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Biomedical subjects

L Z Bito

Publications and source records attributed to L Z Bito.

At least 55 records · Page 3Linked to original sources

Species differences in the responses of the eye to irritation and trauma: a hypothesis of divergence in ocular defense mechanisms, and the choice of experimental animals for eye research.

Information published during the past century, especially the last decade, has identified pronounced species differences, not only in the morphological organization of ocular structures, but also in the functional responses of the eyes of different mammals to experimental and surgical procedures, as well as to drugs and autacoids. For the most part, these differences have been regarded as peculiarities or weakness rather than as fundamental evolutionary adaptations optimally suited to the environment and behavior of each species. This paper proposes a working hypothesis of evolutionary divergence in ocular defense mechanisms, based on some of the known morphological and functional differences among mammals, and discusses the implications of these differences with regard to the choice of appropriate animals for use as models in different areas of ophthalmic research.

Aging↗

Comparison of the ocular hypotensive efficacy of eicosanoids and related compounds.

It has recently been shown that prostaglandin (PG)E2 or F2 alpha reduces the intraocular pressure (IOP) of cats and primates when applied topically to the eye in very small doses, and that reduced IOP can be maintained in these species as long as the topical application of one of these PGs is repeated daily or twice daily. In the present study the ocular hypotensive efficacy and some of the ocular side-effects of 15 eicosanoids and related compounds, especially derivatives of PGF2 alpha, were compared and were also compared to some clinically used ocular hypotensive agents. Derivatives of PGF2 alpha were found that had short-term and long-term ocular hypotensive potencies some 10- to 50-fold greater than PGF2 alpha itself.

Animals↗

Determination of copper concentration in blood plasma and in ocular and cerebrospinal fluids using graphite furnace atomic absorption spectroscopy.

Published values for the concentration of Cu in cerebrospinal and intraocular fluids cover a very wide range (0.016 to 1.0 microgram/ml) and include values which are several times higher than those which would be consistent with normal physiology. An atomic absorption spectrophotometer equipped with a graphite furnace was used to measure the Cu concentration in these fluids and in blood plasma of toads, rabbits, and cats. Under standard conditions, these fluids yielded high background absorbance and only fractional recovery of added Cu. Parameters were therefore established which eliminated both the high background and the matrix interference and allowed the determination of Cu in 10-microliters aliquots of diluted blood plasma and undiluted cerebrospinal and ocular fluid samples. Under these conditions the Cu measured in the ocular (0.011 to 0.032 microgram/ml) and cerebrospinal fluids (0.033 to 0.050 microgram/ml) of these three species was lower than most previously reported values and only a small fraction (1-3%) of the concentration of Cu in the plasma of the same animals (0.85 to 1.22 micrograms/ml).

Animals↗

Long-term maintenance of reduced intraocular pressure by daily or twice daily topical application of prostaglandins to cat or rhesus monkey eyes.

Substantial evidence indicates that a single topical application of prostaglandins (PGs) can reduce intraocular pressure (IOP) in the eyes of several species. However, earlier literature, dealing with ocular hypertensive and inflammatory responses, shows the development of tachyphylaxis to subsequent doses of PGs. If similar tolerance developed to the ocular hypotensive effects of PGs, it would preclude the use of these agents in the treatment of chronic glaucoma. The present study shows, however, that although tachyphylaxis to the ocular hypotensive effects of PGs develops in rabbits, this is not a typical response among mammals. Significant IOP reduction was maintained in cats for up to 9 months by topical application of PGE2 at 12-, 24-, or 48-hr intervals. The IOP reduction was jeopardized seriously only when the PG was applied every other day for several days or when, on a few occasions, 3 days were allowed to elapse between PGE2 applications. Ocular hypotension was also maintained during the course of topical treatment of rhesus monkey eyes with PGF2 alpha. Short periods of pupillary constriction followed the application of each dose of PGF2 alpha to cat eyes, but the miotic response of rhesus monkeys to PGF2 alpha and cats to PGF2 was negligible. Other apparent side effects were noted, but none of these were severe or progressive. These results clearly demonstrate that tachyphylaxis, or tolerance, is not expected to present an obstacle to the development of eicosanoids and/or their derivatives as therapeutic agents for the long-term treatment of ocular hypertension and chronic glaucoma.

