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Cellular and Molecular Life Sciences :... Mar 2009The anti-metabolite 5-fluorouracil (5-FU) is employed clinically to manage solid tumors including colorectal and breast cancer. Intracellular metabolites of 5-FU can... (Review)
Review
The anti-metabolite 5-fluorouracil (5-FU) is employed clinically to manage solid tumors including colorectal and breast cancer. Intracellular metabolites of 5-FU can exert cytotoxic effects via inhibition of thymidylate synthetase, or through incorporation into RNA and DNA, events that ultimately activate apoptosis. In this review, we cover the current data implicating DNA repair processes in cellular responsiveness to 5-FU treatment. Evidence points to roles for base excision repair (BER) and mismatch repair (MMR). However, mechanistic details remain unexplained, and other pathways have not been exhaustively interrogated. Homologous recombination is of particular interest, because it resolves unrepaired DNA intermediates not properly dealt with by BER or MMR. Furthermore, crosstalk among DNA repair pathways and S-phase checkpoint signaling has not been examined. Ongoing efforts aim to design approaches and reagents that (i) approximate repair capacity and (ii) mediate strategic regulation of DNA repair in order to improve the efficacy of current anticancer treatments.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Cycle; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA Repair Enzymes; Fluorouracil; Humans; Molecular Structure; Signal Transduction
PubMed: 18979208
DOI: 10.1007/s00018-008-8557-5 -
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 -
Revista Brasileira de Psiquiatria (Sao... Oct 2008Panic disorder is a chronic and recurrent condition that impairs an individual's psychosocial functioning and quality of life. Despite the efficacy of... (Review)
Review
OBJECTIVE
Panic disorder is a chronic and recurrent condition that impairs an individual's psychosocial functioning and quality of life. Despite the efficacy of psychopharmacological treatment in reducing panic attacks, many patients fail to respond adequately to these interventions. Cognitive behavioral therapy provides an alternative and efficacious method for treating panic disorder and agoraphobic avoidance. The objective of the study is to describe the use of cognitive behavioral therapy for panic disorder.
METHOD
Narrative review of data collected from Medline, SciELO and PsycInfo and specialized textbooks.
RESULTS
We describe the cognitive-behavioral model for the treatment of panic disorder, and review both short and long-term efficacy findings. We also discuss the role of combined treatment (cognitive behavioral therapy and psychopharmacology).
CONCLUSIONS
Cognitive behavioral therapy, either individual or in group, can be used as first-line therapy for panic disorder. This treatment modality can also be indicated as a next step for patients failing to respond to other treatments.
Topics: Agoraphobia; Antimetabolites; Cognitive Behavioral Therapy; Cycloserine; Humans; Panic Disorder; Recurrence; Treatment Outcome
PubMed: 19039448
DOI: 10.1590/s1516-44462008000600005 -
Therapeutic Drug Monitoring Dec 2017The use of thiopurines in the treatment of inflammatory bowel disease (IBD) can be optimized by the application of therapeutic drug monitoring. In this procedure,... (Review)
Review
The use of thiopurines in the treatment of inflammatory bowel disease (IBD) can be optimized by the application of therapeutic drug monitoring. In this procedure, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) metabolites are monitored and related to therapeutic response and adverse events, respectively. Therapeutic drug monitoring of thiopurines, however, is hampered by several analytical limitations resulting in an impaired translation of metabolite levels to clinical outcome in IBD. Thiopurine metabolism is cell specific and requires nucleated cells and particular enzymes for 6-TGN formation. In the current therapeutic drug monitoring, metabolite levels are assessed in erythrocytes, whereas leukocytes are considered the main target cells of these drugs. Furthermore, currently used methods do not distinguish between active nucleotides and their unwanted residual products. Last, there is a lack of a standardized laboratorial procedure for metabolite assessment regarding the substantial instability of erythrocyte 6-TGN. To improve thiopurine therapy in patients with IBD, it is necessary to understand these limitations and recognize the general misconceptions in this procedure.
Topics: Antimetabolites; Azathioprine; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine
PubMed: 29040228
DOI: 10.1097/FTD.0000000000000455 -
Oncology (Williston Park, N.Y.) Oct 1998The cycle-specific schedule-dependent antimetabolite 5-fluorouracil (5-FU) has been in clinical use for 40 years and has evolved as an important agent in the treatment... (Review)
Review
The cycle-specific schedule-dependent antimetabolite 5-fluorouracil (5-FU) has been in clinical use for 40 years and has evolved as an important agent in the treatment of a large spectrum of tumors, including all gastrointestinal cancers, breast cancer, head and neck cancer, and bladder cancer. Over these 4 decades, there has been an increased understanding of the optimal method and schedule of administration of 5-FU. Furthermore, the concept of pharmacomodulation and biochemical modulation of 5-FU to increase therapeutic efficacy has emerged as a new strategy in cancer chemotherapy. The specific mechanism by which 5-FU induces lethal injury may vary depending on the administration schedule or the type of biochemical modulation applied. The optimal infusion duration and dose intensity of 5-FU continues to be debated as does the question of the need for biochemical modulation when using infusional schedules. Infusional administration of 5-FU has become the gold standard in the treatment of head and neck cancer, esophageal cancer, gastric cancer (in Great Britain), and rectal and anal cancer. The recent availability of oral formulations for 5-FU in conjunction with the capability of manipulating the metabolism of 5-FU, particularly with dihydropyrimidine dehydrogenase (DPD) inhibitors, may provide a substantial incremental improvement in these therapies by eliminating the need for parenteral administration and the use of ambulatory infusion pumps.
