Drug and Chemical Toxicology
ISSN: 0148-0545 (Print) 1525-6014 (Online) Journal homepage: http://www.tandfonline.com/loi/idct20
Ocular Toxicity in Beagle Dogs with Lortalamine, A Non Tricyclic Antidepressant Compound Ch. Mally & J. J. Thiebault To cite this article: Ch. Mally & J. J. Thiebault (1990) Ocular Toxicity in Beagle Dogs with Lortalamine, A Non Tricyclic Antidepressant Compound, Drug and Chemical Toxicology, 13:4, 309-323, DOI: 10.3109/01480549009032289 To link to this article: http://dx.doi.org/10.3109/01480549009032289
Published online: 27 Sep 2008.
Submit your article to this journal
Article views: 4
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=idct20 Download by: [University of Tasmania]
Date: 29 September 2015, At: 10:05
DRUG AND CHEMICAL TOXICOLOGY, 1 3 ( 4 ) , 309-323 ( 1 9 9 0 )
OCULAR TOXICITY IN BEAGLE DOGS WITH LORTALAMINE,
Downloaded by [University of Tasmania] at 10:05 29 September 2015
A NON TRICYCLIC ANTIDEPRESSANT COMPOUND.
Ch. MALLY S e r v i c e d'Evaluation d e la S C c u r i t e d e s M e d i c a m e n t s LIPHA, Centre d e Recherche5
3 4 , R u e St Rornain B.P. 8481 69359 LYON CEDEX 08 FRANCE
J . J . THIEBAULT
Laboratoire d e Physioloqie et Thkrapeutique Ecole Nationale Vetkrinaire B.P. 31 69752 CHARBONNIERES CEDEX
FRANCE
ABSTRACT
During a preclinical safety evaluation s t u d y , a n indication of ocular toxicity was noted in beagle d o g s receiving orally 309 Copyright 0 1990 by Marcel Dekker, Inc.
MALLY AND THIEBAULT
310
(gelatin capsules) once a day, 7 days a week for, respectively, 7 and 91 days, 10 mg/kg/day of Lortalamine, a new non-tricyclic anti-depressant compound. Lortalamine treated dogs showed, progressively, bilateral mydriasis, conjunctivitis, epiphora,
Downloaded by [University of Tasmania] at 10:05 29 September 2015
corneal oedema and corneal erosions from day 2 t o day 7. Thereafter, even though treatment goes on, ocular lesions were progressively improved, and inflammation and swelling of both cornea slowly reversed, especially from day 8 to 30. These ocular changes were very similar to those reported with sympathomimetic agents. It was speculated that these lesions, following chronic oral administration of Lortalamine which induced high levels of the compound and its metabolite in the cornea, were related to an increased binding of norepinephrine to adrenergic receptors since the compound inhibits the re-uptake of the transmitter into the storing vesicles.
INTRODUCTION
LORTALAMINE or ( + / - ) 8 - Chloro - 1 , 2, 3 , 4 , 10, 10a - hexahydro - 2 - methyl
3, 2
-
4a, 10 - (imino ethano) - 4 a H - 1 benzopyrano
- c pyridin
- 12
- one ( 4 a
, 10 , 10 a) or LM 1404" is an
antidepressant compound which belongs to a new chemical group recently synthesized in our laboratories. I t is structurally dissimilar to tricyclics such as amitryptylin or desipramine and is apparently more potent1.
OCULAR TOXICITY
311
In the course of different oral toxicity studies in beagle dogs, indications of ocular toxicity were noted. Ocular lesions consisted of mydriasis, conjunctivitis and ulcerative keratitis. It was speculated that the apex of the ocular symptomatology was
Downloaded by [University of Tasmania] at 10:05 29 September 2015
situated on day 7 of treatment and stabilized and even regressed afterwards, even though treatment goes on. Two contemporary studies have been undertaken in order to characterize the ocular lesions and establish a chronology of the symptomatology. During the course of the study, other clinical signs observed included convulsive crises, hyperactivity, hyperexcitability, stereotyped movements, hyperthermia and ptyalism, together with an anorexia associated with a l o s s of weight. Only the ocular abnormalities are presented in this report. These studies were conducted according to the GLP regulationsz in the testing facilities of the research centre of Lipha in Lyon (France).
