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Ocular pharmacokinetics of trimetazidine in the pigmented rat after a single oral administration
X ICER Abstracts
Monday, 5:30-790 184
40 OCULAR PHARMACOKINETICS PIGMENTED RAT AFTER A SINGLE mrreP.Ftetyg .- ~l.~,~es&&@, Gaude, Courveboie.
France, I.R.I.S.
OF TRIMETAZIDINE OPAL ADMHISTfJATtDN.
France, Warmacology France.
IN .THE
REPEATED
Department,
Nice,
R.,
DIADORI
A.&
R.
Tognon
M.S.,Turrini
Institute Optics Padova.
of Ophthalmology. - University of Italy
45 RSTINOIDS DEFICIEUCY AND RETINOSLASTOMA: CLINICAL EVIDENCE AND a&&!,&$~.~~~~~tiZ RDLE IN THE GENESIS OF THE DISEASE ‘i&i,t$f~~ ~:,HA@i%NGELO*. T. HAD.JISTILIANO”. A. SPEP.1, ACQUAVIVA’*, V. DE LEO*** and R. PREZZOTTI IUST. OPBTEW@L. SC&UCSS, * SCLAVO. ** INST. PABDIATRICS, *** DEPT. pley
hronto
Shodopel” BetMel,
Vitamin A is aleo a) to pres.rv. the Call8 throughout b)
to
control
c) to exert
cell
a”
fntitumor
en impportent role end other visual . Viteml” A derivative.
in the function piSme”ts ere
of the
reti,
aynthcsired
lu,o,,,,Co play a fundamental role for its ability: funcrional and structural integrity of epichelial the body; proliferation and differentiation; effect on chemically or virally induced mall-
S”e”cice through e “,mber of different mechanisms. All theee dete , together with some pt-WiOUS ClhiCd and epldemiologicel coneideretions on retinoblastoma. led “8 eo inve*tlgate ..“,I levele of “itemin A. Retinal, Sets-Caro~ane and Retin Bi”di”S Protein @.BP) in retinoblastools parients end their mothC?e. This “ee done in order co find a correlation between any rve”tual perturbation of Vitamin A metabolism and the genesis of
the
diwams.
Affmctad petiente l “d their mothers of 1OV RMfiid levele compared Co probably indlcetincr thet a Ratinol =Y eCt ee e CO-factor in the Senesis
8.,De
Care Padua.
G..Scdrpa
Chair of School
G.,Secchi
A.G.
Physiopathological of Medicine
188
189
15-KETOPROSTAGLANDIN .l3KEIJUC’I’ASE IN BOVINE OCULAR TISSUES Nikaido,H. Moriishi,M., ?lishima,H.K.l, Kitamura,S., Tatsumi,K. Gepartment and Institute of ph...,.,.,I..~fs,P:~~~l~~loayl Hiroshima ’ University School of Medicine, Hiroshima, Japan he present study provides the first evidence for a1 5 -reduction of 15-keto-prostaglandins (15-keto-PGs) by bovine ocular tissues, e 9,000 xi supernatants of cornea, iris, ciliary retina, and RPE-choroid except lens exhihited b& d -reductase activity toward 15-keto-PGs E2 and F2= in the presence of NADPH or NADH as an electron donor. Among these tissues tested, the highest activity was observed with ciliary body and iris, followed by RPEchoroid, retina, and cornea. The activity was not detectable in lens. The NAD(P)H-linked double bond reductase activity was inhibited in varying degrees by dicumarol, quercitrin, indomethacin and disulfirum, but not by potassium cyanide. NADPH-linked 15-ket,o-,PG F1+ A13-reductase was purlf led from bovine ITIS-cl lary body cytosol by fractionation with ammonium sulfate, and high performance liquid chromatography (HPLC) using columns of TSK gel DEAE-5PW and TSK gel Blue-5PW. The purified enzyme was homogenous by the criterion of sodium dodecyl sulfate-polyacrylamide electro-phoresis. gel Its molecular weight was estimated to be about 57,000 by the electrophoresis, and about 55,000 by gel filtration HP1.C using a column of Superose 12.
