Site brasileiro onde você pode comprar qualidade e entrega cialis barato em todo o mundo.

Binding of drugs to eye melanin is not predictive of ocular toxicity

Binding of Drugs to Eye Melanin Is Not Predictive of Ocular Toxicity B. Leblanc,* S. Jezequel,† T. Davies,‡ G. Hanton,* and C. Taradach* *Pfizer, Central Research, BP 159, 37401 Amboise, France; Pfizer, Central Research, Ramsgate Road, Sandwich, Kent CT13 9NJ, England; and Pfizer, Central Research, Eastern Point Road, Groton, Connecticut 06340 cussed. The purpose of this review is to help dispel Ocular melanin is found in the uveal tract and in the
concerns about the binding of radiolabeled molecules to pigmented epithelial layer of the retina. Many struc-
the eye of pigmented rats in autoradiographic studies.
turally and pharmacologically unrelated drugs from
The review also addresses the issue of whether toxicity different therapeutic classes bind to melanin. Exam-
studies are best conducted in albino or pigmented an- ples include numerous drugs acting on the central
nervous system, -blockers, -agonists, antimalarial
drugs, sympathomimetic amines, and antibiotics. The

critical factors are the acid/base status and the li-
pophilicity of the molecule. In all cases, there are no

The wall of the eyeball which encloses the anterior direct consequences of drug–melanin binding. Drug-
and posterior chambers, the lens, and the vitreous related toxic effects on the retina described in humans
humor consists of three layers (Bloom and Fawcett, and animals are unrelated to melanin binding: mela-
1975). The outer fibrous layer is divided into the trans- nin binding and retinal toxicity are two separate en-
parent clear cornea and the opaque white sclera. A tities, the latter being related to the intrinsic toxicity
middle vascular layer also known as the uveal tract is of the compound rather than its ability to bind. Chlo-
composed of the iris anteriorly, an intermediate ciliary roquine and phenothiazines are often used as exam-
body, and the choroid posteriorly. The choroid which ples of drugs with retinal toxicity linked to melanin
supports and nourishes the retina consists of thin, binding. In both cases however, experimental data
loose, highly vascularized, connective tissue which con- show that the toxic mechanism is unrelated to bind-
tains many pigmented melanocytes. Some species such ing. Melanin binding has also been found to be protec-
as dog, cat, and ferret have a specialized layer in the tive against the ocular toxicity of some drugs. In con-
choroid, the tapetum lucidum. Bright reflection from clusion, we believe that potential ocular toxicity of
future drugs can be assessed adequately by conduct-

the tapetum causes the so-called “eye shine” (Rubin, ing well-designed toxicology studies, and using non-
pigmented rodents in addition to pigmented nonro-
The innermost layer of the wall of the eyeball, the dent species remains fully justified. Binding of drugs
retina, covers the inner surface of the choroid. The to eye melanin is not predictive of ocular toxicity.
retina is composed of multiple layers which can be 1998 Academic Press
distinguished in routine histological tissue sections.
The outermost layer of the retina, the retinal pig-mented epithelium (RPE) or pars pigmentosa, is com- INTRODUCTION
posed of a monolayer of polygonal cells which is con-tinuous cranially with the pigmented epithelial layer of Since the early reports on chloroquine and the phe- the ciliary body and the epithelium of the iris. The RPE nothiazines (see below), there has been frequent spec- cells of pigmented animals contain melanin in melano- ulation on the possible relationship between oculotox- somes or melanin granules. In species with a tapetum, icity and binding of drugs to melanin. The concern is the RPE overlying it is not pigmented. The RPE has based upon the potential accumulation and persistence three main functions: phagocytosis and degradation of of drug in melanin-containing tissues of the eye. This the continuously shedding tips of photoreceptor cells, phenomenon raises the possibility of oculotoxicity fol- vitamin A transport and storage, and active ion trans- port. The RPE together with the capillary wall consti- This review will be limited to the putative ocular effects of melanin binding. Available literature is re- The remaining retinal layers comprise the neuro- viewed and the relevance of melanin binding to the retina or pars nervosa. It is a highly differentiated safety assessment of pharmaceutical compounds is dis- structure with many different types of neurons which Copyright 1998 by Academic PressAll rights of reproduction in any form reserved.
DRUG MELANIN BINDING IS NOT OCULAR TOXICITY are very specifically connected to each other. The neu- structure of melanins remains elusive (Raghavan et roretina contains photoreceptor cells (rods and cones al., 1990). Melanin consists of highly heterogeneous which capture and transduce light to chemical signals polymers of various units that include 5,6-dihydroxy- and are in contact with the RPE), cells that respond indole-2-carboxylic acid and pyrole-carboxylic acid (Ito, with a slow change in membrane potential (bipolar 1986). Melanins are therefore polyanions with a rela- cells, horizontal cells, amacrine cells), neurons that tively high content of carboxyl groups and semiquino- produce action potentials (ganglion cells), and glial nes. NMR studies with various enantiomers of ephed- cells (Muller cells, oligodendrocytes).
rine have also indicated that there is potential forsteric preference of binding (Salazar-Bookaman et al., BIOLOGY OF MELANIN
The precise nature of the binding of drugs to melanin Melanins are a ubiquitous class of biological pig- has not been fully elucidated. Although in principle ments (Kollias et al., 1991). There are basically two drugs may bind either reversibly or irreversibly to oc- types of melanin in the animal kingdom: eumelanin, ular melanin (Rubin and Weisse, 1992), there is evi- which is brown or black, and phaeomelanin, which is dence to suggest that the association of most drugs red or yellow. Most visible pigmentation in mammals with melanin is a reversible process: the turnover of results from the synthesis and distribution of the two melanin is low, whereas most drugs which bind are types of melanin, whereas feather coloration in birds is due to carotenoid pigments (Hearing and Tsukamato, static forces play an important role in the binding in 1993). The pigmentation is genetically controlled at most cases, including chloroquine and chlorpromazine multiple levels, including migration of melanocytes (Tjalve et al., 1981). In addition, van der Waals forces during embryogenesis and melanin synthesis at cellu- or charge transfer may contribute to the binding of lar, subcellular, and enzymatic levels. More than 150 such drugs. There is little or no evidence for covalent mutations affecting pigmentation in mice have been binding of drugs to melanin. Mason (1977) suggests identified at more than 50 different genetic loci (Hear- that the tighter binding encountered with some drugs may be the result of such interactions.
