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Cellular and Molecular Life Sciences :... Sep 2019Emergence of novel treatment modalities provides effective therapeutic options, apart from conventional cytotoxic chemotherapy, to fight against colorectal cancer.... (Review)
Review
Emergence of novel treatment modalities provides effective therapeutic options, apart from conventional cytotoxic chemotherapy, to fight against colorectal cancer. Unfortunately, drug resistance remains a huge challenge in clinics, leading to invariable occurrence of disease progression after treatment initiation. While novel drug development is unfavorable in terms of time frame and costs, drug repurposing is one of the promising strategies to combat resistance. This approach refers to the application of clinically available drugs to treat a different disease. With the well-established safety profile and optimal dosing of these approved drugs, their combination with current cancer therapy is suggested to provide an economical, safe and efficacious approach to overcome drug resistance and prolong patient survival. Here, we review both preclinical and clinical efficacy, as well as cellular mechanisms, of some extensively studied repurposed drugs, including non-steroidal anti-inflammatory drugs, statins, metformin, chloroquine, disulfiram, niclosamide, zoledronic acid and angiotensin receptor blockers. The three major treatment modalities in the management of colorectal cancer, namely classical cytotoxic chemotherapy, molecular targeted therapy and immunotherapy, are covered in this review.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Colorectal Neoplasms; Drug Repositioning; Drug Resistance, Neoplasm; Humans; Protein Kinase Inhibitors; Topoisomerase I Inhibitors
PubMed: 31087119
DOI: 10.1007/s00018-019-03134-0 -
International Ophthalmology Clinics 2015The treatment of noninfectious uveitis continues to remain a challenge for many ophthalmologists. Historically, clinical trials in uveitis have been sparse, and thus,... (Review)
Review
The treatment of noninfectious uveitis continues to remain a challenge for many ophthalmologists. Historically, clinical trials in uveitis have been sparse, and thus, most treatment decisions have largely been based on clinical experience and consensus guidelines. The current treatment paradigm favors initiation then tapering of corticosteroids with addition of steroid-sparing immunosuppressive agents for persistence or recurrence of disease. Unfortunately, in spite of a multitude of highly unfavorable systemic effects, corticosteroids are still regarded as the mainstay of treatment for many patients with chronic and refractory noninfectious uveitis. However, with the success of other conventional and biologic immunomodulatory agents in treating systemic inflammatory and autoimmune conditions, interest in targeted treatment strategies for uveitis has been renewed. Multiple clinical trials on steroid-sparing immunosuppressive agents, biologic agents, intraocular corticosteroid implants, and topical ophthalmic solutions have already been completed, and many more are ongoing. This review discusses the results and implications of these clinical trials investigating both alternative and novel treatment options for noninfectious uveitis.
Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antimetabolites; Biological Factors; Clinical Trials as Topic; Humans; Immunosuppressive Agents; Steroids; Uveitis
PubMed: 26035763
DOI: 10.1097/IIO.0000000000000070 -
Biochemical Pharmacology Dec 2023
Review
Topics: Humans; Fluorouracil; Neoplasms; Antimetabolites, Antineoplastic; Drug Resistance, Neoplasm; Cell Line, Tumor
PubMed: 37922975
DOI: 10.1016/j.bcp.2023.115902 -
Cancer Chemotherapy and Pharmacology Jul 2016Gemcitabine is an antimetabolite ranking among the most prescribed anticancer drugs worldwide. This nucleoside analog exerts its antiproliferative action after tumoral... (Review)
Review
Gemcitabine is an antimetabolite ranking among the most prescribed anticancer drugs worldwide. This nucleoside analog exerts its antiproliferative action after tumoral conversion into active triphosphorylated nucleotides interfering with DNA synthesis and targeting ribonucleotide reductase. Gemcitabine is a mainstay for treating pancreatic and lung cancers, alone or in combination with several cytotoxic drugs (nab-paclitaxel, cisplatin and oxaliplatin), and is an option in a variety of other solid or hematological cancers. Several determinants of response have been identified with gemcitabine, i.e., membrane transporters, activating and inactivating enzymes at the tumor level, or Hedgehog signaling pathway. More recent studies have investigated how germinal genetic polymorphisms affecting cytidine deaminase, the enzyme responsible for the liver disposition of gemcitabine, could act as well as a marker for clinical outcome (i.e., toxicity, efficacy) at the bedside. Besides, constant efforts have been made to develop alternative chemical derivatives or encapsulated forms of gemcitabine, as an attempt to improve its metabolism and pharmacokinetics profile. Overall, gemcitabine is a drug paradigmatic for constant searches of the scientific community to improve its administration through the development of personalized medicine in oncology.
