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At least 19 recordsLinked to original sources
PubMed2004

Antimetabolites in the treatment of arthritis: current status of the use of antimetabolites.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by a chronic inflammation of the synovial joints and infiltration of blood-derived cells. In daily practice rheumatologists use the antimetabolites methotrexate (MTX) and leflunomide for the treatment of patients with rheumatoid arthritis. The current clinical status (efficacy/toxicity) of these 2 antimetabolites in the treatment of RA will be discussed.

Antimetabolites↗
PubMed1994

Gene technology-based antimetabolite design: the use of an in vitro protein expression system to facilitate antimetabolite design for virally-induced human diseases and malignant conditions.

A precondition for the chemotherapeutic treatment of a variety of virally-induced human diseases and malignant conditions is a highly selective interaction of the drug molecule to be used with it's biological target. To ensure the development of novel, effective drugs, it is essential that the biological target is well characterised with regard to it's structure and activity. Such characterisation relies upon adequate amounts of pure target being available. One of the most important enzymatic importers for antimetabolites is the enzyme thymidine kinase. In this article an in vitro protein expression system is described which facilitates the production of milligram amounts of pure and biologically active thymidine kinase, from a number of important biological sources. Results have shown that the in vitro produced enzyme has the exact biochemical propeties of the in vivo enzyme. Thus the in vitro protein expression system is an ideal vechicle to facilitate an in depth investigation of the enzyme's biological properties.

Journal Article↗
PubMed2005

Short term experience with "modern" trabeculectomy augmented with intraoperative antimetabolites.

PURPOSE: Owing to its technical refinements, "modern" trabeculectomy aims to reduce the incidence and severity of early postoperative complications while increasing postop IOP success. The purpose of our study was to evaluate namely the safety of "modern" trabeculectomy, the quality of the filtration blebs, the influence on the quality of life and secondarily IOP reduction according to the surgical procedure whether augmented with peroperative application of antimetabolites or not. MATERIAL-METHODS: Retrospective study including our 45 first consecutive procedures in 38 patients (mean age: 61.1 years) with medically uncontrolled various glaucomas. All procedures were performed according to a modified P. Khaw's protocol. Antimetabolites were applied peroperatively in 28/45 eyes (62.2%) with a history of previous filtering surgery (12/28 eyes) and/or advanced glaucomatous damage (22/28 eyes). Antimetabolites were not used in the 17/45 other eyes with lower surgical risk factors and higher target IOP, surgical procedure was not augmented with antimetabolites. Postoperative management included laser suture lysis, withdrawal of adjustable sutures and 5-FU injections when needed. Complete ocular examination was carried out preoperatively and postoperatively at day 1, 7, at 1, 2 and 3 months and every 3 months thereafter. All patients were questioned for symptoms associated with filtration bleb dysesthesia at the last visit. RESULTS: The mean follow-up was 7.9 +/- 3.3 in the group without antimetbolites and 5.3 +/- 2.2 months in the group with antimetabolites (p < 0.05). Final mean IOP (+/-SD) was significantly lower in the group augmented with antimetabolites (11.2 +/- 4.5 mmHg) compared with the group without antimetabolites (14.9 +/- 3.7 mm Hg) (p < 0.05). Complete and qualified success were respectively 64.3% and 89.3% in the group with antimetabolites and 70.6% and 82.4% in the subgroup without antimetabolites (p > 0.05). 1st month postoperative complications were transient and minor. They occurred in 59% in the group without antimetabolites and in 68% in the subgroup augmented with antimetabolites. Complications had comparable frequency of distribution between the 2 subgroups (p > 0.05). 84% of the filtration blebs (30/45) were diffuse and mildly vascularized. Avascular blebs were noticed in 7 eyes (15.5%) and were not related with the intraoperative application of mitomycin C (p > 0.05). Subjective comfort was good to excellent in 42/45 eyes (93.3%). Mean final visual acuity was not altered compared with preop level (p > 0.05). CONCLUSIONS: Our short term results suggest that the safety of "modern" trabeculectomy augmented with antimetabolites is comparable to those without intraoperative antimetabolites. Filtration blebs were very well tolerated in most patients. The peroperative use of antimetabolites precludes to appreciate if the success rates are due to the use of antimetabolites and/or the technique per se.

