Test models to determine potential ocular drug induced side effects.
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Aging↗
Biomedical subjects
S Lerman
Publications and source records attributed to S Lerman.
Sorbitol generation and its inhibition by Sorbinil in the aging normal human and rabbit lens and human diabetic cataracts.
Fresh intact human cataracts (derived from patients with mature-onset diabetes mellitus and from nondiabetic patients), normal human lenses between 2 and 71 years old and lenses derived from 1.5- to 5-kg rabbits were incubated in Earle's media containing enriched 13C-glucose (5 and 15 mM). 31P NMR organophosphate profiles were obtained at the start and end of each incubation. Sorbinil was added to one of each pair of selected lenses, both incubated with 13C-glucose. All the lenses were frozen after 4h of incubation and were subsequently assayed by 13C NMR spectroscopy. The results demonstrate significant sorbitol generation only in young lenses which can be inhibited by Sorbinil. None of the older normal and cataractous human lenses or the mature-onset diabetic cataracts were capable of generating measurable sorbitol levels although they all showed active glucose metabolism and their organophosphate profiles demonstrated normal high-energy phosphate levels. Increased sugar phosphate levels were usually found in the mature-onset diabetic cataracts. Although our NMR spectroscopy is only sensitive to 10(-3) M levels, such concentrations of sorbitol are required to exert their osmotic effects. These data indicate that high sorbitol levels can only be generated in young human and rabbit lenses and correlate well with the age-related changes in aldose reductase activity in these lenses.
Adolescent↗
Acrylamide and iodide fluorescence quenching studies on whole human lenses and their protein extracts.
Tryptophan fluorescence was monitored in whole lenses (and in soluble crystallin fractions derived from these lenses) before and after incubating them in media containing acrylamide or iodide. The effects of exposing one lens to low level broadband UV radiation were compared with the contralateral lens incubated in the dark. In addition we employed 13C labeled acrylamide in order to monitor (by NMR spectroscopy) which crystallins were most effected. These studies demonstrate an acrylamide fluorescence quenching effect in whole lenses and extracted lens proteins, which is directly age related, as is the extent of its incorporation and binding to specific lens proteins. Iodide had no effect on TRP fluorescence in whole lenses and a slight effect on the extracted crystallins. These data demonstrate differences in the microenvironment of TRP residues in the various lens crystallins and their relative susceptibility to low level UV radiation exposure at doses approaching the ambient in vivo levels in a "real life" situation. This approach helps to delineate the microenvironment of TRP residues in native proteins and the effects of UV exposure on proteins with buried versus exposed TRP residues.
Acrylamide↗
Reactive airways dysfunction syndrome.
A possible variant of occupational asthma is induced by acute exposure to high concentrations of nonsensitizing respiratory irritants. This entity is referred to as reactive airways dysfunction syndrome. A case is presented in which the patient developed this syndrome secondary to exposure to a floor sealant. A portable peak expiratory flow meter was used to assess and document work-related airway reactivity changes.
Adult↗
Chemical and physical properties of the normal and aging lens: spectroscopic (UV, fluorescence, phosphorescence, and NMR) analyses.
In vitro [UV absorption, fluorescence, phosphorescence, and nuclear magnetic resonance (NMR)] spectroscopic studies on the normal human lens demonstrate age-related changes which can be correlated with biochemical and photobiologic mechanisms occurring during our lifetime. Chronic cumulative UV exposure results in an age-related increase of photochemically induced chromophores and in color of the lens nucleus. This enables the lens to filter the incident UV radiation, thereby protecting the underlying aging retina from UV photodamage. We have measured the age-related increase in lens fluorescence in vivo on more than 300 normal subjects (1st to 9th decade) by UV slitlamp densitography. These data show a good correlation with the in vitro lens fluorescence studies reported previously and demonstrate that molecular photodamage can be monitored in the lens. In vitro NMR (human and animal lenses) and in vivo experiments currently in progress are rapidly elucidating the physicochemical basis for transparency and the development of light scattering areas. Surface scanning NMR can monitor organophosphate metabolism in the ocular lens in vivo as well as in vitro. These studies demonstrate the feasibility of using biophysical methods (optical spectroscopy and NMR analyses) to delineate age-related parameters in the lens, in vivo as well as in vitro.
Adolescent↗
In vivo and in vitro investigations on cataract risk factors.
The role of UV-visible slitlamp densitography in monitoring 'pre-cataractous' changes in the living human (as well as animals) lens has been amply documented. This apparatus can be easily employed in the field (as a part of an epidemiologic study) and provides biometric as well as densitographic data. These can be correlated with a concomitant evaluation of two cataractogenic risk factors (UV exposure and diet). In addition, all cataractous lenses (or lens matter) removed in the area being studied can be collected, stored in a frozen state, and shipped to the laboratory for further analysis. We have shown that spectroscopic studies (UV, fluorescence, phosphorescence and EPR) can be correlated with these in vivo data and further clarify the role of UV radiation and diet as part of such an epidemiologic study.
