Effect of Age on the Disposition and Tissue Clearances of Fluorinated Pyrimidines in Rats

The age dependency of the elimination and tissue clearances of 5-fluorouracil (FU) and its nucleoside analog, 5-deoxy-5-fluorouridine (dFUR), was investigated in 2 to 12 months old female Fischer rats. In all age groups, the blood clearances of dFUR at infusion rates of 500 and 750 mg kg^–1 day^–1 and of FU at 25 and 35 mg kg^–1 day^–1 were independent of the dose; however, the clearance of FU at a higher infusion rate of 50 mg kg^–1 day^–1 was significantly lower than at 25 mg kg^–1 day^–1. An inverse relationship between animal age and clearance was observed for dFUR at both 500 and 750 mg kg^–1 day^–1 doses, and for FU at the 50 mg kg^–1 day^–1 dose. By contrast, the FU clearance at the 25 and 35 mg kg^–1 day^–1 doses was independent of age. To examine the age effect on the metabolic activities of major eliminating organs, the metabolism of dFUR by liver and small intestine in young and old rats was compared using 13,000 × g supernatant fractions of the tissue homogenates. Data were computer-fitted to the Michaelis-Menten equation. The Km for both tissues of both age groups was approximately 120 µg ml^–1. The intrinsic clearance (Vmax/Km) of dFUR was 5 ml kg^–1 min^–1 in the liver and 8 ml kg^–1 min^–1 in the intestine. The intestinal intrinsic clearance was independent of animal age, but the hepatic intrinsic clearance was significantly decreased in the older rats. The blood concentrations of FU derived as a metabolite from dFUR were also dependent on the animal age; an elevated FU concentration was associated with a lower dFUR metabolic clearance in the old rats. These data indicate that the elimination of FU and dFUR in rats is age-dependent, and that the systemic concentration of FU, a determinant of dFUR selectivity, is elevated in older animals.     

Suture patterns and corneal graft rotation in the cadaver eye

Torque and antitorque running sutures as described by Eisner are commonly used in penetrating keratoplasty. We tested the rotational effect of three different 16-bite running suture patterns on eight cadaver eyes, with the following results: (1) the torque pattern rotates the corneal graft counterclockwise by 0.7 +/- 0.1 mm at the wound or 11 degrees; (2) the antitorque pattern rotates the corneal graft clockwise by 0.7 +/- 0.1 mm at the wound or 11 degrees; (3) an intermediate "no torque" pattern, the bites of which form an isosceles triangle, produces no rotational effect. We recommend the use of a "no torque" pattern to minimize corneal graft rotation.     

Different pH Dependency of Mitomycin C Activity in Monolayer and Three-Dimensional Cultures

Purpose. Previous studies by other investigators have shown an enhancement of mitomycin C (MMC) activity at acidic extracellular pH (pH_e) in monolayer cultures of human cells. The goal of the present study was to determine if the efficacy of intravesical MMC therapy in patients treated for superficial bladder cancer can be enhanced by using acidified dosing solutions. We evaluated (a) the effect of pH_e on MMC activity in patient bladder tumors in vitro, and (b) the pH dependency of MMC activity in 2-dimensional monolayer and 3-dimensional multilayer cultures of human bladder RT4 tumor cells. Methods. Patient bladder tumors were maintained as 3-dimensional histocultures. RT4 cells were harvested and maintained as monolayer cultures or as 3-dimensional cell pellets on a collagen gel matrix. The cell pellets were 300–450 cell layers and 4,000–5,000 µm in diameter. Tumors or cells were incubated for 2 hr with MMC-containing media at pH_eof 5, 6, and 7.4. The drug effect was measured by the inhibition of DNA precursor (thymidine) incorporation. The stability of MMC as a function of pH_e was determined. About 24% of MMC was degraded following 2 hr exposure at pH_e 5 and 2% at pH_e 6 and 7.4. Results. The drug concentrations required to inhibit thymidine incorporation by 50% (IC₅₀) were corrected for the degraded MMC at acidic pH_e. The results showed no pH-dependent MMC activity in human patient bladder tumors nor in RT4 multilayer cultures; the IC₅₀ values were about 10 µg/ml at all three pH_e. In contrast, the monolayer RT4 cultures showed a pH-dependent MMC cytotoxicity; the IC₅₀ were 0.1, 0.8 and 1.2 µg/ ml at pH_e 5,6 and 7.4, respectively (p < 0.05). Pre-incubation of multi-layered RT4 cultures in acidic pH medium for 8 hr enhanced the MMC activity; the IC₅₀ was reduced by about 5 fold at pH_e 5 and about 3 fold at pH_e 6. Similar pH-dependent MMC activity was found when multilayers were pre-treated for 1 hr with 0.5 µml nigericin, a proton ionophore known to cause the intracellular pH (pH_i) to equilibrate with pH_e. Conclusions. These data suggest that the difference in the pH dependency of MMC activity in the monolayer and multilayer systems was due to the different experimental conditions. The time lag for pH_i to equilibrate with pH_e in the multilayer systems and the instability of MMC at low pH_e imply that the efficacy of intravesical MMC therapy is unlikely to be enhanced by using acidic dosing solution.     