METHODS
1 - Animals
37
adult (8 - 12 months old) purebred beagle dogs (CEDS, MEZILLES
89130 TOUCY FRANCE) were used in these experiments. The weight range o f the animals when they arrived in the animal unit was 9.2
312
MALLY AND THIEBAULT
- 13 kg for the males and 7.6 - 11.7 kg for the females. In addition to the classical vaccinations (canine distemper, leptospirosis, hepatitis and rabies) undertaken before their arrival and the vermifugation ( L tetramizole) all the animals
Downloaded by [University of Tasmania] at 10:05 29 September 2015
were subjected to a detailed veterinary examination to ensure the selected dogs were in good health.
2 - Accommodation and hous n9
In the animal units, temperature and relative humidity were controlled and observed daily. The lighting inside the unit was controlled by time switch, allowing a 12 hours liqht/dark cycle, light hours being 07.00 - 19.00 h. On arrival, the dogs were housed at random singly in tiled cages whose bottom has a stainless steel wire mesh floor equipped with drinking water facilities and food hoppers and correctly labelled. The minimum acclimatation period was 14 days.
3 - Diet and water
Each animal was offered 25 g/kg of a complete dry diet of known formulation (DOKO, supplied by TROUW FRANCE 02140 FONTAINES LES VERVINS, FRANCE) with a maximum of 300 g per dog. This amount of food will not change anymore according to the animal weight during the study. Domestic quality drinking water was available ad libitum.
OCULAR TOXICITY
4
313
- Dose levels and grouping
On one hand, nine beagle dogs of each sex received Lortalamine orally in gelatin capsules for seven days and three males and two
Downloaded by [University of Tasmania] at 10:05 29 September 2015
females received empty gelatin capsules and served as controls. On the other hand, 5 dogs of each sex received Lortalamine orally in gelatin capsules for 91 days and 2 males and 2 females receited empty qelatin capsules and served as controls. Treated animals received 10 mg of Lortalamine per kg once a day, seven days a week. The batch of Lortalamine used (JJZ 763) was considered as pure at about 100 % . The melting point was about 2 4 6 ° C and the UV and IR spectra were consistent with the chemical structure. Formulation into gelatin capsules was undertaken weekly, the capsules for each animal were prepared using the most recent body weight (the day before) to calculate daily dose requirements.
5 - Observations and measurements
Ocular examinations Physical examinations including direct ophthalmology (WELCH-ALLYN, U.S.A.) were conducted once prior to the first dose day, and daily. Thereafter, evidence of conjunctivitis, dilatation of pupils, and corneal and nictitating membrane modifications were recorded.
MALLY AND THIEBAULT
314 100
DOGS (%) 80
60
-a- MYDRlASlS + CONJUNCTIVITIS 4 CORNEAL OEDEMA -A- CORNEAL EROSIONS
Downloaded by [University of Tasmania] at 10:05 29 September 2015
40
20
0
D1
D2
D3
D4
DS
D6
D7
DAYS
FIGURE 1 Percent of beagle dogs treated orally with Lortalamine ( 1 0 mg/kg/day) exhibiting ocular changes for a 7 day period (28 dogs).
Body weight The animals were weighed weekly beginning one week pretrial and throughout the dosing phase of the study.
Post mortem examinations
The dogs were necropsied the day after the last administration with the corresponding controls that is to say on days 8 and 92.
RESULTS
Ocular changes were exhibited to varying degrees by different Lortalamine treated dogs. Progressively occuring signs included
315
Downloaded by [University of Tasmania] at 10:05 29 September 2015
OCULAR TOXICITY
FIGURE 2 Dog 638 on the sixth day of dosing with Lortalamine. Extensive c o r n e a l oedema (left eye) and seromucoid conjunctival secretions are present.
