Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure.

The methotrexate (MTX) rescue agent carboxypeptidase G2 (CPDG2) rapidly hydrolyses MTX to the inactive metabolite DAMPA (4-[[2,4-diamino-6-(pteridinyl)methyl]-methylamino]-benzoic acid) and glutamate in patients with MTX-induced renal failure and delayed MTX excretion. DAMPA is thought to be an inactive metabolite of MTX because it is not an effective inhibitor of the MTX target enzyme dihydrofolate reductase. DAMPA is eliminated more rapidly than MTX in these patients, which suggests a nonrenal route of elimination. In a phase II study (May 1997-March 2002), CPDG2 was administered intravenously to 82 patients at a median dose of 50 U kg(-1) (range 33-60 U kg(-1)). Eligible patients for this study had serum MTX concentrations of >10 microM at 36 h or >5 microM at 42 h after start of MTX infusion and documented renal failure (serum creatinine > or =1.5 times the upper limit of normal). Immediately before CPDG2 administration, a median MTX serum level of 11.93 microM (range 0.52-901 microM) was documented. Carboxypeptidase G2 was given at a median of 52 h (range 25-178 h) following the start of an MTX infusion of 1-12 g m(-2) 4-36 h(-1) and resulted in a rapid 97% (range 73-99%) reduction of the MTX serum level. Toxicity related to CPDG2 was not observed. Toxicity related to MTX was documented in about half the patients; four patients died despite CPDG2 administration due to severe myelosuppression and septic complications. In conclusion, administration of CPDG2 is a well-tolerated, safe and a very effective way of MTX elimination in delayed excretion due to renal failure.

Assessing intraocular lens calcification in an animal model.

PURPOSE: To describe an animal model used to evaluate the propensity of various biomaterials to calcify intraocularly. SETTING: Research Department, Allergan Inc., Irvine, California, USA. METHODS: Intraocular lens (IOL) optic materials were implanted intramuscularly and/or subcutaneously in rabbits for up to 90 days. The materials included silicone, poly(methyl methacrylate) (PMMA), hydroxyethyl methacrylate hydrogel, and several hydrophobic acrylic materials. Scanning electron microscopy (SEM) and energy dispersive x-ray spectroscopy (EDS) were used to detect calcification demonstrated by characteristic discrete nodules containing both calcium and phosphate. Histological methods were used to evaluate tissue reactivity. Disc lenses fabricated from the experimental material were also bilaterally implanted in rabbit eyes that were monitored by slitlamp biomicroscopy. The lenses were explanted at 1, 2, 5.5, 10, and 20 months for SEM/EDS analysis. RESULTS: No calcification was noted in the intramuscularly or subcutaneously implanted silicone, PMMA, and acrylic optic materials. Calcification was noted on the intramuscularly, subcutaneously, and intraocularly implanted experimental acrylic and the intramuscularly implanted hydrogel material; the calcification was more extensive on the hydrogel. Signs that suggested intraocular calcification were first noted on the experimental IOLs at 4 months, but calcification was not confirmed until 10 months. CONCLUSIONS: Material calcification occurred more quickly in an intramuscular or subcutaneous environment than in an intraocular environment. Intramuscular and subcutaneous implantation appears to be an excellent model for screening materials for calcification potential. However, calcification is both host environment and material dependent. Using intramuscular or subcutaneous implantation in animal models to predict intraocular calcification in humans must be done with caution.

Contact-angle analysis of intraocular lenses.

PURPOSE: To present contact-angle measurements of commercially available intraocular lenses (IOLs) in air and in water to facilitate the understanding of how various IOLs might interact in different environments. SETTING: Laboratory. METHODS: Five commercially available IOLs were studied: AMO DuraLens PS-59NB. AMO PhacoFlex SI-26NB, AMO PhacoFlex II SI-30NB, Chiron ChiroFlex C10UB, and Alcon AcrySof MA60BM. The AMO soft acrylic model AR40, currently under clinical study, was also evaluated. Contact-angle measurements were made in air and in water using sessile drop and captive bubble methods. RESULTS: The sessile drop method indicated that all materials were hydrophobic in air. The captive bubble method differentiated materials based on their polar and dispersive forces. CONCLUSION: Contact-angle measurements differed depending on the test conditions. Proper choice of contact-angle measurement method can generate useful information about a material surface and its potential biomaterial interactions.

[Outcome of primary surgical management of liver trauma]. / Ergebnisse der primär-operativen Versorgung von Lebertraumata.

We evaluated retrospectively 43 patients with liver trauma undergoing laparotomy between 1/89 and 12/95. Blunt trauma (27 patients) and penetrating trauma (16 patients) to the liver had a mortality of 37% and 0%, respectively. The overall mortality was 23.3% and was significantly related to concomitant injuries (p = 0.002), whereas age, severity of the liver trauma as well as the surgical treatment had no significant influence on the outcome.

Moisture droplet formation on the posterior surface of intraocular lenses during fluid/air exchange.

