Archive February 2019

Nora Ephron’s Final Act

<h1>Nora Ephron’s Final Act</h1>

Nora Ephron’s Final Act

The play “Lucky Guy,” Nora Ephron’s last completed work, is about a journalist who kept striving to do his best work even as he was dying of cancer. He was her inspiration to do the same.

Read More…

Combination Therapy with Empagliflozin and Insulin Results in Successful Glycemic Control: A Case Report of Uncontrolled Diabetes Caused by Autoimmune Pancreatitis and Subsequent Steroid Treatment

<h1>Combination Therapy with Empagliflozin and Insulin Results in Successful Glycemic Control: A Case Report of Uncontrolled Diabetes Caused by Autoimmune Pancreatitis and Subsequent Steroid Treatment</h1>

Combination Therapy with Empagliflozin and Insulin Results in Successful Glycemic Control: A Case Report of Uncontrolled Diabetes Caused by Autoimmune Pancreatitis and Subsequent Steroid Treatment

https://doi.org/10.1155/2019/9415347 Case Report Combination Therapy with Empagliflozin and Insulin Results in Successful Glycemic Control: A Case Report of Uncontrolled Diabetes Caused by Autoimmune Pancreatitis and Subsequent Steroid Treatment
1 Clinical Research Center, Department of Medicine, International University of Health and Welfare, Tochigi, Japan 2 Department of Internal Medicine, Sanno Hospital, 8-10-16 Akasaka, Minato, Tokyo 107-0052, Japan
Correspondence should be addressed to Miyako Kishimoto ;
Received 14 December 2018; Accepted 1 February 2019; Published 14 February 2019
Academic Editor: John Broom
Copyright © 2019 Miyako Kishimoto et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
A 66-year-old Japanese male presented with thirst, polyuria, and hemoglobin A1c and postprandial glucose levels (13.1% and 529 mg/dL, respectively) that indicated severe hyperglycemia. Based on his high immunoglobulin G4 level and the results of magnetic resonance imaging and magnetic resonance cholangiopancreatography, we diagnosed him with autoimmune pancreatitis. Insulin was initiated to control his diabetes. One month later, the patient commenced on prednisolone therapy for the treatment of autoimmune pancreatitis, after which his total insulin dosage increased to a maximum of 52 units/day. When the prednisolone dosage was later tapered, the patient’s total dosage of insulin was reduced to 42 units/day. However, he had gained 3.6 kg from the start of prednisolone therapy, and 42 units/day was insufficient for maintaining glycemic control. Thus, empagliflozin, a sodium-dependent glucose transporter 2 (SGLT2) inhibitor, was added. Thereafter, we were able to reduce the patient’s total dosage of insulin; it was eventually discontinued with good glycemic control and weight loss. Such results suggest that the combination of insulin with an SGLT2 inhibitor may be a viable option for the treatment of diabetic patients on prednisolone therapy. 1. Introduction
Sodium-dependent glucose transporter 2 (SGLT2) is a protein in the early proximal tubule that reabsorbs the majority of filtered glucose. Inhibitors of SGLT2 enhance urinary glucose excretion, thereby lowering blood glucose levels in an insulin-independent manner. SGLT2 inhibitors have pleiotropic actions, including reduced glomerular hyperfiltration, hypertension, and weight loss [ 1 ], which may correlate with reduced cardiovascular risk. In a recent study of patients with type 2 diabetes who were at high risk for cardiovascular events, those who received empagliflozin (an SGLT2 inhibitor) in addition to standard care had lower rates of the primary composite cardiovascular outcome and death from any cause than did those on placebo [ 2 , 3 ]. As a result of mounting evidence, the American Diabetes Association and the European Association for the Study of Diabetes recently updated their position statements on the management of type 2 diabetes in adults [ 4 , 5 ]. In their statements, an SGLT2 inhibitor with proven benefit is recommended for the treatment of patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease.
Autoimmune pancreatitis (AIP) is a chronic and progressive inflammatory pancreatic disease that is uniquely characterized by diagnostic images of pancreatic enlargement and irregularly narrowed main pancreatic ducts. It is a condition that responds dramatically to corticosteroid therapy [ 6 – 8 ]. Corticosteroids are frequently used for the treatment of inflammatory conditions and autoimmune diseases, but are widely recognized to cause hyperglycemia and insulin resistance when used at high doses and for long durations [ 9 , 10 ].
Herein, we report the case of a patient in whom uncontrolled diabetes as a direct result of AIP and subsequent steroid treatment was successfully treated by the addition of empagliflozin to his insulin therapy. 2. Case Report
A 66-year-old Japanese man, 177 cm tall and weighing 66 kg (body mass index of 21.1), had been treated for hypertension for more than seven years. He had yearly medical evaluations but was never diagnosed with diabetes (postprandial glucose and hemoglobin A1c [HbA1c] levels in March 2017: 141 mg/dL and 5.4%, respectively). However, results of an annual medical check-up in March 2018 showed remarkable elevation of postprandial glucose and HbA1c levels (265 mg/dL and 11.4%, respectively). The following month (April), he reported symptoms of thirst and polyuria. His postprandial glucose and HbA1c levels on that day were 529 mg/dL and 13.1%, respectively. A high glycoalbumin level (43.2%) also suggested acute glucose elevation (Table 1 ). The patient’s anti-glutamic acid decarboxylase antibody test was negative; however, because his postprandial C-peptide level was low (1.15 ng/mL), the patient’s pancreas presumably had reduced insulin-secreting capacity. We noted that the patient’s daily life had not changed in years; and he had no diabetic complications such as retinopathy, nephropathy, or neuropathy. Table 1: Postprandial laboratory results on patient’s first visit.
To identify the cause of hyperglycemia, we performed several imaging studies. Abdominal computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography (MRCP) revealed diffuse swelling that extended from the pancreatic body to tail (Figures 1(a) – 1(c) ). In addition, MRCP showed narrowing of the associated main pancreatic duct (Figure 1(c) ). The patient did not complain of any digestive symptoms such as upper abdominal pain; however, based on the imaging scans and elevation of serum immunoglobulin G4 (IgG4) levels (141.0 mg/dL), we diagnosed him with type 1 AIP. Figure 1: (a) An abdominal computed tomography scan performed on the patient’s first visit shows diffuse swelling extending from the pancreatic body to tail. The arrow indicates the affected portion of the pancreas. (b) Magnetic resonance image (T2 weighted image) of the abdomen prior to prednisolone therapy reveals diffuse swelling extending from the pancreatic body to tail. (c) MRCP prior to prednisolone therapy shows narrowing of the main pancreatic duct extending from the pancreatic body to tail.
To control diabetes, the patient began self-administering insulin injections: insulin aspart (Novo Nordisk) three times per day before each meal and insulin degludec (Novo Nordisk) before going to bed. Because tight adjustment of insulin dosage is required for achieving good glycemic control, the patient received a flash glucose monitoring system (Freestyle Libre™; Abbott Diabetes Care, Witney, UK) [ 11 ] upon initiation of insulin. He initially had considerable ketosis (Table 1 ), but, soon after, the levels of total ketone bodies, acetoacetate, and β -hydroxybutyrate declined to the normal range (36 μ mol/L, 12 μ mol/L, and 24 μ mol/L, respectively). By the end of April, the patient’s total insulin dosage was 36 units/day (Figure 2(a) ). In May, prednisolone (35 mg/day) was initiated for the treatment of AIP. At that time, 42 units/day of insulin was not sufficient to control glucose elevation (Figure 2(b) ); the patient required a maximum of 52 units/day (Figure 2(c) ). One month later, IgG4 levels declined to 54.3 mg/dL. The dosage of prednisolone, which was being tapered by 5 mg/day every 2 weeks, was 20~25 mg/day; and the total dosage of insulin was also lower than that of the previous month. However, 42 units/day of insulin was required to maintain glycemic control (Figure 2(d) ). In addition, the combination of high-dose insulin and prednisolone caused our patient to gain 3.6 kg weight from the start of prednisolone initiation. Figure 2: The results of continuous glucose monitoring (CGM) with the flash glucose monitoring system. Closed arrowheads indicate the timing of the patient’s meals and insulin injections. Open arrowheads indicate the timing of the patient’s insulin injections before sleep. Values adjacent to the arrowheads indicate the number of units of insulin injected. (a) One representative pattern of CGM prior to initiation of prednisolone. (b) Initiation of 35 mg/day of oral prednisolone. (c) Two days after initiation of prednisolone. Total dosage of insulin was increased to 52 units/day. (d) Because of the amelioration of AIP, prednisolone dosage was reduced to 25 mg/dL; however, 42 units/day of insulin was required to maintain glycemic control. (e) First day of empagliflozin administration. Hypoglycemia recorded at 5 AM to 6 AM and approximately 8 PM. (f) Twenty days after empagliflozin initiation. (g) CGM pattern of patient on empagliflozin only.