Administration, Topical↗

Noninvasive observations on eyes of cats after long-term maintenance of reduced intraocular pressure by topical application of prostaglandin E2.

Daily or twice daily prostaglandin E2 (PGE2) application to cat eyes was shown to maintain a reduced intraocular pressure (IOP) for several months without causing substantial flare or cellular response. We report now on detailed ophthalmic examinations performed on these cats after 5-9 months of such treatment (ie, after 150 to 250 unilateral PGE2 applications; 100 micrograms/treatment per eye). A comparison of the treated and contralateral control eyes revealed no differences in the axial length of ocular compartments, in the biomicroscopic appearance of the lens, vitreous, retina, or optic nerve head, in the rate of light-induced pupillary constriction or in the wave form of the electroretinogram. The cell density of the corneal endothelium was not decreased, but the endothelial surface did contain a few small "dark spots." A slight iridial heterochromia was generally apparent. In three of the cats PGE2 application had a sialagogic effect that became a conditioned reflex. Cats tended to keep their lids closed after each treatment; lid closure was more prolonged in the PGE2-treated eye than in the contralateral eye that received the same volume (50 microliters) of vehicle solution. It is concluded that daily treatment with PGE2, in doses sufficient to cause a maintained reduction in IOP, does have some side effects. However, none of these side effects are of sufficient importance to exclude the use of eicosanoids as potential anti-glaucoma agents.

Administration, Topical↗

Species variations in the pathophysiologic responses of vertebrate eyes to a chemical irritant, nitrogen mustard.

Much of our knowledge of the ocular responses to irritants is derived from studies on the effects of mustards applied topically to the rabbit eye. The present study shows, however, that vertebrate eyes display profound species variations in the initial (first 6 hours) response to nitrogen mustard (NM). Rabbits and guinea pigs showed two episodes, ducks and cats one, and owl monkeys no episode of increased intraocular pressure. Development of anterior chamber flare and cellular invasion was seen in all species except ducks and owl monkeys. Pupillary constriction of differing time-course and magnitude was observed in all species except guinea pigs and ducks. At least one indomethacin-sensitive component of the NM-induced inflammatory response was demonstrated in each subprimate species, the nature of which depended upon the predominant ocular effect of prostaglandins in each. The present work suggests that while rabbits and guinea pigs may be of particular value for the study of some aspects of the ocular response to irritation and trauma, these species may be unsuitable for studying ocular inflammation and therapeutics as applicable to man.

Animals↗

The role of the arachidonic acid cascade in the species-specific X-ray-induced inflammation of the rabbit eye.

To identify the mediator(s) of the apparently species-specific X-ray-induced inflammation of the rabbit eye, inhibitors of the synthesis and/or release of known or putative mediators of ocular inflammation were administered prior to irradiation. The X-ray-induced ocular inflammation, particularly the rise in intraocular pressure, was found to be inhibited by intravenous pretreatment of rabbits with flurbiprofen, indomethacin, or imidazole (1, 10, and 100 mg/kg i.v., respectively), or by combined intravitreal and topical administration of flurbiprofen. Systemic, intravitreal, and/or topical pretreatment with prednisolone or disodium cromoglycate or the retrobulbar injection of ethyl alcohol or capsaicin failed to block the inflammatory response, whereas vitamin E apparently exerted some protective effect. These findings show that the X-ray-induced inflammation of the rabbit eye is mediated, at least in part, by prostaglandins (PGs) and/or related autacoids. In addition, these results suggest that the unique sensitivity of the rabbit eye to X-ray-induced inflammation is due either to the presence in this species of a unique or uniquely effective triggering mechanism for the release of PG precursors or to the greater sensitivity of this species to the ocular inflammatory effects of PGs. Thus the rabbit eye may provide a unique model for studying some aspects of arachidonic acid release or ocular PG effects, but extreme caution must be exercised in generalizing such findings to other species.