Topics: Administration, Oral; Antimetabolites, Antineoplastic; Clinical Trials, Phase III as Topic; Fluorouracil; History, 20th Century; Humans; Infusions, Intravenous; Injections, Intravenous
PubMed: 9830620
DOI: No ID Found -
Kardiologia Polska 2022Atherosclerotic disease remains the leading cause of death worldwide. Much of atherosclerotic disease initiation and progression is driven by dyslipidemia. With the... (Review)
Review
Atherosclerotic disease remains the leading cause of death worldwide. Much of atherosclerotic disease initiation and progression is driven by dyslipidemia. With the advent of statins, ezetimibe, and more recently the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, physicians across all specialties have access to an armamentarium to address this major pathophysiological driver. Nevertheless, there is still a large unmet need in terms of optimizing pharmacotherapeutic lipid lowering strategies. This article will review the evidence pertaining to the major lipid-lowering agents that have been introduced lately, or still are under development, after the advent of statins, ezetimibe and PCSK9 inhibitors. There is cumulating evidence suggesting that there soon will be a broad specter of differential therapies across a variety of mechanistic pathways that will enter clinical medicine. Knowledge about these potential recent advances and various upcoming therapeutic options will make choice easier for physicians, and will lead to more personalized selections of available treatments.
Topics: Anticholesteremic Agents; Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; PCSK9 Inhibitors; Proprotein Convertase 9
PubMed: 35521719
DOI: 10.33963/KP.a2022.0117 -
Australian Family Physician Jul 2007Actinic keratoses (AK) commonly occur in the caucasian population living in environments of high levels of sun exposure, and are considered to be a marker for chronic... (Review)
Review
Actinic keratoses (AK) commonly occur in the caucasian population living in environments of high levels of sun exposure, and are considered to be a marker for chronic sun damage. This article reviews the epidemiology, pathogenesis, and current debate on AK as precancerous lesions. The various treatment options for AK, including combination therapy, are also discussed.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Australia; Cryotherapy; Diclofenac; Fluorouracil; Humans; Photosensitivity Disorders; Skin Neoplasms; Sunlight
PubMed: 17619671
DOI: No ID Found -
The Cochrane Database of Systematic... Oct 2005Trabeculectomy is performed as a treatment for glaucoma to lower the intraocular pressure (IOP). Mitomycin C (MMC) is an antimetabolite used during the initial stages of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Trabeculectomy is performed as a treatment for glaucoma to lower the intraocular pressure (IOP). Mitomycin C (MMC) is an antimetabolite used during the initial stages of a trabeculectomy to prevent excessive postoperative scarring and thus reduce the risk of failure.
OBJECTIVES
To assess the effects of intraoperative MMC compared to placebo in trabeculectomy.
SEARCH STRATEGY
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) on The Cochrane Library (Issue 1, 2005), MEDLINE (1966 to March 2005), EMBASE (1985 to 20 March 2005), SIGLE (1980 to December 2004), the National Research Register (Issue 1, 2005), LILACS (29 March 2005) and reference lists of articles. We also contacted researchers in the field.
SELECTION CRITERIA
We included randomised trials of intraoperative MMC compared to placebo in trabeculectomy surgery.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trial quality and extracted data. We contacted trial investigators for missing information.
MAIN RESULTS
Eleven trials, involving a total of 698 participants, were included. The trials enrolled three types of participants (high risk of failure, trabeculectomy combined with cataract surgery, no previous surgical intervention). Mitomycin C appears to reduce the relative risk of failure of trabeculectomy both in eyes at high risk of failure (relative risk 0.32, 95% confidence interval 0.20 to 0.53) and those undergoing surgery for the first time (relative risk 0.29, 95% confidence interval 0.16 to 0.53). No significant effect on failure was noted in the group undergoing trabeculectomy combined with cataract extraction. Mean IOP was significantly reduced at 12 months in all three participant groups receiving MMC compared to placebo. No significant increase in permanent sight-threatening complications was detected. However, none of the trials were large enough or of sufficient duration to address the long-term risk of bleb infection and endophthalmitis which has been reported in observational studies. Some evidence exists that MMC increases the risk of cataract.