Melanin synthesis involves the enzymatic conver- The ubiquity with which compounds distribute to the sion of the amino acid tyrosine via intermediates in- eye is well illustrated by a study in which the distri- cluding dihydroxyphenylalanine (dopa) to melanin bution of 27 compounds to the melanin-containing (Wheater et al., 1979). Detailed molecular studies of structures of the eye was shown to correlate well with melanin synthesis have shown that it is a very complex their physicochemical properties (Zane et al., 1990). A process involving multiple enzymes (Hearing and drug’s affinity for melanin is reported to be directly Tsukamato, 1993). Of all enzymes involved in the pro- related to acid/base status and lipophilicity of the mol- cess, only tyrosinase is essential for the production of ecule. We have corroborated these findings by review- both varieties of melanin. Most types of albinism, de- ing the literature for drugs reported to bind to melanin, fined as the hereditary inability to synthesize melanin apparently without associated ocular effects. This com- in man and animals, are due to molecular lesions of the pilation of about 40 compounds is shown in Table 1.
Also included are physicochemical properties for these Melanin in the RPE and in other pigmented eye drugs, obtained or calculated from the Medchem data- structures shows very little turnover (Ings, 1984; base (see van de Waterbeemd, 1997). Essentially, all Sarna, 1992). Ocular pigmentation is believed to be drugs identified as binding to melanin display some formed for life in a brief period during the fetal and basicity with most pK values above 7. Similarly, most perinatal period. In the eye, pigmented cells are non- of these drugs display lipophilic characteristics as evi- dividing and practically no melanin renewal is known denced by their positive log P (octanol/water partition coefficient). These data provide solid support for the Melanin is found in higher concentrations in the eye concept that all basic/lipophilic drugs can reasonably than anywhere else in the human body (Potts, 1996).
be expected to bind to melanin. Since many drugs are Ocular melanin, particularly in the uveal tract, ab- basic and lipophilic, probably over 40% (van de Water- sorbs most of the visible light that penetrates the lens beemd, 1997), we suggest that reversible binding to and protects the retina from overexposure by prevent- melanin is a very widespread phenomenon.
ing light scatter within the eye (Ings, 1984; Sarna, The many possible consequences of interaction of 1992). Melanin in the eye may also play a protective xenobiotics with pigmented ocular tissue were re- role against free radicals (Koneru et al., 1986).
viewed by Mason (1977), Catanese et al. (1978), Ings(1984), Rubin and Weisse (1992), and Larsson (1993).
If melanin binding occurs, pigmented tissues would Melanin is a purely descriptive term which conveys attract and retain the drug. It is reasonable to expect no chemical information (Zane et al., 1990). The exact that binding to melanin of an essentially nontoxic mol- Drugs Reported to Bind to Melanin without Reported Ocular Effects
Note. (c), calculated values. pK and log P data from MedChem database (van de Waterbeemd, 1997).
a Determined in our laboratories.
ecule does not lead to toxicity (Larsson, 1993). In such binding potentially harmful substances, thus prevent- cases the tissue simply acts as a depository for the ing the development of ocular toxicity.
compound without any discernible toxicity (see nextsection). Theoretical possible adverse consequences in- MELANIN BINDING WITHOUT OCULAR EFFECTS
clude the following: (1) high concentration of drugcould produce damage to tissues accumulating the mol- There are numerous literature reports of compounds ecule; (2) binding of drug to melanin would alter its role which bind to melanin without giving rise to ocular of free radical sink, thereby triggering a deleterious effects (Ings, 1984; Salazar-Bookaman et al., 1994).
effect (Koneru et al., 1986); and (3) slow release of the Such compounds are structurally and pharmacologi- drug from melanin would prolong the exposure of tis- cally unrelated, but have similar physicochemical sues to potentially adverse (or beneficial) effects (Ma- properties (see Table 1). Drugs that bind to melanin son, 1977). Since the toxic effects of a drug are tissue or characteristically are basic and lipophilic. Undoubt- organ specific and are related to the intrinsic toxicity of edly, there are many more compounds which, based on the substance, it is clear that the presence per se of a their physicochemical properties, could be added to the xenobiotic in a tissue does not necessarily imply an list. However, published data for these compounds are adverse effect. Conversely, it is also possible that the not readily available; melanin binding properties of presence of melanin could protect susceptible cells by many drugs have not been adequately evaluated or DRUG MELANIN BINDING IS NOT OCULAR TOXICITY reported. In this respect it is of interest to note that scription of these deposits as pigments by some authors melanin binding is only exceptionally described in The is an additional confusing factor in the literature.