Visually significant opacification of hydrophilic acrylic intraocular lenses--a clinico-pathological analysis

PURPOSE: To describe the clinic-pathological analysis of the visually significant opacification of the Cirrus International Hydroflex foldable hydrophilic acrylic intraocular lens (IOL) (model SC600-2, Medical Developmental Research Inc., Clearwater, Florida) and to highlight that this IOL is the same model as the Acryflex SC600-2 IOL, by the same manufacturer. METHODS: Retrospective review of five eyes of four patients with opacification of their Cirrus International Hydroflex foldable hydrophilic acrylic IOLs (model SC600-2) after uncomplicated phacoemulsification and IOL implantation. Two IOLs were explanted from two patients 14 to 24 months after initial implantation. Each explanted lens was divided into equal halves, one half for scanning electron microscopy (SEM) study and the other half for transmission electron microscopy (TEM) examination. SEM and TEM samples were also subjected to energy dispersive X-ray analysis (EDX). RESULTS: The IOL opacification was detected 14 to 24 months after uncomplicated phacoemulsification and IOL implantation. EDX analysis showed that the crystals contained calcium and phosphorus, presumably calcium phosphate. CONCLUSIONS: The Cirrus International Hydroflex foldable hydrophilic acrylic IOL (model SC600-2) is associated with opacification, that appeared worse centrally than peripherally. This is the same model as the Acryflex SC600-2 IOL, made by the same manufacturer. The opacification consists of calcium and phosphate.     

Immunomodulatory and anti-SARS activities of Houttuynia cordata

BACKGROUND: Severe acute respiratory syndrome (SARS) is a life-threatening form of pneumonia caused by SARS coronavirus (SARS-CoV). From late 2002 to mid 2003, it infected more than 8000 people worldwide, of which a majority of cases were found in China. Owing to the absence of definitive therapeutic Western medicines, Houttuynia cordata Thunb. (Saururaceae)(HC) was shortlisted by Chinese scientists to tackle SARS problem as it is conventionally used to treat pneumonia. AIM OF THE STUDY: The present study aimed to explore the SARS-preventing mechanisms of HC in the immunological and anti-viral aspects. RESULTS: Results showed that HC water extract could stimulate the proliferation of mouse splenic lymphocytes significantly and dose-dependently. By flow cytometry, it was revealed that HC increased the proportion of CD4(+) and CD8(+) T cells. Moreover, it caused a significant increase in the secretion of IL-2 and IL-10 by mouse splenic lymphocytes. In the anti-viral aspect, HC exhibited significant inhibitory effects on SARS-CoV 3C-like protease (3CL(pro)) and RNA-dependent RNA polymerase (RdRp). On the other hand, oral acute toxicity test demonstrated that HC was non-toxic to laboratory animals following oral administration at 16 g/kg. CONCLUSION: The results of this study provided scientific data to support the efficient and safe use of HC to combat SARS.     

Effects of Cadmium and Phenol on Motility and Ultrastructure of Sea Urchin and Mussel Spermatozoa

Computer-assisted sperm analysis (CASA) was used to study the effects of Cd(II) and phenol on sperm motility of sea urchin and mussel. In parallel, ultrastructural changes of sperm induced by these two toxicants were also investigated and related to motility impairment. Spermatozoa of sea urchin were more sensitive than mussel spermatozoa to both toxicants. Sea urchin sperm motility showed a good dose-response relationship to Cd(II) levels as well as exposure time. Exposure to the two toxicants changed the size and shape of the midpiece, which might affect the balance of spermatozoa in their swimming. The plasma membrane became more convoluted, and such a change might affect the streamlining and integrity of spermatozoa and hinder their normal movement patterns. Most important, disorganization of mitochondrial membranes and cristae was observed, suggesting disruption of ATP supply for sperm movement. Cadmium also induced greater ultrastructural damages in sea urchin spermatozoa. Received: 8 March 1999/Accepted: 29 September 1999     

New frontiers of retinal therapeutic intervention: a critical analysis of novel approaches

A recent wave of pharmacologic and technologic innovations has revolutionized our management of retinal diseases. Many of these advancements have demonstrated efficacy and can increase the quality of life while potentially reducing complications and decreasing the burden of care for patients. Some advances, such as longer-acting anti-vascular endothelial growth factor agents, port delivery systems, gene therapy, and retinal prosthetics have been approved by the US Food and Drug Administration, and are available for clinical use. Countless other therapeutics are in various stages of development, promising a bright future for further improvements in the management of the retinal disease. Herein, we have highlighted several important novel therapies and therapeutic approaches and examine the opportunities and limitations offered by these innovations at the new frontier.

KEY MESSAGES

• Numerous pharmacologic and technologic advancements have been emerging, providing a higher treatment efficacy while decreasing the burden and associated side effects.
• Anti-vascular endothelial growth factor (anti-VEGF) and its longer-acting agents have dramatically improved visual outcomes and have become a mainstay treatment in various retinal diseases.
• Gene therapy and retinal prosthesis implantation in the treatment of congenital retinal dystrophy can accomplish the partial restoration of vision and improved daily function in patients with blindness, an unprecedented success in the field of retina.