Cataract↗
Application of miniosmotic pumps for liposomal drug delivery to the ocular lens.
The feasibility of using miniosmotic pumps in conjunction with specifically targeted liposomes to deliver agents directly to the ocular lenses of rabbits in vivo was examined in a pilot study. Concanavalin A was used to provide specific targeting of the vesicles to the lenses of the treated eyes. Seven days after pump installation, the animals were sacrificed and tissue samples from both control and treated eyes were examined for the presence of the administered agent. Four animals were treated with liposomally encapsulated Sorbinil and specific delivery to the lenses of the treated eyes was demonstrated by fluorescence spectroscopy. Two other animals were treated with liposomally encapsulated 3H-8-MOP, and specific delivery of the drug to the treated lenses was demonstrated by phosphorescence spectroscopy and by liquid scintillation counting. The drugs delivered to the treated eyes could not be detected in any of the tissues or fluids of the contralateral control eyes. Except for the ocular lens, these agents could not be demonstrated to any substantial degree in the other tissues of the treated eyes.
Animals↗
In vitro studies on the effect of yolk sac antisera on functions of the visceral yolk sac: I. Pinocytosis and transport of small molecules.
The production of congenital malformations by the administration of teratogenic antisera to pregnant animals has been reported from many laboratories. This work has focused our attention on the importance of the yolk sac placenta in supporting the rat embryo during early organogenesis and the significance of yolk sac dysfunction in rodent teratogenesis. The studies reported in this article deal with the effect of teratogenic antisera on the process of yolk sac transport; specifically pinocytosis (as measured by 14C-sucrose uptake) and small-molecule transport utilizing 14C-alpha-aminoisobutyric acid (AIB) and 3H-2-deoxyglucose (DOG). We sought to determine whether several different yolk sac localizing antibodies interfere with these transport processes, and, if so, which transport processes were most affected. The results of the experiments indicated that teratogenic antisera interfered with the process of pinocytosis in the yolk sac and that pinocytosis can be reduced as much as 40%. Nonteratogenic antisera, even when they localized in the yolk sac, did not interfere with the process of pinocytosis. Furthermore, the teratogenic antisera did not interfere with the transport of small molecules (either AIB or DOG) in the yolk sac. These results indicated that while fluorescent localization of an antiserum in the yolk sac did not invariably indicate the potential for teratogenicity, it is likely that the reduction in pinocytosis may directly correlate with the teratologic and embryopathic events. This work reaffirms the view that the yolk sac in important during rodent organogenesis and that yolk sac dysfunction can play an important role in the development of congenital malformations.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminoisobutyric Acids↗
Purification of the bovine lens isozymes which reduce fructose diphosphate to sorbitol diphosphate.
Three isozymes of an enzyme which reduce fructose 1, 6-diphosphate (FDP) to sorbitol 1, 6-diphosphate (SDP) in the presence of NADH have been purified from bovine lens. The isozymes were fractionated by acid precipitation of the lens homogenate followed by DE-52 column chromatography. This step separated the FDP reducing activity into three major peaks, peak 1, peak 2, and peak 3. Each of these peaks were further purified by affinity chromatography using Reactive blue-2-agarose, Sephadex G-150 gel filtration, and DE-52 column chromatography. Polyacrylamide disc gel electrophoresis demonstrated the presence of one major isozyme and one minor isozyme in each of the three peaks. The Km values for FDP were 8.0, 5.7, and 4.7 mM for peaks 1, 2, and 3 respectively. The reaction product SDP was characterized by nuclear magnetic resonance spectroscopy. All the isozymes utilized pyruvate as substrate with the Km for peaks 1, 2, and 3 being 0.63, 0.20, and 0.09 mM respectively. These studies therefore indicate that FDP reducing activity and lactate dehydrogenase activity co-purify and may be expressed by the same enzyme protein.
Animals↗
Photosensitizing drugs and their possible role in enhancing ocular toxicity. Parker Heath memorial lecture.
During the past decade there has been a considerable resurgence of interest in the photochemical effects of ultraviolet radiation capable of penetrating through the cornea (300-400 nm), on the intraocular tissues. The ocular lens and retina have received the most attention. The last few decades have also witnessed the development of a new therapeutic regimen, namely photosensitizing (phototherapy), in which the patients are given known photosensitizing agents and exposed to nonionizing radiation (ultraviolet, and on occasion, visible radiation). Such therapy has caused some ocular side effects, which in most cases could have been prevented. Drugs that are known photosensitizers and are capable of intraocular penetration through the blood-aqueous and blood-retina barrier are discussed with respect to their known or potential photosensitizing and/or phototoxic effects on intraocular tissues.