Physicians’ Desk Reference (PDR, 1998), which sug- Chloroquine developed as an antimalarial agent also gests that melanin binding is not viewed as key infor- has anti-inflammatory effects at much higher doses (Potts, 1996). Chronic high-dose anti-inflammatorytherapy produces a dose-dependent retinopathy. The DRUG-INDUCED RETINAL EFFECTS UNRELATED TO
first cases of chloroquine-induced retinopathy were re- MELANIN BINDING
ported in 1959 (Hobbs et al., 1959). In the early stages,patients present with bilateral visual field defects and The medical and experimental literature contains a normal maculae. In late retinopathy, the classical ap- very large volume of data regarding the putative reti- pearance is granular pigmentation of the macula sur- nal toxicology of drugs (Crews, 1968; Grant, 1974; Lar- rounded by a clear zone, surrounded by another ring of ricart, 1985; Fraunfelder, 1989; Chiou, 1992; Dukes, pigmentation, the so-called bull’s-eye macula (Dollery, 1996). Melanin binding is not implicated in drug-re- 1991). Initially, the chloroquine-induced retinopathy lated retinopathies or retinal toxicities in humans or was believed to be related to high and sustained drug laboratory animals (Frame and Carlton, 1991; Lee and concentrations in the pigmented eye as a consequence Valentine, 1990) (see Table 2). Compounds inducing of melanin binding (Bernstein et al., 1963; Potts, 1964).
adverse effects on the retina have a wide range of A keratopathy unrelated to the retinopathy can also pharmacological activities. It is noteworthy that the be observed at high doses. The keratopathy consists of substances listed in Table 2 are not associated with deposits in the cornea, presumably of chloroquine or any particular set of physicochemical properties (un- metabolite products (Potts, 1996), which could be re- like Table 1). These drugs appear to represent a fair lated to lipid complex accumulation induced by the cross-section of “all drugs” with regard to their physi- cochemical properties and provide further circumstan- Chloroquine-induced retinopathy has been studied tial evidence that melanin binding is not a causal fac- in many animal species including rat, rabbit, mouse, tor to retinal effects. Mechanisms of retinal toxicities, suspected or documented by clinical or experimental tantly, it has been reproduced both in albino and in data, include lipid complex accumulation, effects on pigmented rabbits, rats, and cats (Franc¸ois and Maud- blood vessels, enzyme inhibition, free radical genera- gal, 1964; Gregory et al., 1970; Legros and Rosner, tion, and ion disturbances (Chiou, 1992; Frame and 1971a; Kuhn et al., 1981; Ivanina et al., 1983). The severity and development of the lesion were similar in In addition, there are published reports of com- pigmented and nonpigmented animals. Furthermore, pounds which bind to melanin, but have the potential in cats photoreceptor cells were damaged in the region to cause ocular toxicity unrelated to drug–melanin of RPE without melanin covering the tapetum lucidum binding. For example, practolol binds to melanin, but and remained intact elsewhere (Kuhn et al., 1981; Iva- the ocular toxicity described with this drug is second- nina et al., 1983). The available data show that chlo- ary to a deficient tear production due to an effect on roquine induces lipid complex accumulation in the ret- lacrymal glands (Rahi et al., 1976). Topically applied ina which is characterized by the presence of many adrenaline (epinephrine) has been associated with enlarged lipid complex-containing lysosomes in the cy- macular edema in aphakic eyes (Kolker and Becker, toplasm of affected cells. Only ganglion cells, Muller 1968). Although adrenaline is known to bind to mela- cells, and bipolar cells are affected initially; no abnor- nin (Potts, 1964), the cause of the observed macular malities are seen in the RPE (Gregory et al., 1970).
edema is unknown. It is believed that the absence of a Dense cytoplasmic lamellated material has been de- lens in aphakic eyes allows topically applied adrena- tected in the retinal ganglion cells as early as after 24 h line to reach the retina by diffusion (Grant, 1974; Ob- or 3 days of treatment (Gregory et al., 1970; Lu Rauch, 1991b). In later stages, degeneration, necrosis,and cell loss affect all retinal layers including photore- CHLOROQUINE AND PHENOTHIAZINES
ceptor cells. The RPE shows a thickening and an in-crease in dense cytoplasmic material (Gregory et al., Chloroquine and phenothiazines are often used as 1970; Ivanina et al., 1983). The chronic lesions pro- examples of drugs associated with retinal toxicity duced experimentally in animals, correspond to the linked to melanin binding. Careful review of the liter- histologic description of the chloroquine-induced reti- ature shows, however, that a causal relationship be- tween the two phenomena has not been established.
It appears, therefore, that ganglion cell and photore- Furthermore, these drugs exert adverse effects on non- ceptor cell involvement is central to the development of pigmented ocular structures (cornea, lens), as a conse- chloroquine oculotoxicity, while changes in RPE cells quence of deposits of drug-related materials. The de- are secondary effects (Koneru et al., 1986). It is the Drug-Induced Retinal Effects Unrelated to Melanin Binding
Note. (c), calculated values. pK and log P data from MedChem database (van de Waterbeemd, 1997).
consequence of the affinity of chloroquine, a cationic cones (Meier-Ruge and Cerletti, 1966; Tanenbaum and amphiphilic drug, for equally amphipathic lipid bilay- ers. The drug forms complexes primarily with ganglio- Thus, it is increasingly clear that chloroquine, which is considered by many as the classical example of reti- 1991b) and thereby lead to lipid complex accumulation notoxicity due to melanin, does not exert its deleterious affecting the neuroretina (Meier-Ruge and Cerletti, effect as a result of its affinity to melanin. This is 1966; Tanenbaum and Tuffanelli, 1980). Based on further substantiated by studies which showed that what is known of other lysosomal storage diseases both flunitrazepam, a compound similar to chloro- (Summers et al., 1995), chloroquine-induced lipid com- quine, and the antimalarial agent dabequine accumu- plex accumulation has the potential to ultimately late within pigmented ocular tissues but produce no cause irreversible damage to rods and cones, although ocular toxicity (Kuhn et al., 1981; Ivanina et al., 1983).
