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Chemistry & Biology May 2012The natural product CJ-15,801 is an inhibitor of Staphylococcus aureus, but not other bacteria. Its close structural resemblance to pantothenic acid, the vitamin...
The natural product CJ-15,801 is an inhibitor of Staphylococcus aureus, but not other bacteria. Its close structural resemblance to pantothenic acid, the vitamin precursor of coenzyme A (CoA), and its Michael acceptor moiety suggest that it irreversibly inhibits an enzyme involved in CoA biosynthesis or utilization. However, its mode of action and the basis for its specificity have not been elucidated to date. We demonstrate that CJ-15,801 is transformed by the uniquely selective S. aureus pantothenate kinase, the first CoA biosynthetic enzyme, into a substrate for the next enzyme, phosphopantothenoylcysteine synthetase, which is inhibited through formation of a tight-binding structural mimic of its native reaction intermediate. These findings reveal CJ-15,801 as a vitamin biosynthetic pathway antimetabolite with a mechanism similar to that of the sulfonamide antibiotics and highlight CoA biosynthesis as a viable antimicrobial drug target.
Topics: Anti-Bacterial Agents; Antimetabolites; Coenzyme A; Humans; Pantothenic Acid; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus
PubMed: 22633408
DOI: 10.1016/j.chembiol.2012.03.013 -
The British Journal of Ophthalmology Jul 2004To assess the pattern of use of antimetabolites in trabeculectomy surgery by all consultant ophthalmologists in the United Kingdom.
AIMS
To assess the pattern of use of antimetabolites in trabeculectomy surgery by all consultant ophthalmologists in the United Kingdom.
METHODS
A postal questionnaire of 12 questions regarding antimetabolite use in trabeculectomy surgery was sent to all 749 consultant ophthalmologists in the United Kingdom. The consultants were asked to estimate the number of trabeculectomies they performed per year, how often they used 5-fluorouracil (5-FU) in primary and redo surgery, their usual method of administration of 5-FU, how often they used mitomycin (MMC) in primary and redo surgery, and their usual dosage regimen of MMC. Factors that influenced the decision to use or not use antimetabolites were also assessed.
RESULTS
The response rate of consultants returning the questionnaire was 82% (615 out of 749); 87% (533) of these consultants perform trabeculectomy surgery. Of these 533 consultants, 98 (18%) never use an antimetabolite. Most consultants (82%) use antimetabolites, but use them infrequently (only 9% using antimetabolites in more than half their cases). The preferred antimetabolite is 5-FU rather than MMC. Of the 435 consultants performing trabeculectomy surgery and using antimetabolites, 402 (93%) use 5-FU and 179 (41%) use MMC. Various factors influenced the decision to use or not use an antimetabolite, but experience of complications associated with their use was a factor for 34% of consultants.
CONCLUSION
The use of antimetabolites, particularly MMC, in the United Kingdom is much less than in America or Japan, where trabeculectomy with MMC is the surgical procedure preferred by glaucoma specialists.
Topics: Antimetabolites; Fluorouracil; Glaucoma; Health Care Surveys; Humans; Intraoperative Care; Mitomycin; Postoperative Care; Reoperation; Trabeculectomy; United Kingdom; Wound Healing
PubMed: 15205228
DOI: 10.1136/bjo.2003.034256 -
Current Eye Research Mar 1996Antimetabolites such as 5-fluorouracil and mitomycin C are known to delay wound healing. Epidermal growth factor (EGF) has been shown to accelerate corneal epithelial...
