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World Journal of Gastroenterology Nov 2018Glutathione (GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize... (Review)
Review
Glutathione (GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca absorption. The GSH depleting drugs switch the redox state towards an oxidant condition provoking oxidative/nitrosative stress and inflammation, which lead to apoptosis and/or autophagy of the enterocytes. Either the transcellular Ca transport or the paracellular Ca route are altered by GSH depleting drugs. The gene and/or protein expression of transporters involved in the transcellular Ca pathway are decreased. The flavonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca transport caused by GSH depleting drugs. The use of any of these antioxidants to ameliorate the intestinal Ca absorption under oxidant conditions associated with different pathologies in humans requires more investigation with regards to the safety, pharmacokinetics and pharmacodynamics of them.
Topics: Antimetabolites; Antioxidants; Calcium; Glutathione; Humans; Intestinal Absorption; Intestinal Mucosa; Oxidants
PubMed: 30510373
DOI: 10.3748/wjg.v24.i44.4979 -
Biochemical Pharmacology Sep 2023Nucleoside-based drugs, recognized as purine or pyrimidine analogs, have been potent therapeutic agents since their introduction in 1950, deployed widely in the... (Review)
Review
Nucleoside-based drugs, recognized as purine or pyrimidine analogs, have been potent therapeutic agents since their introduction in 1950, deployed widely in the treatment of diverse diseases such as cancers, myelodysplastic syndromes, multiple sclerosis, and viral infections. These antimetabolites establish complex interactions with cellular molecular constituents, primarily via activation of phosphorylation cascades leading to consequential interactions with nucleic acids. However, the therapeutic efficacy of these agents is frequently compromised by the development of drug resistance, a continually emerging challenge in their clinical application. This comprehensive review explores the mechanisms of resistance to nucleoside-based drugs, encompassing a wide spectrum of phenomena from alterations in membrane transporters and activating kinases to changes in drug elimination strategies and DNA damage repair mechanisms. The critical analysis in this review underlines complex interactions of drug and cell and also guides towards novel therapeutic strategies to counteract resistance. The development of targeted therapies, novel nucleoside analogs, and synergistic drug combinations are promising approaches to restore tumor sensitivity and improve patient outcomes.
Topics: Humans; Nucleosides; Antineoplastic Agents; Neoplasms; Drug Resistance; Membrane Transport Proteins; Antimetabolites
PubMed: 37567317
DOI: 10.1016/j.bcp.2023.115741 -
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 -
Mediators of Inflammation 2012Non infectious vitreous inflammation is often vision threatening and can be associated with potentially life-threatening systemic conditions. Treatment is often... (Review)
Review
Non infectious vitreous inflammation is often vision threatening and can be associated with potentially life-threatening systemic conditions. Treatment is often challenging as it involves systemic medications that can be associated with adverse effects. The classes of drugs are ever expanding and include corticosteroids, antimetabolites, alkylating agents, T-cell and calcineurin agents, biologic agents, and interferons. Each class of systemic therapy for non-infectious vitreous inflammation is reviewed. We discuss the mechanisms of action, usual clinical dosages, the specific conditions that are treated, the adverse effects, and usual course of treatment for each class of therapy.
Topics: Adrenal Cortex Hormones; Antimetabolites; Biological Products; Humans; Inflammation; Interferons; Vitreous Body
PubMed: 23028205
DOI: 10.1155/2012/936721 -
Journal of Cardiology Aug 2017The development of coronary revascularization has dramatically improved early cardiovascular outcomes in patients with acute coronary syndrome (ACS). However, patients... (Review)
Review
The development of coronary revascularization has dramatically improved early cardiovascular outcomes in patients with acute coronary syndrome (ACS). However, patients who have experienced myocardial infarction (MI) are at high risk of recurrence of cardiovascular events compared with those who are healthy or have stable coronary artery disease. Acute coronary events induce further inflammatory responses and plaque vulnerability in either a coronary culprit or whole vessels. The majority of data have supported the importance of coronary risk management to prevent secondary events. Dyslipidemia is common and one of the therapeutic targets in patients with ACS. Statins can reduce coronary plaque burden and lower the risk of cardiovascular death, recurrent MI, stroke, and coronary revascularization in patients with ACS. Growing evidence from clinical trials and meta-analyses supports early, intensive, and continuous therapy with statins in patients with ACS. Statins are accepted worldwide as the first-line lipid-lowering therapy as guidelines recommend. However, some patients do not reach the target level of low-density lipoprotein cholesterol by statins alone or are contra-indicated for statins. Recently, several clinical trials showed the further benefit of ezetimibe combined with statins on cardiovascular outcomes and coronary plaque regression in patients with ACS. In addition, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, novel and powerful lipid-lowering agents, have been developed and used in clinical settings. In this review, we summarize the present statin therapy, and refer to ezetimibe and PCSK9 as novel or additional non-statin strategies in the management of ACS.