Adolescent↗
PubMed2004

National survey of antimetabolite use in glaucoma surgery 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.

Antimetabolites↗
PubMed1993

The kinetic properties of switch antimetabolites.

BACKGROUND: Maintaining homeostasis is the biological function of negative feedback, a process that plays a well-understood role in the biochemistry of antimetabolite drugs. An equally important property of living systems--the ability to respond to external stimuli by switching rapidly from one state to another--is mediated by positive feedback. Kinetic analysis of multi-enzyme biochemical pathways has shown that pathways containing positive feedback coupled with negative feedback may act as biochemical switching systems in which multiple steady states are possible. PURPOSE: A computer model was used to study the kinetic effects of antimetabolites that inhibit biochemical pathways at positive feedback sites and to determine whether the kinetics of such systems differed from those of classical antimetabolites. METHODS: Kinetics were simulated by microcomputer to model the effects of inhibitors on a simplified metabolic pathway. RESULTS: Antimetabolite drugs that act at positive feedback sites are predicted to display highly nonclassical properties. Three nonclassical properties are kinetically possible. First, the drugs may switch off the pathway at substoichiometric concentrations; classical antimetabolites require stoichiometric levels and sometimes much more. Second, instead of demonstrating classical continuous inhibition, antimetabolite drugs that act at positive feedback sites may give "all-or-none" dose-response curves with discontinuity at a specific value. Inhibitor concentrations below this value would have no overall effect on the system, while inhibitor concentrations at or above this value would give an abrupt transition to an inhibited steady state. Third, the inhibited system may show hysteresis and remain switched off after the inhibitor is removed. CONCLUSIONS: These findings suggest that antimetabolites acting at switch points could have kinetic properties very different from those of classical antimetabolites and could provide a noncytotoxic method of switching off pathways in neoplastic cells, perhaps leading to cell stasis. IMPLICATIONS: Experimental validation of these conclusions will require identification of the positive feedback sites of metabolic and signaling pathways and exploration of the effects of inhibitors of these sites. The properties of "switch antimetabolites" should prompt a search for new kinds of targets for drug design.

Antimetabolites, Antineoplastic↗
PubMed2001

A review of dose-limiting events in phase I trials: antimetabolites show unpredictable relationships between dose and toxicity.

INTRODUCTION: In a sample of NCIC CTG phase I trials we noted that studies of antimetabolites were frequently confounded by the occurrence of dose-limiting toxicities (DLT) at doses well below those ultimately recommended (recommended dose, RD) for further study, necessitating frequent expansion of dose levels and usually a change to more conservative dose escalation. This slowed development, exposed patients to ineffective doses of drugs, and raises concerns about the safety of current trial designs which include a single patient per dose level. Conversely, some patients treated at the RD may be receiving inadequate doses of anticancer drugs. To determine if this was a general phenomenon, we undertook a review of the results of a large group of phase I trials of cytotoxic agents. METHODS: Starting dose (SD), number of dose levels, dose at first DLT (D-DLT), maximum tolerated doses (MTD, dose at which DLT is seen in two or more patients) and RD were extracted from the NCI-Canada phase I trial database, and from a literature survey of phase I studies published between 1985 and 1999. Combination phase I and phase Ib studies were excluded. RESULTS: The review included 33 trials with antimetabolites and 60 with other cytotoxic agents. The median ratio D-DLT/MTD was 0.33 for antimetabolites and 0.75 for other cytotoxic agents (P < 0.01). Similarly, the median ratio D-DLT/RD was 0.43 for antimetabolites and 1 for other cytotoxic agents (P < 0.01). The median number of dose levels tested was nine for antimetabolites and six for other cytotoxic agents. DISCUSSION: Statistically significant differences in the ratios D-DLT/MTD and D-DLT/RD between antimetabolites and other cytotoxic compounds were noted, confirming our initial observations that unpredictable DLT occurs earlier and at lower dose levels in phase I clinical trials of antimetabolites than would be expected as compared to other classes ofcytotoxic agents. Toxicity thus appears to be incompletely predicted by dose alone for antimetabolites. DLT may occur in certain patients at doses well below the RD. Current phase I design may not be ideal for development of these compounds, and should focus on pharmacodynamic endpoints in addition to traditional pharmacokinetic and clinical endpoints.