MALLY AND THIEBAULT
Downloaded by [University of Tasmania] at 10:05 29 September 2015
316
FIGURE 3
Right eye of dog 1350 on the eleventh day of dosing with Lortalamine. A large corneal ulceration, pannus (a), and corneal oedema are present.
bilateral mydriasis, conjunctivitis, epiphora, corneal oedema and more o r less extensive corneal erosions (Figure 1). Mydriasis was observed in all dogs on day 1 and only in some animals on day 7. Redness developed in the conjunctiva of some dogs on day 1 ( 3 dogs) and was always noted on day 4. Subacute or marked as severe ocular lesions developed. The latter consisted of mild corneal opacities (loss of surface corneal reflectivity) or extensive corneal oedema leading to a completely cloudy cornea
317
Downloaded by [University of Tasmania] at 10:05 29 September 2015
OCULAR TOXICITY
FIGURE 4
Right eye of dog 335 on the eiqhth day of dosing with Lortalamine. Focal corneal oedema, corneal ulceration, descemetocele (b) and chemosis are present.
(Figure 2 ) . These troubles were detected in an increasing number of dogs from day 2 t o day 7.
From day 3 to day 6 , dogs with corneal abnormalities exhibited to varying degrees corneal erosions (Figure 3). down to Descemet’s membrane in some subjects (Figure 4 ) , leading to acute ulcerative keratitis. Associated signs included injection of scleral vessels, increased quantities of seromucoid material in the conjunctival sac, photophobia. myosis, conjunctival and corneal
MALLY AND THIEBAULT
Downloaded by [University of Tasmania] at 10:05 29 September 2015
318
FIGURE 5
Right eye of dog 1350 on the fiftysixth day of dosing with Lortalamine. Central corneal opacity and corneal neovascularization are present, as a result of scarred corneal ulceration.
inflammation and oedema and iris staphyloma (one dog). Unilateral o r bilateral iridial hemorrhages ( 2 dogs) and unilateral hyphema
(1 dog) were also noted on days 6 and 7. From day 8 to day 30
ocular lesions were progressively improved:
inflammation and swe ling of both cornea and conjunctiva slowly reversed as corneal ulcerations were filled with scar tissue (Figure 5). Corneal neovascularization was constantly observed. From day 30 to day 91, no ocular changes were detected (Figure 6)
319
OCULAR TOXICITY
DOGS( %) ' 080 °1
Downloaded by [University of Tasmania] at 10:05 29 September 2015
60
40
20
0 0
10
20
30
40
I
1-91,
DAYS FIGURE 6 Percent of beagle dogs treated orally with Lortalamine ( 1 0 mg/kg/day) f o r 90 days exhibiting corneal ulcerations (10 dogs).
except progressively reversing corneal opacities as a result of scarred corneal ulcerations.
DISCUSSION
The ocular effects of Lortalamine, a non-tricyclic antidepressant were evaluated in beagle dogs receiving 10 mg/kg/day doses in the course of 7 and 90 day oral toxicity studies. Lortalamine induced ocular abnormalities, including initial mydriasis, conjunctivitis
320
MALLY AND THIEBAULT
and progressive ulcerative keratitis which were very similar to those reported by previous workers with sympathomimetic agents3. Systemically administered compounds have to cross the blood-aqueous barrier to reach the cornea..