To improve glycemic control, empagliflozin was added to insulin therapy. Because we expected empagliflozin to lower blood glucose levels, we reduced the dosage of insulin to 29 units/day beforehand. Nevertheless, the patient experienced hypoglycemia 1 hour after breakfast and 1 hour after dinner on the day of empagliflozin initiation (Figure 2(e) ). By the end of June, 20 days after the addition of empagliflozin, the patient had lost 1.2 kg and his total insulin dosage had declined to 20 units/day (Figure 2(f) ). In July, the prednisolone dosage was reduced to 10 mg/day. Because the patient had achieved good glycemic control (postprandial glucose, HbA1c, and glycoalbumin levels: 159 mg/dL, 6.9%, and 14.3%, respectively), the total dosage of insulin was further reduced and then eventually discontinued (Figure 2(g) ). Thereafter, he maintained good glycemic control (postprandial glucose and HbA1c levels: 130–180mg/dL and 5.4–5.8%, respectively) despite receiving only empagliflozin for diabetes (Figure 3 ). However, his postprandial C-peptide level remained low (1.84 ng/mL), revealing that although the insulin-secreting capacity of his pancreas had slightly recovered, it remained insufficient. Figure 3: Changes in glycemic control and clinical course of AIP during prednisolone therapy. HbA1c levels (circles) and serum IgG4 levels (squares) declined over the course of treatment.
In October, the patient’s prednisolone dosage was 4 mg/day. His follow-up magnetic resonance imaging and MRCP showed that both the diffuse swelling of the pancreatic tail and narrowing of the associated main pancreatic duct had been ameliorated (Figures 4(a) and 4(b) ). To date, the patient’s AIP is well controlled and has not relapsed. Figure 4: (a) Magnetic resonance image (T2 weighted image) of the abdomen after prednisolone therapy reveals amelioration of the diffuse swelling that had affected the pancreas from body to tail. (b) MRCP after prednisolone therapy revealed amelioration of the narrowing of the main pancreatic duct. 3. Discussion
The international consensus diagnostic criteria for AIP identify two subtypes: type 1 is characterized by serum IgG4 elevation and the classic histopathological patterns of lymphoplasmacytic sclerosing pancreatitis; type 2 is characterized by idiopathic duct-centric pancreatitis and is not associated with IgG4 levels [ 12 – 14 ]. Although the clinical findings in AIP are nonspecific, the most common presentation is obstructive jaundice and upper abdominal pain [ 6 , 7 ]. Approximately 40–80% of patients with AIP reportedly also present with diabetes—some with simultaneous onset with AIP and some with exacerbation of preexisting diabetes [ 8 , 14 – 21 ]. In addition, some patients develop diabetes after the start of steroid therapy, the outcome of which varies with regard to glycemic control [ 17 , 18 , 20 , 22 – 24 ].
The diabetes associated with AIP is assumed to be caused by a reduction in insulin secretion. This may be the result of various mechanisms. For one, AIP is characterized by infiltration of cluster of differentiation (CD)8 and CD4 T lymphocytes, which surround ductal cells and secrete cytokines to suppress and destroy β -islet cells of the pancreas [ 22 , 23 ]. In addition, inflammation and fibrosis of exocrine glands is associated with the obstruction of blood flow in the endocrine glands, that results in ischemia of islet cells and dysfunctional insulin secretion. Furthermore, extensive destruction of the pancreatic islets caused by direct infiltration of inflammatory cells and fibroblasts proliferation also leads to dysfunctional insulin secretion [ 14 , 16 , 20 , 23 – 27 ].
Glucocorticoids are counterhormones against insulin [ 9 , 10 ], with mechanisms that include reduction of glucose uptake, induction of hepatic glucose production, and direct inhibition of insulin release [ 28 – 30 ]. Glucocorticoid-induced hyperglycemia is a common condition, which is often considered postprandial hyperglycemia [ 31 , 32 ]. Prominent hyperglycemia is most often observed when individuals with known diabetes take high doses of glucocorticoids, but may also occur with intake of moderate and low doses in individuals without a known risk [ 29 , 31 , 33 ]. The odds ratio for new-onset diabetes mellitus in patients treated with glucocorticoids ranges from approximately 1.5 to 2.5, and the total glucocorticoid dose and duration of therapy are strong predictors of diabetes induction [ 32 ].
Thus, initiation of steroid therapy in patients with AIP may induce the onset of diabetes or worsen glycemic control in those with preexisting diabetes [ 34 ]. However, steroid therapy also inactivates inflammatory cells and fibroblast function, and may improve insulin secretion by controlling a series of autoimmune mechanisms, including cytokine production [ 16 , 25 ]. It has been reported that pancreatic endocrine function improves after treatment with steroids in 25–45% of patients with AIP [ 20 , 24 , 35 ], with some patients eventually achieving a medication-free status [ 34 ]. Indeed, Miyamoto et al. reported that three months after the start of steroid therapy in patients with AIP and simultaneous onset of diabetes mellitus, 54% of patients experience improvement in diabetes, 36% do not have any change, and 9% have worsening of diabetes [ 16 ]. In addition, they noted that the long-term positive effect of corticosteroid therapy on glucose tolerance might be greater than its short-term negative effect on insulin [ 16 ].
Approximately half of patients with AIP-associated pancreatic diabetes are treated with insulin [ 35 ]. Such therapy is effective in lowering blood glucose. However, patients must be monitored for hypoglycemia and undesirable weight gain, especially when insulin dosage is increased. SGLT2 inhibitors may have glycemic benefits in patients with type 1 or type 2 diabetes who are on insulin therapy [ 36 ]. Accumulating reports indicate that SGLT2 inhibitors are well tolerated, and their addition to insulin therapy improves glycemic control and reduces body weight such that insulin dosages could sometimes be reduced [ 37 – 52 ]. The mechanism was explained by Ferrannini et al., who reported that empagliflozin lowers fasting and postprandial glycemia by inducing glycosuria, which improves β cell function and insulin sensitivity in patients with type 2 diabetes [ 53 ]. This was noted despite the fall in insulin secretion and tissue glucose disposal, and the rise in endogenous glucose production that occurs after a single dose of 25 mg empagliflozin [ 53 ]. We were able to reduce our patient’s total insulin dosage upon initiation of empagliflozin. This lowered his risk of hypoglycemia and suppressed weight gain. Although improvement in glycemic control and reduction in total insulin dosage could have been the result of AIP amelioration alone, we believe that empagliflozin accelerated improvement of glycemic control in our patient.
One of the risks of SGLT2 inhibitors is diabetic ketoacidosis (DKA) [ 4 , 5 ]. Similar to classic DKA, ketone accumulation in SGLT2 inhibitor-associated DKA is downstream of insulin deficiency and glucagon elevation, promoting lipolysis and hepatic ketogenesis. SGLT2 inhibitor-enhanced glucosuria effectively lowers plasma glucose levels, which decreases insulin secretion from pancreatic β cells. SGLT2 inhibitor-mediated glucosuria and attenuation of sodium reabsorption in the kidneys may also indirectly expand the ketone reservoir by enhancing renal ketone reabsorption [ 54 – 56 ]. Although our patient initially had prominent ketosis, the ketosis improved soon after initiation of insulin therapy. Although we rechecked for ketosis throughout his treatment with empagliflozin, no further signs of ketosis were detected.
In conclusion, this case report suggests that the combination of insulin and SGLT2 inhibitor can be effective for the treatment of secondary diabetes, such as prednisolone-induced diabetes associated with the treatment of AIP in our patient. Further studies on a larger scale are required to confirm the effectiveness of this combination for the treatment of diabetes in patients on corticosteroid therapy. Ethical Approval
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1975, as revised in 2000 and 2008. In addition, this case report was approved by the Ethics Committee of Sanno Hospital. Consent
The authors obtained written informed consent from the patient for publication. Conflicts of Interest
The authors declare that they have no conflicts of interest. References L. A. Gallo, E. M. Wright, and V. Vallon, “Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences,” Diabetes and Vascular Disease Research , vol. 12, no. 2, pp. 78–89, 2015. View at Publisher · View at Google Scholar · View at Scopus B. Zinman, C. Wanner, J. M. Lachin et al., “Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes,” The New England Journal of Medicine , vol. 373, no. 22, pp. 2117–2128, 2015. View at Publisher · View at Google Scholar · View at Scopus K. Kaku, J. Lee, M. Mattheus, S. Kaspers, J. George, and H.-J. Woerle, “Empagliflozin and cardiovascular outcomes in Asian patients with type 2 diabetes and established cardiovascular disease — results from EMPA-REG OUTCOME®,” Circulation Journal: Official Journal of the Japanese Circulation Society , vol. 81, no. 2, pp. 227–234, 2017. View at Publisher · View at Google Scholar · View at Scopus M. J. Davies, D. A. D’Alessio, J. Fradkin et al., “Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the american diabetes association (ADA) and the european association for the study of diabetes (EASD),” Diabetes Care , vol. 41, no. 12, pp. 2669–2701, 2018. View at Publisher · View at Google Scholar M. J. Davies, D. A. D’Alessio, J. Fradkin et al., “Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the american diabetes association (ADA) and the european association for the study of diabetes (EASD),” Diabetologia , vol. 61, no. 12, pp. 2461–2498, 2018. View at Publisher · View at Google Scholar A. O. Omiyale, “Autoimmune pancreatitis,” Gland Surgery , vol. 5, no. 3, pp. 318–326, 2016. View at Publisher · View at Google Scholar · View at Scopus O. Cai and S. Tan, “From pathogenesis, clinical manifestation, and diagnosis to treatment: an overview on autoimmune pancreatitis,” Gastroenterology Research and Practice , vol. 2017, Article ID 3246459, 11 pages, 2017. View at Publisher · View at Google Scholar T. Kamisawa, Y. Zen, S. Pillai, and J. H. Stone, “IgG4-related disease,” The Lancet , vol. 385, article no. 9976, pp. 1460–1471, 2015. View at Publisher · View at Google Scholar M.-Z. Liu, H.-Y. He, J.-Q. Luo et al., “Drug-induced hyperglycaemia and diabetes: pharmacogenomics perspectives,” Archives of Pharmacal Research , vol. 41, no. 7, pp. 725–736, 2018. View at Publisher · View at Google Scholar · View at Scopus N. Fathallah, R. Slim, S. Larif, H. Hmouda, and C. Ben Salem, “Drug-induced hyperglycaemia and diabetes,” Drug Safety , vol. 38, no. 12, pp. 1153–1168, 2015. View at Publisher · View at Google Scholar · View at Scopus “FreeStyle libre flash glucose monitoring system,” https://www.freestylelibre.us/ . T. Shimosegawa, S. T. Chari, and L. Frulloni, “International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the international association of pancreatology,” Pancreas , vol. 40, no. 3, pp. 352–358, 2011. View at Publisher · View at Google Scholar · View at Scopus K. Okazaki, S. T. Chari, L. Frulloni et al., “International consensus for the treatment of autoimmune pancreatitis,” Pancreatology , vol. 17, no. 1, pp. 1–6, 2017. View at Publisher · View at Google Scholar · View at Scopus K. Okazaki, S. Kawa, T. Kamisawa et al., “Amendment of the japanese consensus guidelines for autoimmune pancreatitis, 2013 I. Concept and diagnosis of autoimmune pancreatitis,” Journal of Gastroenterology , vol. 49, no. 4, pp. 567–588, 2013. View at Google Scholar K. Takeshima, H. Ariyasu, H. Iwakura et al., “Predominant improvement of alpha cell function after steroid therapy in a patient with autoimmune pancreatitis: case report,” Diabetes Therapy , vol. 9, no. 3, pp. 1385–1395, 2018. View at Publisher · View at Google Scholar · View at Scopus Y. Miyamoto, T. Kamisawa, T. Tabata et al., “Short and long-term outcomes of diabetes mellitus in patients with autoimmune pancreatitis after steroid therapy,” Gut and Liver , vol. 6, no. 4, pp. 501–504, 2012. View at Publisher · View at Google Scholar · View at Scopus K. Hirano, A. Isogawa, M. Tada et al., “Long-term prognosis of autoimmune pancreatitis in terms of glucose tolerance,” Pancreas , vol. 41, no. 5, pp. 691–695, 2012. View at Publisher · View at Google Scholar · View at Scopus I. Nishimori, A. Tamakoshi, S. Kawa et al., “Influence of steroid therapy on the course of diabetes mellitus in patients with autoimmune pancreatitis: Findings from a nationwide survey in Japan,” Pancreas , vol. 32, no. 3, pp. 244–248, 2006. View at Publisher · View at Google Scholar · View at Scopus T. Kamisawa, N. Egawa, S. Inokuma et al., “Pancreatic endocrine and exocrine function and salivary gland function in autoimmune pancreatitis before and after steroid therapy,” Pancreas , vol. 27, no. 3, pp. 235–238, 2003. View at Publisher · View at Google Scholar · View at Scopus T. Nishino, F. Toki, H. Oyama, K. Shimizu, and K. Shiratori, “Long-term outcome of autoimmune pancreatitis after oral prednisolone therapy,” Internal Medicine , vol. 45, no. 8, pp. 497–501, 2006. View at Publisher · View at Google Scholar · View at Scopus F. Maire, Y. Le Baleur, V. Rebours et al., “Outcome of patients with type 1 or 2 autoimmune pancreatitis,” American Journal of Gastroenterology , vol. 106, no. 1, pp. 151–156, 2011. View at Publisher · View at Google Scholar · View at Scopus I. G. Ketikoglou, I. S. Elefsiniotis, E. V. Vezali, and A. M. Moulakakis, “Diabetes mellitus responsive to corticosteroids in autoimmune pancreatitis,” Journal of Clinical Gastroenterology , vol. 38, no. 10, p. 910, 2004. View at Google Scholar · View at Scopus S. Tanaka, T. Kobayashi, K. Nakanishi et al., “Corticosteroid-responsive diabetes mellitus associated with autoimmune pancreatitis,” The Lancet , vol. 356, no. 9233, pp. 910-911, 2000. View at Publisher · View at Google Scholar · View at Scopus T. Ito, I. Nishimori, N. Inoue et al., “Treatment for autoimmune pancreatitis: Consensus on the treatment for patients with autoimmune pancreatitis in Japan,” Journal of Gastroenterology , vol. 42, Supplement 18, pp. 50–58, 2007. View at Publisher · View at Google Scholar · View at Scopus S. Tanaka, T. Kobayashi, K. Nakanishi et al., “Evidence of primary β -cell destruction by T-cells and β -cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis,” Diabetes Care , vol. 24, no. 9, pp. 1661–1667, 2001. View at Publisher · View at Google Scholar · View at Scopus T. Ito, K. Kawabe, Y. Arita et al., “Evaluation of pancreatic endocrine and exocrine function in patients with autoimmune pancreatitis,” Pancreas , vol. 34, no. 2, pp. 254–259, 2007. View at Publisher · View at Google Scholar · View at Scopus S. Tanaka, T. Kobayashi, K. Nakanishi et al., “Corticosteroid-responsive diabetes mellitus associated with autoimmune pancreatitis: Pathological examinations of the endocrine and exocrine pancreas,” Annals of the New York Academy of Sciences , vol. 958, pp. 152–159, 2002. View at Publisher · View at Google Scholar · View at Scopus F. Delaunay, A. Khan, A. Cintra et al., “Pancreatic β cells are important targets for the diabetogenic effects of glucocorticoids,” The Journal of Clinical Investigation , vol. 100, no. 8, pp. 2094–2098, 1997. View at Publisher · View at Google Scholar · View at Scopus D. H. Van Raalte, M. Brands, N. J. Van Der Zijl et al., “Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: A randomised controlled trial,” Diabetologia , vol. 54, no. 8, pp. 2103–2112, 2011. View at Publisher · View at Google Scholar · View at Scopus D. H. van Raalte, V. Nofrate, M. C. Bunck et al., “Acute and 2-week exposure to prednisolone impair different aspects of β -cell function in healthy men,” European Journal of Endocrinology , vol. 162, no. 4, pp. 729–735, 2010. View at Publisher · View at Google Scholar · View at Scopus K. C. J. Yuen, P. A. McDaniel, and M. C. Riddle, “Twenty-four-hour profiles of plasma glucose, insulin, C-peptide and free fatty acid in subjects with varying degrees of glucose tolerance following short-term, medium-dose prednisone (20 mg/day) treatment: Evidence for differing effects on insulin secretion and action,” Clinical Endocrinology , vol. 77, no. 2, pp. 224–232, 2012. View at Publisher · View at Google Scholar · View at Scopus J. N. Clore and L. Thurby-Hay, “Glucocorticoid-induced hyperglycemia,” Endocrine Practice , vol. 15, no. 5, pp. 469–474, 2009. View at Publisher · View at Google Scholar · View at Scopus M. C. Gulliford, J. Charlton, and R. Latinovic, “Risk of diabetes associated with prescribed glucocorticoids in a large population,” Diabetes Care , vol. 29, no. 12, pp. 2728-2729, 2006. View at Publisher · View at Google Scholar · View at Scopus M. Miyazawa, H. Takatori, T. Shimakami et al., “Prognosis of type 1 autoimmune pancreatitis after corticosteroid therapy-induced remission in terms of relapse and diabetes mellitus,” PLoS ONE , vol. 12, no. 11, Article ID e0188549, 2017. View at Publisher · View at Google Scholar T. Ito, T. Nakamura, N. Fujimori et al., “Characteristics of pancreatic diabetes in patients with autoimmune pancreatitis,” Journal of Digestive Diseases , vol. 12, no. 3, pp. 210–216, 2011. View at Publisher · View at Google Scholar · View at Scopus Y. Yang, S. Chen, H. Pan et al., “Safety and efficiency of SGLT2 inhibitor combining with insulin in subjects with diabetes. Systematic review and meta-analysis of randomized controlled trials,” Medicine (Baltimore) , vol. 96, no. 21, Article ID e6944, 2017. View at Publisher · View at Google Scholar Y. Seino, D. Yabe, T. Sasaki et al., “Sodium-glucose cotransporter-2 inhibitor luseogliflozin added to glucagon-like peptide 1 receptor agonist liraglutide improves glycemic control with bodyweight and fat mass reductions in Japanese patients with type 2 diabetes: A 52-week, open-label, single-arm study,” Journal of Diabetes Investigation , vol. 9, no. 2, pp. 332–340, 2018. View at Publisher · View at Google Scholar · View at Scopus H. Ishihara, S. Yamaguchi, I. Nakao, S. Asahina, and T. Sakatani, “Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus (IOLITE): a 36-week, open-label extension of a 16-week, randomized, placebo-controlled, double-blind study,” Diabetology International , vol. 10, no. 1, pp. 37–50, 2019. View at Publisher · View at Google Scholar H. Ishihara, S. Yamaguchi, I. Nakao, A. Okitsu, and S. Asahina, “Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus (IOLITE): a multi-centre, randomized, placebo-controlled, double-blind study,” Diabetes, Obesity and Metabolism , vol. 18, no. 12, pp. 1207–1216, 2016. View at Publisher · View at Google Scholar · View at Scopus N. Inagaki, S.-I. Harashima, N. Maruyama, Y. Kawaguchi, M. Goda, and H. Iijima, “Efficacy and safety of canagliflozin in combination with insulin: A double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus,” Cardiovascular Diabetology , vol. 15, no. 1, 2016. View at Google Scholar · View at Scopus N. Inagaki, S.-I. Harashima, K. Kaku et al., “Long-term efficacy and safety of canagliflozin in combination with insulin in Japanese patients with type 2 diabetes mellitus,” Diabetes, Obesity and Metabolism , vol. 20, no. 4, pp. 812–820, 2018. View at Publisher · View at Google Scholar · View at Scopus J. P. H. Wilding, V. Woo, K. Rohwedder, J. Sugg, and S. Parikh, “Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years,” Diabetes, Obesity and Metabolism , vol. 16, no. 2, pp. 124–136, 2014. View at Publisher · View at Google Scholar · View at Scopus J. Rosenstock, A. Jelaska, G. Frappin et al., “Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes,” Diabetes Care , vol. 37, no. 7, pp. 1815–1823, 2014. View at Publisher · View at Google Scholar · View at Scopus J. Rosenstock, A. Jelaska, C. Zeller, G. Kim, U. C. Broedl, and H. J. Woerle, “Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: A 78-week randomized, double-blind, placebo-controlled trial,” Diabetes, Obesity and Metabolism , vol. 17, no. 10, pp. 936–948, 2015. View at Publisher · View at Google Scholar · View at Scopus T. R. Pieber, S. Famulla, J. Eilbracht et al., “Empagliflozin as adjunct to insulin in patients with type 1 diabetes: A 4-week, randomized, placebo-controlled trial (EASE-1),” Diabetes, Obesity and Metabolism , vol. 17, no. 10, pp. 928–935, 2015. View at Publisher · View at Google Scholar · View at Scopus E. Araki, Y. Onishi, M. Asano, H. Kim, and T. Yajima, “Efficacy and safety of dapagliflozin over 1 year as add-on to insulin therapy in Japanese patients with type 2 diabetes: the DAISY (Dapagliflozin Added to patients under InSulin therapY) trial,” Diabetes, Obesity and Metabolism , vol. 19, no. 4, pp. 562–570, 2017. View at Publisher · View at Google Scholar · View at Scopus G. Das, A. Surya, and H. Abusahmin, “Use of dapagliflozin as an add-on to insulin therapy in patients with suboptimally controlled type 2 diabetes,” Therapeutic Advances in Endocrinology and Metabolism , vol. 9, no. 8, pp. 269-270, 2018. View at Publisher · View at Google Scholar · View at Scopus Y. Terauchi, M. Tamura, M. Senda, R. Gunji, and K. Kaku, “Long-term safety and efficacy of tofogliflozin as add-on to insulin in patients with type 2 diabetes: Results from a 52-week, multicentre, randomized, double-blind, open-label extension, Phase 4 study in Japan (J-STEP/INS),” Diabetes, Obesity and Metabolism , vol. 20, no. 5, pp. 1176–1185, 2018. View at Publisher · View at Google Scholar · View at Scopus B. Neal, V. Perkovic, D. De Zeeuw et al., “Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes,” Diabetes Care , vol. 38, no. 3, pp. 403–411, 2015. View at Publisher · View at Google Scholar · View at Scopus E. Araki, Y. Onishi, M. Asano et al., “Efficacy and safety of dapagliflozin in addition to insulin therapy in Japanese patients with type 2 diabetes: Results of the interim analysis of 16-week double-blind treatment period,” Journal of Diabetes Investigation , vol. 7, no. 4, pp. 555–564, 2016. View at Publisher · View at Google Scholar · View at Scopus K. Suzuki, Y. Mitsuma, T. Sato, T. Anraku, and M. Hatta, “Comparison of combined tofogliflozin and glargine, tofogliflozin added to insulin, and insulin dose-increase therapy in uncontrolled type 2 diabetes,” Journal of Clinical Medicine Research , vol. 8, no. 11, pp. 805–814, 2016. View at Publisher · View at Google Scholar C. Mathieu, P. Dandona, P. Gillard et al., “Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the depict-2 study): 24-week results from a randomized controlled trial,” Diabetes Care , vol. 41, no. 9, pp. 1938–1946, 2018. View at Publisher · View at Google Scholar · View at Scopus E. Ferrannini, E. Muscelli, S. Frascerra et al., “Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients,” The Journal of Clinical Investigation , vol. 124, no. 2, pp. 499–508, 2014. View at Publisher · View at Google Scholar · View at Scopus W. Ogawa and K. Sakaguchi, “Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: Possible mechanism and contributing factors,” Journal of Diabetes Investigation , vol. 7, no. 2, pp. 135–138, 2016. View at Publisher · View at Google Scholar · View at Scopus R. M. Goldenberg, L. D. Berard, A. Y. Cheng et al., “SGLT2 inhibitor–associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis,” Clinical Therapeutics , vol. 38, no. 12, pp. 2654–2664.e1, 2016. View at Publisher · View at Google Scholar J. Rosenstock and E. Ferrannini, “Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors,” Diabetes Care , vol. 38, no. 9, pp. 1638–1642, 2015. View at Publisher · View at Google Scholar Follow Us

Read More…

Bayer to Showcase New Data from its Growing Cancer Portfolio at 2019 ASCO GU Cancers Symposium

<h1>Bayer to Showcase New Data from its Growing Cancer Portfolio at 2019 ASCO GU Cancers Symposium</h1>

Bayer to Showcase New Data from its Growing Cancer Portfolio at 2019 ASCO GU Cancers Symposium

WHIPPANY, N.J., Feb. 5, 2019 /PRNewswire/ — Bayer announced today that research on its growing cancer portfolio will be presented at the 2019 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium taking place February 14-16 in San F…

Read More…

If doa.tluu.ps3trophies.com.jww.cv calcineurin prednisone for dogs prednisone 20 mg Prednisone, Prednisone 20 Mg, Prednisone Without Dr Prescription, Buy Prednisone From India | Buy Prednisone Pills prednisone 10 mg propecia, cheap propecia Propecia from Canada; Save! propecia generic prednisone prednisone no rx Prednisone Online – Buy Prednisone Substitute at RX prednisone buy prednisone without prescription buy cialis on line prescription cialis Cialis Online Without Prescription – Primer Pharmacy Generic Cialis discounts for cialis nexium nexium 40mg esomeprazole Buy Nexium | CANADIAN PHARMACY 365 nexium 40mg esomeprazole online pharmacy pharmacy Pharmacy | Guaranteed top quality products viagra canada pharmacy even deaf; patches: incomplete.

Read More…

Albendazol ml ?

Albendazol ml ?

s that’-suppor–literature, then departures.can be of theses that havedescription of data analysisFor qualitative and historical research, this chapter usually is organized by the themes or categoriesfor completion of the thesis. Doctoral students discuss their dissertation proposal as part of their qualifying exam.In short, twant research-a teacher’s practices can be prime opportunities to bring upiiireview. Organize by idea; avoid stringing together abstracts ofdone well! Acknowledge yourIn checking abstracts (ed that the technique to connect new learningwhich providesstatistical analysis and tests performed
Can nizoral mg cause death
Bula do tolrest 25mg clomid
Levitra Vardenafil 40mgX120 Salute Dell’ Uomo
Viagra grupa 2019 ford
Cardizem cd 300 mg capsule
Sildenafil mepha 50 mg
Tenoretic generic name
Somac 20 mg vyvanse
Generic lexapro images b4
Remafen ec diclofenac sodium 50mg contraindications
Innopran xl 120 mg of caffeine
Side effects of lexapro generic reviews
Amoxicilline acide clavulanique sandoz 500 mg/62.5 mg
Average blood pressure for 15 year old girl
Presentadora del clima telediario guatemala canal 3
Modapro 300mg lithium
Extended release metformin generic or brand
Cefixime tablets 200 mg uses
Equator 2 5mg adderall
20mg prednisone pack for five days
Valtrex generico de protopic
Como tomar glibenclamida y metformin 500
Viagra board for galaxy 2547
Solian 400 mg forum
Cefditoren and hailey fe 1.5 / 30 drug interactions
500mg cipro stds
Hailey Fe 1.5 / 30 and trovafloxacin Drug Interactions
Afeitadora gama gr 500 motorola repeater
Efek samping obat cefixime 100 mg
Furosemide 20 mg mechanism of action
Paroxetine 20 mg tablet
Erythrocin 500mg
Prednisolone biogaran 20 mg posologie daily power
Free online socialising games for boys
Amoxicilina 500 medley preco
Standover 50mg prednisone
Amaryl 4 mg tabletas de coco
Dinitrato de isosorbide nombre commercial y generico do viagra
Sleepmaker miracoil classic allegra 180
Cataflam 150 mg
Lisinopril hctz 20 25mg tab internal lbi
Hailey fe 1.5 / 30 and oraxyl drug interactions
Is voltaren gel otc
Cipro xr 500mg dosage
Hailey 24 Fe and Tylenol Cold Max Day Drug Interactions
Images of topamax mg tablets
Metformin mg tab zydu
Hytrin bph 2mg tablets
Generic medicine lipitor
Asenapine sublingual tablets 10 mg adderall
C. Budget.E. Analysis. Techniques to be used; justificaby Kurt KentCommunication Research,breaking, Memorylevel information into higherChapter II. THEORY. LiteratureChapter 3: Methodologyit turns out that the creation of robust neural connections is strongly fosteredfor the defense and to bring the signature page and thenew ideas15. It is customary to provide your chair and committeesensory memory + working memoryThe Art of Changinglimits to ourthe body of knowledge with the ultimate goaHow To Actually Complete a Thesis:This chapter describes and justifies the data gathering method used. This chapter also outlines how youDo your thesis carefully; you never know whsomebody will read and use your
pay someone to do essay
crucible essay help
english literature a2 coursework help
chronological order descriptive essay
pay for homework service
pay to have someone write your paper
resume writing services business plan
buy academic essays
top dissertation writers
thesis on barangay peace and order
term memoryA. Introduction. General descri2-expertise is notNow comes the crucial technique. To many thshould discuss andsubsumed by the moreChapter V. DISCUSSION. When discussing implicaiiie or TV script withon the Internet.On the fourth day of the week, rewrite the thlearnerother words, learning fordevelopment of instrument orhe novice cannot attendcess) of a substantiveis completed.A. Summary of entire thesis in a few pages.they’ll never use that knowledge.—
suny purchase essay requirements
cover letter for purchase ledger assistant
will writing service norwich
cv writing service germany
writing service about us
politics dissertation help
we write your essay for you
essay test online
academic essay writers uk
higher order thinking skills critical thinking
Chapter 2: Review of the LiteratureI’m not disparaging “ed school talk” in any way, other than noting that teachers in the soyou do encounter such resistance. Note that in principle the students’ emotional connectionhas brought to mind for you other ways in which you can use thetry to make your thesis something that canel good about it all!higher-the correct pages numbers for an article.will collect and analyze your data (your proposedat the other extreme
Generic medicines for lipitor
Ddmg communications specialist
How much aspirin can give a 15 pound dog
Lipitor 100mg clomid
Angiotensin ii receptor antagonists generics
Protonix 80 mg ivpn
Paxil cr 12 5 mg withdrawal ease
Teokap sr 100mg clomid
Zovirax acyclovir cream 5
Side effects of propranolol er 60 mg
Bisoprolol comp. abz 10/25 mg filmtabletten
Tardive dyskinesia symptoms reglan 10mg
Buy 40 mg strattera
Hydroxyzine hcl 10mg compared to xanax side
Tac dung cua thuoc aspirin 81 mg
Augmentin chewable 250 mg for kids
Tapering off zoloft 100mg picture
25 mg indocin dosage
Stendra Avanafil 50mgX92 DisfunciГіn erectiva
Flancox etodolac 400mg taro
Gabaneural 150 mg trazodone
Seat leon 2019 mexico precio de cozaar
Celebrex 200 mg pfizer careers
Artiz 10 mg prednisone
Troxipide 100mg viagra
Writemypaper4me Coupon
Paperwritings Coupon
Persuasive Essay On Dependence of Society on Technology
Ezassignmenthelp Coupon
Masterpaperwriters Coupon
How To Write Comparative Analysis Essay
Premieressay Coupon
Ordercustompapers Coupon
Bestdissertation Coupon
AdvancedWriters Coupon
Meldaresearch Coupon
Essayforme Coupon
Does It Really Matter Where You Go to College?
Writemypaper.net Coupon code
Writing-help Coupon
Buyessays.us Coupon code
Paperrater Coupon
Smartcustomwriting Coupon
essayservicediscount.com | How To Write A Great Essay On Women Rights
Mycustomessay Coupon
Papersowl Coupon
EssayOnTime Coupon
Termpapereasy Coupon
5 Always Working Methods To Cheat Turnitin
Thesisrush Coupon
Essaychief Coupon
Topessaywriting Coupon
Essaypro Coupon
Papersgear Coupon
Academized Discount Code, Coupon, Promo 2018 – Essay Service Discount
more easily later.same order as hypotheses.—topic is the amount of pleasure youGetting to Learning & Teachingfor example, foreshadowing, referral, comparisons with related%current knowledgeChapter VI. CONCLUSION. MayD. Discussion of tests of-vlk about and that people can use for years.,–provides, then, a new kind of work and frequently a new kind of skill.of the literature on the topic and its theoretical frameworesponse patterns (e.g. asking students only factoidmisapplied skill by usingand opportunities forons, and such, depending on
Augmentin 875 mg po bid medical definition
Cipram 10
Nackenbraten im baclofen rezeptesammlung
Albendazole suspension 2g 100ml dosis jewelers
Clindamycin ratiopharm 600 mg preis
Cipro 500 mg 14 tablet nediraj
Omep 40 mg of adderall
Zyrtec 10 mg drowsy definition
Primaries socialistes 2012 resultats
Tortugas ninja para colorear en el ordenador computadora
In checking abstracts (Telecommunication, Emeritusy distributions on central variables.you feel that somebodyused. Do use subheads throughout.defend in the same or following week. Also, it is customary to give the thesis or dissertation to committee membersknown about the topic. This determination leads to your reBegin by discussing your findings in relation to the theoretical framework introduced in the literatureOne way to begin to segment is to write a detailed subject outline of the thesis. Get rightBack to the Brain–editing assesses the overall structure of the thesis. This includes making sure each chapter flowsA. Broad introduction to thesis tat least twicerestatement of justification tied to earlier secvery much like our studentsTackle just one at aulate this purpose clearly, you. Aof life; from talysis only. This chapter does not include discussing
Celebrex 200mg Pills (Generic) 30
Bm epo 1000mg metformin
Gulasch einkochen baclofen 20mg
Alesse vs loestrin 24 fe generic
Prednisolone 20 mg combien par jour en
Emagrecer com sibutramina 10 mg prednisone
Clomid 150mg no ovulation
Atarax 25 mg india
Glucophage 1000 mg prezzo kenya
Augmentin duo tablet 500mg 125 mg forskolin
der Essay Help Mymoump

Read More…

Sitagliptin + Metformin In Type 2 Diabetes

<h1>Sitagliptin + Metformin In Type 2 Diabetes</h1>

Sitagliptin + Metformin In Type 2 Diabetes

by Cesar Kershaw on 19 minutes ago 2 views – ; Preclinical fashions have prompt a possible beneficial impact of finasteride on bladder most cancers development, however the findings are the primary from a big-scale trial to show a doable preventive or therapeutic role of finasteride for bladder most cancers, the authors stated. Sitagliptin, which is often known as Januvia gets processed within the liver with the CYP2C8 and CYP3A4 enzymes. If wanted, antacids may be taken along with this remedy. In other phrases, the way NSAIDS are metabolized makes liver toxicity (hepatotoxicity) very rare. You probably have excessive or extended gastrointestinal upsets while taking metformin, contact your physician as he may need to alter your medicine. It didn’t happen to me till at this time that meloxicam may be taking part in an element. Exercises are one thing very good, when you’re having low blood pressure. If your dog occurs to have liver problems, likelihood is your veterinarian will prescribe Prednisolone in your dog quite than Prednisone. What exactly is Prednisone? Food plan therapy is strictly per the general plan of treatment. You may also reach the Admin of the positioning on the Boards at username Admin fairly quickly. We is not going to be sure on what is actually proper and what is just not and to keep away from a big confusion, laws and regulations are made. Many people dream of going onto vacations and finding the perfect trip spots from around the globe. You can take one as simply as the opposite and expertise the identical results and benefits. If this is the case, weight reduction can happen somewhere between 1 and 5 weeks after beginning a regimen of metformin. Finasteride works on the hormones slightly than on the hair follicles; testosterone is turned into dihydrotestosterone by the enzyme 5-alpha reductase. Cytotechnologists are also beginning to be educated in the field of molecular diagnostics. In lots of Canine Lymphoma instances, Prednisone will be prescribed as half of a larger therapy protocol – for instance, as one element of the Madison Wisconsin Protocol. Finding some safe websites to look round and see what they have to supply could be type of window purchasing for the units. There are not any explicit unintended effects to drinking alcohol with amoxicillin, which is a penicillin primarily based antibiotic. Your doctor will fastidiously assess you before beginning treatment with excessive-dose ibuprofen to test if you have threat factors such as high blood strain, excessive blood cholesterol, diabetes, or in the event you smoke. Speak with your doctor or pharmacist about the most effective technique to take doxycycline. Jesse is a Market Research analyst at Questale. View charges for this code from 4 totally different constructed-in charge schedules and from these you have added using the Evaluate-A-Fee™ tool. Is there a option to restrict the side effects of albuterol, which I take to relieve asthma attacks? Lastly, some early analysis on Clomid discovered a attainable elevated most cancers danger in girls treated for more than six cycles. Estimated solubility values obtained by utilizing each semi-empiric fashions have been comparable but introduced notable deviations relating to experimental values presented within the literature, particularly for IBP. I do not think it has had any effect on my weight but my glucose values are a lot better. Neurontin side effects neurontin side seems strange or that is used with a dose regarding vapour. One of them was called Vioxx. On the other hand, certain supplements may be beneficial for anyone taking NSAIDS. Should you only have railings for them on one aspect, it is only a matter of time before many people fall. fransisco Medical Center recommends limiting yourself to 3, 000 milligrams of sodium every day to help keep your weight under control. Sulfonylureas together with thiazolidediones may cause weight gain. Chen-Pin Wang, PhD, University regarding Texas Health Science Center, San Antonio, US. A: You’re proper, albuterol is a “bronchodilator” used to start the muscles around the airways of people by using asthma. Malignant tumours comparatively rare cause of thyroid glandular and no undue dyspnoea from lack of pancreatic failure to an acute health problems. The information about side effects and additionally safety warnings is incomplete. This is to ensure that you could reap the medical benefits of propecia generic rather than the risks Normally, it requires multiple procedures over time to get the most effective outcomes. If clomiphene has not labored within this time-frame, infertility specialists will normally move to different therapies, such as stimulated (addition of FSH) IUI or IVF. Cytotechnologists are extremely skilled laboratory specialist who research human cells and different types of cellular anomalies. This progress, which is close to the typical throughout all occupations, may result in 22,seven hundred new positions over the decade. For individuals hoping to boost their immune programs, whether or not or not they’re taking prednisone, inexperienced tea could be the healthiest selection of the three traditional teas. Some people wish to brew their own beer with low taste and high alcoholic content. Nausea, vomiting and diarrhea will be troublesome for some people. We will found not solely different imported beverages; we can even discover other stuffs like steins, glassware, coasters etc. Overall demand for medical and clinical laboratory technologists is predicted to increase by 14 p. As a cytotechnologist, you’ll prepare and study physique cells for study underneath the microscope so as to detect abnormalities that could be important in the early analysis of most cancers and different diseases.

Read More…

Researchers Piecing Together Autoimmune Disease Puzzle

Researchers Piecing Together Autoimmune Disease Puzzle

Whether it’s through drinking too hard or driving too fast, or picking fights with fists or pistols, men as a rule are said to engage in more self-destructive behaviors than women. But why should women bother, when their bodies so often do the…

Read More…

Q&A/Janet M. Murphy; Illness That Can Make a Victim a Stranger

Q&A/Janet M. Murphy; Illness That Can Make a Victim a Stranger

IT is a pretty frightening experience, Janet M. Murphy said, to look in the mirror and not recognize yourself. Ms. Murphy, of Hastings-on-Hudson, has lupus, and there was a time years ago when she was on so much medication that her face bore no re…

Read More…

Merck Increases Focus on Advanced Prostate Cancer, Expanding Immuno-Oncology Program with Three New Phase 3 Trials

<h1>Merck Increases Focus on Advanced Prostate Cancer, Expanding Immuno-Oncology Program with Three New Phase 3 Trials</h1>

Merck Increases Focus on Advanced Prostate Cancer, Expanding Immuno-Oncology Program with Three New Phase 3 Trials

14/02/2019
Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the presentation of interim data from the Phase 1b/2 KEYNOTE-365 umbrella trial investigating KEYTRUDA, Mercks anti-PD-1 therapy, in combination with various agents for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). These early findings show anti-tumor activity across three cohorts of the study, which investigated KEYTRUDA in combination with LYNPARZA (Cohort A, Abstract #145); docetaxel and prednisone (Cohort B, Abstract #170); and enzalutamide (Cohort C, Abstract #171) “ with a safety profile consistent with each therapy alone. These results are being presented today at the 2019 Genitourinary Cancers Symposium (ASCO GU) in San Francisco. Based on the findings, Merck is initiating three new pivotal Phase 3 trials with KEYTRUDA in combination with LYNPARZA (KEYLYNK-010, NCT03834519), docetaxel and prednisone (KEYNOTE-921, NCT03834506) and enzalutamide (KEYNOTE-641, NCT03834493).
At the core of our research program is a commitment to investigate the potential of KEYTRUDA “ both as combination and monotherapy “ to serve as a foundational treatment, especially for cancers where additional therapies are needed, said Dr. Roy Baynes, senior vice president, head of global clinical development, and chief medical officer, Merck Research Laboratories. These promising data presented at ASCO GU coupled with the significant unmet medical need in patients with metastatic castration-resistant prostate cancer, propelled us to initiate three new Phase 3 trials to further evaluate these KEYTRUDA combination regimens.
Mercks existing clinical development program in metastatic prostate cancer includes studies evaluating KEYTRUDA and LYNPARZA as monotherapy and in combination with other anti-cancer therapies with various mechanisms of action. Ongoing trials include the Phase 2 KEYNOTE-199 trial for KEYTRUDA monotherapy and, in collaboration with AstraZeneca, the Phase 3 trials PROfound evaluating LYNPARZA monotherapy and PROPEL evaluating LYNPARZA in combination with abiraterone as a first-line therapy in patients with mCRPC. With the initiation of KEYLYNK-010, KEYNOTE-921 and KEYNOTE-641, Merck now has the largest clinical program with an anti-PD-1 therapy in prostate cancer and the only program to evaluate overall survival (OS) as a co-primary endpoint across three Phase 3 trials.
Data from KEYNOTE-365 Presented at ASCO GU WANT TO BUILD A FINANCIAL EMPIRE? Subscribe to the Global Banking & Finance Review Newsletter for FREE Get Access to Exclusive Reports to Save Time & Money By using this form you agree with the storage and handling of your data by this website. We Will Not Spam, Rent, or Sell Your Information. All emails include an unsubscribe link. You may opt-out at any time. See our privacy policy .
KEYNOTE-365 (NCT02861573) is an ongoing global, open-label, non-randomized, multi-cohort, multi-center, Phase 1b/2 study evaluating the safety and efficacy of KEYTRUDA (200 mg fixed dose every three weeks) in combination with LYNPARZA (Cohort A), docetaxel and prednisone (Cohort B) and enzalutamide (Cohort C) for the treatment of patients with mCRPC. The primary endpoints are safety, prostatic specific antigen (PSA) response rate (measured by confirmed decrease in PSA of 50% or greater) and overall response rate (ORR) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; secondary endpoints include disease control rate (DCR), radiographic progression-free survival (rPFS) and OS. The study is designed to enroll 400 patients across four cohorts, with outcome measures assessed individually for each cohort. Data at ASCO GU include interim efficacy and safety findings from three of the study cohorts (A, B and C).
Data and Safety from Cohort A (Abstract #145)
Cohort A is reported on 41 enrolled patients previously treated with docetaxel, and up to one other chemotherapy and up to two second-generation anti-hormone therapies. Patients in Cohort A received KEYTRUDA in combination with LYNPARZA (400 mg capsules orally twice daily).
The efficacy analysis from Cohort A presented at ASCO GU showed a PSA response rate of 12 percent in the total cohort population (n=5/41), 14 percent among patients with measurable disease (n=4/28) and 8 percent (n=1/13) among patients with non-measurable disease. The median time to PSA progression was 15.3 (95% CI, 9.3-27.1) and 18.1 (95% CI, 9.3-21.0) weeks for patients with measurable and non-measurable disease, respectively. Among patients with measurable disease, the ORR was 7 percent (95% CI, 1-23), with a partial response rate of 7 percent (n=2/28). The disease control rate (of 6 months or more) was 29 percent (95% CI, 16-45) in the total cohort population, 32 percent (95% CI, 16-52) among patients with measurable disease and 23 percent (95% CI, 5-54) among patients with non-measurable disease. In an analysis of rPFS and OS endpoints, the median rPFS was 4.7 months (95% CI, 4.0-7.7) and the six-month rPFS rate was 48 percent; the median OS was 13.5 months at the time of analysis (95% CI, 7.7-NR) and the six-month OS rate was 73 percent.
Analysis of the safety data showed that 49 percent of patients had a grade 3 or 4 treatment-related adverse event (TRAE), the most common (occurring in ‰¥10% of patients) of which was anemia (27%). Immune-mediated adverse events observed in this cohort were grade 1 or 2 and occurred in 49 percent of patients; the most commonly reported immune-mediated adverse event was hypothyroidism (5%). One patient died of a TRAE of unknown cause.
Data and Safety from Cohort B (Abstract #170)
Cohort B is reported on 72 enrolled patients previously treated with either abiraterone acetate or enzalutamide and who had not received chemotherapy. Patients in Cohort B received KEYTRUDA in combination with docetaxel (75 mg) plus prednisone (5 mg) orally twice daily.
The efficacy analysis from Cohort B presented at ASCO GU showed a PSA response rate of 31 percent in the total cohort population (n=22/72), 22 percent among patients with measurable disease (n=8/36) and 39 percent among patients with non-measurable disease (n=14/36). The median time to PSA progression was 24.1 (95% CI, 15.1-30) and 30.4 (95% CI, 15.0-36.3) weeks for patients with measurable and non-measurable disease, respectively. Among patients with measurable disease, the ORR was 14 percent (95% CI, 5-29), with a partial response rate of 14 percent (n=5/36). The disease control rate (of 6 months or more) was 57 percent (95% CI, 45-69) in the total cohort population, 50 percent (95% CI, 33-67) among patients with measurable disease and 64 percent (95% CI, 46-79) among patients with non-measurable disease. The median duration of response was 4.9 months (95% CI, 4.0-8.3+). In an analysis of rPFS and OS endpoints, the median rPFS was 8.3 months (95% CI, 7.5-10.2) and the six-month rPFS rate was 79 percent; the median OS had not been reached at the time of analysis (95% CI, 12.9-NR); the six-month OS rate was 96 percent.
Analysis of the safety data showed that 36 percent of patients had a grade 3-5 TRAE, the most common (occurring in ‰¥10% of patients) of which was febrile neutropenia (12%). Immune-mediated adverse events occurred in 33 percent of patients, the most common (occurring in ‰¥ 10% of patients) of which were infusion-related reactions (11%) and colitis (10%); two patients died due to TRAEs (pneumonitis).
Data and Safety from Cohort C (Abstract #171)
Cohort C is reported on 69 enrolled patients previously treated with abiraterone acetate and who had not received chemotherapy. Patients in Cohort C received KEYTRUDA in combination with enzalutamide (160 mg per day orally).
The efficacy analysis from Cohort C presented at ASCO GU showed a PSA response rate of 26 percent in the total population (n=18/69), 40 percent among patients with measurable disease (n=10/25), and 18 percent among patients with non-measurable disease (n=8/44). The median time to PSA progression was 18.4 (95% CI, 15.4-48.3) and 12.4 (95% CI, 12.0-15.1) weeks for patients with measurable and non-measurable disease, respectively. Among patients with measurable disease, the ORR was 20 percent (95% CI, 7-41), with a complete response of 8 percent (n=2/25) and partial response of 12 percent (n=3/25). The disease control rate (of 6 months or more) was 33 percent (95% CI, 22-46) in the total population, 32 percent (95% CI 15-53) among patients with measurable disease and 34 percent (95% CI, 20-50) among patients with non-measurable disease. The median duration of response was 8.3 months (range, 0.0+-13.0+) “ and at the time of analysis, 75 percent of patients had responses lasting for six months or longer. In an analysis of rPFS and OS endpoints, the median rPFS was 6.1 months (95% CI, 4.0-8.1); the six-month rPFS rate was 59 percent; the median OS had not been reached at the time of analysis (95% CI, 12.2-NR); the six-month OS rate was 91 percent.
Analysis of the safety data showed that 41 percent of patients had a grade 3 or 4 TRAE, the most common (occurring in ‰¥ 10% of patients) of which was rash (10%). Immune-mediated adverse events occurred in 41 percent of patients, the most common (occurring in ‰¥ 10% of patients) of which were severe skin reactions (20%) and hypothyroidism (13%). No patients died of TRAEs.
About Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Prostate cancer is typically driven by male sex hormones called androgens, including testosterone. Castration-resistant prostate cancer (CRPC) is characterized when the cancer continues to grow despite surgery or treatment to lower the amount of male sex hormones. When CRPC spreads to other parts of the body, it is referred to as metastatic castration-resistant prostate cancer or mCRPC. Prostate cancer is the second most common cancer in men, with an estimated 1.3 million new cases diagnosed worldwide in 2018. In the United States, an estimated 174,650 men will be diagnosed with prostate cancer in 2019 and one in nine men will be diagnosed in his lifetime. Approximately 10-20 percent of men with prostate cancer will develop CRPC within five years; within two years of a CRPC diagnosis, 33 percent of men will develop mCRPC.
About KEYTRUDA (pembrolizumab) Injection, 100mg
KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 900 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
KEYTRUDA (pembrolizumab) Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ‰¥50%] as determined by an FDA-approved test, with no EGFR or ALKgenomic tumor aberrations.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ‰¥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA, as appropriate.
Head and Neck Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.
In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ‰¥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Microsatellite Instability-High (MSI-H) Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.
In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Gastric Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ‰¥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Cervical Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ‰¥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. The recommended dose of KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Selected Important Safety Information for KEYTRUDA
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
Immune-Mediated Hepatitis
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.
Immune-Mediated Endocrinopathies
KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 15% (28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.
Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.
Immune-Mediated Skin Reactions
Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.
Other Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials and postmarketing use.
Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (1 fatal case) and 2 developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor“blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.
In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.
Increased Mortality in Patients With Multiple Myeloma
In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.
Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.
Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (‰¥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (‰¥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or nab-paclitaxel in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). The most common adverse reactions (‰¥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).
In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (‰¥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ‰¥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (‰¥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (‰¥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ‰¥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (‰¥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ‰¥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (‰¥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).
Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (‰¥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).
Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).
Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).
Lactation
Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.
Pediatric Use
There is limited experience in pediatric patients. In a trial, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with various cancers, including unapproved usages, were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1“17 doses), with 34 patients (85%) receiving 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at a higher rate (‰¥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%), and hyponatremia (18%).
About LYNPARZA (olaparib)
LYNPARZA is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. LYNPARZA is being tested in a range of tumor types with defects and dependencies in the DDR.
LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad and advanced clinical trial development program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.
IMPORTANT SAFETY INFORMATION
There are no contraindications for LYNPARZA.
WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from 2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.
Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (‰¤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.
If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.
Pneumonitis: Occurred in 25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).
DRUG INTERACTIONS
Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.
CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.
CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.
USE IN SPECIFIC POPULATIONS
Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.
Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.
Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).
Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min) but patients should be monitored closely for toxicity. In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ‰¤30 mL/min).
INDICATIONS
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:
First-Line Maintenance BRCAm Advanced Ovarian Cancer
For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients with gBRCAm advanced epithelial ovarian, fallopian tube or primary peritoneal cancer for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
Maintenance Recurrent Ovarian Cancer
For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.
Advanced gBRCAm ovarian cancer
For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
gBRCAm, HER2-negative metastatic breast cancer
In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
Please click here for complete Prescribing Information, including Patient Information (Medication Guide).
About the AstraZeneca and Merck Strategic Oncology Collaboration
In July 2017, AstraZeneca and Merck, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize LYNPARZA, the worlds first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop LYNPARZA and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop LYNPARZA and selumetinib in combination with their respective PD-L1 and PD-1 medicines.
Mercks Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials .
About Merck
For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the worlds most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimers disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter , Facebook , Instagram , YouTube and LinkedIn .
Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the company) includes forward-looking statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the companys management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.
Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the companys ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the companys patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.
The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the companys 2017 Annual Report on Form 10-K and the companys other filings with the Securities and Exchange Commission (SEC) available at the SECs Internet site ( www.sec.gov ).
Please see Prescribing Information for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and
Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf .
Media Contacts :

Read More…

Salute Ja Warriors In the course of Juvenile Arthritis Awareness Month

Salute Ja Warriors In the course of Juvenile Arthritis Awareness Month

by Jayme Willmott The results counsel that long run physical activity treatments for people with osteoarthritis really should focus on patients’ self esteem as part of their capability to become active, reported Zhao yang. Rheumatologists can enable patients manage their constant arthritis symptoms, though chiropractic professionals can assist patients improve their physical condition or slow the progression of arthritis. Obesity – Within a in excess ofexcess fat man or woman, the weight displaying joints drop control and are generally not in a position to bear the complete-human body weight any longer which causes Osteoarthritis.
Sphingolipids – prolonged-sequence fatty acidity substances found in cell membranes – are broken decrease by sphingomyelinase digestive support enzymes into bioactive products these kinds of as ceramide. Health changes like feasting on much more citrus fruit fresh fruits, grapes, milk products, whole cereals source the human body with needed vitamins and nutrients which assistance in combating arthritis. Working with Maccabi’s large automated datasets, the researchers then assessed diagnostic requirements to evaluate the likelihood of freshly diagnosed rheumatoid arthritis during this group in between and.
We have built a vaccine-fashion treatment or ‘immunotherapy’ tailored for folks offering superior-possibility rheumatoid arthritis genes and specific rheumatoid arthritis antibodies, called contra –CCP. African american participants described larger total knee osteoarthritis pain and those people with lower nutritional D concentrations shown greater level of sensitivity to heat or cold for arthritis (visit my web site) and mechanised pain experimental pain. Solution supplements are geared up from by submerging absolute all-natural metallic dust in water, will not consist of any chemical compounds and they are ready as a result of low-chemical type process.
Scientists studied the associations among the complete hold off to physician assessment, achievement of DMARD-free-remission, and then the charge of joint damage over a six-12 months stick to-up period of time. Typically, an alternative patient with rheumatoid arthritis is promptly started on MTX in combination with possibly very low quantity prednisone or maybe a low-steroidal anti-inflammatory substance NSAID. Osteochondritis dissecans, osteonecrosis, aseptic necrosis, mechanical joint derangement, infection, chronic inflammatory diseases this sort of as rheumatoid arthritis, systemic lupus erythematosus, and gout are doable diagnoses.
Eliminating stress, improving immune system, increasing joint mobility, maximizing toxin removal and suppressing despair are also showcasing benefits of possessing physique rubbing applying herbal fats. Orthopedics and arthritis professionals notably always like to dub osteoarthritis for the reason that have on and tear arthritis as affected joints have a tendency to degenerate as a result of continual use. All inflammatory arthritic conditions may possibly benefit from interdisciplinary strategies in which prescription drug, homeopathic, organic, and osteopathic interventions are made use of at the same time.

Read More…