‘N?D GIt?ECOLOCY A in th. from
AFTER
Migration of human Tenon’s capsule fibroblasts is one of the rensons for scar fomration rnd ultimate filtering surgery failure in glaucoma patients. Four nntimicrotuble drugs,: vinblnstine, vincristlne, tnxo! 2nd colchicine, were tested for their effect on th~migrz!icn cf !I:!n~!n tibroblasts in vitro. All experiments were using 19% FBS \*!!!I blEM as a stimulant. Drugs diluted in to% FBS mi!!~ h4EM were tested for its inhibition on cell migration. EX!I drug ccncec!rrtion v/as repeated six times for one experiment and each experiment was repented on three different human fibroblast cell lines. Vinblastine concentration (Mea&SE.) of (7.05f3.75)xt0-*tM, vincristine concentration of (5.10~2.27)~10-7h4, taxol of concentration of (2.01fl.20)x10-5M, and :%o!rhicine concentration of (2.2W.27)xlO-sM showed a 50% inhibl?on on human fibroblast cell migration. A comparison of these fear microtubule inhibitors indicate that vinblastine is the most potent chemotherapeutic drug for inhibition of cell migration. However, the instability of vinblastine and vincristine resulted in less consistent results than for tnxol and colchicine.
TITLE:
OBS-IC
OF FOSCARNET EYE
THE EFFECT OF MICROTUBULE INHIBITORS ON HUMAN TENONS CAPSULE FIBROBLASTS David A. Lee. u Jules Stein Eye Instituye, UCLA School of Medicine, CA USA.
Ibopamine is a new dopaminergic drug with mydriatic properties not associated with cycloplegic effect, which induces a transient increase in intraocular pressure in a high percentage of eyes with hydrodinamic disorders, while in normal subjects no variation in intraocular pressure are observed. Therefore its usage as B Provocative Test for Blaucoma has bee” speculated. We have started a clinical trial to verify the significance and the predictive role of the Ibopamine Test in patients with hydrodinamic disorders. Various groups have been tested: - patienrs with Ocular Ipertensio” or Border-line intraocular pressure values, in absence of perinetric and ophthalmoscopic alterations - patients with Low Tension Glaucoma - glaucomatous patients who underwent Argo” Laser Trabeculoplasty in order to evaluate the variations of the respbnses to the test before and after treatment - Blaucomatous patients’ in which a Trapanotrabeculectomy was perrormed, evaluating the respnses to the test before and after surgery.
Vitemi” n. ‘inc. startiq.
TOXICITY THE RABBIT
44
OF
FREZZOTTI
INJECTIONS
RETINAL INTO
Cytomegalovirus (CMV) retinitis represents the most frequent Ocular opportunistic infection in AIDS ganciclovir-resistant CMV patients. In presence of strains, in nephrophatic patients and/or in absence of intravitreal injection of foscarnet a specific viremia. the only therapeutical possibility. represent may HOWeVer) before introducing this modality of admlnlstratlon of the drug in the clinical practice. it is mandatory to investigate its retinal toxicity after because of the repeated injections, necessary effect of the drug. virustatic. not virucidal, We have investigated the retinal toxicity of 2. 4, 6 intravitreal injections of 3.6 mg of foscarnet in the rabbit eye using ophthalmoscopy. electrophysiology and hystopathology. The results of our experimentation have shown that mild ophthalmoscoplcal these injections induced only and no significative electrophysiological changes. The findings relevance of histopathology to the functional ~111 be discussed.
185
CIAPPETTA
OF THE
3
41
NUT1 A.,
187
43 EVALUATION
In order o evaluate the ocular pharmacokinetics f trimetazidine gH-trimetazidine (Vastarel 4 after a single per OS administration, (100 uCi/Kg. 2.5 me/kg) was admtntstered by gavage in 8 groups of pigmented rats (3 animate/group). Radioactivity was determined in ocular structures of both eyes (conjunchva, cornea, aqueous humor, iris-ciliary body, lens, vitreous and chorio-retina), in some organs (brain, internal ear. heart, liver and kidney), and blood, 10 mins, 30 mins, 1 hr, 3 hrs, 6 hrs, 12 hrs, 24 hrs and 48 hrs after administration. y rme and feces were collected over 46 hours. Distribution of H-trimetazidme was obtained 10 minutes after $dministration. Data indicated that low concentrations of H radioactivity was found in ocular structures and the following concentration gradttnt was observed, iris-ciliary body t chorio-retina > > aqueous humor 7 lens > vitreous. These results conjunctiva 2 car indicated that !PH-trimetaridine was preferentially localized in pigmented vasculartzed structurea in the eye. In examined organs the concentration gradient was as foltows : liver > kidney > heart > internal ear 2 brain. Urinary and fecal excretion was 52.5 and 15.4 % of administered dose over 43 hours, respecttvely. These findings show that after a single per OS administration, trtmetaridine is detected in the ocular sites which are abundantty vascutarized (chorio-retina) and in the regulator site of the intraocular pressure (iris-ciliary body).
IBOPAMINE PROVOCATIVE TEST IN THE DIAGNOSIS HYDRODINAMIC DISORDERS.