Antimetabolites, Antineoplastic↗
PubMed1993

Changes in glycosylation of L1210 cells after exposure to various antimetabolites.

This study establishes that antimetabolites do have the potency to change cellular glycosylation, as was suggested in our previous review (Eur J Cancer 1990, 26, 516-523). Murine leukaemia L1210 cells were exposed to various antimetabolites under non-lethal conditions. The antimetabolites 5-fluorouracil (5FU), arabinofuranosylcytosine (AraC), methotrexate (MTX) and 6-mercaptopurine (6MP), but not 6-thioguanine, induced considerable changes in the metabolic incorporation of radioactively labelled monosaccharides. Each antimetabolite exhibited a different effect. Significant differences were found between the radioactivity incorporated from the monosaccharides glucosamine, fucose, mannose and galactose, relative to control values. Polyacrylamide gel electrophoresis indicated that changes were induced in the glycosylation of individual glycoproteins. 5FU, AraC, MTX and 6MP all influenced both pyrimidine- and purine-mediated sugar incorporation. This excludes, therefore, direct effects of the antimetabolites on their analogue nucleotide-sugars. The antimetabolite-induced changes in glycosylation did not directly correlate with the observed cell-cycle effects of the antimetabolites.

Animals↗
PubMed1998

Correction of lower eyelid retraction in thyroid eye disease: a randomised controlled trial of retractor tenotomy with adjuvant antimetabolite versus scleral graft.

BACKGROUND/AIMS: Lower eyelid retraction in thyroid eye disease contributes to ocular discomfort and an unsightly appearance, especially if asymmetrical. The use of donor scleral grafts is effective in lengthening the lower eyelids but carries a risk of virus transmission. Other techniques, including those which do not use grafts, need to be compared with scleral grafts. Recurrent retraction is a recognised complication of thyroid eyelid surgery; therefore, the authors investigated the use of antimetabolites to reduce postoperative fibrosis. METHODS: In this prospective randomised controlled trial of 25 patients (35 eyelids), the use of donor sclera in 20 lower eyelids (13 patients) was compared with partial tenotomy of the anterior part of the lower eyelid retractors (ALER) with adjuvant peroperative antimetabolite in 15 lower eyelids (12 patients). A 5 minute peroperative application of either 5-fluorouracil (25 mg/ml) in nine lower eyelids (eight patients) or mitomycin C (0.2 mg/ml) in six lower eyelids (four patients) was used to focally inhibit fibroblasts. Follow up ranged from 3 to 18 months (mean 7.8). RESULTS: One month after surgery the results of both groups were similar. However, at 3 months after surgery the results of scleral grafting were better than tenotomy with antimetabolites: 3/12 patients (25%) treated with tenotomy and adjuvant antimetabolite required subsequent surgery using grafts for correction of recurrent retraction. There were no significant complications associated with the use of antimetabolites in the eyelid in the doses used in this study. CONCLUSIONS: This randomised prospective trial shows that donor scleral grafts were more effective in the long term than partial tenotomy with adjuvant antimetabolite in the correction of lower eyelid retraction associated with thyroid eye disease. The use of peroperative antimetabolites in the lower eyelid was safe.

Adult↗
PubMed1995

[Usefulness of adjuvant chemotherapy with antimetabolites for cervical invasive cancer].

A series of 584 patients with cervical invasive cancer were included in the retrospective study on the efficacy of long-term oral maintenance chemotherapy with antimetabolites (Fluorouracil or Tegaful). The patients were histologically classified into the squamous cell carcinoma (SCC) group and the adenocarcinoma (AD) group. In the SCC group (n = 518), 163 patients were given more than 300 mg/day of antimetabolite tablets for one year or more after the main therapy (hysterectomy or pelvic irradiation). In the AD group (n = 66), 36 patients were treated with the same dose of antimetabolites. The Kaplan-Meier overall and cancer specific survival analysis estimates that the chronic administration of antimetabolites did not improve the cumulative 5-year survival in the SCC group. In contrast, the cumulative 5-year survival rate in the AD group treated with antimetabolites (88%) was significantly higher than that without chemotherapy (64%) by Kaplan-Meier analysis. This significant improvement in the survival rate in the AD group due to antimetabolites was notable in patients in FIGO stage I or II treated with radical or semiradical hysterectomy, these results indicate that oral adjuvant chemotherapy with antimetabolites is useful for cervical adenocarcinoma, but not for squamous cell carcinoma.