Chronic oral
Downloaded by [University of Tasmania] at 10:05 29 September 2015
administration of Lortalamine has induced high levels of the compound and its metabolite in the cornea, and to a lesser degree in the lens and the aqueous humor of orally dosed dogs”. Lortalamine has been shown to act as a potent norepinephrine uptake inhibitore and norepinephrine is known to activate both alpha and beta adrenergic receptors. Furthermore, alpha and beta adrenergic receptors have been identified in the eye and its adnexa, and ocular functions are known to be highly controled via adrenergic innervation7. Thus, the effects of chronically administered Lortalamine on the eye may be related to an increased binding of physiologically released norepinephrine to adrenergic receptors since the compound inhibits re-uptake of the transmitter into the storing vesicles. Sympathomimetic compounds have been known to induce mydriasis and an increase in tear flow‘. The occurence of pupillary dilatation on day 1 and of
epiphora on day 4 in all dogs may be related to the stimulation of adrenergic receptors by endogenous release of norepinephrine. Furthermore, the corneal epithelium has been shown to be densely provided with the beta-type of adrenergic receptors, and it has been established- that stimulation of these receptors may lead to effects (inhibition of cell-sliding, inhibition of mitosis,
321
OCULAR TOXICITY
loosening of epithelial adhesion to the stroma) that will delay healing of corneal wounds and ulcerslO. Thus, such corneal beta adrenergic receptor stimulation by increased release of norepinephrine may cause the progressively occuring corneal
Downloaded by [University of Tasmania] at 10:05 29 September 2015
erosions observed in Lortalamine treated dogs. Here, it should be pointed out that corneal erosions and chemosis became evident in treated dogs from day 3 to day 7 . Since the outer epithelial layer of the cornea has high mitotic activity and is regenerated every 5-7 days’, it may be expected that a rapidly occuring inhibition of corneal cell mitosis in Lortalamine treated dogs is related to the few days delayed appearance of corneal ulcerations. Progressive improvement of ocular lesions from day 8 to day 30 as daily Lortalamine continued to be administered may be explained on the basis of an increased metabolism of the compound in treated dogs. However the most abundant metabolite of Lortalamine (N-demethylated product
=
N-desmethy1-Lortalamine)ll has been
shown to be almost as potent as the authentic cornpoundlz. In addition, long term oral toxicity studies in the dog13 have suggested that no modification of the metabolic fate or plasma kinetics occured during chronic administration. Since daily administered Lortalamine might lead to an increasgd release of adrenergic transmitters and subsequent increased stimulation of adrenergic structures of the eye, reversing
3 22
MALLY AND THIEBAULT
corneal changes might therefore be related to a decreased density or catecholamine sensitivity of corneal beta adrenergic receptors
Downloaded by [University of Tasmania] at 10:05 29 September 2015
("down requlation")14*15.
REFERENCES
P. Briet, J.J. Berthelon, J.C. Depin
U.S.
Patent, 4 , 201,
783 (1980). Federal Register (21 CFR, part 58), Amendment April 11, (1980)and September 0 4 , (1987). Good Laboratory Practice For Non Clinical Laboratory Studies. G. R. Steffen, J.D. Henderson Jr., R.A. Nelson, M.T. Case and
D.R. Saunders - Drug Chem. Toxicol., 4 -
3 , 165 (1980).
R. Heywood, Environ. Health Perspect. 44, 35 (1982).
5 - M. Belleville, unpublished data (Feb. 1986). 6 - J.C. Depin, A . Betbeder-Matibet, Y. Bonhomme, A.J. Muller and J.J. Berthelon, Arzneim.-Forsch./ Drug Res.
7 - M. Wiederholt, NIPS,
3,
3 , 1655 (1985)
97 (1988).
8 - N. Tanaka, T. Ohkawa. T.Hiyama and A. Nakajima - J.Pharmaco1.
Exp. Ther., 224, 4 2 4 (1983). 9 - L. Krejci and R. Harrison, Arch. Ophthalmol.
83, 451 (1957).
10 - A.H. Neufeld, K.A. Zawistowski, E.D. Page and B.B.Bromberg,
Invest. Ophthalmol.
11, 1069
(1978).
323
OCULAR TOXICITY
11
- L. F. Elsom, S.R. Biggs, L.F. Chasseaud, D.R. Hawkins, J. Pulsford and A . Darragh - Europ. J. of Drug Metab. Pharmacokinet.
12
lo, 209
(1985).
- M . Belleville, M. Grand and P. Briet - Drug Metab. Dispos.,
Downloaded by [University of Tasmania] at 10:05 29 September 2015
9 , 233 ( 1 9 8 1 ) . 1 3 - M. Belleville, unpublished data (Jan. 1 9 8 6 ) .
14
- R.L. Huganir and D. Greengard, TIPS, g,
15
- C.D. Strader, I.S. Sigal and A.F. Dixon, FASEB J., 3, (1989).
