Project the study. Also, the study does not explicitly state that patients participating in the survey remained blinded during the entire survey period. During the course of the trial, patients from both treatment groups required increases in their total daily insulin dose. The percent change in insulin dose adjustment were statistically significant between pramlintide-treated and insulin plus placebo-treated patients at the end of 52 weeks (+2. A higher proportion of pramlintide-treated patients achieved an A1c of <7% “at any time” at the end of the trial. This trial was rated fair-poor quality: only 71% of patients completed the 52 weeks of therapy and data from only completers were examined. The total withdrawal rates of 28-29% were similar between the treatments, however, more pramlintide-treated patients discontinued due to adverse events than placebo-treated patients during the study (12. In addition, the authors reported no further details on insulin dose adjustments than that they were made according to “good medical practices.

Systematic reviews Author Year Harms results Quality assessment method Afilalo J et al Intensive statin therapy was associated with a threefold increase in adverse Described method of assessment generic 100 mg celebrex with mastercard, but did 2007 hepatic events from 0 buy celebrex 200 mg overnight delivery. As a result, the number needed to harm to cause one All qualifying studies were assessed for adverse hepatic event was 96. The odds ratios for adverse hepatic events blinding, concealment of randomized demonstrated significant heterogeneity (I2=63%). We recorded whether patients in the intervention group and control group were similar at the start of the study and treated equally except for the designated treatment. Statins Page 363 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 8. Systematic reviews Author Year Limitations of primary studies Data synthesis methods Comments Afilalo J et al External validity and generalizability to other Random-effects model 2007 statins is limited Some classified revascularization and resuscitated cardiac arrest as MACE Most did not report measurements of left ventricular function after statin therapy Statins Page 364 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 8. Systematic reviews Databases searched; Author Literature search dates; Number of trials/ Year Aims Other data sources Eligibility criteria Number of patients Afilalo J, 2008 To determine whether MEDLINE (1966 to December 2007) The inclusion criteria for our meta- 9/19,569 statins reduce all- EMBASE (1980 to December 2007) analysis were: 1) randomized allocation cause mortality in Cochrane Central Register of Controlled to statin or placebo; elderly patients with Trials and Database of Abstracts of 2) documented CHD at the time of CHD and to quantify Reviews of Effects (from inception to the randomization; 3) > 50 elderly patients the magnitude of the fourth quarter of 2007) included in the study (defined as age 65 treatment effect. To ACP Journal Club (1991 to years); 4) > 6 months of follow-up; and 5) determine whether November/December 2007) all-cause mortality, CHD mortality, statins reduce CHD nonfatal MI, need for revascularization, or mortality, nonfatal MI, stroke reported as an outcome measure. Henyan N, 2007 To elucidate the effect MEDLINE (1) controlled clinical trials versus 27/100,683 of statin therapy on all EMBASE placebo, (2) well-described protocol, and cerebrovascular Cumulative Index to Nursing & Allied (3) data reported on incidence of all events (CVEs), Health Literature CVEs, ischemic stroke, or hemorrhagic ischemic stroke, and Web of Science stroke. June 1975-September 2006 Statins Page 365 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 8. Systematic reviews Author Characteristics of identified Characteristics of identified Characteristics of identified articles: Year articles: study designs articles: populations interventions Afilalo J, 2008 RCTs Mean Age range: 66. Systematic reviews Author Year Main efficacy outcome Main efficacy results Afilalo J, 2008 Mean change in lipid levels Relative risk reduction of 22% for all-cause mortality (RR 0. Coronary heart disease mortality was reduced by 30% (RR 0. Need for revascularization was reduced by 30% (RR 0. Henyan N, 2007 Cerebrovascular events Statin therapy significantly reduced the risk of all CVEs (RR 0. Statin therapy was shown to significantly reduce the risk of ischemic stroke (RR 0. Statin therapy was shown to nonsignificantly increase the risk of hemorrhagic stroke (RR 1. Statins Page 367 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 8. Systematic reviews Author Year Harms results Quality assessment method Afilalo J, 2008 NR Described method of assessment, but did not cite a specific tool. All qualifying studies were assessed for concealment of randomized assignment, completeness of follow-up, and intention-to- treat analysis. We recorded whether patients in the intervention and control groups were similar at the start of the study and treated equally except for the designated treatment. We also recorded whether patients in the control group were taking lipid lowering drugs during the study. Henyan N, 2007 NR Described method of assessment, but did not cite a specific tool. Randomization, concealment, masking of treatment allocation, and withdrawals Statins Page 368 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 8. Systematic reviews Author Year Limitations of primary studies Data synthesis methods