Animals↗

The development of presbyopia in primates.

Presbyopia, the age-dependent decline in accommodative amplitude, clinically afflicts every individual reaching the age of 40 to 45 years. Various pathophysiologic mechanisms have been proposed, but none is proven, and until now no animal model for their study has existed. Refraction, axial dimensions, and pharmacologically-induced accommodation were determined in caged rhesus monkeys aged 0.5 to 32 years. Accommodative amplitude decline in an age-dependent manner from greater than 40 diopters to 0 diopters. Mean accommodative amplitude in 0.5 to 5-year old animals was 34.4 diopters; in greater than 25-year old animals it was 5 diopters. Considering the relative life expectancy and accommodative amplitude of rhesus and human, the rate of the age-dependent decline in accommodation was remarkably similar in the two species, as were the relationships between resting axial lenticular thickness and age, and between drug-induced accommodative amplitude and change in lenticular thickness. Thus, the rhesus monkey appears to provide the first known animal model for the study of accommodation and presbyopia as they occur in the human.

Accommodation, Ocular↗

Comparison of the hypotensive and other ocular effects of prostaglandins E2 and F2 alpha on cat and rhesus monkey eyes.

It is generally accepted that exogenous or endogenous prostaglandins (PGs) can give rise to acute increases in intraocular pressure (IOP) and to the development of flare and other signs of uveitis. It was recently shown, however, that low doses of PGE2 and/or PGF2 alpha topically applied to rabbit or owl monkey eyes significantly reduce IOP. The present experiments show that topical application of 10 to 500 micrograms of PGE2 also causes a highly significant IOP reduction in cat eyes lasting up to 48 hr with little or no development of flare or miosis, whereas similar application of PGF2 alpha causes, in addition to an IOP reduction, the development of profound pupillary constriction. Topical application of either PGF2 alpha or PGE2 to the eyes of rhesus monkeys also causes significant dose-dependent reduction in IOP. The hypotensive response in the rhesus monkey is not associated with detectable flare or consistent pupillary constriction, although at higher PG doses, hypotension tends to be preceded in both species by a brief (15 to 30 min) hypertensive phase. It is concluded that the eyes of different species show different patterns of IOP, miotic, and flare responses to topically applied PGs, the only consistent effect being a reduction in IOP. In some species, most notably in primates, a reduction in IOP is the predominant effect of PGs. Thus, PGs or their analogues may provide a new approach to the clinical control of IOP and the treatment of glaucoma.

Administration, Topical↗

Age-dependent loss of accommodative amplitude in rhesus monkeys: an animal model for presbyopia.

The refractive power and axial dimensions of the eye were measured under resting and fully accommodated conditions in 123 caged rhesus monkeys ranging in age from 0.5 to greater than 30 years. The mean resting refraction measured under ketamine anesthesia was -5 diopters. Accommodative amplitude, calculated as the difference between resting refraction and the most negative refraction measured 0.5 to 1 hr after topical application of a maximally effective dose of a cholinomimetic, showed an age-dependent decline. The mean accommodative amplitude of 1- to 5-year-old rhesus monkeys was a remarkable 34 D, while animals over 25 years of age averaged 5 D of accommodation. Some greater than 25-year-old animals showed no measurable change in refraction regardless of the dose or the type of cholinomimetic (carbachol, pilocarpine, or echothiophate) used. The resting axial thickness of the lens was found to increase with age throughout adulthood, well past the end of the growth period. A strong correlation was found between pharmacologically induced change in the refractive power of the eye and change in lenticular thickness. These similarities to the human condition suggest that the rhesus monkey represents a highly suitable animal model for the study of accommodation and presbyopia.

Accommodation, Ocular↗

Gradual increase in the sensitivity of extraocular muscles to acetylcholine during topical treatment of rabbit eyes with isoflurophate.