P.M., Sep 21, 1992 Palazzo Dei Congressi
seera to show a higher incidence reference control population. deficiency, during preS”a”cy, of the disease.
s.55
Monday, 5:30-790 184
40 OCULAR PHARMACOKINETICS PIGMENTED RAT AFTER A SINGLE mrreP.Ftetyg .- ~l.~,~es&&@, Gaude, Courveboie.
France, I.R.I.S.
OF TRIMETAZIDINE OPAL ADMHISTfJATtDN.
France, Warmacology France.
IN .THE
REPEATED
Department,
Nice,
R.,
DIADORI
A.&
R.
Tognon
M.S.,Turrini
Institute Optics Padova.
of Ophthalmology. - University of Italy
45 RSTINOIDS DEFICIEUCY AND RETINOSLASTOMA: CLINICAL EVIDENCE AND a&&!,&$~.~~~~~tiZ RDLE IN THE GENESIS OF THE DISEASE ‘i&i,t$f~~ ~:,HA@i%NGELO*. T. HAD.JISTILIANO”. A. SPEP.1, ACQUAVIVA’*, V. DE LEO*** and R. PREZZOTTI IUST. OPBTEW@L. SC&UCSS, * SCLAVO. ** INST. PABDIATRICS, *** DEPT. pley
hronto
Shodopel” BetMel,
Vitamin A is aleo a) to pres.rv. the Call8 throughout b)
to
control
c) to exert
cell
a”
fntitumor
en impportent role end other visual . Viteml” A derivative.
in the function piSme”ts ere
of the
reti,
aynthcsired
lu,o,,,,Co play a fundamental role for its ability: funcrional and structural integrity of epichelial the body; proliferation and differentiation; effect on chemically or virally induced mall-
S”e”cice through e “,mber of different mechanisms. All theee dete , together with some pt-WiOUS ClhiCd and epldemiologicel coneideretions on retinoblastoma. led “8 eo inve*tlgate ..“,I levele of “itemin A. Retinal, Sets-Caro~ane and Retin Bi”di”S Protein @.BP) in retinoblastools parients end their mothC?e. This “ee done in order co find a correlation between any rve”tual perturbation of Vitamin A metabolism and the genesis of
the
diwams.
Affmctad petiente l “d their mothers of 1OV RMfiid levele compared Co probably indlcetincr thet a Ratinol =Y eCt ee e CO-factor in the Senesis
8.,De
Care Padua.
G..Scdrpa
Chair of School
G.,Secchi
A.G.
Physiopathological of Medicine
188
189
15-KETOPROSTAGLANDIN .l3KEIJUC’I’ASE IN BOVINE OCULAR TISSUES Nikaido,H. Moriishi,M., ?lishima,H.K.l, Kitamura,S., Tatsumi,K. Gepartment and Institute of ph...,.,.,I..~fs,P:~~~l~~loayl Hiroshima ’ University School of Medicine, Hiroshima, Japan he present study provides the first evidence for a1 5 -reduction of 15-keto-prostaglandins (15-keto-PGs) by bovine ocular tissues, e 9,000 xi supernatants of cornea, iris, ciliary retina, and RPE-choroid except lens exhihited b& d -reductase activity toward 15-keto-PGs E2 and F2= in the presence of NADPH or NADH as an electron donor. Among these tissues tested, the highest activity was observed with ciliary body and iris, followed by RPEchoroid, retina, and cornea. The activity was not detectable in lens. The NAD(P)H-linked double bond reductase activity was inhibited in varying degrees by dicumarol, quercitrin, indomethacin and disulfirum, but not by potassium cyanide. NADPH-linked 15-ket,o-,PG F1+ A13-reductase was purlf led from bovine ITIS-cl lary body cytosol by fractionation with ammonium sulfate, and high performance liquid chromatography (HPLC) using columns of TSK gel DEAE-5PW and TSK gel Blue-5PW. The purified enzyme was homogenous by the criterion of sodium dodecyl sulfate-polyacrylamide electro-phoresis. gel Its molecular weight was estimated to be about 57,000 by the electrophoresis, and about 55,000 by gel filtration HP1.C using a column of Superose 12.
‘N?D GIt?ECOLOCY A in th. from
AFTER
Migration of human Tenon’s capsule fibroblasts is one of the rensons for scar fomration rnd ultimate filtering surgery failure in glaucoma patients. Four nntimicrotuble drugs,: vinblnstine, vincristlne, tnxo! 2nd colchicine, were tested for their effect on th~migrz!icn cf !I:!n~!n tibroblasts in vitro. All experiments were using 19% FBS \*!!!I blEM as a stimulant. Drugs diluted in to% FBS mi!!~ h4EM were tested for its inhibition on cell migration. EX!I drug ccncec!rrtion v/as repeated six times for one experiment and each experiment was repented on three different human fibroblast cell lines. Vinblastine concentration (Mea&SE.) of (7.05f3.75)xt0-*tM, vincristine concentration of (5.10~2.27)~10-7h4, taxol of concentration of (2.01fl.20)x10-5M, and :%o!rhicine concentration of (2.2W.27)xlO-sM showed a 50% inhibl?on on human fibroblast cell migration. A comparison of these fear microtubule inhibitors indicate that vinblastine is the most potent chemotherapeutic drug for inhibition of cell migration. However, the instability of vinblastine and vincristine resulted in less consistent results than for tnxol and colchicine.