Comments Afilalo J, 2008 No placebo controlled studies of secondary Bayesian meta-analysis prevention for newer statins. Henyan N, 2007 Several studies reported data on all CVEs, but Egger weighted regression method fewer than half reported the incidence of hemorrhagic or ischemic stroke. The definition of stroke, fatal stroke, and CVE was not uniform across all studies Statins Page 369 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 8. Systematic reviews Databases searched; Author Literature search dates; Number of trials/ Year Aims Other data sources Eligibility criteria Number of patients Rogers S, 2007 To provide current MEDLINE (1966-Week 1, August 2004) For inclusion in the meta-analyses, 18/8,420 evidence for the EMBASE (1980-Week 31, 2004) studies had to be randomized, head-to- comparative potency Cochrane Central Register of Controlled head trials comparing atorvastatin at of atorvastatin and Trials, Cochrane Database of Systematic doses of 10, 20, 40, and/or 80 mg with simvastatin in altering Reviews, the UK National Health Service simvastatin at doses of 10, 20, 40, and/or levels of serum total (NHS) Centre for Reviews and 80 mg. Participants in the trials had to be cholesterol (TC), low- Dissemination database, the NHS aged _>18 years with elevated levels of density lipoprotein Economic Evaluation Database, and the serum TC and LDL-C. Studies were cholesterol (LDL-C), Database of Abstracts of Reviews of excluded if they involved animals; if they triglycerides (TG), and Effects had a crossover, dose-titration, or forced high-density dose-titration design; or if they did not lipoprotein cholesterol include a washout period of previous (HDL-C). Thavendiranatha To clarify the role of MEDLINE (1966 to June 2005) Randomized trials of statins compared 7/42,848 n et al 2006 statins for the primary EMBASE (1980 to June 2005) with controls (placebo, active control, or prevention of Cochrane Collaboration (CENTRAL, usual care) with the following cardiovascular events. DARE, AND CDSR) characteristics: a mean follow-up > 1 American College of Physicians Journal year; > 100 reported cardiovascular Club disease outcomes (e. Statins Page 370 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 8. Systematic reviews Author Characteristics of identified Characteristics of identified Characteristics of identified articles: Year articles: study designs articles: populations interventions Rogers S, 2007 RCTs Mean age: 58. Systematic reviews Author Year Main efficacy outcome Main efficacy results Rogers S, 2007 Change in lipids Total Cholesterol Reductions favored atorvastatin over simvastatin in all but one dose-pair comparison (simvastatin 80mg/day over atorvastatin 10mg/day (P<0.

Fatal cerebral lymphomatoid granu- lomatosis in an HIV-1-infected patient buy celebrex 100 mg otc. Hodgkin lymphoma (HL) The incidence of HL is elevated in HIV+ patients by a factor of 5-15 compared to the HIV-negative population buy cheap celebrex 200 mg on line. For particular subtypes, such as lymphocyte-depleted and mixed-cellularity HL,the relative risk is presumably much higher (Frisch 2001). Despite this and the growing realization that these subtypes at least are clearly asso- ciated with immunodeficiency, HIV-related HL is not included as an AIDS-defining illness. There is growing evidence that the incidence of HIV-related HL is increasing in the setting of improved immunity. Several studies reported on an increased incidence during the last years (Clifford 2005, Biggar 2006, Engels 2008, Bohlius 2011). In our own cohort we found significant differences between NHL and HL (Wyen 2008). Whereas the majority of NHL cases is diagnosed in ART-naïve patients, HL mainly occurred in subjects receiving a virologically effective ART. For example, in our own cohort of 415 cases of systemic high-grade NHL and HL, significantly more patients with HL were treated with ART and had a viral load below 50 HIV RNA copies/ml at lymphoma diagnosis than patients with NHL (57. In the subgroup of ART-naïve patients it was only 7% but increased to 35% in patients with current viral load below 50 HIV RNA copies/ml (Hoffmann 2014). As CD4 T cells usually predominate in the tumor microenvironment of HL, it is speculated that immune reconstitution 436 AIDS induced by ART provides an appropriate micro-environment allowing adequate growth signals for proliferation and survival of the neoplastic Reed-Sternberg (RS) cells in HL (Gloghini 2007). In addition, CD40/CD40L interactions and EBV infection may contribute to constitutive activation of NFkB which is an antiapoptotic factor in RS cells. Interestingly, patients whose CD4 T cell counts decline despite suppres- sion of HIV-1 replication, are at risk for HL (Bohlius 2011). An advanced stage of disease at diagnosis is typical, as is frequent extranodal involve- ment and a trend towards prognostically poorer subtypes (Tirelli 1995, Rapezzi 2001, Thompson 2004). Mediastinal disease is significantly less frequent than in HIV-neg- ative patients. A further difference to HL in seronegative patients is the predomi- nance of cases with RS cells, as well as the clear association with EBV infection, which is 80–100%, depending on the study. EBV infection is therefore seen as an important etiologic factor for development of HIV-related HL. In comparison to HIV-negative HL, which is a highly treatable tumor, the progno- sis of HIV-related HL was poor in the pre-HAART era. In nearly all cohorts with more than 20 patients, the median survival was only between 