Topics: Adult; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Deoxycytidine; Humans; Neoplasms; Pharmacogenetics; Polymorphism, Genetic; Precision Medicine; Gemcitabine
PubMed: 27007129
DOI: 10.1007/s00280-016-3003-0 -
Medwave Jan 2018Trabeculectomy is considered the standard for glaucoma surgery. Postoperative scarring is one the factors associated with surgery failure. Different antimetabolites have... (Comparative Study)
Comparative Study Review
INTRODUCTION
Trabeculectomy is considered the standard for glaucoma surgery. Postoperative scarring is one the factors associated with surgery failure. Different antimetabolites have been used in order to reduce this risk, particularly 5-fluorouracil and mitomycin C. Although both are considered effective, it is not clear if they are different in terms of success of trabeculectomy and adverse effects.
METHODS
To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.
RESULTS AND CONCLUSIONS
We identified four systematic reviews including 17 studies overall, of which 12 were randomized trials. We concluded mitomycin C might be more effective in reducing intraocular pressure and increasing qualified success compared to 5-fluorouracil. However, its use might be associated to a higher risk of complications.
Topics: Antimetabolites; Cicatrix; Fluorouracil; Glaucoma; Humans; Intraocular Pressure; Mitomycin; Randomized Controlled Trials as Topic; Trabeculectomy
PubMed: 29351270
DOI: 10.5867/medwave.2018.01.7138 -
American Journal of Cardiovascular... Mar 2022Increased levels of low-density lipoprotein cholesterol (LDL-C) are recognized as a primary risk factor for atherosclerotic cardiovascular disease, which remains the... (Review)
Review
Increased levels of low-density lipoprotein cholesterol (LDL-C) are recognized as a primary risk factor for atherosclerotic cardiovascular disease, which remains the leading cause of death worldwide. Lowering LDL-C levels clearly reduces the risk of cardiovascular events, with benefits related to both absolute reduction and duration of treatment; however, a threshold below which low LDL-C levels can be dangerous has never been established. Since the discovery of statins, cardiovascular research has focused on developing new lipid-lowering agents. Ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors have been found to further reduce LDL-C values and subsequent cardiovascular risk. Novel recently approved inclisiran and bempedoic acid, currently being tested in cardiovascular outcomes studies, are further expanding our pharmacological armamentarium, enabling the clinician to diminish residual risk related to LDL-C. Moreover, new agents are paving the way to successful treatment of homozygous familial hypercholesterolemia. This review summarizes the main characteristics of current and emerging lipid-lowering therapies to assist with comprehensive evidence-based decision making.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Proprotein Convertase 9
PubMed: 34514551
DOI: 10.1007/s40256-021-00497-3 -
Current Cardiology Reports May 2018This review aims to explore and summarize the current literature on the cardiovascular disease (CVD) healthcare burden and determine the cost-effectiveness of the PCSK9... (Review)
Review
PURPOSE OF REVIEW
This review aims to explore and summarize the current literature on the cardiovascular disease (CVD) healthcare burden and determine the cost-effectiveness of the PCSK9 inhibitors.
RECENT FINDINGS
The CVD remain the largest cause of mortality in the USA presenting substantial healthcare cost burden reaching $555 billion in 2016 and projected to rise to $1.1 trillion by 2035. The PCSK9 inhibitors have shown strong efficacy in LDLC lowering, but its price of ~ 14,000-14,600 per patient per year coupled with ~ 2.2-2.8 years of cardiovascular outcome data has created many controversies surrounding its cost-effectiveness. To determine the cost-effectiveness of the PCSK9 inhibitors, various simulation models and risk-based stratification and case-by-case patient approachs have yielded divisive data which need to be reassessed as per the ODYSSEY and long-term CVD outcomes. Further studies are warranted to evaluate the long-term CVD event rates of patients on the PCSK9 inhibitors to determine its true cost-effectiveness.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Drug Costs; Health Care Costs; Humans; PCSK9 Inhibitors; Risk Factors
PubMed: 29779055
DOI: 10.1007/s11886-018-0993-8 -
Journal of Glaucoma Sep 2021Trabeculectomy can effectively lower intraocular pressure (IOP). A more junior surgeon profile is emerging. Mitomycin C (MMC) has replaced 5-fluorouracil (5-FU)...
PRECIS
Trabeculectomy can effectively lower intraocular pressure (IOP). A more junior surgeon profile is emerging. Mitomycin C (MMC) has replaced 5-fluorouracil (5-FU) intraoperatively with comparable success rates and a decrease in postoperative antimetabolite administration.
PURPOSE
We compare 2-year outcomes for primary trabeculectomy in 2 cohorts, 10 years apart, performed at a large UK teaching hospital.
METHODS
Consecutive case series of trabeculectomies at Manchester Royal Eye Hospital between 2004-2005 (Cohort 1/C1) and 2014-2015 (Cohort 2/C2). Preoperative and postoperative data was collected for IOP outcomes and complications. Success was defined as IOP ≥6 and ≤21, ≤18, ≤16, ≤14, or ≤12 mm Hg with/without a ≥20% decrease from preoperative IOP. The need for and absence of postoperative antihypertensive medication defined qualified and complete success, respectively.