We investigated the conditions under which moisture droplets would form on intraocular lens (IOL) posterior surfaces during fluid/air exchange procedures in rabbits implanted with silicone or poly(methyl methacrylate) (PMMA) IOLs. Moisture droplets did not form when the posterior capsule was intact, regardless of IOL material or infusion fluid temperature. If a capsular tear was present, droplets formed with both IOL materials when balanced salt solution (BSS) at ambient temperature was used as the infusion fluid. This effect was significantly more pronounced with silicone IOLs, resulting in an immediate loss of visualization of the fundus. In these cases, visualization was quickly restored by applying a viscoelastic to the posterior IOL surface.

Impaired renal 11 beta-oxidation of 9 alpha-fluorocortisol: an explanation for its mineralocorticoid potency.

9 alpha-Fluorocortisol (9 alpha FF) is about 200 times more potent as a mineralocorticoid than cortisol (F) in man, although it binds with the same affinity as F and aldosterone to the human mineralocorticoid receptor. The low mineralocorticoid activity of F has been shown to be due to its rapid conversion by the kidney to cortisone (E), which does not bind to the receptor. Therefore, we compared the conversion of F to E with that of 9 alpha FF to 9 alpha-fluorocortisone (9 alpha FE) by 11-hydroxysteroid dehydrogenases in man in vivo and in vitro. Single oral doses of 9 alpha FF, 9 alpha FE, and F were given to normal males, and the excretion of free 9 alpha FF, 9 alpha FE, F, and E was measured in urine. Human kidney and liver slices were incubated with unlabeled steroids, and the free 11-hydroxy- and 11-oxosteroids were quantitated after high performance liquid chromatography separation by UV absorption. Oral F (5 mg) is excreted 70% as free E and 30% as free F (percentage of free steroids only). Oral 9 alpha FF (5 mg) is excreted 90% as free 9 alpha FF and 10% as free 9 alpha FE. Free 9 alpha FF excretion is 14 times greater than that of F after ingesting an identical dose. Oral 9 alpha FE (4 mg) is also excreted 90% as 9 alpha FF and 10% as 9 alpha FE. Kidney slices convert F much faster to E than 9 alpha FF to 9 alpha FE. The conversion of 9 alpha FE to 9 alpha FF is, on the contrary, much faster than that of E to F. Thus, the equilibrium of the reaction is on the 11-oxo side for F/E and on the 11-hydroxy side for 9 alpha FF/9 alpha FE. The interconversion of both pairs of steroids is inhibited by glycyrrhetinic acid in a dose-dependent manner. Liver slices do not measurably convert 9 alpha FF to 9 alpha FE, but do rapidly convert 9 alpha FE into 9 alpha FF. Reflecting this negligible conversion of 9 alpha FF to 9 alpha FE and the low plasma-protein binding of 9 alpha FF, free urinary 9 alpha FF excretion is much higher than that of F after the same oral dose.(ABSTRACT TRUNCATED AT 400 WORDS)

A comparative evaluation of the biostability of a poly (ether urethane) in the intraocular, intramuscular, and subcutaneous environments.

A transparent poly (ether urethane) (PEU) was considered for use as a foldable intraocular lens material. The PEU was found to possess excellent mechanical, optical, and surface characteristics for this application. In vitro hydrolytic and ultraviolet aging studies suggested the PEU to be tolerant to conditions simulating 3-10 years of normal intraocular exposure. Different behavior was obtained, however, from intraocular and subcutaneous implantation of the PEU. After 6 months of intraocular exposure in the feline model, prototype PEU lenses had lost most or all of their optical resolving power. SEM analysis demonstrated scattered pitting and cracking on the lens surfaces. Degradation was found to be more extreme after as little as 30 days of subcutaneous exposure in rabbits. Severe pitting over the entire surface of implanted flat PEU specimens was observed by SEM. Macroscopic examination showed the samples to be frosty in appearance. It was postulated that the subcutaneous implant environment provides an accelerated in vivo model for materials intended for intraocular use. A minimum acceleration of 6-10x was estimated on a preliminary basis. The PEU studied here was found to be unsuitable for use as a foldable intraocular lens material.

Evaluation of the biocompatibility and fixation of a new silicone intraocular lens in the feline model.

The biocompatibility and fixation of a new silicone intraocular lens was evaluated in the cat eye. Following extracapsular lens extraction, 14 cats were implanted with a silicone lens (SLM 2/UV type) with polypropylene modified J loops in one eye and a poly(methyl methacrylate) (PMMA) lens (Perspex CQ) of a similar design in the fellow eye. Half the lenses were placed in the ciliary sulcus and half in the capsular bag. The eyes were evaluated for up to one year. Neither lens material showed any signs of toxicity clinically or histopathologically. Both lenses achieved stable fixation in the capsular bag; however, some inflammatory reaction and lens dislocation were noted with sulcus placement of both lens types. The amount of proteinaceous and cellular debris on the explanted silicone lenses was significantly less than that on the PMMA lenses as assessed with methylene blue staining. All retrieved lenses were optically clear and no significant change in the lens surface morphology, clarity and/or optical properties was observed.