the pathogenic mechanism has not been established Phenothiazines have been extensively used as anti- ¨ llman-Rauch, 1991b). It has been suggested that psychotic drugs since their introduction in 1953. On since at high concentrations chloroquine binds signifi- the basis of structure–activity relationships, phe- cantly to DNA, it may ultimately interfere with protein nothiazines have been classified into three groups synthesis leading to secondary destruction of rods and (groups I, II, and III). Ocular complications following DRUG MELANIN BINDING IS NOT OCULAR TOXICITY long-term, high-dose, phenothiazine therapy may in- Weisse (1992). Vigabatrin, an inhibitor of GABA volve the cornea, lens, or retina. Only groups I and II transaminase, produced retinal degeneration in albino are known to affect retinal functions (Potts, 1996). The Sprague–Dawley rats but no retinal changes in pig- retinal effects need to be distinguished from granular mented Lister-hooded rats (Butler et al., 1987). Fen- deposits in the lens capsule or the corneal endothelium thion, an irreversible cholinesterase inhibitor, induced which have been described in both pigmented and non- adverse retinal effects more rapidly in albino than in pigmented patients, generally after years of treatment.
pigmented Long–Evans rats (Imai, 1975, 1977, 1983).
It is assumed that these deposits are drug-related ma- An antagonist of nicotinamide, 6-aminonicotinamide, terial precipitated from the aqueous humor (Potts, produced more severe ocular damage in nonpigmented than in pigmented rabbits (Render and Carlton, 1985).
The first phenothiazine reported to induce retinal In guinea pigs exposed to ultraviolet light after admin- alterations in humans was the group II phenothiazine istration of 8-methoxypsoralen (8-MOP), iridal and Sandoz NP-207 (Potts, 1996; Kinross-Wright, 1956).
eyelid lesions were far more severe in albino than in Disturbances of the visual function usually developed pigmented animals, probably as a consequence of bind- within 2 to 3 months. The initial symptoms were im- ing of 8-MOP to pigmented tissue (Cloud et al., 1960).
paired adaptation to dim light, followed by more severe In chronic lead retinopathy in rats, pathologic changes visual disturbances and abnormal pigmentation of the in the retina were less severe in pigmented rats than in retina in the form of fine “salt-and-pepper” clumps of a nonpigmented strain (Santos-Anderson et al., 1984).
pigment in the periphery or macula. Total reversal did These observations imply that the presence of melanin not occur and in some cases severe visual loss and may be protective against chemically induced oculotox- blindness resulted. For these reasons, NP-207 was re- moved from clinical study. Thioridazine, an antischizo-phrenia drug also effective for nonpsychotic severeanxiety, was shown to produce a similar pigmentary ALBINO VS PIGMENTED ANIMALS
retinopathy in humans at doses usually in excess of therecommended therapeutic levels. Normal dosage did Toxicity studies are commonly conducted in two lab- not cause retinal damage even after years of treatment oratory animal species, one albino (rodent species) and one pigmented (dog or primate). Since albino animals The group I phenothiazine, chlorpromazine, is gen- do not have melanin in RPE cells or the uveal tract, erally not retinotoxic but is known to produce a revers- questions are periodically raised concerning the suit- ible fine granular pigmentation of the retina in rare ability of albino animals for preclinical testing of drugs.
Although the lack of ocular melanin increases the sen- Phenothiazine retinal toxicity has been studied ex- sitivity of albino rodents to light (e.g., light-dependent perimentally in cats, dogs, and rats (Meier-Ruge and retinopathy), proper husbandry conditions control this Cerletti, 1966; Legros et al., 1971b, 1973). Retinal potential and make the albino rodent as suitable a test changes first occur in the outer segment of the photo- species as any other experimental animal (Rubin and receptor cells, with secondary RPE changes (Heywood, Weisse, 1992). We conclude from the above that clinical 1982). Histologically, there is a vacuolization followed and histopathological examinations performed in toxi- by disorganization and finally atrophy and loss of rods cology studies in the standard pigmented and albino and cones. It has also been shown that phenothiazine animal species are able to demonstrate the absence of derivatives accumulate in very high concentrations in toxic effects in pigmented tissues such as the retina the uveal tract due to melanin binding (Potts, 1996).
(Rubin and Weisse, 1992; Steiner and Buhring, 1990).
However, chlorpromazine causes electroretinographicchanges in both albino and pigmented rats and rabbits(Legros et al., 1973; Jagadesh et al., 1980). Further- CONCLUSIONS
more, since both retinal toxic and nontoxic phenothia-zines bind to melanin, and since no specific activity has The binding of drugs to melanin is a consequence of been identified that is not common to both retinotoxic their physicochemical properties. Approximately 40% and innocuous phenothiazines, the exact mechanism of of drugs are basic and lipophilic, and it is reasonable to this phenothiazine-induced retinal toxicity is not expect that all of them bind to melanin to some extent.
The precedents of chloroquine and phenothiazines,which bind to melanin and also cause retinal toxicity, EVIDENCE THAT MELANIN PROTECTS AGAINST
contribute to the confusion between these two phenom- OCULOTOXICITY
ena, resulting in the misconception that melanin bind-ing is evidence of adverse ocular effects. A review of the Compounds that selectively damage the eye of non- literature shows that melanin binding is not predictive pigmented animals were reviewed by Rubin and ACKNOWLEDGMENTS
(M. N. G. Dukes, Ed.), 13th ed., pp. 1427–1454. Elsevier Science,Amsterdam.
