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Toxic retinopathy following prolonged treatment with dl-(p-trifluoromethylphenyl) isopropylamine hydrochloride (P-1727) in experimental animals
TOXICOLOGY
Toxic with
AND
APPLIED
6,
298-305
(1963)
Retinopathy Following Prolonged Treatment dl-(p-Trifluoromethylphenyl) Isopropylamine Hydrochloride (P-l 727) in Experimental Animals
C. S. DELAHUNT, Department
PHARMACOLOGY
R. A.
of Pharmacology,
R. A.
O’CONNOR,
YEARY,~
Medical Research Laboratories, Groton, Connecticut Received
July
AND
T.
Chas. Pfizer
RUWABARA~ G Co., Inc.,
9, 1962
Scheerer (1926) reported on a condition similar to “retinitis pigmentosa” in patients receiving intravenous doses of iodine-potassium iodide. Verrey (1956), Rintelen et al. (1957), and others detected pigmentary retinopathy due to the phenothiazine compound NP-207. An analog of this compound, thioridazine, has also been shown by May et al. (1960) and Weekley et al. (1960) to produce retinal pigmentary lesions. Other compounds which are known to cause retinal pigment disturbances in humans include: 1,7-di- (p-dimethylaminophenoxy) heptane (Grant, 1958) and chloroquine (Hobbs et al., 1961). There are someagents which have produced an analogous pathologic condition in animals, such as: sodium iodoacetate (Noell, 195l), diaminodiphenoxyalkanes (Sorsby and Nakajima, 1958)) Dithizone (Butterini et al., 1953)) diethyldithiocarbamate (Scholler et al., 1961)) and hydroxypyridinethione (Delahunt et al., 1962). The purpose of this communication is to present material on another compound that causesexperimental retinopathy. This study was part of a chronic toxicity program to assessthe possibilities of any adverse effect of para trifluoromethylphenyl isopropylamine hydrochloride (P-1727)) a potential anorexogenic drug. The general toxic effects of P-l 727 will be only briefly described, but the ocular damage will be reported in more detail. 1 Present address: Chief, Toxicology Section, Lakeside Laboratories, Milwaukee 1, Wisconsin. Harvard University Medical School, 2 Howe Laboratory of Ophthalmology, Boston, Massachusetts. 298
RETINOPATHY
DUE
TO AN
AMPHETAMINE
ANALOG
299
METHODS
Rats Ten weanling rats of the Wistar Strain of each sex received daily oral dosesof 10, 25, and 50 mg/kg of P-1727. The compound was administered via stomach tube, in a 0.1% to 0.5% solution, 6 days per week. An equal number served as controls and received an equal volume of diluent. The animals were equally distributed with respect to weight and sex per dosage level and maintained in individual cages. After 12 weeks, four rats per sex per level were sacrificed and necropsied. Dogs Three groups of six dogs each received daily oral dosesof 10, 25, and 50 mg/kg of P-1727, respectively, 6 days per week. Two mongrels per level were sacrificed at 3 months, and the remainder were immolated at 6 months. Two additional groups of two dogs each acted as positive controls and were given 10 and 5 mg/kg/day of amphetamine for 3 months. Another group of six dogs served as normal controls. The animals were equally distributed with respect to weight and sex per dosagelevel. Daily doseswere administered in hard gelatin capsules; empty capsules were given to the normal controls. Ophthalmoscopic examinations were periodically accomplished. All eye sections were prepared as previously reported (Delahunt et al., 1962). The flat retinal trypsin digestion technique used was that described by Kuwabara and Cogan, 1960. RESULTS
Rats Clinical aspects. There was a dose-responserelated inhibition of food intake with a corresponding retardation of growth rate. Ophthdmoscopic examination. There were no observable changes in the rats on test. HistoZogic evaluation. The retinas from rats receiving 50 mg/kg for 3 months had degenerative change as evidenced by a disappearance of most of the rods and cones. The outer nuclei cells were intertwined within the inner nuclei cells and the outer reticular area had disappeared. There were occasional locales of almost complete retinal atrophy. Loss of rods and cones with some slight alteration noted in the inner and outer nuclear layer architecture was observed in animals receiving 25 mg/ k/day.
