By W. Kamak. Calumet College of St. Joseph. 2018.
The combined comorbidity/relapse score strati- signiﬁcantly 100 mg viagra soft flavored fast delivery, and patients reported not being offered alternative 77 ﬁed older patients into 9 risk groups discount viagra soft flavored 100mg without prescription, with 5-year OS rates ranging treatment options buy viagra soft flavored 100 mg visa. Effective communication between patients and from 69% in those with an HCT-CI score of 0 and AML in CR1 to physicians during the critical time of decision making is of a prime 23% in those with HCT-CI scores of 3 and advanced or secondary importance for success of therapy. Biomarkers could improve decision making by increasing the objectivity and precision of current health measures. The Socioeconomic status of cancer patients can affect choice of HCT-CI has been augmented by the addition of serum albumin as a treatment, access to specialized care, and/or OS. African Americans measure of nutritional impairment, serum ferritin as a measure of were shown to be less likely to be offered allogeneic HCT than 78 inﬂammation and/or iron overload, and platelet count as a measure Caucasians. They also have higher risks for mortality that could be 89 79 of BM recovery. Validation of this augmented comorbidity model due to limited access to care or unidentiﬁed genetic polymor- 80 in other cohorts, as well as testing the inclusion of other biomarkers phisms. In a study from CIBMTR, lower income levels were 81 could greatly improve risk stratiﬁcation before HCT. Although race and socioeconomic status could affect outcomes of allogeneic Decision making and prognostic risk schema HCT, their role independent from comorbidities and other health (Table 4) impairments has not yet been well established. Other factors that “Genetic randomization” based on the availability of an HLA- might inﬂuence risks for NRM and overall mortality and should be identical sibling donor has frequently been used to test the value of taken into account include recipient CMV serology status and 47 allogeneic HCT in younger patients with AML in CR1. Several single nucleo- meta-analysis of 6000 patients 60 years of age who received tide polymorphisms (SNPs) were found to be associated with 82,83 high-dose HCT in CR1 in studies comparing allogeneic HCT with critical post-HCT morbidities and thus mortality. The use of autologous HCT or conventional chemotherapy used such donor/no SNPs in pre-HCT risk assessment will require further validation, but donor analysis and found an OS beneﬁt for allogeneic HCT can potentially improve our methods to select appropriate candi- 76 compared with autologous HCT or conventional chemotherapy in dates for allogeneic HCT. The majority of these studies included patients with either unfavorable [HR (HR) 0. Such patients are more Composite models for risk assessment (Table 3) likely to receive HCT from unrelated donors than are younger The previously described risk factors could be used individually or patients. The relative complexity of the unrelated donor search in aggregate to build composite models that would improve our process makes donor/no donor analyses more difﬁcult to do with ability to assign patients to the most appropriate treatment. The unrelated donors and requires use of Mantel Byar statistical Pretransplantation Assessment of Mortality (PAM) score incorpo- methodology. Only 4% of patients were therapy among patients in CR1. One study compared outcomes in 60 years of age, which together with lack of independent patients 50-70 years of age according to whether they received cross-validation studies limits PAM as a risk assessment tool in allogeneic HCT (n 152) or chemotherapy only (n 884). The EBMT risk score, which was originally devel- Landmark analyses excluded 46 patients from the chemotherapy oped in patients with chronic myeloid leukemia, accounts for age, group because they relapsed or died within 60 days of achieving disease stage, donor type, time from diagnosis to HCT, and CR1. Allogeneic HCT was associated with a signiﬁcantly lower donor/recipient sex combinations. The risk score was also validated 3-year rate of relapse (22% vs 62%, P. The OS beneﬁt recipients of RIC/nonmyeloablative regimens. The HCT-CI/EBMT primarily reﬂected results in patients with intermediate-risk cytoge- model further reﬁned risk stratiﬁcation with an improved c-statistic netics (67% vs 54%, P. In a CIBMTR study, recipients of RIC allogeneic HCT who were 60-70 years of age had better OS rates The strong inﬂuence of pre-HCT comorbidities on NRM and OS than recipients of conventional chemotherapy. Age was found in all cytogenetic risk groups, as classiﬁed by a consensus added to the HCT-CI as an additional variable, acquiring