Frame, S. R., and Carlton, W. W. (1991). Toxic retinopathy, rat, We record our gratitude to Drs. D. A. Smith, A. Monro, and H. van mouse, and hamster. In Eye and Ear, Monographs on Pathology of de Waterbeemd for very helpful discussions and thoughtful com- Laboratory Animals (T. C. Jones, U. Mohr, and R. D. Hunt, Eds.), ments. We gratefully acknowledge the help of Laurence Dupont in pp. 116 –124. Springer-Verlag, Berlin.
Franc¸ois, J., and Maudgal, M. C. (1964). Experimental chloroquine retinopathy. Ophthalmologica 148, 442– 452.
Fraunfelder, F. T. (1989). Drug-Induced Ocular Side Effects and Drug Interactions, 3rd ed. Lea & Febiger, Philadelphia.
Araie, M., Takase, M., Sakai, Y., Ishii, Y., Yokoyama, Y., and Kita- Geerlings, P. J. (1996). Drugs of abuse. In Meyler’s Side Effects of gawa, M. (1982). ␤-Adrenergic blockers: Ocular penetration and Drugs (M. N. G. Dukes, Ed.), 13th ed., pp. 88 –102. Elsevier Sci- binding to the uveal pigment. Jpn. J. Opthalmol. 26, 248 –263.
Atlasik, B., Stepien, K., and Wilczok, T. (1980). Interaction of drugs Grant, W. M. (1974). Toxicology of the Eye, 2nd ed. Charles Thomas, with ocular melanin in vitro. Exp. Eye Res. 30, 325–331.
Barza, M., Kane, A., and Baum, J. (1979). Marked differences be- Green, S. J., and Wilson, J. F. (1996). The effect of hair color on the tween pigmented and albino-rabbits in the concentration of clin- incorporation of methadone into hair in the rat. J. Anal. Toxicol. damycin in iris and choroid-retina. J. Infect. Dis. 139, 203–208.
20, 121–123.
Basu, P. K., Menon, I. A., Persad, S. D., and Wiltshire, J. D. (1989).
Gregory, M. H., Rutty, D. A., and Wood, R. D. (1970). Differences in Binding of chlorpromazine to cultured retinal pigment epithelial the retinotoxic action of chloroquine and phenothiazine deriva- cells loaded with melanin. Lens Eye Toxicol. Res. 6, 229 –240.
tives. J. Pathol. 102, 139 –150.
Bernstein, H. N., Zvaifler, N., Rubin, M., and Mansour, S. A. M.
Griffin, J. E., and Garnick, M. B. (1981). Eye toxicity of cancer (1963). The ocular deposition of chloroquine. Invest. Ophthalmol. chemotherapy: A review of the literature. Cancer 48, 1539 –1549.
2, 384 –392.
Hamburger, H. A., Beckman, H., and Thompson, R. (1984). Visual Bloom, W., and Fawcett, D. W. (1975). A Textbook of Histology, 10th evoked potentials and Ibuprofen(motrin) toxicity. Ann. Ophthal- mol. 16, 328 –329.
Boman, G. (1973). Melanin affinity of a new anti-tuberculous drug, Hanakago, R., and Uomo, M. (1981). Clioquinol intoxication occur- rifampicin, investigated by whole body autoradiography. Acta ring in the treatment of Acrodermatitis Enterohepatica with ref- Ophthalmol. 51, 367–370.
erence to SMON outside of Japan. Clin. Toxicol. 18, 1427–1434.
Brinton, G. S., Norton, E. W. D., Zahn, J. R., and Knighton, R. W.
Hearing, V. J., and Tsukamoto, K. (1993). Enzymatic control of (1980). Ocular quinine toxicity. Am. J. Ophthalmol. 90, 403– 410.
pigmentation in mammals. FASEB J. 5, 2902–2909.
Brown, G. C., Tasman, W. S., and Shields, J. A. (1982). Massive Heywood, R. (1982). Histopathological and laboratory assessment of subretinal hemorrhage and anticoagulant therapy. Can. J. Oph- visual dysfunction. Environ. Health Perspect. 44, 35– 45.
thalmol. 17, 227–230.
Heywood, R. (1985). Clinical and laboratory assessment of visual Butler, W. H., Ford, G. P., and Newberne, J. W. (1987). A study of the dysfunction. In Toxicology of the Eye, Ear, and Other Special effects of vigabatrin on the central nervous system and retina of Senses (A. W. Hayes, Ed.). Raven Press, New York.
Sprague–Dawley and Lister-hooded rats. Toxicol. Pathol. 15, 143–
Hobbs, H. E., Sorsby, A., and Freedman, A. (1959). Retinopathy following chloroquine therapy. Lancet ii, 478 – 480.
Carlson, L. A. (1990). The broad spectrum hypolipidaemic drug nic- otinic acid. J. Drug Dev. 3, 223–226.
Hotson, J. R., and Sachdev, H. S. (1982). Amitriptyline: Another Catanese, B., Barillari, G., Interdonato, N., and Picinelli, D. (1978).
cause of internuclear ophthalmoplegia with coma. Ann. Neurol. 12,
Indagini in vitro sulla affinita per la melamina di alcuni farmaci.
Boll. Soc. Biol. Sper. 54, 2066 –2069.
Howells, L., Godffrey, M., and Sauer, M. J. (1994). Melanin as an Chiou, G. C. Y. (1992). Ophthalmic Toxicology, Target Organ Toxi- adsorbent for drug residues. Analyst 119, 2691–2693.
cology Series. Raven Press, New York.