300
C.
S. DELAHUNT
ET
AL.
Dogs Clinical aspects. The signs manifested by dogs at the 50 mg/kg/day level were: slight increase in temperature, pulse, and respiration; mydriasis; anorexia; increase in abdominal muscle tone, stiffness of the hind legs; poor hair coat with exfoliation; searching motion of the head; and excitation when touched or stimulated. Frank blindness ensued after the dogs were on test for 5 months. The dogs on the two lower dosage levels showed a proportionally less severe symptomatology.
FIG.
Camera.
1.
Funduscopic The retinal
view of the retina taken with a Noyori Hand vessels are extremely constricted and appear threadlike.
Fundus
Ophthalmoscopic examination. Upon ophthalmoscopic examination, the retinal vessels were occasionally seen to be constricted (see Fig. 1) about a half hour post dose for varying periods. The “eye grounds” had a reddish or hyperemic appearance following vasoconstriction. Some slight retinal pigmentary disturbance was noted from the fifth month. This appeared in the form of a slight black peppery appearance in the tapetal area. A constant and complete vascular constriction with retinal ischemia occurred subsequent to the fifth month. Histologic evaluation. The histologic appearance of the retinas from dogs receiving 50 mg of P-l 727 per kilogram of body weight for 3 months
RETINOPATHY
FIG. 2. This was Hematoxylin
DUE
TO AN
AMPHETAMINE
Note the loss of the visual receptors and a retina from a dog receiving SOmg/kg/day and eosin. Magnification: X 200.
ANALOG
the
301
accumulation of pigment. of P-1727 for 3 months.
FIG. 3. There has been collapsing of the inner and outer nuclear layer, an absence of plexiform layer, a heavy accumulation and migration of pigment, and a loss of rods and cones. This retina came from a dog on P-1727 at SOmg/kg/day for 6 months. Hematoxylin and eosin. Magnification: x 300.
302
C.
S. DELAHUNT
ET
AL.
showed disappearance of rods and cones (Fig. 2). In this area there was an accumulation of melanin-bearing cells and clumps of pigment. The melanin appeared to be coming from the hyperplasic pigment epithelial layer. The eyes from dogs receiving 25 mg/kg/day of P-1727 had only a loss of visual receptor cells. After 6 months at 50 mg/kg/day, the pigmentary migration extended into the optic nerve layer, and the retina TABLE 1 EVALUATION OF DOG AND RAT RETINAS
HISTOLOGIC
Retinal Dose
Duration (months)
Species
Drug
(w/kg)
Dog
P-1727
0 (Controls) 10 2.5 50
P-1727
0 (Controls) 10
25 50 Rat
Dog
P-1727
Amphet.
0 0 0
5
6
0
6 6 6
0 ++ +++
0 Key: +++ severe degenerative slight degenerative damage. b Pigment involvement. C No pigment involvement.
0 0 + ++
3 3 damage;
0 0
++
Frequency (number of animals affected/number of animals examined)
o/2 o/2 o/2 z/zb
++
0 (Controls) 10 25 50
10
+
Degreea
degeneration
moderate
o/4 o/4 4/Q 4/4b O/8 O/8 7p 8/P
o/2 o/2 degenerative
damage;
showed thinning in many areas. This was evident in that the inner and outer nuclear layers had merged (Fig. 3). Retinas from dogs treated with 2.5 mg/kg/day for 6 months resembled those of dogs receiving 50 mg/kg for 3 months. A summary of the histologic evaluation of this study is presented in Table 1. The capillaries of the retinal vessels studied by the trypsin digestion method showed various degrees of ischemic acellular changes (Fig. 4). There also was migration of melanin pigments into the venous walls.