472 ( 1 9 8 7 ) . 1825
ISSN: 0148-0545 (Print) 1525-6014 (Online) Journal homepage: http://www.tandfonline.com/loi/idct20
Ocular Toxicity in Beagle Dogs with Lortalamine, A Non Tricyclic Antidepressant Compound Ch. Mally & J. J. Thiebault To cite this article: Ch. Mally & J. J. Thiebault (1990) Ocular Toxicity in Beagle Dogs with Lortalamine, A Non Tricyclic Antidepressant Compound, Drug and Chemical Toxicology, 13:4, 309-323, DOI: 10.3109/01480549009032289 To link to this article: http://dx.doi.org/10.3109/01480549009032289
Published online: 27 Sep 2008.
Submit your article to this journal
Article views: 4
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=idct20 Download by: [University of Tasmania]
Date: 29 September 2015, At: 10:05
DRUG AND CHEMICAL TOXICOLOGY, 1 3 ( 4 ) , 309-323 ( 1 9 9 0 )
OCULAR TOXICITY IN BEAGLE DOGS WITH LORTALAMINE,
Downloaded by [University of Tasmania] at 10:05 29 September 2015
A NON TRICYCLIC ANTIDEPRESSANT COMPOUND.
Ch. MALLY S e r v i c e d'Evaluation d e la S C c u r i t e d e s M e d i c a m e n t s LIPHA, Centre d e Recherche5
3 4 , R u e St Rornain B.P. 8481 69359 LYON CEDEX 08 FRANCE
J . J . THIEBAULT
Laboratoire d e Physioloqie et Thkrapeutique Ecole Nationale Vetkrinaire B.P. 31 69752 CHARBONNIERES CEDEX
FRANCE
ABSTRACT
During a preclinical safety evaluation s t u d y , a n indication of ocular toxicity was noted in beagle d o g s receiving orally 309 Copyright 0 1990 by Marcel Dekker, Inc.
MALLY AND THIEBAULT
310
(gelatin capsules) once a day, 7 days a week for, respectively, 7 and 91 days, 10 mg/kg/day of Lortalamine, a new non-tricyclic anti-depressant compound. Lortalamine treated dogs showed, progressively, bilateral mydriasis, conjunctivitis, epiphora,
Downloaded by [University of Tasmania] at 10:05 29 September 2015
corneal oedema and corneal erosions from day 2 t o day 7. Thereafter, even though treatment goes on, ocular lesions were progressively improved, and inflammation and swelling of both cornea slowly reversed, especially from day 8 to 30. These ocular changes were very similar to those reported with sympathomimetic agents. It was speculated that these lesions, following chronic oral administration of Lortalamine which induced high levels of the compound and its metabolite in the cornea, were related to an increased binding of norepinephrine to adrenergic receptors since the compound inhibits the re-uptake of the transmitter into the storing vesicles.
INTRODUCTION
LORTALAMINE or ( + / - ) 8 - Chloro - 1 , 2, 3 , 4 , 10, 10a - hexahydro - 2 - methyl
3, 2
-
4a, 10 - (imino ethano) - 4 a H - 1 benzopyrano
- c pyridin
- 12
- one ( 4 a
, 10 , 10 a) or LM 1404" is an
antidepressant compound which belongs to a new chemical group recently synthesized in our laboratories. I t is structurally dissimilar to tricyclics such as amitryptylin or desipramine and is apparently more potent1.
OCULAR TOXICITY
311
In the course of different oral toxicity studies in beagle dogs, indications of ocular toxicity were noted. Ocular lesions consisted of mydriasis, conjunctivitis and ulcerative keratitis. It was speculated that the apex of the ocular symptomatology was
Downloaded by [University of Tasmania] at 10:05 29 September 2015
situated on day 7 of treatment and stabilized and even regressed afterwards, even though treatment goes on. Two contemporary studies have been undertaken in order to characterize the ocular lesions and establish a chronology of the symptomatology. During the course of the study, other clinical signs observed included convulsive crises, hyperactivity, hyperexcitability, stereotyped movements, hyperthermia and ptyalism, together with an anorexia associated with a l o s s of weight. Only the ocular abnormalities are presented in this report. These studies were conducted according to the GLP regulationsz in the testing facilities of the research centre of Lipha in Lyon (France).