Imai, H. (1975). Research on the ocular toxicity of organophosphorus Cloud, T. M., Hakim, R., and Griffin, A. C. (1960). Photosensitization agents, part 2. Residue properties in the rat after 1 time admin- of the eye with methoxsalen. I. Acute effects. Arch. Ophthalmol. istration of Baytex (low toxicity organophosphorus agent), espe- 64, 346 –351.
cially ERG changes and changes over time in the serum: Liver,
retina, cholinesterase activity. Acta Soc. Ophthalmol. Jpn. 79,
Crews, S. J. (1968). Some adverse effects of drugs on the retina.
Proceedings of the Symposium “Evaluation of Drug Effects on theEye,” held at the Royal Society of Medicine, London, May 2, 1968 Imai, H. (1977). Experimental retinal degeneration due to organo- phosphorus agents. Acta Soc. Ophthalmol. Jpn. 81, 925–932.
D’Amico, D. J., Libert, J., and Kenyon, K. R. (1984). Retinal toxicity Imai, H., Miyamata, M., Uga, S., and Ishikawa, S. (1983). Retinal of intravitreal gentamycin. Invest. Ophthalmol. Vis. Sci. 25, 564.
degeneration in rats exposed to an organophosphate pesticide De Vergillis, S., Congia, M., Turco, M. P., et al. (1988). Depletion of (Fenthion). Environ. Res. 30, 453– 465.
trace elements and acute ocular toxicity induced by desferrioxam- Ingebrigtsen, K., Skoglund, L. A., and Nafstad, I. (1990). A study on ine in patients with thalassaemia. Arch. Dis. Child 63, 250 –255.
melanin affinity of 14c-trimethoprim in male Mol:WIST and Mol: Dollery, C. (1991). Therapeutic Drugs. Churchill Livingstone, Lon- PVG rats. Z. Versuchstierkd. 33, 73–77.
Ings, R. M. J. (1984). The melanin binding of drugs and its implica- Dukes, M. N. G. (1996). Meyler’s Side Effects of Drug, An Encyclope- tions. Drug Metab. Rev. 15, 1183–1212.
dia of Adverse Reactions and Interactions, 13th ed. Elsevier, Am- Ito, S. (1986). Reexamination of the structure of eumelanin. Biochim. Biophys. Acta 883, 155–161.
Ernst, E., and De Smet, P. A. G. M. (1996). Risks associated with Ivanina, T. A., Zueva, M. V., Lebedava, M. N., Bogoslovsky, A. I., and complementary therapies. In Meyler’s Side Effects of Drugs Bunin, A. J. (1983). Ultrastructural alterations in rat and cat DRUG MELANIN BINDING IS NOT OCULAR TOXICITY retina and pigment epithelium induced by chloroquine. Graefe’s Mehelas, T. J., Kollarits, C. R., and Martin, W. G. (1982). Cystoid Arch. Clin. Exp. Ophthalmol. 220, 32–38.
macular edema presumably induced by dipivefrin hydrochloride Jagadesh, J. M., Lee, H. C., and Salazar-Bookaman, M. M. (1980).
(Propine). Am. J. Ophthalmol. 94, 682.
Influence of chlorpromazine on the rabbit electroretinogram. In- Meier-Ruge, W., and Cerletti, A. (1966). Zur experimentellen pa- vest. Ophthalmol. Vis. Sci. 19, 1449 –1456.
thologie der phenothiazin-retinopathie. Ophthalmologica 151,
Jezequel, S. G., Uden, S., and Wastall, P. (1996). Modipafant, a new PAF antagonist: Pharmacokinetics and disposition in rat, dog and Menon, I. A., Trope, G. E., Basu, P. K., Wakeham, D. C., and Persad, man. Xenobiotica 26, 963–975.
S. D. (1990). Binding of timolol to iris-ciliary body and melanin: An Kinross-Wright, V. (1956). Clinical trial of a new phenothiazine in vitro model for assessing kinetics and efficacy of long-acting compound NP-207. Psychiatr. Res. Rep. Am. Psychiatr. Assoc. 4,
antiglaucoma drugs. In Proceedings of the Second Congress of the International Society of Ocular Toxicology, p. 22 (abstract).
Kolker, A. E., and Becker, B. (1968). Epinephrine maculopathy.
Meyer, S. M., and Fraunfelder, F. T. (1987). National registry of Arch. Ophthal. 79, 552–562.
drug-induced ocular side effects. In Drug-Induced Ocular Side Kollias, N., Sayre, R. M., Zeise, L., and Chedeke, M. R. (1991).
Effects and Ocular Toxicology (O. Hockwin, Ed.), pp. 40 – 44.
Photoprotection by melanin. J. Photochem. Photobiol. B Biol. 9,
Nagata, A., Mishima, H. K., and Kiuchi, Y. (1993). Binding of anti- Koneru, P. B., Lien, E., and Koa, R. T. (1986). Review: Oculotoxicities glaucomatous drugs to synthetic melanin and their hypotensive of systematically administered drugs. J. Ocular Pharmacol. 2,
effects on pigmented and non-pigmented rabbit eyes. Jpn. J. Oph- thalmol. 37, 32–38.
Kuhn, H., Keller, P., and Steiger, A. (1981). Lack of correlation Obstbaum, S. A., Galin, M. A., and Poole, T. A. (1976). Topical epineph- between melanin affinity and retinopathy in mice and cats treated rine and cystoid macular edema. Ann. Ophthalmol. 8, 455– 458.
with chloroquine or flunitrazepam. Albrecht Von Graefes Arch. Parhad, I. M., Griffin, J. W., Clark, A. W., and Koves, J F. (1984).