RETINOPATHY
DUE
TO AN
AMPHETAMINE
ANALOG
303
rl mphetamine Dogs The mongrels receiving amphetamine at 10 mg/kg/day had severe symptoms similar to ones manifested by the dogs on SOmg/kg/day of P-1727. The 5 mg/kg/day dose of amphetamine was proportionally less severe. Funduscopically, slight ischemia was occasionally observed in the dogs treated with 10 mg/kg/day of amphetamine. At the 5 mg/kg/day
FIG. 4. Retinal vessel preparation of a dog which received 50 mg/kg/day of P-1727 for 6 months. The endothelial cells in the capillaries have disappeared. Fragments of lytic nuclei are present. There is an accumulation of melanin pigment in the venous walls. Periodic acid-Schiff and hematoxylin. Magnification: X 63.
level of amphetamine the eye grounds were normal. Dogs from both dosage levels had no histologic changes noted in the retina after 3 months. DISCUSSION
These toxicity studies with P-1727 and amphetamine were conducted at extremely high doses, nowhere near the dose that a human would ever ingest. Nevertheless, the retinal findings with P-l 727 in dogs do tend to support Hobbs’ (1959) theory that the possible mechanism of action of the retinopathy due to certain drugs may result from vascular
304
C.
S. DELAHUNT
ET
AL.
spasms. Duggan (1956) stated: “In a pure retinal lesion, we do not get pigment proliferation. In a choroidal lesion with impaired circulation, we get a moderate degree of anoxia and proliferation of pigment occurs.” It may be, therefore, that vasoconstriction occurs not only in the retinal vessels but also in the choroidal (choriocapillaris) blood vasculature of the dogs on P-1727. This latter effect appears to be more critical than the former, since the lesions occur in the rod and cone layer first. The flat retinal vessel ischemia observations on P-l 727 are comparable to those experimentally induced in the feline (Reinecke et al., 1962). There are several common conditions, for example, distemper and hereditary ones (Smith and Jones, 1957), that may cause this type of retinal change in the dog. To eliminate the possibility of spontaneous retinal change, two beagles were treated with P-1727 at 50 mg/kg/day for 3 months. An eye from each dog was surgically removed at the initiation of the investigation and the other eye was removed when they were sacrificed at three months. No histologic changes were noted in the eyes taken at the onset of the study. After three months on P-1727 at 50 mg/kg/day, the ocular changes noted in these retina verified the original findings. In the rodent, retinal degeneration was noted at the 50 mg/kg level at 3 months, but without pigmentary involvement. The albino rat retina does not have a pigmented epithelium and therefore, pigmentary involvement does not take place. The dog was the better experimental animal in following the pathogensis of this lesion. SUMMARY An amphetamine analog, P-1727, dl-(p-trifluoromethylphenyl) drochloride, has been shown to cause blood-vascular changes partment of the dog’s eye on prolonged oral treatment. It is anoxia in the retinochoroid area produced degeneration of the pigmentary proliferation. This phenomenon is related to dose ment. ACKNOWLEDGMENT The
authors
wish
to thank
Miss
Rosemary
Casey
for
isopropylamine hyin the posterior combelieved the resultant visual receptors and a and duration of treat-
her secretarial
assistance.
REFERENCES U., GRIGNOLO, A., and BARONCHELLI, A. (1953). “Diabete” de ditizone: aspetti metabolici, oculari ed istologici, Gior. Clin. Med. (Bologna) 34, 12.53-1347. DELAHUNT, C. S., STEBBINS, R. B., ANDERSON, J., and BAILEY, J. (1962). The cause of blindness in dogs given hydroxypyridinethione. Toxicol. Appl. Pharmacol. 4. 286-291. BUTTERINI,
RETINOPATHY
W. F., in discussion chorioretinopathy following
DUGCAN,
DUE
TO AN
AMPHETAMINE
on GOAR, E. L., and the use of NP-207.
ANALOG
M.
FLETCHER,
Trans.
Am.
305
C. (1956). Toxic Ophthalmol. Sot. 54,
129-139.