Adenocarcinoma↗
PubMed2000

Success criteria and success rates in trabeculectomy with and without intraoperative antimetabolites using intensified postoperative care (IPC).

PURPOSE: To define the success rate of trabeculectomy for surgical treatment of glaucoma under intensified postoperative care (IPC) conditions in cases of severe visual field damage or progression of visual field loss. METHODS: In a retrospective study, we evaluated the outcome of trabeculectomy in 99 eyes of 99 patients from October 1995 to June 1997. In 23 eyes, antimetabolites were used intraoperatively. Regarding intraocular pressure (IOP), success was defined as lowering the preoperative, maximally treated IOP by more than 20% in addition to a postoperative IOP level lower than 21 mmHg without using further glaucoma medication. Success rate was defined by stabilisation of visual acuity and visual field in addition to IOP reduction. RESULTS: The postoperative IOP was 14.7 mmHg (+/- 3.4 mmHg) following standard trabeculectomy (preoperative IOP 24.3 +/- 6.7 mmHg) and 15.8 mmHg (+/- 4.9 mmHg) following trabeculectomy with intraoperative antimetabolites (preoperative IOP 27.0 +/- 9.5 mmHg). The success rate concerning the IOP was 83% in standard trabeculectomy and 74% following trabeculectomy with intraoperative antimetabolites. The visual acuity showed stabilisation in 93% of cases following standard trabeculectomy and in 100% following trabeculectomy with intraoperative antimetabolites. The visual field showed stabilisation according to the Aulhorn criteria in 95% and 94% of cases following standard trabeculectomy and trabeculectomy with intraoperative antimetabolites, respectively. The total success rate using all criteria together was 76% following standard trabeculectomy and 74% following trabeculectomy with intraoperative antimetabolites. CONCLUSION: The overall outcome after trabeculectomy is good with appropriate follow-up and timely decisions for after-treatment to ensure good development of the filtering bleb.

Adult↗
PubMed2005

Trypan blue identifies antimetabolite treatment area in trabeculectomy.

AIM: Colourless solutions of mitomycin C (MMC) and 5-fluorouracil (5-FU) are widely used during trabeculectomy to inhibit postoperative scarring. The poor visibility of these agents on the eye has several drawbacks including the inability to accurately assess the area of treatment. This study examined the utility of using trypan blue dye to colour antimetabolites used during trabeculectomy and the effect of trypan blue on antimetabolite cytotoxicity in vitro. METHODS: For in vitro experiments, MMC (0.4 mg/ml) and 5-FU (25 mg/ml) were reconstituted with or without trypan blue. A lactate dehydrogenase release assay was used to measure drug induced cell death and viable cell number 7 days after treatment. For clinical assessment, trypan blue 0.1% was added to MMC and 5-FU to final concentrations of between 0.01% and 0.05%. The mixture was applied to Tenon's capsule and sclera via pre-wet or into dry 5x8 mm sponges (MMC and 5-FU) for 3 minutes or by direct subconjunctival injection after completion of surgery (5-FU). Twenty two consecutive patients undergoing trabeculectomy either with or without trypan blue were followed for 2 years postoperatively. RESULTS: The addition of 0.05% trypan blue to MMC or 5-FU did not alter MMC induced cell death or the number of viable fibroblast in vitro. In vivo, trypan blue clearly delineated the antimetabolite treatment area and facilitated control of excess antimetabolite at the wound margins as well as sponge removal. With direct subconjunctival injection, total staining area varied for a given volume with location of the needle tip. Any leakage from the injection site could be easily seen. No adverse effects attributable to trypan blue were found in 2 years of follow up. CONCLUSIONS: Trypan blue permits delineation of antimetabolite/tissue interactions without affecting cytoxicity for the assays investigated. Trypan blue can be used to visualise antimetabolite soaked sponges, estimate treatment area, and show areas of unintended tissue contact during trabeculectomy. The addition of trypan blue to antimetabolites has potential benefits in clinical, research, and teaching aspects of ocular surgery and therapy.

Aged↗