During the course of four to 14 days of topical application of isoflurophate ointment to rabbit eyes, there was a gradual increase in the sensitivity to acetylcholine of the superior recti muscles of treated eyes in vitro in the absence but not in the presence of eserine. The development of increased sensitivity to acetylcholine was accelerated when isoflurophate was applied twice daily. This increased sensitivity to acetylcholine was maintained when, after two weeks of twice-daily isoflurophate treatment, the frequency of administration was decreased to two applications per week. Partial reversal of this effect occurred seven to 14 days after the last isoflurophate treatment.

Acetylcholine↗

The impermeability of the basic cell membrane to thromboxane-B2' prostacyclin and 6-keto-PGF 1 alpha.

Washed rabbit red blood cells (RBCs) were suspended in electrolyte solution containing 3H-labeled prostacyclin (PGI2), thromboxane (TxB2) or 6-keto-PGF 1 alpha and 14C-labeled sucrose or thiourea. following 1 to 30 min incubation with 14C-sucrose, 3H-TxB2 or 3H-6-keto-PGF 1 alpha, the 14C or 3H space of packed RBCs remained essentially constant, yielding mean values (+/- S.E.) for all time periods of 6.1 +/- 0.3, 9.5 +/- 0.5 and 6.5 +/- 0.4%, respectively. After 1 min of incubation at 4 degrees or 23 degrees C at a pH of 7.4 or 8.5 with trace amounts (10(-9)M) of 3H-PGI2 or in the presence of added PGI2 (10(-5)M) or ethacrynic acid (1.6 x 10(-4)M), the apparent PGI2 space of packed RBCs ranged from 16 to 27%, decreasing to about 7% by 30 min. When RBCs were resuspended in fresh 3H-PGI2 every 5 min, their 3H content increased very slowly (apparent PGI2 space less than 40% at 30 min) as compared to thiourea (distribution space greater than 80% within 5 min). Over 90% of this 3H activity was lost from the RBCs in less than 2 min during elution at 4 degrees or 23 degrees C. It is concluded that RBC membranes and thus, presumably, the basic cell membrane in general, is not fundamentally permeable to PGI2, 6-keto-PGF 1 alpha or TxB2. Hence, the effective entry of these cyclooxygenase products into some cells or their passage across tight-junctional capillaries or epithelial membranes must require facilitated or active transport processes as was shown to be the case for E, F and A PGs. This implies that the distribution, pharmacological action and metabolism of these and presumably all related cyclooxygenase products are selective rather than unrestricted.

6-Ketoprostaglandin F1 alpha↗

Reduction of intraocular pressure in normal and glaucomatous primate (Aotus trivirgatus) eyes by topically applied prostaglandin F2 alpha.

Topical application of a single dose of 1.0 mg prostaglandin F2 alpha (PGF2 alpha) onto the cornea of five trained owl monkeys (Aotus trivirgatus) caused a prolonged and highly significant ocular hypotony. The intraocular pressure (IOP) of the treated eye was 4.7 +/- 0.9 mm Hg below that of the control eye 18 to 24 hr after PGF2 alpha application and remained significantly reduced for over 72 hr. Miosis, aqueous flare, and accumulation of cells in the anterior chamber were minimal in extent. The hypotensive effect of PGF2 alpha was even more pronounced when applied to a glaucomatous owl monkey eye with angle recession, which had IOPs consistently in the 45 to 55 mm Hg range (mean: 47.2 +/- 0.7) as measured periodically over a one-year period. The application of a single dose of 1.0 mg of PGF2 alpha to this hypertensive eye reduced IOP by over 25 mm Hg within 4 hr, with a relative hypotony lasting for at least 6 days. These results show that topical application of certain PGs to normotensive or hypertensive primate eyes can cause a long lasting and highly significant decrease in IOP, and suggest that prostaglandins or their analogues may aid in the therapeutic control of ocular hypertension and glaucoma.

Administration, Topical↗