a weight of panel on behalf of the European LeukemiaNet. Allogeneic HCT seemed to convey superior OS at 5 years in each of the 3 groups. Summary and future directions (Table 5) In light of the infrequency with which RIC-HCT is performed in The feasibility of allogeneic HCT was addressed in a prospective older patients (particularly those 70 years of age), it is important study of patients 50 years of age. Ninety-nine (38%) of a total of to stress the potential beneﬁts of the procedure compared with 259 enrolled patients achieved remission, of whom 26 had suitable HLA-matched donors and only 14 (5%) actually underwent HCT. First, the latter is associated with high relapse One or more chemotherapy pair-mates were found for each patient rates, even in patients who would be viewed as “favorable” if who underwent transplantation based on cytogenetic risks, age, and younger. Second, NRM rates after HCT have been declining in all lead time bias. There was a 99% probability that the outcome after age groups, and indeed age itself appears to have no effect on NRM, RIC was superior to that seen in patients not receiving HCT. Therefore, it is plausible that RIC-HCT will Clearly, this study suffered from small sample size of the patients, improve survival in most, if not all, cytogenetic and molecular lacked assessment of other donor types, and did not examine the role groups. Perhaps the most important future direction would be of comorbidities and other health status measures in the decision not examination of whether this hypothesis will prove to be correct in to perform HCT. While awaiting results from ongoing observational (www. Crucial to more appropriate allocation of patients to HCT is ClinicalTrials. Whole-genome sequenc- ing, gene expression proﬁling,97 and expression of miRNAs98 are European LeukemiaNet AML Working Party recently suggested an integrated dynamic risk-adapted approach to decide between HCT likely to improve prediction of relapse in patients with intermediate and chemotherapy in younger patients with AML. Incorporation of information gained only after induc- was favored whenever an improvement in DFS of at least 10% tion and postremission chemotherapy, for example, MRD as could be suggested based on the risk-adapted approach. It will be important to determine whether there are disease allogeneic HCT, noting that death in AML with or without HCT is features in which the relative risks of relapse after HCT versus generally accompanied by persistent AML. In general, the greater chemotherapy are much lower (or higher) than this average. Such data include SNPs,82 non-HLA genetic variants,99 and biomarkers greater the decrease in this risk after allogeneic HCT, the higher the predictive of development of acute GVHD,100,101 which could maximum HCT-CI score and, accordingly, the higher the risk of NRM that still lead to a decision to perform allogeneic HCT based further reduce risks for NRM, particularly among patients who are older or medically inﬁrm. Based on this risk schema, the only group of older patients to be potentially denied allogeneic HCT because of lack of DFS beneﬁt is the group with HCT-CI scores of Results suggest that HCT from HLA-matched identical siblings and 8 plus impairment in one or more of the additional patient-speciﬁc unrelated donors are associated with relatively similar outcomes.
Patients were randomized to have sitagliptin added to pioglitazone 30mg daily or metformin added to pioglitazone 15mg daily buy 100 mg viagra soft flavored. The rational for different doses of pioglitazone in the two groups was not addressed in the publication buy viagra soft flavored 100mg free shipping. After 52 weeks of treatment buy viagra soft flavored 100 mg lowest price, there was no difference in HbA1c reduction between the two treatment groups. Both groups had similar reduction in HbA1c (between group difference 0. Patients taking metformin in addition to pioglitazone experienced more weight loss the patients taking sitagliptin in addition to pioglitazone (between group difference 1. Efficacy outcomes of Sitagliptin compared with an active agent added to another oral hypoglycemic agent Author, year Change in HbA1c from baseline (%) Change in weight from baseline (kg) 52 weeks 52 weeks S/MET Glip/MET S/MET Glip/MET 34 Nauck, 2007 −0. Placebo-controlled trials 30, Thirteen fair-quality trials compared various doses of sitagliptin to placebo (Tables 12 and 13). The others compared add-on therapy with sitagliptin or placebo to a variety of 36, 37, 47-51 ongoing treatments (Table 13). Characteristics of sitagliptin monotherapy placebo-controlled trials in adults with type 2 diabetes a Sample Age (years) (SD) a Author, year size (N) % Female Baseline a Country Follow-up % White