Antimetabolites such as 5-fluorouracil and mitomycin C are known to delay wound healing. Epidermal growth factor (EGF) has been shown to accelerate corneal epithelial wound healing. This study was designed to investigate the effects of EGF on corneal epithelial healing that has been modified by antimetabolite treatment. New Zealand White rabbits were pretreated with either saline (controls) or 5-fluorouracil (5FU) injected subconjunctivally, or mitomycin C (MMC) applied topically. Circular anterior stromal wounds were created, followed by a 6-hour perfusion of normal saline or 50 micrograms/ml of EGF. Subconjunctival saline or 5FU, or topical MMC treatments were continued after wounding for a total of 6 days. Corneas were photographed and quantitative morphometry of the wound site was performed. Compared with saline controls, MMC significantly delayed wound healing (P < 0.05) whereas 5FU did not (P > 0.05). Compared with 5FU, MMC significantly delayed wound healing with either normal saline or EGF perfusion (P < 0.05). In the presence of either 5FU or MMC, EGF perfusion had no significant effect on the corneal wound-healing rate (P > 0.05). Corneal wound healing is not affected by subconjunctivally injected 5FU while it is delayed by topically applied MMC. EGF treatment does not overcome the inhibitory effects of MMC. EGF therapy may not be useful in the treatment of complications related to antimetabolite therapy.
Topics: Administration, Topical; Animals; Antimetabolites; Chemotherapy, Adjuvant; Cornea; Corneal Stroma; Drug Interactions; Epidermal Growth Factor; Epithelium; Fluorouracil; Injections; Mitomycin; Ophthalmic Solutions; Perfusion; Rabbits; Recombinant Proteins; Wound Healing
PubMed: 8654104
DOI: 10.3109/02713689609007618 -
Seminars in Oncology Apr 2022Radiation recall dermatitis (RRD) is a skin reaction limited to an area of prior radiation triggered by the subsequent introduction of systemic therapy. To characterize... (Review)
Review
PURPOSE/OBJECTIVES
Radiation recall dermatitis (RRD) is a skin reaction limited to an area of prior radiation triggered by the subsequent introduction of systemic therapy. To characterize RRD, we conducted a literature search, summarized RRD features, and compared the most common drug classes implicated in this phenomenon.
MATERIALS/METHODS
PubMed, Embase, Scopus, Web of Science, and Cochrane DBSR databases were queried through July 1, 2019 using key words: radiation recall, RRD, and radiodermatitis (limited to humans and English language). Studies included case reports in which patients treated with radiotherapy were initiated on a new line of systemic therapy and subsequently developed a skin reaction in the irradiated area. RRD cases were organized by whether RRD occurred after a single drug or multiple drug administration.
RESULTS
One-hundred fifteen studies representing 129 RRD cases (96 single-drug RRD, 33 multi-drug) were included. Sixty-three drugs were associated with RRD. Docetaxel (22) and gemcitabine (18) were the two drugs most commonly associated with RRD. Breast cancer (69 cases) was the most commonly associated tumor type. For single-drug RRD, the median radiotherapy dose was 45.0 Gy (range, 30.0-63.2 Gy). The median time from radiotherapy to drug exposure, time from drug exposure to RRD and time to significant improvement was 8 weeks (range, 2-132 weeks), 5 days (range, 2-56 days), and 14 days (range, 7-49 days), respectively. Variables significantly associated with grade ≥2 toxicity were docetaxel (P = 0.04) and non-antifolate antimetabolite (P = 0.05). The only variable significantly associated with grade ≥3 toxicity was capecitabine (P = 0.04).
CONCLUSIONS
RRD is a complex toxicity that can occur after a wide range of radiotherapy doses and many different systemic agents. Most commonly, it presents in patients diagnosed with breast cancer and after administration of a taxane or antimetabolite medication. RRD treatment generally consists of corticosteroids with consideration of antibiotics if superinfection is suspected. Drug re-challenge may be considered after RRD if the initial reaction was of mild intensity.
Topics: Antimetabolites; Breast Neoplasms; Docetaxel; Female; Humans; Radiodermatitis
PubMed: 35585004
DOI: 10.1053/j.seminoncol.2022.04.001 -
Journal of Veterinary Pharmacology and... Dec 1981
Review
Topics: Animals; Antibody Formation; Antimetabolites; Antineoplastic Agents; Immunity; Immunity, Cellular
PubMed: 6759685
DOI: 10.1111/j.1365-2885.1981.tb00861.x -
Ophthalmic Epidemiology Feb 2017To conduct a Bayesian analysis of a randomized clinical trial (RCT) for non-infectious uveitis using expert opinion as a subjective prior belief. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To conduct a Bayesian analysis of a randomized clinical trial (RCT) for non-infectious uveitis using expert opinion as a subjective prior belief.