Topics: Acute Coronary Syndrome; Dyslipidemias; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipid Metabolism; PCSK9 Inhibitors; Plaque, Atherosclerotic
PubMed: 28325524
DOI: 10.1016/j.jjcc.2017.02.004 -
The Cochrane Database of Systematic... 2000To determine the effects of allopurinol in the treatment of chronic prostatitis (Review)
Review
OBJECTIVES
To determine the effects of allopurinol in the treatment of chronic prostatitis
SEARCH STRATEGY
Trials were searched in computerized general and specialized databases (MEDLINE, Cochrane Library, Cochrane Prostate Group database), bibliographies of obtained articles, and direct contact with authors.
SELECTION CRITERIA
All randomized trials of allopurinol versus placebo used to treat patients with chronic prostatitis. Acute prostatitis, bacterial prostatitis, and asymptomatic prostatitis were excluded. The main outcome measure was the change in patient-reported discomfort.
DATA COLLECTION AND ANALYSIS
The reviewers extracted the data independently for the outcomes of change in patient-reported discomfort, investigator graded prostate pain, leukocyte counts, and biochemical indices.
MAIN RESULTS
Only one trial with 54 men lasting 240 days (with 330 days of follow-up) met study inclusion criteria. There was a statistically significant change favoring allopurinol in patient-reported discomfort between the study and control groups at follow-up. Between days 45-225, the mean score was -0.95 (s.d. 0.19) for the allopurinol group (7 men), compared with -0.47 (s.d. 0.21) for the placebo group (7 men). The weighted mean difference (WMD) was -0.48 (95%CI -0.690, -0.270). The mean score between days 45-135 was -1.08 (s.d. 1.29) for the 25 men in the allopurinol group, compared with -0.21 (sd 0.97) for the 14 men in the control group. The WMD was -0.87 (95%CI -1.587, -0.153). The allopurinol group had significantly less investigator graded prostate pain and had lower levels of serum urate, urine urate, and expressed prostatic secretion urate and xanthine. No significant differences between the two groups regarding leukocyte counts were found. No patient receiving allopurinol had any significant side effects. Three patients in the placebo group dropped out because of side effects.
REVIEWER'S CONCLUSIONS
One small trial of allopurinol for treating chronic prostatitis showed improvements in patient-reported symptom improvement, investigator-graded prostate pain, and biochemical parameters. However, the data provided, the measures used, and the statistics presented do not make these findings convincing that changes in urine and prostatic secretion composition regarding purine and pyrimidine bases resulted in the relief of symptoms. Further studies of allopurinol treatment using standardized and validated outcomes measures and analyses are necessary to determine whether allopurinol is effective.
Topics: Allopurinol; Antimetabolites; Chronic Disease; Humans; Male; Prostatitis
PubMed: 10796738
DOI: 10.1002/14651858.CD001041 -
Molecules (Basel, Switzerland) Jun 2022, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT),...
, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT), not synthesized in their animal hosts that can regulate cell viability. Here, we report the lethal effects of two recently described natural product antimetabolites that disrupt sterol methylation and growth, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT) that can equally target . We found that CHT/ERGT inhibited cell growth in vitro, yielding EC values in the low nanomolar range with washout experiments showing cidal activity against the bloodstream form, consistent with their predicted mode of suicide inhibition on SMT activity and ergosterol production. Antimetabolite treatment generated altered cell morphology and death rapidly within hours. Notably, in vivo ERGT/CHT protected mice infected with , doubling their survival time following daily treatment for 8-10 days at 50 mg/kg or 100 mg/kg. The current study demonstrates a new class of lead antibiotics, in the form of common fungal sterols, for antitrypanosomal drug development.