Klin. Exp. Ophthalmol. 216, 177–190.
Doxorubicin intoxication: neurofilamentous axonal changes with sub- Larricart, P. (1985). Les affections re´tiniennes. Bull. Soc. Ophtalmol. acute neuronal death. J. Neuropath. Exp. Neurology 43, 188 –200.
Fr. Spec No., 193–211.
Parrish, R. K., Heuer, D. K., and Gressel, M. G. (1984). Toxic effects Larsson, B. S. (1993). Interaction between chemicals and melanin.
of fluorouracil on the rabbit retina. Am. J. Ophthalmol. 97, 533–
Pigment Cell Res. 6, 127–133.
Lee, K. P., and Valentine, R. (1990). Retinotoxicity of 1,4-bis(4- Pavlidis, N. A., Petris, C., Briassoulis, E., et al. (1992). Clear evi- aminophenoxy)-2-phenylbenzene (2-phenyl-APB-144) in albino dence that long-term, low-dose tamoxifen treatment can induce and pigmented rats. Arch. Toxicol. 64, 135–142.
ocular toxicity. Cancer 69, 2961.
Legros, J., and Rosner, I. (1971a). Modifications e´lectrore´ti- Physicians’ Desk Reference (PDR) (1998). Medical Economics Data nographiques apre`s administration chronique de fortes doses d’hydroxychloroquine et de de´se´thylhydroxychloroquine chez le rat Pitlick, S., Manor, R. S., Lipshitz, I., et al. (1983). Transient retinal albinos. Arch. Ophthalmol. (Paris) 31, 165–180.
ischaemia induced by nifedipine. Br. Med. J. 287, 1845.
Legros, J., Rosner, I., and Berger, C. (1971b). Ocular effects of chlor- Polak, B. C. P. (1996). Drugs used in ocular treatment. In Meyler’s promazine and oxypertine on beagle dogs. Br. J. Ophthalmol. 55,
Side Effects of Drugs (M. N. G. Dukes, Ed.), 13th ed., pp. 1415– Legros, J., Rosner, I., and Berger, C. (1973). Retinal toxicity of Potsch, L., Skopp, G., and Moeller, M. R. (1997). Influence of pig- chlorpromazine in the rat. Toxicol. Appl. Pharmacol. 26, 459 – 465.
mentation of the codeine content of hair fibers in guinea pigs. J. Leuenberger, P., and Sonntag, R. (1996). Drugs used in tuberculosis Forensic Sci. 42, 1095–1098.
and leprosy. In Meyler’s Side Effects of Drugs (M. N. G. Dukes, Potts, A. M. (1964). The reaction of uveal pigment in vitro with Ed.), 13th ed., pp. 880 –902. Elsevier Science, Amsterdam.
polycyclic compounds. Invest. Ophthalmol. 3, 405– 416.
¨ pkes, S. (1987). Drug-induced degenera- tion of photoreceptor cells. Adv. Biosci. 62, 471– 476.
Potts, A. M. (1996). Toxic responses of the eye. In Casarett and Doull’s Toxicology. The Basic Science of Poisons (C. D. Klaassen, M. O.
¨ llman-Rauch, R. (1991a). Lipidosis and mucopolysaccharidosis of Amdur, and J. Doull, Eds.), pp. 583– 615. McGraw-Hill, New York.
the cornea due to cationic amphiphilic drugs, rat. In Eye and Ear,Monographs on Pathology of Laboratory Animals (T. C. Jones, U.
Poynter, D., Martin, L. E., Harrison, C., and Cook, J. (1976). Affinity Mohr, and R. D. Hunt, Eds.), pp. 25–29. Springer-Verlag, Berlin.
of labetalol for ocular melanin. Br. J. Clin. Pharmacol. Suppl.,711–721.
¨ llman-Rauch, R. (1991b). Lipidosis of the retina due to cationic amphiphilic drugs, rat. In Eye and Ear, Monographs on Pathology Raghavan, P. R., Zane, P. A., and Tripp, S. L. (1990). Calculation of of Laboratory Animals (T. C. Jones, U. Mohr, and R. D. Hunt, drug–melanin binding energy using molecular modeling. Experi- Eds.), pp. 87–92. Springer-Verlag, Berlin.
entia 46(1), 77– 80.
Lyttkens, L., Larsson, B., Stahle, J., and Englesson, S. (1979). Accu- Rahi, A. H. S., Chapman, C. M., Garner, A., and Wright, P. (1976).
mulation of substances with melanin affinity to the internal ear.
Pathology of practolol-induced ocular toxicity. Br. J. Ophthalmol. Therapeutic or ototoxic mechanism? Adv. Oto-Rhino-Laryngol. 25
60, 312–323.
(Front. Vestibular Oculo-Mot. Res.), 17–25.
Render, J. A., and Carlton, W. W. (1985). Ocular lesions of 6-amino- Malmfors, T. (1983). Toxicological studies on zimeldine. Acta Pharm. nicotinamide toxicosis in rabbits. Vet. Pathol. 22, 72–77.
Suec. 20, 295–310.
Rubin, L. F. (1992). Comparative anatomy of the eye. In Manual of Mason, C. G. (1977). Ocular accumulation and toxicity of certain Oculotoxicity Testing of Drugs (O. Hockwin, K. Green, and L. F.
systematically administered drugs. J. Toxicol. Environ. Health 2,
Rubin, Eds.), pp. 21– 44. Gustav Fischer Verlag, Stuttgart.