HbA1c (%) (SD) Intervention a Quality (weeks) % Hispanic Weight (kg) Dosages Aschner, 53. Characteristics of sitagliptin add-on therapy placebo-controlled trials in adults with type 2 diabetes Sample a size (N) Age (years) (SD) a Author, year Follow- % Female Baseline a a Country up % White HbA1c (%) (SD) Intervention a a Quality (weeks) % Hispanic Weight (kg) Dosages Sitagliptin 100 mg or Charbonnel, 54. Monotherapy: Sitagliptin compared with placebo Seven fair-quality trials ranging from 12-24 weeks in duration compared sitagliptin 100 mg/d to 30, 31, 42, 43, 45, 46, 52 placebo (Table 12). Approximately 50% to 60% of subjects were on 1 or more oral hypoglycemic agents at screening. These agents were discontinued before diet and exercise run-in periods. Patients not responding to diet and exercise were eligible for study inclusion but were required to participate in a 2-week single-blind, placebo run-in period prior to randomization. Three trials allowed use of prespecified rescue medications based on certain glycemic criteria. Patients randomized to receive sitagliptin 100 mg/d showed significant reductions in HbA1c (weighted mean difference −0. One dose- 46 ranging study found similar HbA1c lowering across sitagliptin 50 mg daily, 100 mg daily, and 50 mg twice daily (−0. Change in weight varied across the trials, generally decreasing in both treatment arms (range for change from baseline: sitagliptin −0. However, one trial found weight gain in the sitagliptin arm (mean change from baseline, 0. Overall, however, subjects randomized to sitagliptin lost slightly less weight than subjects randomized to placebo (weighted mean difference: 0. Efficacy outcomes of sitagliptin monotherapy compared with placebo Author, year Change in HbA1c from baseline at (%) Change in weight from baseline (kg) S25 S50 S100 S50BID PBO S25 S50 S100 S50BID PBO Hanefeld, 12 weeks 12 weeks 46 2007 −0. Results of meta-analyses for mean change in HbA1c and weight for sitagliptin 100 mg compared with placebo Pooled analysis Heterogeneity 2 Outcome N Measure Units Estimate 95% CI P value I a HbA1c 7 WMD % −0. Three trials assessed the effects of sitagliptin compared to placebo in 36, 47, 50 patients who were considered to have “failed” therapy with metformin, 2 studies assessed sitagliptin compared to placebo in patients who were considered to have “failed” therapy with 48, 49 pioglitazone or glimepiride, and 1 study assessed sitagliptin compared to placebo in patients 51 who were inadequately controlled on metformin and insulin >15 units daily. Approximately 60% of patients were on more than 1 oral hypoglycemic agent, while 30% were on more than 2 oral agents (Table 13). Patients were considered to have “failed” therapy with metformin, pioglitazone, or glimepiride at screening or after 10-19 weeks of dose stabilization and if HbA1c was between 7% and 10% or 7. Patients also entered 2-week single-blind, placebo run-in periods prior to randomization. The addition of sitagliptin to metformin, pioglitazone, or glimepiride appears to show larger reductions in HbA1c and compared with the addition of placebo over 18 to 30 weeks (Table 16). Subjects who received placebo plus glimepiride showed worsening glycemic control, while subjects on placebo plus metformin or placebo plus pioglitazone had slight improvements or no change in HbA1c from baseline. Weight gain was generally seen in patients taking sitagliptin in combination with pioglitazone or glimepiride to a similar extent of those taking pioglitazone alone, however no weight gain was seen in those taking glimepiride alone. Patients randomized to add sitagliptin or placebo to metformin lost weight by 0. Pooled analysis was not conducted due to small number of studies and significant heterogeneity. Unlike the other studies , this trial evaluated the effects of sitagliptin in patients with worse glycemic control (baseline HbA1c between 8% and 11%). These patients were on metformin and diet and exercise for 6 weeks, had baseline HbA1c between 8% and 11%, and had ≥85% adherence to their regimens during a 2-week, placebo run- in period. No patients were naïve to oral hypoglycemic agents and approximately 50% were already taking metformin monotherapy or combination oral therapy at baseline. The addition of sitagliptin to ongoing metformin therapy was more effective than placebo plus metformin at lowering HbA1c (placebo-corrected difference: −1. One study was unique in that it included patients who were inadequately controlled on 51 insulin and/or metformin therapy. Patients were randomized to sitagliptin 100 mg or placebo in addition to their pre-study doses insulin and metformin (if they were taking). Approximately 70% of patients in both groups were taking metformin at baseline.