W. M. (1958). Drug intoxications and chemical injuries. Systemic Ophthalmology, 2nd ed. Butterworth, London. HOBBS, H. E., SORSBY, A., and FREEDMAN, A. (1959). Retinopathy following chloroquine therapy. Lancet ii, 478-480. (1961). Ocular lesions after treatHOBBS, H. E., EADIE, S. P., and SOMERVILLE, F. ment with chloroquine. Brit. J. Ophthalmol. 45, 284-297. KUWABARA, T., and COGAN, D. G. (1960). Studies of retinal vascular patterns. I. Normal architecture. Arch. Ophthalmol 54, 904-911. MAY, R. H., SELYMES, P., WEEKLEY, R. O., and POTTS, A. M. (1960). Thioridazine therapy: results and complications. J. Nervous Mental Disease 130, 331-339. NOELL, W. K. (1951). Effect of iodoacetate on the vertebrate retina. J. Cellular Camp. Physiol. 37, 283-307. REINECKE, R. D., KUWABARA, T., COGAN, D. G., and WEIS, D. R. (1962). Retinal vascular patterns. V. Experimental ischemia of the cat eye. Arch. OphthaZmoL 67, 470-47s. RINTELEN, F., HOTZ, G., and WAGNER, P. (1957). Zur Klinik und experimentellen Pathologie der Pigmentepithelerkrankung nach Medikation mit einem Piperidinphenothiazin. Ophthalmologica 133, 277-283. SCHEERER, R. (1926). Akuter Zerfall des retinalen Pigmentepithels nach intravenoser Injektion von Septojod im Wochenbett. Klin. Monatsbl. Augenheilk. 76, 524528. Toxicology and pathology of SCHOLLER, J., BROWN, D., and TIMMENS, E. (1961). diethyldithiocarbamate. Pharmacologist 3, 62. (1957). Veterinary Pathology, pp. 915SMITH, H. A., and JONES, T. C., editors. 918. Lea & Febiger, Philadelphia. SORSBY, A., and NAKAJIMA, A. (1958). Experimental degeneration of the retina. Brit. J. Ophthulmol. 42, 563-571. V~REY, A. (1956). Deg&nCrescence pigmentaire de la retine d’origine mCdicamenteuse. Ophthalmologica 131, 296-303. WEEKLEY, R. D., POTTS, A. M., REBOTON, J., and MAY, R. H. (1960). Pigmentary retinopathy in patients receiving high doses of a new phenothiazine. Arch. Ophthalmol. 54. 65-76. GRANT,
Toxic with
AND
APPLIED
6,
298-305
(1963)
Retinopathy Following Prolonged Treatment dl-(p-Trifluoromethylphenyl) Isopropylamine Hydrochloride (P-l 727) in Experimental Animals
C. S. DELAHUNT, Department
PHARMACOLOGY
R. A.
of Pharmacology,
R. A.
O’CONNOR,
YEARY,~
Medical Research Laboratories, Groton, Connecticut Received
July
AND
T.
Chas. Pfizer
RUWABARA~ G Co., Inc.,
9, 1962
Scheerer (1926) reported on a condition similar to “retinitis pigmentosa” in patients receiving intravenous doses of iodine-potassium iodide. Verrey (1956), Rintelen et al. (1957), and others detected pigmentary retinopathy due to the phenothiazine compound NP-207. An analog of this compound, thioridazine, has also been shown by May et al. (1960) and Weekley et al. (1960) to produce retinal pigmentary lesions. Other compounds which are known to cause retinal pigment disturbances in humans include: 1,7-di- (p-dimethylaminophenoxy) heptane (Grant, 1958) and chloroquine (Hobbs et al., 1961). There are someagents which have produced an analogous pathologic condition in animals, such as: sodium iodoacetate (Noell, 195l), diaminodiphenoxyalkanes (Sorsby and Nakajima, 1958)) Dithizone (Butterini et al., 1953)) diethyldithiocarbamate (Scholler et al., 1961)) and hydroxypyridinethione (Delahunt et al., 1962). The purpose of this communication is to present material on another compound that causesexperimental retinopathy. This study was part of a chronic toxicity program to assessthe possibilities of any adverse effect of para trifluoromethylphenyl isopropylamine hydrochloride (P-1727)) a potential anorexogenic drug. The general toxic effects of P-l 727 will be only briefly described, but the ocular damage will be reported in more detail. 1 Present address: Chief, Toxicology Section, Lakeside Laboratories, Milwaukee 1, Wisconsin. Harvard University Medical School, 2 Howe Laboratory of Ophthalmology, Boston, Massachusetts. 298
RETINOPATHY
DUE
TO AN
AMPHETAMINE
ANALOG
299
METHODS