Rubin, L. F., and Weisse, I. (1992). Species differences relevant for McFarlane, J. R., Yanoff, M., and Scheie, H. G. (1966). Toxic reti- ocular toxicity studies. In Manual of Oculotoxicity Testing of Drugs nopathy following sparsomycin therapy. Arch. Ophthalmol. 76,
(O. Hockwin, K. Green, and L. F. Rubin, Eds.), pp. 177–191.
Salazar, M., Rahwan, R. G., and Patil, P. N. (1976). Binding of Tjalve, H., Nilsson, M., and Larsson, B. (1981). Studies of the binding 14C-imipramine by pigmented and non-pigmented tissues. Eur. of chlorpromazine and chloroquine to melanin in vivo. Biochem. J. Pharmacol. 38, 233–241.
Pharmacol. 30, 1845–1847.
Salazar-Bookaman, M. M., Wainer, I., and Patil, P. N. (1994). Rele- Tolentino, F. I., Foster, C. S., Lahav, M., Liu, L. H. S., and Robin, vance of drug–melanin interactions to ocular pharmacology and A. R. (1982). Toxicity of intravitreous miconazole. Arch. Ophthal- toxicology. J. Ocular Pharmacol. 10, 217–239.
mol. 100, 1504 –1509.
Santos-Anderson, R. M., Tso, M. O., Valdes, J. J., and Annau, Z. (1984).
Van Cauteren, H., Megens, A. A. H. P., Lampo, A., and Meulder- Chronic lead administration in neonatal rats: Electron microscopy of mans, W. (1994). Risperidone: An overview of animal pharmacol- the retina. J. Neuropathol. Exp. Neurol. 43, 175–187.
ogy, toxicology, and pharmacokinetics. Med. Psych. 3, 253–275.
Sarna, T. (1992). Properties and function of the ocular melanin—A Van de Waterbeemd, H. (1997). Pfizer, personal communication photobiophysical view. J. Photochem. Photobiol. B Biol. 12, 215–258.
based on the analysis of 307 commonly used drugs. Source: The Sauer, M. J., and Anderson, S. P. L. (1994). In vitro and in vivo Pharmacological Basis of Therapeutics, (Goodman and Gilman, studies of drug residue accumulation in pigmented tissues. Ana- Eds.), 9th ed. McGraw-Hill, New York, 1996; and Medchem Data- lyst 119, 2553–2556.
base from Daylight Chemical Information Systems Inc.
Shimada, K., Baweja, R., Sokoloski, T., and Patil, P. N. (1976).
Vize, M., and Oster, M. W. (1982). Ocular side effects of cancer Binding characteristics of drugs to synthetic levodopa melanin.
chemotherapy. Cancer 49, 1999 –2002.
J. Pharm. Sci. 65, 1057–1060.
Wakakura, M., and Ishikawa, S. (1984). Central serous chorioreti- Siddall, J. R. (1968). Ocular complications related to phenothiazines.
nopathy complicating systemic corticosteroid treatment. Br. J. Dis. Nerv. Syst. 29, 10 –13.
Ophthalmol. 68, 329 –331.
Slanina, P., and Tjalve, H. (1975). Accumulation of alprenolol in some polypeptide hormone producing cells and in melanin-contain- Weber, U., Goerz, G., Michaelis, L., and Melnik, B. (1988). Disorders ing tissues. Acta Endocrinol. (Copenhagen) 79, 202–208.
of retinal function in long-term therapy with retinoid etretinate.
Klin. Monatsbl. Augenheilkd 192, 706 –711.
Steiner, K., and Buhring, K. U. (1990). The melanin binding of bisopro- lol and its toxicological relevance. Lens Eye Toxicity Res. 7, 319 –333.
Wheater, P. R., Burkitt, H. G., and Daniels, V. G. (1979). Functional Sugano, S., Yanagimoto, M., Suzuki, T., et al. (1994). Retinal com- Histology. Churchill Livingstone, London.
plications with elevated circulationg plasma C5a associated with Willets, G. S. (1969). Ocular side effects of drugs. Br. J. Ophthalmol. interferon-alpha therapy for chronic active hepatitis C. Am. J. Gastroenterol. 89, 2054 –2056.
Zane, P. A., Brindle, S. D., Gause, D. O., O’Buck, A. J., Raghaven, Summers, B. A., Cummings, J. F., and de Lahunta, A. (1995). Vet- P. R., and Tripp, S. L. (1990). Physicochemical factors associated erinary Neuropathology. Mosby Year Book, St. Louis.
with binding and retention of compounds in ocular melanin of rats: Tanenbaum, L., and Tuffanelli, D. L. (1980). Antimalarial agents, Correlations using data from whole body autoradiography and chloroquine, hydroxychloroquine and quinacrine. Arch. Dermatol. molecular modeling for multiple linear regression analyses.
116, 587–591.
Pharm. Res. 7, 935–941.


Microsoft word - colonoscopy_miralax_prep.docx

MiraLAX and Gatorade Colonoscopy Prep Warning Some of your medications such as blood thinners (e.g.: Coumadin/warfarin, xarelto, Aggrenox, pradaxo, Plavix/clopidregel) may need to be stopped for a few days before your procedure. At the time your procedure was scheduled, we would have given you specific instructions of how to manage these changes – you would also want to check with the pres

Online Catalog November 2005 Online Catalog November 2005 Hoodia Cactus kills the appetite and attacks obesity. It has no known side-effects, and contains a molecule thatfools your brain into believing you are full. Deep inside the African Kalahari desert, grows an ugly cactus called the Hoodia. It thrives in extremely hightemperatures, and takes years to mature. The San B

Copyright © 2010-2014 Articles Finder