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Penetration of oral cefuroxime axetil in the aqueous humor of humans
RABBIT OCULAR HYPERTENSION, EFFECT ON THE RETINAL GANGLION CELLS
De Fco G, Centofanfi M., Mat~ E., Manni G.L.*,Lambiase A.*, Clemente M. Institute of P ~ l g y and Pharmacognosy University of Rome "La Sapienza'. P.le Aldo Moro 5, 00185, Rome. *Institute of Ophthalmology University of Rome "Tot Vergata"
PROTECTIVE EFFECTS OF A NON-COMPETITIVE ANTAGONIST OF NMDA RECEPTORS, DEXTROMETHORPHAN, ON RETINAL ISCHEMIA OF THE RABBIT F. Drago*, S. Cordaro**, A. Marino*, G. Villareale*, V. D'Agata*, A.A. Genazzani*, V. Marino* and V. Bartoloni** Center of Ocular Pharmacology* and Institute of Pathology**, University of Catania Medical School, Catania, Italy.
In this study we present a modal of intraocular hypertension in rabbit which causes damages in the retinal ganglion cells (RGC). 0,25 Id methilcellulose (MTC) 2% were injected into the ocular anterior chamber of 8 New ~ d albino rabbits. Ocular pressure was determined with Sehioetz tonometer at 2,6,12 h after MTC application and every day for 15 consecutive days. On days 4,10,15 rabbits were sat:rifledand samples of tissue were taken from the temporal retina. To identify RGC polyclonal antibody PGP 9.5 COltraclone,UK)was used. We divided RGC in patvicellular (soma area=38.5-113.51F-)and magnicellular (soma area=l13.51-188.SF2), b-~mlisticalanalysis was performed by Mann-Whitney U-Test. Results showed a significant increase of intraocular pressure flOP) 6 h after the treatment, 24 h IOP returned to base value.On the next day IOP raised and remained elevated until the completion of experiment. Histological examinations showed a significant de.z:re~ of magnicellular RGC on day 4 and of parvicdlular and magnicellular RGC on day 10. On day 15 retina was atrophic. From the anatomopathological point of view, in the gJaucomatous disease a similar pattern of cellular d a n ~ e in the retina appears (1). Therefore, our results indicate that the MTC induced ocular hypertension in rabbit, is a suitable model to study retinal damage resulting from mechanical compression of the neurorelinal structures. 1) Retinal Ganglion cell loss is size dependent in glaucoma Glovinsky Y.,Quigley HA. Dunnkelberg G. Invest.Ophthdmol. 32,3,484- 91.1991.
The activation of excitatory ,amino acid receptors contribute to the induction of neurodegeneration in various pathological conditions, including retinal ischemia. Namely, the N-mcthyl-D-aspartate (NMDA) receptors seem to be involved in the primary damage while the metabotropic glutamate receptors (mGluR) play a role in the maintenance of the ischemic alteration. In the present study, we have evaluated the neuroprotective effect of a non-competitive antagonist of NMDA receptors, dextromethorphan, in retinal ischemia induced in rabbit by a 15-rain bilateral carotid occlusion under penthobarbital anaesthesia by measuring the formation of 3H-inositolmonophosphate (hasP, an index of metabotropic glutamate receptors sensitivity) and through histological examinations. Poliphosphoinositide (PPI) hydrolysis was estimated by measuring the formation of 3H-InsP in the presence of I0 mM Li+, which blocks the conversion of InsP into free inositol. In retinal slices from control of sham operated rabbits the selective mGluR agonist, trans,.1-aminocyclopentane-l,3- -dicarboxylic acid (trans-ACPD), increased 3H-InsP formation by 70-100 % at maximal concentrations (500 mM). Dextromethorphan, administered either before or after the surgical procedure, was able to antagonize the enhancement in sensitivity of metabotropic glutamate receptors and to reduce the histological damage induced by isehemia. These data suggest that dextromethorphan can pi'otect retina from neurodegeneration induced by ischemia.