METHODS
1 - Animals
37
adult (8 - 12 months old) purebred beagle dogs (CEDS, MEZILLES
89130 TOUCY FRANCE) were used in these experiments. The weight range o f the animals when they arrived in the animal unit was 9.2
312
MALLY AND THIEBAULT
- 13 kg for the males and 7.6 - 11.7 kg for the females. In addition to the classical vaccinations (canine distemper, leptospirosis, hepatitis and rabies) undertaken before their arrival and the vermifugation ( L tetramizole) all the animals
Downloaded by [University of Tasmania] at 10:05 29 September 2015
were subjected to a detailed veterinary examination to ensure the selected dogs were in good health.
2 - Accommodation and hous n9
In the animal units, temperature and relative humidity were controlled and observed daily. The lighting inside the unit was controlled by time switch, allowing a 12 hours liqht/dark cycle, light hours being 07.00 - 19.00 h. On arrival, the dogs were housed at random singly in tiled cages whose bottom has a stainless steel wire mesh floor equipped with drinking water facilities and food hoppers and correctly labelled. The minimum acclimatation period was 14 days.
3 - Diet and water
Each animal was offered 25 g/kg of a complete dry diet of known formulation (DOKO, supplied by TROUW FRANCE 02140 FONTAINES LES VERVINS, FRANCE) with a maximum of 300 g per dog. This amount of food will not change anymore according to the animal weight during the study. Domestic quality drinking water was available ad libitum.
OCULAR TOXICITY
4
313
- Dose levels and grouping
On one hand, nine beagle dogs of each sex received Lortalamine orally in gelatin capsules for seven days and three males and two
Downloaded by [University of Tasmania] at 10:05 29 September 2015
females received empty gelatin capsules and served as controls. On the other hand, 5 dogs of each sex received Lortalamine orally in gelatin capsules for 91 days and 2 males and 2 females receited empty qelatin capsules and served as controls. Treated animals received 10 mg of Lortalamine per kg once a day, seven days a week. The batch of Lortalamine used (JJZ 763) was considered as pure at about 100 % . The melting point was about 2 4 6 ° C and the UV and IR spectra were consistent with the chemical structure. Formulation into gelatin capsules was undertaken weekly, the capsules for each animal were prepared using the most recent body weight (the day before) to calculate daily dose requirements.
5 - Observations and measurements
Ocular examinations Physical examinations including direct ophthalmology (WELCH-ALLYN, U.S.A.) were conducted once prior to the first dose day, and daily. Thereafter, evidence of conjunctivitis, dilatation of pupils, and corneal and nictitating membrane modifications were recorded.
MALLY AND THIEBAULT
314 100
DOGS (%) 80
60
-a- MYDRlASlS + CONJUNCTIVITIS 4 CORNEAL OEDEMA -A- CORNEAL EROSIONS
Downloaded by [University of Tasmania] at 10:05 29 September 2015
40
20
0
D1
D2
D3
D4
DS
D6
D7
DAYS
FIGURE 1 Percent of beagle dogs treated orally with Lortalamine ( 1 0 mg/kg/day) exhibiting ocular changes for a 7 day period (28 dogs).
Body weight The animals were weighed weekly beginning one week pretrial and throughout the dosing phase of the study.
Post mortem examinations
The dogs were necropsied the day after the last administration with the corresponding controls that is to say on days 8 and 92.
RESULTS
Ocular changes were exhibited to varying degrees by different Lortalamine treated dogs. Progressively occuring signs included
315
Downloaded by [University of Tasmania] at 10:05 29 September 2015
OCULAR TOXICITY
FIGURE 2 Dog 638 on the sixth day of dosing with Lortalamine. Extensive c o r n e a l oedema (left eye) and seromucoid conjunctival secretions are present.
