Retina compounds

Vision is vital for human activities, and eyes are very sensitive to a number of toxic insults induced by chemical compounds. The most serious outcome is permanent eye damage which may be so severe as to cause loss of vision. The eye consists of the cornea and conjunctiva, the choroid, the iris, and the ciliary body. It also contains the retina, which is of neural origin, and the optic nerve. The retina contains photoreceptors, a highly specific light-sensitive type of neural tissue. The eye also contains the lens and a small cerebrospinal fluid system, the aqueous humor system, that is important for the maintenance of the steady state of hydration of the lens and thus the transparency of the eye. 

Methanol intoxication can cause blindness due to damage to ganglion cells in the retina. The blindness results from the accumulation of formaldehyde and formic acid, which are metabolites of methanol. Chemical compounds can also damage the visual cortex, for example, visual damage was observed among the victims of organic mercury intoxication in Japan (the fishermen of Minamata Bay). ... 

Sulfur hexafluoride is a gas used as a long-term tamponade (plug) for a retinal hole to repair detached retinas in the eye. If 2.50 g of this compound is introduced into an evacuated 500.0-mL container at 83°C, what pressure in atmospheres is developed ... 

Elimination from the vitreous occurs by one of two pathways. This can be visualized by injecting fluorescent compounds and examining the concentration distribution in frozen sections obtained after a steady state has been established [230]. If the major route of elimination is by means of the re-tina/choroid, at steady state the lowest concentration would be in the vicinity of the retina. The contours observed in frozen sections of the rabbit eye obtained after intravitreal injection of fluorescein exhibit this pattern, with the highest concentration immediately behind the lens (Fig. 16A). Compounds not chiefly eliminated through the retina exit the vitreous by passive diffusion and enter the posterior aqueous, where they are eliminated by the natural production and outflow of aqueous humor. In such a situation, the contours would be perpendicular to the retina, with the highest concentration towards the rear of the vitreous cavity. This appears to be the case for fluorescently labeled dextran polymer, whose contours decrease in concentration toward the hyaloid membrane (Fig. 16B). 

The apparent retinal influx clearance,. Kin,retina expressed as mL/(min g retina), of the test substrate labeled with either [3 H] or [14C] from the circulating blood to the retina is determined by integration plot analysis. In brief, rats are anesthetized, followed by injection of the test substrate (e.g., an [3H]-labeled compound, about 10 /u.Ci/head) into the femoral vein. After collection of plasma samples, rats are decapitated and the retinas removed. The retinas are dissolved in 2 N NaOH and subsequently neutralized with 2 N HC1. The radioactivity of retinal cell lysates is measured by liquid scintillation spectrometry. As an index of the retinal distribution characteristics of the radiolabeled test substrate, the apparent retina-to-plasma concentration ratio (Vd) as a function of time is used. This ratio [Vd(Q] (mL/g retina) is defined as the amount of [3H] per gram retina divided by that per milliliter plasma, calculated over the time-period of the experiment. The Kjn,retina can be described by the following relationship ... 

Figure 14.3 Integration plot of the initial uptake of [3H]adenosine by the retina after intravenous administration (A) and retinal uptake index (RUI) of [3H]adenosine and [3H]D-mannitol (B). A [3H]Adenosine (10 //.Ci/head) was injected into the femoral vein. B A test compound, [3H]adenosine or [3H]D-mannitol (10 //Ci/head), and a reference compound, [14C]n-butanol (0.1 //Ci/head), were injected into the common carotid artery in the presence or absence of 2 mM inhibitors. p < 0.05, significantly different from the control. Data from Biochimica et Biophysica Acta, 1758, Nagase et al., Functional and molecular characterization of adenosine transport at the rat inner blood-retinal barrier. 13-19, 2006, with permission from Elsevier.

In brief, the rats are anesthetized, followed by an injection of 0.2 mL of the test solution into the common carotid artery. The injection solution consists of a HEPES buffered Ringer s solution (containing 141 mM NaCl, 4 mM KC1, 2.8 mM CaCl2, and 10 mM HEPES, pH 7.4) which contains both the test substrate (e.g., a [3H]-labeled compound, about 10 /xCi) and a reference compound, which is highly extracted by the tissue (e.g., 0.1 /xCi [14C]n-butanol) in the presence or absence of transport inhibitors. If a [14C]-labeled compound is used as a test substrate, [3H]H20 can be selected as a reference compound. Rats are decapitated at 15 s after injection and the retina is removed. The retina is dissolved in 2 N NaOH and subsequently neutralized with 2 N HC1. The radioactivity is measured by liquid scintillation spectrometry. The RUI value, an index of the retinal distribution characteristics of the [3H] test substrate, is estimated using the following relationship ... 