Rats Ten weanling rats of the Wistar Strain of each sex received daily oral dosesof 10, 25, and 50 mg/kg of P-1727. The compound was administered via stomach tube, in a 0.1% to 0.5% solution, 6 days per week. An equal number served as controls and received an equal volume of diluent. The animals were equally distributed with respect to weight and sex per dosage level and maintained in individual cages. After 12 weeks, four rats per sex per level were sacrificed and necropsied. Dogs Three groups of six dogs each received daily oral dosesof 10, 25, and 50 mg/kg of P-1727, respectively, 6 days per week. Two mongrels per level were sacrificed at 3 months, and the remainder were immolated at 6 months. Two additional groups of two dogs each acted as positive controls and were given 10 and 5 mg/kg/day of amphetamine for 3 months. Another group of six dogs served as normal controls. The animals were equally distributed with respect to weight and sex per dosagelevel. Daily doseswere administered in hard gelatin capsules; empty capsules were given to the normal controls. Ophthalmoscopic examinations were periodically accomplished. All eye sections were prepared as previously reported (Delahunt et al., 1962). The flat retinal trypsin digestion technique used was that described by Kuwabara and Cogan, 1960. RESULTS
Rats Clinical aspects. There was a dose-responserelated inhibition of food intake with a corresponding retardation of growth rate. Ophthdmoscopic examination. There were no observable changes in the rats on test. HistoZogic evaluation. The retinas from rats receiving 50 mg/kg for 3 months had degenerative change as evidenced by a disappearance of most of the rods and cones. The outer nuclei cells were intertwined within the inner nuclei cells and the outer reticular area had disappeared. There were occasional locales of almost complete retinal atrophy. Loss of rods and cones with some slight alteration noted in the inner and outer nuclear layer architecture was observed in animals receiving 25 mg/ k/day.
300
C.
S. DELAHUNT
ET
AL.
Dogs Clinical aspects. The signs manifested by dogs at the 50 mg/kg/day level were: slight increase in temperature, pulse, and respiration; mydriasis; anorexia; increase in abdominal muscle tone, stiffness of the hind legs; poor hair coat with exfoliation; searching motion of the head; and excitation when touched or stimulated. Frank blindness ensued after the dogs were on test for 5 months. The dogs on the two lower dosage levels showed a proportionally less severe symptomatology.
FIG.
Camera.
1.
Funduscopic The retinal
view of the retina taken with a Noyori Hand vessels are extremely constricted and appear threadlike.
Fundus
Ophthalmoscopic examination. Upon ophthalmoscopic examination, the retinal vessels were occasionally seen to be constricted (see Fig. 1) about a half hour post dose for varying periods. The “eye grounds” had a reddish or hyperemic appearance following vasoconstriction. Some slight retinal pigmentary disturbance was noted from the fifth month. This appeared in the form of a slight black peppery appearance in the tapetal area. A constant and complete vascular constriction with retinal ischemia occurred subsequent to the fifth month. Histologic evaluation. The histologic appearance of the retinas from dogs receiving 50 mg of P-l 727 per kilogram of body weight for 3 months
RETINOPATHY
FIG. 2. This was Hematoxylin
DUE
TO AN
AMPHETAMINE
Note the loss of the visual receptors and a retina from a dog receiving SOmg/kg/day and eosin. Magnification: X 200.
ANALOG
the
301
accumulation of pigment. of P-1727 for 3 months.
FIG. 3. There has been collapsing of the inner and outer nuclear layer, an absence of plexiform layer, a heavy accumulation and migration of pigment, and a loss of rods and cones. This retina came from a dog on P-1727 at SOmg/kg/day for 6 months. Hematoxylin and eosin. Magnification: x 300.
302
C.