MALLY AND THIEBAULT
Downloaded by [University of Tasmania] at 10:05 29 September 2015
316
FIGURE 3
Right eye of dog 1350 on the eleventh day of dosing with Lortalamine. A large corneal ulceration, pannus (a), and corneal oedema are present.
bilateral mydriasis, conjunctivitis, epiphora, corneal oedema and more o r less extensive corneal erosions (Figure 1). Mydriasis was observed in all dogs on day 1 and only in some animals on day 7. Redness developed in the conjunctiva of some dogs on day 1 ( 3 dogs) and was always noted on day 4. Subacute or marked as severe ocular lesions developed. The latter consisted of mild corneal opacities (loss of surface corneal reflectivity) or extensive corneal oedema leading to a completely cloudy cornea
317
Downloaded by [University of Tasmania] at 10:05 29 September 2015
OCULAR TOXICITY
FIGURE 4
Right eye of dog 335 on the eiqhth day of dosing with Lortalamine. Focal corneal oedema, corneal ulceration, descemetocele (b) and chemosis are present.
(Figure 2 ) . These troubles were detected in an increasing number of dogs from day 2 t o day 7.
From day 3 to day 6 , dogs with corneal abnormalities exhibited to varying degrees corneal erosions (Figure 3). down to Descemet’s membrane in some subjects (Figure 4 ) , leading to acute ulcerative keratitis. Associated signs included injection of scleral vessels, increased quantities of seromucoid material in the conjunctival sac, photophobia. myosis, conjunctival and corneal
MALLY AND THIEBAULT
Downloaded by [University of Tasmania] at 10:05 29 September 2015
318
FIGURE 5
Right eye of dog 1350 on the fiftysixth day of dosing with Lortalamine. Central corneal opacity and corneal neovascularization are present, as a result of scarred corneal ulceration.
inflammation and oedema and iris staphyloma (one dog). Unilateral o r bilateral iridial hemorrhages ( 2 dogs) and unilateral hyphema
(1 dog) were also noted on days 6 and 7. From day 8 to day 30
ocular lesions were progressively improved:
inflammation and swe ling of both cornea and conjunctiva slowly reversed as corneal ulcerations were filled with scar tissue (Figure 5). Corneal neovascularization was constantly observed. From day 30 to day 91, no ocular changes were detected (Figure 6)
319
OCULAR TOXICITY
DOGS( %) ' 080 °1
Downloaded by [University of Tasmania] at 10:05 29 September 2015
60
40
20
0 0
10
20
30
40
I
1-91,
DAYS FIGURE 6 Percent of beagle dogs treated orally with Lortalamine ( 1 0 mg/kg/day) f o r 90 days exhibiting corneal ulcerations (10 dogs).
except progressively reversing corneal opacities as a result of scarred corneal ulcerations.
DISCUSSION
The ocular effects of Lortalamine, a non-tricyclic antidepressant were evaluated in beagle dogs receiving 10 mg/kg/day doses in the course of 7 and 90 day oral toxicity studies. Lortalamine induced ocular abnormalities, including initial mydriasis, conjunctivitis
320
MALLY AND THIEBAULT
and progressive ulcerative keratitis which were very similar to those reported by previous workers with sympathomimetic agents3. Systemically administered compounds have to cross the blood-aqueous barrier to reach the cornea..