Parasympatholytics are used to induce a mydriasis in the ophthalmology for the examination of the retina. They are applied locally as drops or ointment. The drug-induced inability of the eyes to accommodate results in a serious, although transient, impairment of the visus. Therefore the long-acting atropine (7-10 days) is replaced by short-acting compounds like homatropine (1-3 days), cyclopentolate (1 day) or tropicamide (6 hours). 

The advantage of the partially fluorinated compounds lies more in their potential to mix with silicone oil. Various groups started activities to diversify the portfolio of silicone oils used as long-term endotamponades to enable a reattachment of a detached retina. Dimethylsiloxanes of different viscosities are well established but their use is limited to the treatment of the upper quadrants of the retina. This is because a 100% filling of the vitreous cavity cannot be achieved, which means that because of their specific gravity, which is 0.97 g/ml, they float on top of the aqueous material present in the vitreous... 

All attempts to introduce fluorosilicone oils, in which the fluoro-alkyl group was covalently bound to the Si-O-Si backbone, were without success [31,32], A new approach to create a heavier than water silicone oil was the mixture of partially fluorinated compounds and ultra-purified silicone oil. The first product on the market was Oxane Hd (Bausch Lomb Inc., Rochester, NY, USA), a mixture of 1-perfluorooctyl-5-methylhex-2-en and silicone oil 5000 mPas. The specific density of this clear mixture is 1.02 g/ml. This creates the possibility to treat the lower quadrant of the retina. An intra-ocular bubble of Oxane Hd has an ideal spherical shape as demonstrated in Fig. 4. 

In the pineal gland, as well as in the retina of the eye, light-sensitive pterins may be photochemically cleaved to generate such products as 6-fontiylpterin, a compound that could serve as a metabolic regulator.346 Another pterin acts as a chemical attractant for aggregation of the ameboid cells of Dictyostelium lacteumM7(Box 11-C). Molybdopterin (Fig. 15-17) is a component of several... 

Figure 5.10 Three types of eye in evolution (from left to right) the compound eye of insects, the pinhole eye and the eye of higher animals. The photosensitive surface is shown as a thick black line c is the cornea, l the lens and r the retina...

Unusual features of riboflavin as recorded by some researchers include (1) High levels in liver inhibit tumor formation by azo compounds in animals (2) free radicals are formed by light or dehydrogenation flavine semiquinone dihydroflavin+ (3) free vitamin is found only in retina, urine, milk, and semen (4) substitution of adenine by other purines and pyrimidines destroys activity of flavin adenine dinucleotide (FAD) ... 

Ambati et al. [44] measured the permeability of rabbit sclera to a series of fluorescein-labeled hydrophilic compounds and found that scleral permeability decreased with increasing molecular weight and molecular radius but was quite permeable to large molecules, such as IgG (145 kDa). Thus when targeting the retina by the topical or subconjunctival routes the sclera is not a rate-limiting barrier and the main barriers are beyond this tissue at the choroid, RPE, and ELM. 

Retinoic acid (vitamin A acid), in which the alcohol group has been oxidized, shares some but not all of the actions of retinol. Retinoic acid is ineffective in restoring visual or reproductive function in certain species in which retinol is effective. Flowever, retinoic acid is very potent in promoting growth and controlling differentiation and maintenance of epithelial tissue in vitamin A-deficient animals. Indeed, all-trans-retinoic acid (tretinoin) appears to be the active form of vitamin A in all tissues except the retina, and is 10- to 100-fold more potent than retinol in various systems in vitro. Isomerization of this compound in the body yields 13-n.v-rctinoic acid (isotretinoin), which is nearly as potent as tretinoin in many of its actions on epithelial tissues but may be as much as fivefold less potent in producing the toxic symptoms of hypervitaminosis A. 

Spom, Roberts and Goodman81 have recently provided a broad overview of the field of the retinoids, based on the IUPAC-IUB Joint commission definition that Retinoids are a class of compounds consisting of four isoprenoid units joined in a head-to-tail manner. (The work was updated in 1994) Whereas there is only a handful of naturally occurring retinoids using this definition, more than a thousand man-made retinoids are known. The IUPAC-IUB bulletin recommended that the term, retinal, not be used as a chemical designation but be reserved as an adjective referring to the retina. They suggested that retinaldehyde be used instead in scientific literature as the name of chemical related to vision. 

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