Topics: Animals; Antimetabolites; Ergosterol; Humans; Mice; Steroids; Sterols; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 35807334
DOI: 10.3390/molecules27134088 -
Toxins Sep 2011Pseudomonas syringae is a phytopathogenic bacterium present in a wide variety of host plants where it causes diseases with economic impact. The symptoms produced by... (Review)
Review
Pseudomonas syringae is a phytopathogenic bacterium present in a wide variety of host plants where it causes diseases with economic impact. The symptoms produced by Pseudomonas syringae include chlorosis and necrosis of plant tissues, which are caused, in part, by antimetabolite toxins. This category of toxins, which includes tabtoxin, phaseolotoxin and mangotoxin, is produced by different pathovars of Pseudomonas syringae. These toxins are small peptidic molecules that target enzymes of amino acids' biosynthetic pathways, inhibiting their activity and interfering in the general nitrogen metabolism. A general overview of the toxins' chemistry, biosynthesis, activity, virulence and potential applications will be reviewed in this work.
Topics: Antimetabolites; Bacterial Proteins; Bacterial Toxins; Biological Assay; Enzyme Inhibitors; Pseudomonas syringae
PubMed: 22069758
DOI: 10.3390/toxins3091089 -
The Cochrane Database of Systematic... Jul 2014Patients having cataract surgery have often earlier undergone a trabeculectomy for glaucoma. However, cataract surgery may be associated with failure of the previous... (Review)
Review
BACKGROUND
Patients having cataract surgery have often earlier undergone a trabeculectomy for glaucoma. However, cataract surgery may be associated with failure of the previous glaucoma surgery and antimetabolites may be used with cataract surgery to prevent such failure. There is no systematic review on whether antimetabolites with cataract surgery prevent failure of a previous trabeculectomy.
OBJECTIVES
To assess the effects of antimetabolites with cataract surgery on functioning of a previous trabeculectomy.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2014), EMBASE (January 1980 to June 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to June 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 10 June 2014. We also searched the Science Citation Index database (July 2013) and reference lists of potentially relevant studies.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of antimetabolites with cataract surgery in people with a functioning trabeculectomy.
DATA COLLECTION AND ANALYSIS
Two review authors independently reviewed the titles and abstracts from the electronic searches. Two review authors independently assessed relevant full-text articles and entered data.
MAIN RESULTS
We identified no RCTs to test the effectiveness of antimetabolites with cataract surgery in individuals with the intention of preventing failure of a previous trabeculectomy.
AUTHORS' CONCLUSIONS
There are no RCTs of antimetabolites with cataract surgery in people with a functioning trabeculectomy. Appropriately powered RCTs are needed of antimetabolites during cataract surgery in patients with a functioning trabeculectomy.
Topics: Antimetabolites; Cataract Extraction; Humans; Trabeculectomy
PubMed: 25066789
DOI: 10.1002/14651858.CD010627.pub2 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2022A new fluorescent ribonucleoside alphabet ( N) consisting of pyrimidine and purine analogues, all derived from methylthieno[3,4-d]pyrimidine as the heterocyclic core, is...
A new fluorescent ribonucleoside alphabet ( N) consisting of pyrimidine and purine analogues, all derived from methylthieno[3,4-d]pyrimidine as the heterocyclic core, is described. Large bathochromic shifts and high microenvironmental susceptibility of their emission relative to previous alphabets derived from thieno[3,4-d]pyrimidine ( N) and isothiazole[4,3-d]pyrimidine ( N) scaffolds are observed. Subjecting the purine analogues to adenosine deaminase, guanine deaminase and T7 RNA polymerase indicate that, while varying, all but one enzyme tolerate the corresponding N/ NTP substrates. The robust emission quantum yields, high photophysical responsiveness and enzymatic accommodation suggest that the N alphabet is a biophysically viable tool and can be used to probe the tolerance of nucleoside/tide-processing enzymes to structural perturbations of their substrates.
Topics: Antimetabolites; Coloring Agents; Nucleosides; RNA; Ribonucleosides
PubMed: 35018663
DOI: 10.1002/chem.202104472