PENETRATION OF ORAL CEFUROXIME AXETIL IN THE AQUEOUS.HUMOR OF H U M A N S . M. Ghia, R. Lotti , F. Mattioli,,C. Traverso and A. Martelli Institute of Pharmacology and Department of Ophthalmology, Viale Benedetto XV, 2, 16132 Genoa, Italy
OCULAR DISTRIBUTION OF DRUGS: PHARMACOKI NETIC CONSIDERATIONS G. GIORGI, F.M. RUNCI, G. Sl[GRI[ INSTITUTE OF PHARMAI~OLOGY, UNIVERBITY OF SIENA, VIA DBLL£ SCOTTE 6, 53100 SIENA, ITALY.
In this work we examined cefuroxime levels in the aqueous humor of 14 patients undergoing cataract estraction. Patients were administered a single oral doses of cefuroxime axetil (500 mg) two to eight hours preoperatively. Eight patients were men and six patients were women. About 100 /d of aqueous humor were withdrawn during surgery; blo~d samples were obtained at the beginning of the surgical anaesthesia, approximately 30 minutes before aqueous humor collection. Cefitroxime levels were determined by HPLC (Kontron 325 System). For determination in aqueous humor, elution was performed with acetate buffer (pH 4.5):acetonitrile (90:10) at a flow rate of 1 ml/min. Detection was performed at 254 nm by photometry. Under these conditions the retention time o f ce~roxime was 10 rain. The detection limit of cefuroxime was 0.04 /~g/ml. The coefficient of variation of the calibration curve was 1.5%. Serum samples were assayed using a published procedure. The mean age of the patients was 76 years (range 59-88 years). Aqueous humor samples were all obtained between 3 and 8 hours after the drug administration (4.95+0.38 h, mean+_SEM). The mean concentration of cefuroxime in the aqueous humor was 0.48+0.13/zg/ml, ranging from 0.06 to 1.44/~g/ml. Serum cefuroxime levels of 12 out of 14 patients averaged 3.80+0.58 /zg/ml, ranging from 1.18 to 6.53 /~g/ml. The levels of cefuroxime found in the aqueous humor exceeded the minimum inhibitory concentration of some bacterial species most frequently involved in intraocular infections. These findings suggest that oral cefuroxime axetil might play a role in the prevention and treatment of ophthalmologic infections.
OCULAR PHARMACOKINETICS IS A F U N D A M E [ N T A L TOOL FOR THE PROPER USE OF DRUGS IN THERAPY. MANY COMPARTMENTAL MODELS ARE USED, IN PARTICULAR FOR P I L O C A R P I N E,. TIMOLOL, FLUORIEBCEIN, CLONIDINK AND LEVOBUNOLOL. MEASURING DRUGS SIMULTANEOUSLY IN VARIOUS TISSUES AND FLUIDS, MANY BARRIERS AND COMPARTMENT5 ARE IDENTIFIED A N D IT IS P O S S I B L E BY USING MULTICOMPARTMENTAL SYSTEMS TO DESCRIBE THEIR KINETICS. THE CLASSICAL PHARMACOKIN£TIC APPROACH OF MEASURING DRUG CONCENTRATIONS IN A C I R C U L A T I N G FLUID OF THE CENTRAL COMPARTMENT OVER TIMI[, AND EXPRESSING THE RESULTS IN THE[ FORM OF A MULTIE[XPONENTIAL £QUATION~ HAS BEEN APPLIED TO THE EYE BUT WITH LIMITED SUCCESS. PHARMACOKINETIC PARAMETERS CONSlDERE[D FOR T H E E Y E ARE;: A B S O R P T I O N (PRECORNEAL FACTORS, CORNEAL PERMEABILITY, NONCORNEAL ROUTES OF ENTRY TO ANTERIOR CHAMBER) DISTRIBUTION (VOLUME[ OF DIBTRIBUTION, TISSUE DISTRIBUTION), M£TABOLIBM (PRODRUGB USi[D IN THE RYE, OCULAR ENZYME SYSTEMS, "SOFT" DRUGS), ELIMINATION.