AUTHORS' CONCLUSIONS
Intraoperative MMC reduces the risk of surgical failure in eyes that have undergone no previous surgery and in eyes at high risk of failure. Compared to placebo it reduces mean IOP at 12 months in all groups of participants in this review. Apart from an increase in cataract formation following MMC, there was insufficient power to detect any increase in other serious side effects such as endophthalmitis.
Topics: Antimetabolites; Cicatrix; Glaucoma; Humans; Intraoperative Period; Mitomycin; Randomized Controlled Trials as Topic; Trabeculectomy; Treatment Failure
PubMed: 16235305
DOI: 10.1002/14651858.CD002897.pub2 -
British Journal of Haematology Sep 2009As the cure rates for haematological malignancies have improved, the exploration of the balance between efficacy and side effects has become a major research target. The... (Review)
Review
As the cure rates for haematological malignancies have improved, the exploration of the balance between efficacy and side effects has become a major research target. The antifolate methotrexate is widely used in the treatment of acute lymphoblastic leukaemia, non-Hodgkin lymphoma, and osteosarcoma. Even when given identical methotrexate doses, patients vary significantly in their response and pattern of toxicities. This diversity can, to some extent, be linked to sequence variations in genes involved in drug absorption, metabolism, excretion, cellular transport, and effector targets or target pathways. In the coming years pharmacogenomics is expected to change our approaches to individualised therapy with methotrexate. However, genetic polymorphisms affect the pharmacokinetics and dynamics of all the drugs a patient receive as well as the normal tissues tolerance to a given drug exposure. Thus, although high-throughput techniques will allow mapping of tens of thousands of genetic polymorphisms in one run, it will be a major challenge to dissect out which of these have the strongest impact on efficacy and toxicity and hence should be the targets for intervention. This paper discusses the pharmacology of methotrexate and reviews studies on haematological malignancies that have attempted to predict the risk of toxicity by specific clinical or genetic features.
Topics: Antimetabolites, Antineoplastic; Dose-Response Relationship, Drug; Hematologic Neoplasms; Humans; Methotrexate; Pharmacogenetics; Polymorphism, Genetic
PubMed: 19538530
DOI: 10.1111/j.1365-2141.2009.07765.x -
Panminerva Medica Jun 2023The management of patients with coronary artery disease (CAD) is complex, especially after they have been discharged from hospital after an acute coronary syndrome... (Review)
Review
The management of patients with coronary artery disease (CAD) is complex, especially after they have been discharged from hospital after an acute coronary syndrome (ACS), because each patient may have numerous healthcare providers, and follow-up after discharge may be disjointed, or even incomplete. During follow-up after ACS, few patients have treatment intensification; rather, there is actually a major tendency towards reductions in treatment intensity, to the potential detriment of outcomes. We present here guidance from a French expert panel for the optimal management of lipid-lowering therapy up to 1 year after ACS. A French expert panel provides a practical guide for the implementation of guidelines for the management of post-ACS patients in routine practice, from hospital discharge up to one year after the index event, focusing in particular on the achievement of target LDL cholesterol (LDL-C) levels. We discuss the early follow-up (up to 6 months after discharge) and review the lipid-lowering treatment strategies that should be implemented. We discuss the evidence underpinning the prescription of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as well as recent evidence about icosapent ethyl. This review should facilitate implementation of a clear and effective lipid-lowering strategy for all patients after ACS. The panel recommends early use of high-intensity statins, in combination with ezetimibe for patients with LDL-c above 100 mg/dL at baseline. PCSK9i should be rapidly added during the first 3 months in high-risk diabetic patients with residual LDL-C above 70 mg/dL (with further benefit for those with residual LDL-C above ≥100 mg/dL) despite maximal tolerated dose statin and ezetimibe, patients with recent ACS, and patients with recurrent ischemic events under optimal medical therapy, multivessel coronary disease (MVD) and/or polyvascular disease (PVD), especially symptomatic PAD diabetic patients. Concerning icosapent ethyl (EPA), this drug should be introduced in patients ≥45 years of age with clinical atherosclerotic cardiovascular disease (ASCVD) or already on high-intensity or maximally tolerated statin therapy or with fasting triglycerides 135-499 mg/dL (with or without ezetimibe). Lipid-lowering treatment should be introduced as early as possible to obtain a rapid and profound decrease of LDL-c from baseline, using high-intensity statins (atorvastatin or rosuvastatin) and ezetimibe in fixed combination before discharge. Then, the strategy should be rapidly intensified by adding a PCSK9 inhibitor if the patient does not reach LDL-c levels below 55 mg/dL. We advocate this intensive strategy, which has demonstrated a further reduction in ischemic events, without safety concerns, even for patients who reach very low LDL-cholesterol levels. This approach, comprising few therapeutic steps, aims to rapidly reach LDL-c goals, improve patient compliance, and is an efficient method to fight therapeutic inertia, which remains a major issue.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents; Proprotein Convertase 9; Cholesterol, LDL; Acute Coronary Syndrome; Ezetimibe; Coronary Artery Disease
PubMed: 36222543
DOI: 10.23736/S0031-0808.22.04777-2