S. DELAHUNT
ET
AL.
showed disappearance of rods and cones (Fig. 2). In this area there was an accumulation of melanin-bearing cells and clumps of pigment. The melanin appeared to be coming from the hyperplasic pigment epithelial layer. The eyes from dogs receiving 25 mg/kg/day of P-1727 had only a loss of visual receptor cells. After 6 months at 50 mg/kg/day, the pigmentary migration extended into the optic nerve layer, and the retina TABLE 1 EVALUATION OF DOG AND RAT RETINAS
HISTOLOGIC
Retinal Dose
Duration (months)
Species
Drug
(w/kg)
Dog
P-1727
0 (Controls) 10 2.5 50
P-1727
0 (Controls) 10
25 50 Rat
Dog
P-1727
Amphet.
0 0 0
5
6
0
6 6 6
0 ++ +++
0 Key: +++ severe degenerative slight degenerative damage. b Pigment involvement. C No pigment involvement.
0 0 + ++
3 3 damage;
0 0
++
Frequency (number of animals affected/number of animals examined)
o/2 o/2 o/2 z/zb
++
0 (Controls) 10 25 50
10
+
Degreea
degeneration
moderate
o/4 o/4 4/Q 4/4b O/8 O/8 7p 8/P
o/2 o/2 degenerative
damage;
showed thinning in many areas. This was evident in that the inner and outer nuclear layers had merged (Fig. 3). Retinas from dogs treated with 2.5 mg/kg/day for 6 months resembled those of dogs receiving 50 mg/kg for 3 months. A summary of the histologic evaluation of this study is presented in Table 1. The capillaries of the retinal vessels studied by the trypsin digestion method showed various degrees of ischemic acellular changes (Fig. 4). There also was migration of melanin pigments into the venous walls.
RETINOPATHY
DUE
TO AN
AMPHETAMINE
ANALOG
303
rl mphetamine Dogs The mongrels receiving amphetamine at 10 mg/kg/day had severe symptoms similar to ones manifested by the dogs on SOmg/kg/day of P-1727. The 5 mg/kg/day dose of amphetamine was proportionally less severe. Funduscopically, slight ischemia was occasionally observed in the dogs treated with 10 mg/kg/day of amphetamine. At the 5 mg/kg/day
FIG. 4. Retinal vessel preparation of a dog which received 50 mg/kg/day of P-1727 for 6 months. The endothelial cells in the capillaries have disappeared. Fragments of lytic nuclei are present. There is an accumulation of melanin pigment in the venous walls. Periodic acid-Schiff and hematoxylin. Magnification: X 63.
level of amphetamine the eye grounds were normal. Dogs from both dosage levels had no histologic changes noted in the retina after 3 months. DISCUSSION
These toxicity studies with P-1727 and amphetamine were conducted at extremely high doses, nowhere near the dose that a human would ever ingest. Nevertheless, the retinal findings with P-l 727 in dogs do tend to support Hobbs’ (1959) theory that the possible mechanism of action of the retinopathy due to certain drugs may result from vascular
304
C.
S. DELAHUNT
ET
AL.
spasms. Duggan (1956) stated: “In a pure retinal lesion, we do not get pigment proliferation. In a choroidal lesion with impaired circulation, we get a moderate degree of anoxia and proliferation of pigment occurs.” It may be, therefore, that vasoconstriction occurs not only in the retinal vessels but also in the choroidal (choriocapillaris) blood vasculature of the dogs on P-1727. This latter effect appears to be more critical than the former, since the lesions occur in the rod and cone layer first. The flat retinal vessel ischemia observations on P-l 727 are comparable to those experimentally induced in the feline (Reinecke et al., 1962). There are several common conditions, for example, distemper and hereditary ones (Smith and Jones, 1957), that may cause this type of retinal change in the dog. To eliminate the possibility of spontaneous retinal change, two beagles were treated with P-1727 at 50 mg/kg/day for 3 months. An eye from each dog was surgically removed at the initiation of the investigation and the other eye was removed when they were sacrificed at three months. No histologic changes were noted in the eyes taken at the onset of the study. After three months on P-1727 at 50 mg/kg/day, the ocular changes noted in these retina verified the original findings. In the rodent, retinal degeneration was noted at the 50 mg/kg level at 3 months, but without pigmentary involvement. The albino rat retina does not have a pigmented epithelium and therefore, pigmentary involvement does not take place. The dog was the better experimental animal in following the pathogensis of this lesion. SUMMARY An amphetamine analog, P-1727, dl-(p-trifluoromethylphenyl) drochloride, has been shown to cause blood-vascular changes partment of the dog’s eye on prolonged oral treatment. It is anoxia in the retinochoroid area produced degeneration of the pigmentary proliferation. This phenomenon is related to dose ment. ACKNOWLEDGMENT The
authors
wish
to thank
Miss
Rosemary
Casey
for
isopropylamine hyin the posterior combelieved the resultant visual receptors and a and duration of treat-
her secretarial
assistance.