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De Fco G, Centofanfi M., Mat~ E., Manni G.L.*,Lambiase A.*, Clemente M. Institute of P ~ l g y and Pharmacognosy University of Rome "La Sapienza'. P.le Aldo Moro 5, 00185, Rome. *Institute of Ophthalmology University of Rome "Tot Vergata"
PROTECTIVE EFFECTS OF A NON-COMPETITIVE ANTAGONIST OF NMDA RECEPTORS, DEXTROMETHORPHAN, ON RETINAL ISCHEMIA OF THE RABBIT F. Drago*, S. Cordaro**, A. Marino*, G. Villareale*, V. D'Agata*, A.A. Genazzani*, V. Marino* and V. Bartoloni** Center of Ocular Pharmacology* and Institute of Pathology**, University of Catania Medical School, Catania, Italy.
In this study we present a modal of intraocular hypertension in rabbit which causes damages in the retinal ganglion cells (RGC). 0,25 Id methilcellulose (MTC) 2% were injected into the ocular anterior chamber of 8 New ~ d albino rabbits. Ocular pressure was determined with Sehioetz tonometer at 2,6,12 h after MTC application and every day for 15 consecutive days. On days 4,10,15 rabbits were sat:rifledand samples of tissue were taken from the temporal retina. To identify RGC polyclonal antibody PGP 9.5 COltraclone,UK)was used. We divided RGC in patvicellular (soma area=38.5-113.51F-)and magnicellular (soma area=l13.51-188.SF2), b-~mlisticalanalysis was performed by Mann-Whitney U-Test. Results showed a significant increase of intraocular pressure flOP) 6 h after the treatment, 24 h IOP returned to base value.On the next day IOP raised and remained elevated until the completion of experiment. Histological examinations showed a significant de.z:re~ of magnicellular RGC on day 4 and of parvicdlular and magnicellular RGC on day 10. On day 15 retina was atrophic. From the anatomopathological point of view, in the gJaucomatous disease a similar pattern of cellular d a n ~ e in the retina appears (1). Therefore, our results indicate that the MTC induced ocular hypertension in rabbit, is a suitable model to study retinal damage resulting from mechanical compression of the neurorelinal structures. 1) Retinal Ganglion cell loss is size dependent in glaucoma Glovinsky Y.,Quigley HA. Dunnkelberg G. Invest.Ophthdmol. 32,3,484- 91.1991.
The activation of excitatory ,amino acid receptors contribute to the induction of neurodegeneration in various pathological conditions, including retinal ischemia. Namely, the N-mcthyl-D-aspartate (NMDA) receptors seem to be involved in the primary damage while the metabotropic glutamate receptors (mGluR) play a role in the maintenance of the ischemic alteration. In the present study, we have evaluated the neuroprotective effect of a non-competitive antagonist of NMDA receptors, dextromethorphan, in retinal ischemia induced in rabbit by a 15-rain bilateral carotid occlusion under penthobarbital anaesthesia by measuring the formation of 3H-inositolmonophosphate (hasP, an index of metabotropic glutamate receptors sensitivity) and through histological examinations. Poliphosphoinositide (PPI) hydrolysis was estimated by measuring the formation of 3H-InsP in the presence of I0 mM Li+, which blocks the conversion of InsP into free inositol. In retinal slices from control of sham operated rabbits the selective mGluR agonist, trans,.1-aminocyclopentane-l,3- -dicarboxylic acid (trans-ACPD), increased 3H-InsP formation by 70-100 % at maximal concentrations (500 mM). Dextromethorphan, administered either before or after the surgical procedure, was able to antagonize the enhancement in sensitivity of metabotropic glutamate receptors and to reduce the histological damage induced by isehemia. These data suggest that dextromethorphan can pi'otect retina from neurodegeneration induced by ischemia.