METHODS
A RCT was conducted to determine which antimetabolite, methotrexate or mycophenolate mofetil, is more effective as an initial corticosteroid-sparing agent for the treatment of intermediate, posterior, and pan-uveitis. Before the release of trial results, expert opinion on the relative effectiveness of these two medications was collected via online survey. Members of the American Uveitis Society executive committee were invited to provide an estimate for the relative decrease in efficacy with a 95% credible interval (CrI). A prior probability distribution was created from experts' estimates. A Bayesian analysis was performed using the constructed expert prior probability distribution and the trial's primary outcome.
RESULTS
A total of 11 of the 12 invited uveitis specialists provided estimates. Eight of 11 experts (73%) believed mycophenolate mofetil is more effective. The group prior belief was that the odds of treatment success for patients taking mycophenolate mofetil were 1.4-fold the odds of those taking methotrexate (95% CrI 0.03-45.0). The odds of treatment success with mycophenolate mofetil compared to methotrexate was 0.4 from the RCT (95% confidence interval 0.1-1.2) and 0.7 (95% CrI 0.2-1.7) from the Bayesian analysis.
CONCLUSIONS
A Bayesian analysis combining expert belief with the trial's result did not indicate preference for one drug. However, the wide credible interval leaves open the possibility of a substantial treatment effect. This suggests clinical equipoise necessary to allow a larger, more definitive RCT.
Topics: Adolescent; Adult; Anti-Inflammatory Agents; Antimetabolites; Bayes Theorem; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Mycophenolic Acid; Uveitis; Young Adult
PubMed: 27982726
DOI: 10.1080/09286586.2016.1255764 -
Journal of Molecular Medicine (Berlin,... Feb 2002Ribavirin, an antiviral drug discovered in 1972, is interesting and important for three reasons: (a) it exhibits antiviral activity against a broad range of RNA viruses;... (Review)
Review
Ribavirin, an antiviral drug discovered in 1972, is interesting and important for three reasons: (a) it exhibits antiviral activity against a broad range of RNA viruses; (b) it is currently used clinically to treat hepatitis C virus infections, respiratory syncytial virus infections, and Lassa fever virus infections; and (c) ribavirin's mechanism of action has remained unclear for many years. Here we recount the history of ribavirin and review recent reports regarding ribavirin's mechanism of action, including our studies demonstrating that ribavirin is an RNA virus mutagen and ribavirin's primary antiviral mechanism of action against a model RNA virus is via lethal mutagenesis of the RNA virus genomes. Implications for the development of improved versions of ribavirin and for the development of novel antiviral drugs are discussed.
Topics: Animals; Antimetabolites; Antiviral Agents; Genes, Lethal; Humans; Mutagenesis; Ribavirin
PubMed: 11907645
DOI: 10.1007/s00109-001-0308-0 -
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 -
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 -
Annals of Oncology : Official Journal... 1999Gemcitabine is a new nucleoside antimetabolite with established activity against solid tumours. In previously treated patients the response rate with the drug alone was... (Review)
Review
Gemcitabine is a new nucleoside antimetabolite with established activity against solid tumours. In previously treated patients the response rate with the drug alone was around 13%. Combination therapy with gemcitabine-cisplatin or gemcitabine-paclitaxel induced responses in 53 and 40% respectively. In previously untreated patients with poor prognostic features a 24% response rate was reported for the drug alone, but in combination with cisplatin remissions were found in 53%-71% of patients. Gemcitabine, paclitaxel, and carboplatin (or cisplatin) in combination appeared to be a feasible and active combination. In a pilot with eight previously treated patients all obtained a remission and in untreated patients a remission occurred in all evaluable patients either clinically or measured by a decrease of CA 125. Dose-limiting toxicity is mainly haematological.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Female; Humans; Ovarian Neoplasms; Paclitaxel; Treatment Outcome; Gemcitabine
PubMed: 10219453
DOI: 10.1023/a:1008359418422