Nonsteroidal antiinflammatory drugs (NSAIDs) 48 of 72 Final Report Update 4 Drug Effectiveness Review Project 119 buy 100 mg viagra soft flavored mastercard. Cardiorenal effects of celecoxib as compared with the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen order viagra soft flavored 100 mg without a prescription. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure quality viagra soft flavored 100mg. Fracture risk associated with use of nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and acetaminophen and the effects of rheumatoid arthritis and osteoarthritis. Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta- analytic approach. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Gastrointestinal safety profile of meloxicam: a meta-analysis and systematic review of randomized controlled trials. Risk of serious upper gastrointestinal and cardiovascular thromboembolic complications with meloxicam. Efficacy and tolerability of meloxicam in an observational, controlled cohort study in patients with rheumatic disease. Gastrointestinal-related complications in a long-term care population taking NSAIDs versus COX-2 inhibitor therapy. The risk of gastrointestinal bleed, myocardial infarction, and newly diagnosed hypertension in users of meloxicam, diclofenac, naproxen, and piroxicam. Gastrointestinal safety profile of nabumetone: a meta- analysis (Structured abstract). A population based historical cohort study of the mortality associated with nabumetone, Arthrotec, diclofenac, and naproxen. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: a historical cohort analysis. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. Nonsteroidal antiinflammatory drugs (NSAIDs) 49 of 72 Final Report Update 4 Drug Effectiveness Review Project 134. Association between nonsteroidal anti- inflammatory drugs and upper gastrointestinal tract bleeding/perforation. An overview of epidemiologi studies published in the 1990s. Laporte J-R, Ibanez L, Vidal X, Vendrell L, Leone R. Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents. Misoprostol reduces gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: A randomized, double-blind, placebo-controlled trial. Hooper L, Brown TJ, Elliott R, Payne K, Roberts C, Symmons D. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti- inflammatory drugs: systematic review. Prevention of NSAID-induced gastroduodenal ulcers [Systematic Review]. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. The effects of nonselective non-aspirin non- steroidal anti-inflammatory medications on the risk of nonfatal myocardial infarction and their interaction with aspirin. Association between naproxen use and protection against acute myocardial infarction. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Lower risk of thromboembolis cardiovascular events with naproxen among patients with rheumatoid arthritis. Review of Epidemiologic Studies on Cardiovascular Risk with Selected NSAIDs. A meta-analysis of the effects of nonsteroidal anti- inflammatory drugs on blood pressure. Laine L, Goldkind L, Curtis SP, Connors LG, Yanqiong Z, Cannon CP. Analysis of 17,289 arthritis patients in a long-term prospective clinical trial. Systematic review: the hepatotoxicity of non-steroidal anti- inflammatory drugs. The Relative Toxicity of Nonsteroidal Antiinflammatory Drugs. Fries JF, Ramey DR, Singh G, Morfeld D, Bloch DA, Raynauld JP. A reevaluation of aspirin therapy in rheumatoid arthritis.
The US Food and Drug Administration approved the first of the biologics (infliximab) in 1998 and approved 12 additional agents since that time for treating various rheumatic conditions viagra soft flavored 100mg visa, inflammatory bowel diseases discount viagra soft flavored 100 mg amex, and plaque psoriasis: etanercept (1998) generic 100 mg viagra soft flavored mastercard, anakinra (2001), adalimumab (2002), alefacept (2003), efalizumab (2003), abatacept (2005), rituximab (2006), natalizumab (2008), certolizumab pegol (2008), golimumab (2009), ustekinumab (2009), and tocilizumab (2010). Table 1 summarizes currently approved biologics in the United States, including trade name, manufacturer, route of administration, approved (labeled) uses, and dosage. Included interventions Generic Trade name Mechanism name Manufacturer of action Indication Dosage and administration approved by the FDA Intravenous infusion dosed according to body weight (<60 kg = 500 mg; 60-100 kg = 750 mg; >100 kg = 1000 mg); dose repeated at 2 weeks and 4 weeks after initial dose, and every 4 weeks thereafter. Following single intravenous loading dose according to body weight specified above, the first 125 mg subcutaneous injection within 1 day, followed by 125 mg Rheumatoid once weekly. Juvenile rheumatoid a arthritis (6 See Canadian product label years and older) Juvenile idiopathic 10 mg/kg for patients <75 kg; adults schedule for arthritis (6 patients >75kg (maximum dose 1000 mg) on weeks 0, 2, years and and 4 and then every 4 weeks thereafter. Two weeks later (Day 29) begin a maintenance dose of 40 mg every other week. Plaque 80 mg initial subcutaneous dose followed by 40 mg psoriasis every other week starting 1 week after initial dose. Treatment should be continued for 12 weeks; re- Amevive CD2 Plaque treatment with an additional 12 week course may be Alefacept Astellas antagonist psoriasis initiated provided that CD4+ T lymphocytes counts are >250 cells/μL and a 12-week interval has passed since the end of the initial treatment cycle. If response occurs 400 mg subcutaneously every disease 4 weeks. Rheumatoid arthritis, psoriatic 50 mg once weekly as subcutaneous injection. Rheumatoid 50 mg subcutaneous injection once a month in d arthritis combination with methotrexate. Simponi TNF Psoriatic Golimumab Janssen Inhibitor arthritis, 50 mg subcutaneous injection once a month with or Biotech e ankylosing without methotrexate or other DMARDs. Remicade TNF 5 mg/kg intravenous infusion at 0, 2, and 6 weeks Infliximab Janssen Inhibitor followed by maintenance every 8 weeks thereafter; may Biotech Crohn’s increase to 10 mg/kg. Targeted immune modulators 10 of 195 Final Update 3 Report Drug Effectiveness Review Project Generic Trade name Mechanism name Manufacturer of action Indication Dosage and administration approved by the FDA 5 mg/kg intravenous induction at 0, 2, and 6 weeks Psoriatic followed by maintenance every 8 weeks thereafter, with arthritis or without methotrexate. Ankylosing 5 mg/kg intravenous induction at 0, 2, and 6 weeks spondylitis followed by maintenance every 6 weeks thereafter. Biogen-Idec disease subunit Rituxan Two 1000 mg intravenous infusion on days 1 and 15 in Genentech Rheumatoid combination with methotrexate. Subsequent courses Rituximab Anti-CD 20a Hoffman-La arthritis administered every 24 weeks or based on clinical h Roche evaluation but not sooner than every 16 weeks. Start dose 4 mg/kg, increase up to 8 mg/kg given every 4 Rheumatoid weeks with or without DMARD. Increase to 8 mg/kg arthritis based on clinical response. Dose exceeding 800 mg/ IL-6 infusion not recommended. Abbreviations: AS, ankylosing spondylitis; DMARD, disease-modifying antirheumatic drug; FDA, US Food and Drug Administration; JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; UC, ulcerative colitis. Readers should refer to the Health Canada product monograph of individual drug products for dosing information for Canada. Targeted immune modulators work by selectively blocking mechanisms involved in the inflammatory and immune response. Tumor necrosis factor inhibitors block specific proinflammatory mediators known as cytokines. Adalimumab, certolizumab pegol, golimumab, Targeted immune modulators 11 of 195 Final Update 3 Report Drug Effectiveness Review Project and infliximab all bind to both the circulating and transmembrane forms of tumor necrosis factor alpha, inhibiting its biological activity. Adalimumab is a fully human monoclonal antibody that blocks tumor necrosis factor alpha’s interaction with both the p55 and p75 cell surface tumor necrosis factor receptor. Certolizumab pegol is a recombinant, humanized antibody FAB fragment with specificity for human tumor necrosis factor alpha. Golimumab is a human monoclonal antibody that binds to tumor necrosis factor alpha. Infliximab is a chimeric (mouse/human) antitumor necrosis factor alpha antibody. Etanercept is a soluble dimeric form of the p75 tumor necrosis factor alpha receptor linked to the Fc portion of human immunoglobulin G1. It exerts its action by binding circulating tumor necrosis factor alpha and lymphotoxin-α and preventing it from interacting with a cell surface receptor. Interleukin-1, another naturally occurring cytokine, has both immune and pro inflammatory actions. Anakinra is a human recombinant protein and the therapeutic version of a naturally occurring cytokine that competitively blocks the interleukin-1 receptor, thus blocking various inflammatory and immunological responses. The immunosuppressant agents abatacept and alefacept exert their immune regulation by interfering with T lymphocyte activation and efalizumab blocks lymphocyte activation and migration. Abatacept is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T lymphocyte-associated antigen (CTLA-4) and the modified Fc portion of immunoglobulin G1. Alefacept is a dimeric fusion protein that consists of the extracellular CD2- binding portion of the human leukocyte function antigen (LFA-3) and the Fc portion of human immunoglobulin G1. Efalizumab is a recombinant humanized immunoglobulin G1 monoclonal antibody that binds to human CD11a and inhibits the binding to intercellular adhesion molecule- 1 (ICAM-1). Progressive multifocal leukoencephalopathy is a rapidly progressive, viral infection of the central nervous system that leads to death or severe disability.