PENETRATION OF ORAL CEFUROXIME AXETIL IN THE AQUEOUS.HUMOR OF H U M A N S . M. Ghia, R. Lotti , F. Mattioli,,C. Traverso and A. Martelli Institute of Pharmacology and Department of Ophthalmology, Viale Benedetto XV, 2, 16132 Genoa, Italy
OCULAR DISTRIBUTION OF DRUGS: PHARMACOKI NETIC CONSIDERATIONS G. GIORGI, F.M. RUNCI, G. Sl[GRI[ INSTITUTE OF PHARMAI~OLOGY, UNIVERBITY OF SIENA, VIA DBLL£ SCOTTE 6, 53100 SIENA, ITALY.
In this work we examined cefuroxime levels in the aqueous humor of 14 patients undergoing cataract estraction. Patients were administered a single oral doses of cefuroxime axetil (500 mg) two to eight hours preoperatively. Eight patients were men and six patients were women. About 100 /d of aqueous humor were withdrawn during surgery; blo~d samples were obtained at the beginning of the surgical anaesthesia, approximately 30 minutes before aqueous humor collection. Cefitroxime levels were determined by HPLC (Kontron 325 System). For determination in aqueous humor, elution was performed with acetate buffer (pH 4.5):acetonitrile (90:10) at a flow rate of 1 ml/min. Detection was performed at 254 nm by photometry. Under these conditions the retention time o f ce~roxime was 10 rain. The detection limit of cefuroxime was 0.04 /~g/ml. The coefficient of variation of the calibration curve was 1.5%. Serum samples were assayed using a published procedure. The mean age of the patients was 76 years (range 59-88 years). Aqueous humor samples were all obtained between 3 and 8 hours after the drug administration (4.95+0.38 h, mean+_SEM). The mean concentration of cefuroxime in the aqueous humor was 0.48+0.13/zg/ml, ranging from 0.06 to 1.44/~g/ml. Serum cefuroxime levels of 12 out of 14 patients averaged 3.80+0.58 /zg/ml, ranging from 1.18 to 6.53 /~g/ml. The levels of cefuroxime found in the aqueous humor exceeded the minimum inhibitory concentration of some bacterial species most frequently involved in intraocular infections. These findings suggest that oral cefuroxime axetil might play a role in the prevention and treatment of ophthalmologic infections.
OCULAR PHARMACOKINETICS IS A F U N D A M E [ N T A L TOOL FOR THE PROPER USE OF DRUGS IN THERAPY. MANY COMPARTMENTAL MODELS ARE USED, IN PARTICULAR FOR P I L O C A R P I N E,. TIMOLOL, FLUORIEBCEIN, CLONIDINK AND LEVOBUNOLOL. MEASURING DRUGS SIMULTANEOUSLY IN VARIOUS TISSUES AND FLUIDS, MANY BARRIERS AND COMPARTMENT5 ARE IDENTIFIED A N D IT IS P O S S I B L E BY USING MULTICOMPARTMENTAL SYSTEMS TO DESCRIBE THEIR KINETICS. THE CLASSICAL PHARMACOKIN£TIC APPROACH OF MEASURING DRUG CONCENTRATIONS IN A C I R C U L A T I N G FLUID OF THE CENTRAL COMPARTMENT OVER TIMI[, AND EXPRESSING THE RESULTS IN THE[ FORM OF A MULTIE[XPONENTIAL £QUATION~ HAS BEEN APPLIED TO THE EYE BUT WITH LIMITED SUCCESS. PHARMACOKINETIC PARAMETERS CONSlDERE[D FOR T H E E Y E ARE;: A B S O R P T I O N (PRECORNEAL FACTORS, CORNEAL PERMEABILITY, NONCORNEAL ROUTES OF ENTRY TO ANTERIOR CHAMBER) DISTRIBUTION (VOLUME[ OF DIBTRIBUTION, TISSUE DISTRIBUTION), M£TABOLIBM (PRODRUGB USi[D IN THE RYE, OCULAR ENZYME SYSTEMS, "SOFT" DRUGS), ELIMINATION.
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