REFERENCES U., GRIGNOLO, A., and BARONCHELLI, A. (1953). “Diabete” de ditizone: aspetti metabolici, oculari ed istologici, Gior. Clin. Med. (Bologna) 34, 12.53-1347. DELAHUNT, C. S., STEBBINS, R. B., ANDERSON, J., and BAILEY, J. (1962). The cause of blindness in dogs given hydroxypyridinethione. Toxicol. Appl. Pharmacol. 4. 286-291. BUTTERINI,
RETINOPATHY
W. F., in discussion chorioretinopathy following
DUGCAN,
DUE
TO AN
AMPHETAMINE
on GOAR, E. L., and the use of NP-207.
ANALOG
M.
FLETCHER,
Trans.
Am.
305
C. (1956). Toxic Ophthalmol. Sot. 54,
129-139.
W. M. (1958). Drug intoxications and chemical injuries. Systemic Ophthalmology, 2nd ed. Butterworth, London. HOBBS, H. E., SORSBY, A., and FREEDMAN, A. (1959). Retinopathy following chloroquine therapy. Lancet ii, 478-480. (1961). Ocular lesions after treatHOBBS, H. E., EADIE, S. P., and SOMERVILLE, F. ment with chloroquine. Brit. J. Ophthalmol. 45, 284-297. KUWABARA, T., and COGAN, D. G. (1960). Studies of retinal vascular patterns. I. Normal architecture. Arch. Ophthalmol 54, 904-911. MAY, R. H., SELYMES, P., WEEKLEY, R. O., and POTTS, A. M. (1960). Thioridazine therapy: results and complications. J. Nervous Mental Disease 130, 331-339. NOELL, W. K. (1951). Effect of iodoacetate on the vertebrate retina. J. Cellular Camp. Physiol. 37, 283-307. REINECKE, R. D., KUWABARA, T., COGAN, D. G., and WEIS, D. R. (1962). Retinal vascular patterns. V. Experimental ischemia of the cat eye. Arch. OphthaZmoL 67, 470-47s. RINTELEN, F., HOTZ, G., and WAGNER, P. (1957). Zur Klinik und experimentellen Pathologie der Pigmentepithelerkrankung nach Medikation mit einem Piperidinphenothiazin. Ophthalmologica 133, 277-283. SCHEERER, R. (1926). Akuter Zerfall des retinalen Pigmentepithels nach intravenoser Injektion von Septojod im Wochenbett. Klin. Monatsbl. Augenheilk. 76, 524528. Toxicology and pathology of SCHOLLER, J., BROWN, D., and TIMMENS, E. (1961). diethyldithiocarbamate. Pharmacologist 3, 62. (1957). Veterinary Pathology, pp. 915SMITH, H. A., and JONES, T. C., editors. 918. Lea & Febiger, Philadelphia. SORSBY, A., and NAKAJIMA, A. (1958). Experimental degeneration of the retina. Brit. J. Ophthulmol. 42, 563-571. V~REY, A. (1956). Deg&nCrescence pigmentaire de la retine d’origine mCdicamenteuse. Ophthalmologica 131, 296-303. WEEKLEY, R. D., POTTS, A. M., REBOTON, J., and MAY, R. H. (1960). Pigmentary retinopathy in patients receiving high doses of a new phenothiazine. Arch. Ophthalmol. 54. 65-76. GRANT,