Chronic oral
Downloaded by [University of Tasmania] at 10:05 29 September 2015
administration of Lortalamine has induced high levels of the compound and its metabolite in the cornea, and to a lesser degree in the lens and the aqueous humor of orally dosed dogs”. Lortalamine has been shown to act as a potent norepinephrine uptake inhibitore and norepinephrine is known to activate both alpha and beta adrenergic receptors. Furthermore, alpha and beta adrenergic receptors have been identified in the eye and its adnexa, and ocular functions are known to be highly controled via adrenergic innervation7. Thus, the effects of chronically administered Lortalamine on the eye may be related to an increased binding of physiologically released norepinephrine to adrenergic receptors since the compound inhibits re-uptake of the transmitter into the storing vesicles. Sympathomimetic compounds have been known to induce mydriasis and an increase in tear flow‘. The occurence of pupillary dilatation on day 1 and of
epiphora on day 4 in all dogs may be related to the stimulation of adrenergic receptors by endogenous release of norepinephrine. Furthermore, the corneal epithelium has been shown to be densely provided with the beta-type of adrenergic receptors, and it has been established- that stimulation of these receptors may lead to effects (inhibition of cell-sliding, inhibition of mitosis,
321
OCULAR TOXICITY
loosening of epithelial adhesion to the stroma) that will delay healing of corneal wounds and ulcerslO. Thus, such corneal beta adrenergic receptor stimulation by increased release of norepinephrine may cause the progressively occuring corneal
Downloaded by [University of Tasmania] at 10:05 29 September 2015
erosions observed in Lortalamine treated dogs. Here, it should be pointed out that corneal erosions and chemosis became evident in treated dogs from day 3 to day 7 . Since the outer epithelial layer of the cornea has high mitotic activity and is regenerated every 5-7 days’, it may be expected that a rapidly occuring inhibition of corneal cell mitosis in Lortalamine treated dogs is related to the few days delayed appearance of corneal ulcerations. Progressive improvement of ocular lesions from day 8 to day 30 as daily Lortalamine continued to be administered may be explained on the basis of an increased metabolism of the compound in treated dogs. However the most abundant metabolite of Lortalamine (N-demethylated product
=
N-desmethy1-Lortalamine)ll has been
shown to be almost as potent as the authentic cornpoundlz. In addition, long term oral toxicity studies in the dog13 have suggested that no modification of the metabolic fate or plasma kinetics occured during chronic administration. Since daily administered Lortalamine might lead to an increasgd release of adrenergic transmitters and subsequent increased stimulation of adrenergic structures of the eye, reversing
3 22
MALLY AND THIEBAULT
corneal changes might therefore be related to a decreased density or catecholamine sensitivity of corneal beta adrenergic receptors
Downloaded by [University of Tasmania] at 10:05 29 September 2015
("down requlation")14*15.
REFERENCES
P. Briet, J.J. Berthelon, J.C. Depin
U.S.
Patent, 4 , 201,
783 (1980). Federal Register (21 CFR, part 58), Amendment April 11, (1980)and September 0 4 , (1987). Good Laboratory Practice For Non Clinical Laboratory Studies. G. R. Steffen, J.D. Henderson Jr., R.A. Nelson, M.T. Case and
D.R. Saunders - Drug Chem. Toxicol., 4 -
3 , 165 (1980).
R. Heywood, Environ. Health Perspect. 44, 35 (1982).
5 - M. Belleville, unpublished data (Feb. 1986). 6 - J.C. Depin, A . Betbeder-Matibet, Y. Bonhomme, A.J. Muller and J.J. Berthelon, Arzneim.-Forsch./ Drug Res.
7 - M. Wiederholt, NIPS,
3,
3 , 1655 (1985)
97 (1988).
8 - N. Tanaka, T. Ohkawa. T.Hiyama and A. Nakajima - J.Pharmaco1.
Exp. Ther., 224, 4 2 4 (1983). 9 - L. Krejci and R. Harrison, Arch. Ophthalmol.
83, 451 (1957).
10 - A.H. Neufeld, K.A. Zawistowski, E.D. Page and B.B.Bromberg,
Invest. Ophthalmol.
11, 1069
(1978).
323
OCULAR TOXICITY
11
- L. F. Elsom, S.R. Biggs, L.F. Chasseaud, D.R. Hawkins, J. Pulsford and A . Darragh - Europ. J. of Drug Metab. Pharmacokinet.
12
lo, 209
(1985).
- M . Belleville, M. Grand and P. Briet - Drug Metab. Dispos.,
Downloaded by [University of Tasmania] at 10:05 29 September 2015
9 , 233 ( 1 9 8 1 ) . 1 3 - M. Belleville, unpublished data (Jan. 1 9 8 6 ) .
14
- R.L. Huganir and D. Greengard, TIPS, g,
15
- C.D. Strader, I.S. Sigal and A.F. Dixon, FASEB J., 3, (1989).
472 ( 1 9 8 7 ) . 1825