TITLE:
OBS-IC
OF FOSCARNET EYE
THE EFFECT OF MICROTUBULE INHIBITORS ON HUMAN TENONS CAPSULE FIBROBLASTS David A. Lee. u Jules Stein Eye Instituye, UCLA School of Medicine, CA USA.
Ibopamine is a new dopaminergic drug with mydriatic properties not associated with cycloplegic effect, which induces a transient increase in intraocular pressure in a high percentage of eyes with hydrodinamic disorders, while in normal subjects no variation in intraocular pressure are observed. Therefore its usage as B Provocative Test for Blaucoma has bee” speculated. We have started a clinical trial to verify the significance and the predictive role of the Ibopamine Test in patients with hydrodinamic disorders. Various groups have been tested: - patienrs with Ocular Ipertensio” or Border-line intraocular pressure values, in absence of perinetric and ophthalmoscopic alterations - patients with Low Tension Glaucoma - glaucomatous patients who underwent Argo” Laser Trabeculoplasty in order to evaluate the variations of the respbnses to the test before and after treatment - Blaucomatous patients’ in which a Trapanotrabeculectomy was perrormed, evaluating the respnses to the test before and after surgery.
Vitemi” n. ‘inc. startiq.
TOXICITY THE RABBIT
44
OF
FREZZOTTI
INJECTIONS
RETINAL INTO
Cytomegalovirus (CMV) retinitis represents the most frequent Ocular opportunistic infection in AIDS ganciclovir-resistant CMV patients. In presence of strains, in nephrophatic patients and/or in absence of intravitreal injection of foscarnet a specific viremia. the only therapeutical possibility. represent may HOWeVer) before introducing this modality of admlnlstratlon of the drug in the clinical practice. it is mandatory to investigate its retinal toxicity after because of the repeated injections, necessary effect of the drug. virustatic. not virucidal, We have investigated the retinal toxicity of 2. 4, 6 intravitreal injections of 3.6 mg of foscarnet in the rabbit eye using ophthalmoscopy. electrophysiology and hystopathology. The results of our experimentation have shown that mild ophthalmoscoplcal these injections induced only and no significative electrophysiological changes. The findings relevance of histopathology to the functional ~111 be discussed.
185
CIAPPETTA
OF THE
3
41
NUT1 A.,
187
43 EVALUATION
In order o evaluate the ocular pharmacokinetics f trimetazidine gH-trimetazidine (Vastarel 4 after a single per OS administration, (100 uCi/Kg. 2.5 me/kg) was admtntstered by gavage in 8 groups of pigmented rats (3 animate/group). Radioactivity was determined in ocular structures of both eyes (conjunchva, cornea, aqueous humor, iris-ciliary body, lens, vitreous and chorio-retina), in some organs (brain, internal ear. heart, liver and kidney), and blood, 10 mins, 30 mins, 1 hr, 3 hrs, 6 hrs, 12 hrs, 24 hrs and 48 hrs after administration. y rme and feces were collected over 46 hours. Distribution of H-trimetazidme was obtained 10 minutes after $dministration. Data indicated that low concentrations of H radioactivity was found in ocular structures and the following concentration gradttnt was observed, iris-ciliary body t chorio-retina > > aqueous humor 7 lens > vitreous. These results conjunctiva 2 car indicated that !PH-trimetaridine was preferentially localized in pigmented vasculartzed structurea in the eye. In examined organs the concentration gradient was as foltows : liver > kidney > heart > internal ear 2 brain. Urinary and fecal excretion was 52.5 and 15.4 % of administered dose over 43 hours, respecttvely. These findings show that after a single per OS administration, trtmetaridine is detected in the ocular sites which are abundantty vascutarized (chorio-retina) and in the regulator site of the intraocular pressure (iris-ciliary body).
IBOPAMINE PROVOCATIVE TEST IN THE DIAGNOSIS HYDRODINAMIC DISORDERS.
P.M., Sep 21, 1992 Palazzo Dei Congressi
seera to show a higher incidence reference control population. deficiency, during preS”a”cy, of the disease.
s.55