15–20 months, respectively (Tirelli 1995, Levine 2000). The response to chemotherapy was also moderate com- pared to the normal population. Complete remission rates were between 40 and 80%, and hematological and infectious complications were frequent. This gloomy scenario has clearly changed since the introduction of combination ART. In our own multicenter cohort of 56 patients, the median survival was 40 months. In patients with adequate ART, the two-year survival rate was 84%, which was very encourag- ing (Hoffmann 2004). In the meantime, other groups have also reported better prog- noses with ART (Ribera 2002, Gérard 2003, Berenguer 2008). There is now over- whelming evidence that HIV status no longer influences outcome in patients with classical HL in the HAART era (Montoto 2013). Signs and symptoms B symptoms occur in the majority of cases. Extranodal and advanced stages are almost always the rule. Lymphomas are firm, immobile or hardly mobile and painless, and the distinction from HIV-related lymphadenopathy or tuberculous lymphadenitis is not always possible. Diagnosis Staging is necessary as for non-Hodgkin lymphomas (see NHL above). Diagnostic lymph node extirpation is even more important here than with NHL, as puncture only rarely allows diagnosis of Hodgkin’s disease. Single accurate diagnostics are better than half-heartedly bothering the patient with repeated punctures and losing time unnecessarily. Surgical extirpation is possible as an outpatient in many centers. As with NHL, specimens should be sent to reference laboratories if possible. Since bleomycine will be administered, a lung function test should always precede the first chemotherapy.

Defining molecular target that can be pursued with the intention of modifying the optimal route and proposed schedule of administration in the tumor cell survival discount 100 mg celebrex overnight delivery. The processes of discovery and preclinical appropriate formulation is equally important cheap celebrex 100mg visa. Analytical methods must be developed and validated to measure quantitatively the plasma concentrations of the agent itself and the Preclinical discovery and developmental tasks major metabolites. The time investment in preclinical pharmacol- Designing a novel agent involves knowledge of structural biology ogy is important to insure that the targeted levels of the agent are coupled with expertise in organic chemistry to optimize the achievable in vivo and whether an effective schedule of administra- chemical structure of a “lead” compound. The time and effort in developing the 24 American Society of Hematology Figure 1. If the agent under investigation is a synthetic compound, then plans Despite the profound impact of the length of time needed for for scale-up synthesis and production of a stable product should be developmental on the potential return on investment, failure to secured before extensive preclinical testing is initiated. If a natural establish the necessary preclinical information may result in an product, or a derivative thereof, is selected as the optimal agent, then unsafe initial trial in patients. The time and effort in preclinical a plan for securing a sufficient supply of this purified material must studies can determine the fate of the project. The chemical characteristics including feasibility of process of drug development encompassing preclinical studies scale-up synthesis or isolation need to be defined. Toxicology followed by early trials in patients shows the strategic points where studies are conducted on the proposed schedule of administration consultation may be useful. The necessary studies are often conducted on information on tissue tolerance. Within the pharmaceutical industry, 2 animal species. If there is general agreement regarding the dose the FDA, and the National Cancer Institute’s (NCI’s) Developmen- and toxicity studies in the animal models, then the initial dose level tal Therapeutics Program, studies exploring modern ways of recommended for patients can be determined as being in the range evaluating toxicity remain a high priority. Several of the proposed of 1/10 the dose that caused serious toxicities. If there is a difference novel strategies (eg, ex vivo assays to predict toxicities) are still in development. The use of Projections for a safe starting dose will take into consideration the small rodents and dogs provides data that supports a safe starting dose in humans. The entire process for preclinical evaluation of a new agent is Historical example: phase 1 trial of fludarabine expensive, labor intensive, and time consuming. The total estimated cost ery as a halogenated purine analog of adenosine. In 1979, preclinical studies on this billion dollars. Acquisition and assembly of the entire preclinical promising antileukemic agent were initiated. Despite differences in data package and compiling the Investigational New Drug applica- species tolerance, the dog data were used to establish the initial dose tion for submission to the US Food and Drug Administration recommended for phase 1 study in humans (ie, 260 mg/m2 (FDA), along with designing a clinical protocol, entails years of administered as a single intravenous dose over a short infusion: work. Project coordination and management are absolutely essential more than 10-fold higher than currently advised). The initial because the time for patent protection is declining throughout this patients on this phase 1 trial developed profound neutropenia, but required period. From the