RESULTS
A total of 186 cases were analyzed [52 (C1), 134 (C2)]. Mean preoperative IOP was 24±10 mm Hg (C1) and 21±7 mm Hg (C2) (P=0.01). Overall, 34 (79%), 33 (77%), 33 (77%), 29 (67%), and 25 (58%) patients in C1 and 88 (70%), 82 (65%), 73 (58%), 64 (51%), and 40 (32%) patients in C2 achieved complete success for IOP ≤21 mm Hg (P=0.33), ≤18 mm Hg (P=0.22), ≤16 mm Hg (P=0.04), ≤14 mm Hg (P=0.09), or ≤12 mm Hg (P=0.004). Similarly, 43 (93%), 40 (87%), 40 (87%), 35 (76%), and 27 (59%) in C1 and 123 (98%), 116 (92%), 106 (84%), 87 (69%), and 58 (49%) in C2 achieved qualified success (P=0.34, 0.37, 0.83, 0.48, and 0.19). In all, 32 (74%), 31 (72%),31 (72%), 28 (65%), and 24 (56%) in C1 and 64 (51%), 63 (50%), 61 (48%), 54 (43%), and 39 (31%) in C2 achieved complete success with ≥20% reduction from preoperative IOP and IOP of ≤21 mm Hg (P=0.01), ≤18 mm Hg (P=0.02), ≤16 mm Hg (P=0.01), ≤1 mm Hg (P=0.02), or ≤12 mm Hg (P=0.006). By same definition, 37 (80%), 36 (78%), 36 (78%), 33 (72%), and 26 (57%) in C1 and 94 (75%), 93 (74%), 90 (71%), 75 (60%), and 58 (46%) in C2 achieved qualified success (P=0.55, 0.69, 0.48, 0.20, and 0.30). Mean IOP at 2 years was 13±5 mm Hg (C1) and 13±4 mm Hg (C2) (P=0.35). Overall, 62% had intraoperative 5-FU in C1; only MMC was used in C2 (P<0.0001). Postoperative 5-FU was administered in 54% versus 22% in C1 and C2, respectively (P<0.0001). Needling rates were not statistically different [42% (C1), 54% (C2)] (P=0.22).
CONCLUSIONS
Trabeculectomy is effective in lowering IOP with success comparable across various definitions. MMC replaced 5-FU as intraoperative antimetabolite resulting in reduced need for postoperative antimetabolite but not increased complications.
Topics: Antimetabolites; Follow-Up Studies; Humans; Intraocular Pressure; Mitomycin; Retrospective Studies; Trabeculectomy; Treatment Outcome
PubMed: 34049346
DOI: 10.1097/IJG.0000000000001887 -
Journal of Medicinal Chemistry Apr 2018Carbon monoxide (CO) is attracting increasing attention because of its role as a gasotransmitter with cytoprotective and homeostatic properties. Carbon monoxide... (Review)
Review
Carbon monoxide (CO) is attracting increasing attention because of its role as a gasotransmitter with cytoprotective and homeostatic properties. Carbon monoxide releasing molecules (CORMs) are spatially and temporally controlled CO releasers that exhibit superior and more effective pharmaceutical traits than gaseous CO because of their chemistry and structure. Experimental and preclinical research in animal models has shown the therapeutic potential of inhaled CO and CORMs, and the biological effects of CO and CORMs have also been observed in preclinical trials via the genetic modulation of heme oxygenase-1 (HO-1). In this review, we describe the pharmaceutical use of CO and CORMs, methods of detecting CO release, and developments in CORM design and synthesis. Many valuable clinical CORMs formulated using macromolecules and nanomaterials are also described.
Topics: Animals; Antimetabolites; Carbon Monoxide; Coordination Complexes; Delayed-Action Preparations; Heme Oxygenase-1; Humans
PubMed: 28876065
DOI: 10.1021/acs.jmedchem.6b01153 -
Current Atherosclerosis Reports Oct 2021For many years, the lipid-lowering armamentarium consisted of statins and/or ezetimibe and/or bile acid sequestrants and/or fibrates. Now, with the availability of new... (Review)
Review
PURPOSE OF REVIEW
For many years, the lipid-lowering armamentarium consisted of statins and/or ezetimibe and/or bile acid sequestrants and/or fibrates. Now, with the availability of new drugs mostly injectables, the field has changed and the role of oral non-statin drugs (including bempedoic acid) must be reevaluated.
RECENT FINDINGS
Ezetimibe remains a very important combination partner for statins with continuously increasing treatment numbers. Bempedoic acid is another interesting combination partner for statin/ezetimibe or ezetimibe alone but lacks in contrast to ezetimibe evidence from outcome trials. The role of fibrates is less clear as they have shown disappointing results in outcome trials but may still be used in selected, high-risk patients with combined dyslipidemia. Bile acid sequestrants are now rarely used as there are stronger, better tolerable ways to lower LDL-cholesterol. With the introduction of new injectable lipid-lowering drugs, some oral drugs such as ezetimibe and bempedoic acid still have an important spot in our treatment algorithm others such as fibrates have a less clear role while again others are now rarely used.
Topics: Anticholesteremic Agents; Cholesterol, LDL; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids
PubMed: 34648074
DOI: 10.1007/s11883-021-00971-y