Aldehyde Reductase↗
Tetracycline instillation for recurrent cystic thyroid nodules.
Ten patients, 5 with recurrent pure cystic and 5 with recurrent mixed cystic-solid thyroid nodules, were studied. When repeated needle aspirations failed to decrease reaccumulation of fluid, tetracycline was injected directly into the cysts. As a result, all the pure cysts resolved completely, and four of the five mixed cystic-solid nodules diminished in size and fluid did not reaccumulate. Follow-up ranged from 12 to 20 months (mean 15 months). The procedure was generally well tolerated. It is concluded that instillation of tetracycline into both recurrent pure cystic and mixed cystic-solid thyroid lesions is a simple, safe and effective treatment.
Adolescent↗
Allopurinol and cataracts.
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Allopurinol↗
Automated biometry and densitography of anterior segment of the eye.
Twenty-eight fresh donor eyes (Georgia Lions Eye Bank), ranging in age from 4 months to 87 years, were utilized for an in vitro study to determine the feasibility of obtaining accurate AC diameter measurements with our Scheimpflug UV-visible slit lamp densitography apparatus. The in vivo study was performed on 16 hybrid monkeys (of varying age). These data were within 0.1 mm of measurements obtained with a modified paracentesis needle specially designed to obtain such measurements (sensitivity within 0.01 mm). The results of the foregoing study demonstrate that Scheimpflug slit lamp photographic analysis can measure the AC diameter accurately without entering the globe surgically. This will enable the surgeon to determine the AC diameter and order an anterior chamber IOL of a specified size prior to surgery. We have devised an automated program to analyze the negatives and provide direct AC diameter measurements. In addition, this program can provide other data including: (1) radius of curvature of anterior and posterior cornea and corneal thickness; (2) depth of anterior chamber; (3) radius of curvature of anterior and posterior lens surfaces and lens thickness; and (4) densitographic analysis of cornea and lens with UV as well as visible light, thus providing fluorescence data for these two tissues as well.
Animals↗
Measurement of anterior chamber diameter and biometry of anterior segment by Scheimpflug slitlamp photography.
Twenty-eight fresh donor eyes (Georgia Lions Eye Bank) ranging in age from four months to 87 years were used for an in vitro study to determine the feasibility of obtaining accurate anterior chamber diameter measurements with our Scheimpflug ultraviolet-visible slitlamp densitography apparatus. The in vivo study was performed on 16 hybrid monkeys (of varying age). These data were within 0.1 mm of measurements obtained with a modified paracentesis needle specially designed to obtain such measurements (sensitivity within 0.01 mm). The results of the foregoing study demonstrate that the Scheimpflug slitlamp photographic analyses can provide an accurate measurement of the anterior chamber diameter without entering the globe surgically. This will enable the surgeon to determine the diameter and order an anterior chamber IOL of a specified size prior to surgery. We have devised an automated program to analyze the negatives and provide direct anterior chamber diameter measurements.
Adult↗
Further studies on the effects of UV radiation on the human lens.
Young (1st decade) and old (7th decade) normal human lenses were exposed to low-level (less than 1 mW/cm2) broadband UV radiation (300-400 nm). UV-induced effects in the whole lens and the extracted lens proteins were monitored by fluorescence spectroscopy. The lens proteins were also subjected to proton and pulse magnetization NMR spectroscopy. These studies provide further evidence that low-level UV radiation exposure enhances nontryptophan fluorescence and may generate additional (longer wavelength) chromophores. The NMR studies suggest that the young gamma crystallin fraction is particularly sensitive to UV radiation compared with the other crystallins.
Age Factors↗
Lenticular psoralen photoproducts and cataracts of a PUVA-treated psoriatic patient.
Psoralen photoproducts were identified in association with cataracts in a psoriatic patient several years after oral methoxsalen plus ultraviolet A light (PUVA) therapy. Patients should be required to wear adequate optical protection not only during PUVA therapy but 24 hours following ingestion of methoxsalen.
Adult↗
NMR analyses of the cold cataract. III. 13C acrylamide studies.
13C-enriched acrylamide was employed to further delineate the action of this compound in preventing the cold cataract phenomenon when it is incorporated (in vitro) into young human and rabbit lenses. The extent of acrylamide incorporation, in the dark and with concurrent UV exposure, was monitored by 13C NMR spectroscopy. These studies provide further evidence that UV exposure causes permanent acrylamide photobinding within the lens. In such lenses, the gamma crystallin fraction of the soluble lens proteins is affected to the greatest extent. It appears to become aggregated and/or combined with the alpha and beta fractions resulting in an apparent loss of most of the gamma monomers. There is also an age-related effect with respect to the amount of acrylamide that can be incorporated into the lens. The decrease in acrylamide incorporation with age directly parallels the age-related decline in gamma crystallin levels.
Acrylamide↗