initiation of submission of a patent for a recovered. Subsequent investigation confirmed that the dog was able Although protected time for marketing may ultimately be extended to metabolize this agent differently than either man or rodent. In addition to dose adjustment, the preclinical studies, a meticulous approach to evaluating toxicology schedule of administration was changed to a multiple-day dosing is warranted. Current example of an exceptionally promising antileukemia agent: ibrutinib Clinically, observations were made in the phase 1/2 trials in patients Over the past 3 years, Bruton tyrosine kinase (BTK) has been that established low-dose fludarabine as an active antileukemic recognized as a rational target for treating B-cell malignancies. In addition to an impact on B-cell high daily doses (eg, 96 mg/m2/d for 5 days) in patients with signaling, this target can effect B-cell migration and adhesion. Fludarabine was approved by the FDA in signaling identified ibrutinib (PCI-32765) as such a candidate. Although the initial interest focused upon finding an agent that would be targeted for rheumatoid Once approved, additional studies were conducted in other patients arthritis, the recognition that such an agent might have benefit in with a hematologic malignancy. Fludarabine has subsequently been other autoimmune diseases and lymphoma progressed rapidly to incorporated into many preparative regimens to facilitate nonmyelo- evaluating the concept in lymphoid malignancy. Incor- model prompted further development of this agent for patients with poration of purine analogs into the preparative regimen has enabled B-cell malignancies. Investigators showed that this agent interfered older individuals to tolerate this procedure. Therefore, this agent with CLL proliferation, survival, and migration. In 2012, Advani et plays a major role in treating patients with low-grade B-cell al reported that Ibrutinib had promising clinical activity in patients malignancies.

Atenolol as a comparator in outcome trials in hypertension: a correct choice in Wrong publication type the past cheap celebrex 100 mg with amex, but not for the future? Similar effects of treatment on central and brachial blood pressures in older Wrong drug hypertensive subjects in the Second Australian National Blood Pressure Trial discount celebrex 100mg line. Long term efficacy and safety of carvedilol, a new beta-blocking agent with vasodilating Wrong study design properties, in patients with chronic ischaemic heart disease. Beta blockers Page 92 of 122 Final Report Update 4 Drug Effectiveness Review Project Publication Reason for Exclusion Delea TE, Taneja C, Moynahan A, et al. Valsartan versus lisinopril or extended-release metoprolol in preventing cardiovascular and Wrong outcome renal events in patients with hypertension. Tolerability of beta-blockers in outpatients with refractory heart failure who were Wrong outcome receiving continuous milrinone. Impact of preventive therapy with nadolol and topiramate on the quality of life of Wrong study design migraine patients. Comparative effectiveness of beta-adrenergic antagonists (atenolol, metoprolol tartrate, carvedilol) on the risk of rehospitalization in adults with heart Wrong study design failure. Comparison of the effects of carvedilol and metoprolol on exercise ventilatory efficiency in Wrong outcome patients with congestive heart failure. Double-blind, palcebo- controlled study of the long-term efficacy of carvedilol in patients Wrong study design with severe chronic heart failure. Carvedilol versus controlled-release metoprolol for elderly veterans with heart failure. Wrong outcome Journal of the American Geriatrics Society. A population-based analysis of the class effect of beta-blockers after myocardial Wrong outcome infarction. Weight change associated with the use of migraine- preventive medications. Nebivolol in the treatment of cardiac failure: a double-blind controlled clinical trial. Efficacy and tolerability of nebivolol compared with other antihypertensive drugs: a meta- Wrong publication type analysis. Beta blockers Page 93 of 122 Final Report Update 4 Drug Effectiveness Review Project Part II. Double-blind comparison of Inderal LA (160 mg), Half-Inderal LA (80 mg), and Half-Inderal LA plus bendrofluazide (2. The treatment of hypertension with propranolol and bendrofluazide. Journal of the Royal College of General Practitioners. Use of beta-blockers in older adults with chronic heart failure. Adjunctive sympathoplegic therapy to ACE inhibition in Blacks with congestive heart failure: a comparison of alpha-1 with beta-1 blockade on exercise tolerance and cardiac sympathovagal reflex activity. Spironolactone and propranolol in the management of hypertension. Nifedipine versus propranolol for the initial prophylaxis of migraine. Propranolol or endoscopic sclerotherapy in the prevention of recurrence of variceal bleeding. Painless ST-segment depression in patients with angina pectoris. Correlation with daily activities and cigarette smoking. Evaluation of long-term use of propranolol in angina pectoris. Andren L, Hansson L, Eggertsen R, Hedner T, Karlberg BE. Isosorbide-5-mononitrate versus propranolol in the prevention of first bleeding in cirrhosis. Unstable angina pectoris: National Cooperative Study Group to Compare Medical and Surgical Therapy. Oxprenolol vs propranolol: a randomized, double-blind, multiclinic trial in hypertensive patients taking hydrochlorothiazide. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction.