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Successful treatment of chronic hepatitis C virus infection with crushed glecaprevir/pibrentasvir administered via a percutaneous endoscopic gastrostomy tube: case report and review of the literature.
Tanaka, Y, Tateishi, R, Koike, K
Clinical journal of gastroenterology. 2019;(6):588-591
Abstract
Glecaprevir (GLE)/pibrentasvir (PIB) is a direct-acting antiviral regimen approved for patients infected with hepatitis C virus. No data are available on the safety and efficacy of this regimen when crushed and administered through a percutaneous endoscopic gastrostomy (PEG) tube. Here, we report a patient who successfully achieved a sustained viral response after treatment with GLE/PIB administered via a PEG tube. A 41-year-old female with chronic hepatitis C viral infection was referred to our department for treatment. She had a history of spina bifida and hydrocephalus, and she received a PEG tube for nutrition and medication due to an aftereffect of hydrocephalus. She received crushed GLE/PIB treatment through a PEG tube for 8 weeks and achieved a sustained viral response 12, without any treatment-related severe adverse events. This is the first documented case treated with GLE/PIB administered through a PEG tube. Based on this case report and a review of the literature, we discuss the safety and efficacy of direct-acting antiviral treatment via a PEG tube.
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Tenapanor: First Approval.
Markham, A
Drugs. 2019;(17):1897-1903
Abstract
The selective sodium hydrogen exchanger 3 (NHE3) inhibitor tenapanor is being developed by Ardelyx Inc. for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) [under the tradename IBSRELA®] and for hyperphosphataemia in patients with chronic kidney disease (CKD) on dialysis or with end stage renal disease (ESRD). Based on positive results from the phase III T3MPO trial program, tenapanor was recently approved in the USA for the treatment of IBS-C in adults. This article summarises the milestones in the development of tenapanor leading to this first approval.
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Can we selectively target AML stem cells?
Jordan, CT
Best practice & research. Clinical haematology. 2019;(4):101100
Abstract
De novo acute myeloid leukemia (AML) leukemia stem cell (LSC) populations are uniquely dependent on amino acid metabolism to drive the TCA cycle and oxidative phosphorylation. Oxidative phosphorylation can be selectively downregulated in de novo AML LSC populations by perturbing amino acid metabolism via BCL2 inhibition with venetoclax. While venetoclax-based therapies have shown high response rates, not all patients achieve remission. It may be possible to prospectively identify the patients who will most likely respond to venetoclax-based treatment by analyzing the metabolic properties of individual patients. Specifically, it appears that patients who are likely to be resistant to venetoclax-based therapy are able to employ alternate metabolic pathways to drive oxidative phosphorylation.
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[What is recommended in the treatment of acute myeloid leukemia?].
Thol, F
Der Internist. 2019;(12):1240-1250
Abstract
Acute myeloid leukemia (AML) is characterized by a malignant transformation and proliferation of myeloid progenitor cells that cause a replacement of normal hematopoiesis. Diagnostic workup for AML includes cytogenetic analysis and mutational screening covering frequently mutated genes in AML. The genetic analysis is required for risk stratification and treatment decisions. Very recently, three novel drugs have been approved for patients who can be intensively treated: a tyrosine kinase inhibitor (midostaurin) for patients with FLT3 mutations, a liposomal formulation of chemotherapy (CPX) for patients with features of secondary AML, and a CD33 antibody-drug conjugate (gemtuzumab-ozogamicin) for AML with CD33 expression. Allogeneic stem cell transplantation remains an important treatment strategy for patients with intermediate- or high-risk AML and for patients with relapsed AML. For elderly patients who cannot undergo intensive treatment, demethylating agents are the treatment of choice. The aim is to prolong life expectancy with acceptable quality of life. In recent clinical trials, novel drugs have shown promising results in this patient population. Some of these drugs have already been approved in the US. Among these drugs are the Bcl‑2 inhibitor venetoclax, which is already approved in Germany for chronic lymphatic leukemia, as well as IDH1/IDH2 inhibitors (the latter for patients with IDH1/IDH2 mutated AML). Acute promyelocytic leukemia represents a special type of AML that should be treated with a combination of all-trans retinoic acid and arsenic trioxide leading to excellent outcome.
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Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies.
Taylor, PC, Kremer, JM, Emery, P, Zuckerman, SH, Ruotolo, G, Zhong, J, Chen, L, Witt, S, Saifan, C, Kurzawa, M, et al
Annals of the rheumatic diseases. 2018;(7):988-995
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Abstract
OBJECTIVES Lipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs. METHODS Lipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study. RESULTS Treatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated. CONCLUSIONS Baricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications. TRIAL REGISTRATION NUMBER NCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.
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Understanding the Role and Mechanism of Carbonic Anhydrase V in Obesity and its Therapeutic Implications.
Queen, A, Khan, P, Azam, A, Hassan, MI
Current protein & peptide science. 2018;(9):909-923
Abstract
Obesity is a metabolic syndrome leading to several health problems such as hypertension, heart attack, type II diabetes, and even cancer. Carbonic anhydrase VA (CAVA) is a mitochondrial enzyme which is directly associated with the glucose homeostasis and considered as a promising target for obesity and other associated diseases in humans. So far, numerous inhibitors have been designed to inhibit the catalytic activity of CAVA with an assumption for its possible therapeutic uses against type II diabetes and other metabolic diseases. Among these, sulphonamide inhibitors and various non-classical inhibitors are extensively used. The focus of this review is to understand the mechanism and role CAVA in glucose homeostasis to ascertain as a potential drug target of obesity. We have further highlighted different types of inhibitors and their mode of binding and possible consequences with an aim to investigate possible therapeutic used for the treatment of obesity and associated diseases. Along with classical inhibitors, various non-classical inhibitors have proved to be potential inhibitors of CAV which may be employed to combat obesity. Certain phytochemicals are utilized as therapeutic molecules to fight obesity. These phytochemicals have been discussed in detail here.
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Vonoprazan: A Novel and Potent Alternative in the Treatment of Acid-Related Diseases.
Yang, X, Li, Y, Sun, Y, Zhang, M, Guo, C, Mirza, IA, Li, YQ
Digestive diseases and sciences. 2018;(2):302-311
Abstract
Although proton pump inhibitors (PPIs) have been used widely, acid-related diseases are still associated with a huge burden on the health care system. Recently, the efficacy and safety of a new acid suppressant named vonoprazan in the treatment of acid-related diseases have been evaluated by a series of studies. As a novel potassium-competitive acid blocker, vonoprazan may provide reversible acid suppression by preventing K+ from binding to gastric H+/K+-ATPase. It has been clinically used for the short-term treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease and Helicobacter pylori (H. pylori) infection in Japan. The healing rate of GERD and gastric ulcers by vonoprazan is more than 95 and 90%, respectively; also, it is effective in curing PPI-resistant GERD. It increases H. pylori eradication rate to more than 88% as part of both first-line and second-line therapy. It is also effective in the eradication of clarithromycin-resistant H. pylori strains. All of these short-term studies show vonoprazan is safe and well-tolerated. As a safe and effective acid inhibitor, vonoprazan might be a novel alternative in the treatment of acid-related diseases.
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Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
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Brumbaugh Paradis, H, Alter, D, Llerandi, D
Clinical journal of oncology nursing. 2017;(5):604-610
Abstract
BACKGROUND Venetoclax (Venclexta™) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
. OBJECTIVES The aim was to describe treatment management considerations when caring for patients using venetoclax.
. METHODS A review was done of safety and management considerations based on current clinical practice and 240 patients with CLL who received venetoclax monotherapy on clinical trials from 2011-2016.
. FINDINGS Common adverse events were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Because of rapid tumor reduction with venetoclax, nurses should be aware of the potential for tumor lysis syndrome (TLS) and the need to educate patients on steps to minimize risks, including gradual dose ramp-up, adequate hydration, and use of prophylactic antihyperuricemia agents. Following implementation of these risk-reducing measures, no clinical TLS events were reported in ongoing trials.
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A review of toxic epidermal necrolysis management in Japan.
Kinoshita, Y, Saeki, H
Allergology international : official journal of the Japanese Society of Allergology. 2017;(1):36-41
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Abstract
Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction characterized by necrosis of the epidermis. Its incidence is approximately 1 per million a year and average mortality rate is high at 25-50%. TEN has a flu-like prodrome, followed by atypical, targetoid erythematous or purpuric macules on the skin. These macules coalesce to form flaccid blisters that slough off as areas of epidermal necrosis. Drugs such as allopurinol, sulfonamides, and carbamazepine are the most common causes. The human leukocyte antigen (HLA)-B*15:02 in Asians being administered carbamazepine and the HLA-B*58:01 antigen in patients of all ethnicities being administered allopurinol are known to be high-risk factors. Rapid diagnosis, discontinuation of the causative drug, and supportive treatment are essential for better prognosis and improvement of sequelae. Till now, systemic corticosteroids and intravenous immunoglobulins have been used as the most common active interventions; however, no gold standard has been established. In Japan, physicians follow a unique diagnostic criteria and treatment guideline to improve the diagnosis rate and streamline treatments. This may be a contributing factor for the lower mortality rate (14.3%). The efficacy of systemic corticosteroids, immunoglobulins, and plasmapheresis may have been beneficial as well. In Japan, TEN is defined as an epidermal detachment of over 10% of the body surface area (BSA), while the globally accepted definition established by Bastuji-Garin describes it as an epidermal detachment of over 30% of the BSA. In Japanese individuals, HLA-A*02:06, HLA-A*02:07, HLA-A*31:01 and HLA-B*51:01 may be linked to higher risks of TEN.
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Treatment Strategy for Standard-Dose Proton Pump Inhibitor-Resistant Reflux Esophagitis.
Iwakiri, K
Journal of Nippon Medical School = Nippon Ika Daigaku zasshi. 2017;(5):209-214
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Abstract
Reflux esophagitis is characterized by excessive esophageal acid exposure. To treat reflux esophagitis, it is necessary to reduce excessive esophageal acid exposure to within the normal range. The first-line drug for the treatment of reflux esophagitis is a standard-dose proton-pump inhibitor (PPI), which is also recommended by the Evidence-based Clinical Practice Guidelines 2015 for gastroesophageal disease of the Japanese Society of Gastroenterology. It has been reported that the response to a standard dose of PPI in patients with mild reflux esophagitis is 90-100%, and that in patients with severe reflux esophagitis is 80-85%. However, PPI-resistant reflux esophagitis has been increasing. When the standard dose of PPI is not effective, modification of the lifestyle with PPI therapy, switching to another PPI, or a change in the administration method (before meals), as well as double-dose PPI (in divided doses), may be effective. In addition, vonoprazan (potassium-competitive acid blocker), which has rapid and potent acid-suppressive effects, became available in February 2015 in Japan. In the clinical trial data, vonoprazan is very effective for reflux esophagitis. However, clinical data on vonoprazan are still insufficient. The establishment of a new treatment for reflux esophagitis taking advantage of the rapid and potent acid-suppressive effects is awaited.