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Experimental study of the zeolit-Cux-Cyclophosphamide system
PosterSession2E. DrugsofAbuse oil (N) (2 glkglday), allopurinol with dimethylsulphoxide (A & D) (l ml of 5% A + 1 ml 5% D. (l glkg) (once daily) and prednisolone (P) (0.5 mglkg/body w.t.) when given before (protective) and after (curative) induction of experimental colitis in rats by trinitrobenzene sulphonic acid (0.3 ml = 30 mglrat dissolved in 50% ethanol) which was rectally administered in rats. The study showed that both N and K had significant protective and curative effects as evidenced by lowering of the inflammatory indices, mediators as well as preservation of the reduced glutathione level. Meanwhile, A & D had significant protective effects only. On the other hand, P had significant curative and protective effects.
IP2D1031 EXPERIMENTAL STUDYOF THE
ZEOLIT-Cu.-CVCLOPHOSPHAMIDE SYSTEM
Elena Dinu *, Ecaterina Andronescu, Eugenia Naghi, Manole Cojocaru. StreetIon Slatineanu, 22, 71137 Bucharest,
Romania The vectoring of the drugs by intermediate systems which are capable to release active substances only to affected area is a challenging issue for researches world wide. The aim of the present study were the synthesis of zeolit-Cu, -Cyclophosphamide and the analyses of its performance. The interpretation was done on groups of rats, healthy and with tumor which showed the change of their anatomo-pathological, hematological and biochemical parameters. The obtained results allow us to consider that administration of Cyclophosphamide though the zeolit-Cu,-Cyclophosphamide system is an advantage, especially in the case of long treatment.
IP2D1041
FORMULATION OF INSOLUBLE TESTSUBSTANCES FORLONGTERMORALADMINISTRATION IN TOXICOLOGY INVESTIGATIONS
T. Smith *, J. Kelly. Covance Laboratories (Europe), Harrogate, North Yorkshire, England An increasing proportion of pharmaceutical and chemical entities under development are either insoluble or difficult to suspend in standard media To achieve a suitable formulation for administration to laboratory animals the physical properties of the formulation and any potential effects of the vehicle on the test system must be considered Due to the large number of toxicological studies performed at this laboratory various different strategies for handling insoluble test materials have been established for oral gavage administration Knowledge of the physical properties of vehicles and practical experience with the formulations can achieve increased exposure of the test system through increased achievable dose concentrations and bioavailability. The administration of many suspension media are associated with adverse effects, for example skin disorders associated with administration of oil based suspensions, kidney disorders associated with administration of polyethylene glycol. The physical properties of non-aqueous media may also present practical problems, for example the viscosity of the vehicle or formulation at room temperature. Reference to background findings associated with a vehicle can provide important information on the snitability of the vehicle for long term exposure, allowing an evaluation of
119
IP2D234 I SAFETYPHARMACOLOGICAL STUDIES OF DRUGS K. Vertes*, M. Kovacs, Gy. Sebestyen, Pharmaceutical Control and Developing Laboratory Co.Ltd. Budapest, Hungary Increased demands can be found on safety pharmacological evaluation prior to registration or introduction of new drugs but no effective guideline has known yet. This new experimental requirement can be reasoned that side effects can't be estimated correctly by traditional toxicological methods. A set of methods to study side effects of new drugs on different organ systems was chosen as follows: Generalsigns: Irwin test CNS: locomotor activity, proconvulsant (pentetrazol), anticonvulsant (writhing, t-f1ick), body temperature, hexobarbital, pentobarbital sleeping time Circulation, respiration: blood pressure, heart rate, EKG, tidal volume, respiratory rate Autonomicnervoussystemand smoothmuscle: isolated guinea-pig ileum
Gastro-intestinal system (GI transittime) Water and electrolyte excretion (Na", K', cr ) Drug interaction (zoxazolamine paralysis) Negative and positive controls (as reference substances) were applied. Dose levels were selected on the basis of previously performed routine repeated dose toxicological studies. The studies were performed under GLP conditions. All important organ systems were investigated and no any sideeffects of the tested drugs were found under the applied test conditions. The results obtained by the aforementioned study package were accepted by the German authorities.
P2E. Drugs of Abuse
IP2E1051
MECHANISMS OF NEUROTOXICITY OF SUBSTITUTED AMPHETAMINES
R. Laverty *, B.R. Russell, Y. Zheng. Departmentof Pharmacology,
University of OtagoMedical School, Dunedin, New Zealand While the occurrence of neurotoxicity from high doses of substituted amphetamine derivatives has been known for some time, the mechanism(s) which cause this long-term damage, particularly to serotonin-containing nerves, remains indefinite. We have studied in rats the effects of several specific antagonists on the ability of, particularly, MDMA (methylenedioxymethamphetamine) and fenf1urarnine to produce persisting depletion of brain serotonin. The glycine-site specific antagonist at the NMDA receptor, ACEA 1021 (4 * 30 mglkg 2-hourly) and the specific DI antagonist, SCH 23390 (4 * 0.1 mglkg 2-hourly) both prevented the serotonin neurotoxicity due to MDMA (4 * 10 mglkg 2-hourly), but did not affect the depletion due to fenfluramine (4 * 10 rug/kg 2-hourly). Inhibition of nitric oxide synthase (NOS) by nitroarginine had a partially protective effect on neurotoxicity induced by MDMA; there was no protection against repeated doses of fenfluramine. MDMA causes an increase in NOS activity in several brain regions, but fenfluramine had a less pronounced effect, causing a significant increase only in cerebellum. The neuroprotective effects did not appear to be related to acute effects of the drugs on amine release or on body temperature. It would appear that several mechanisms combine to produce the destruction of serotonin nerves by substituted amphetamines, and that different compounds may produce the same end result by different mechanisms.
IP2D1031 EXPERIMENTAL STUDYOF THE
ZEOLIT-Cu.-CVCLOPHOSPHAMIDE SYSTEM
Elena Dinu *, Ecaterina Andronescu, Eugenia Naghi, Manole Cojocaru. StreetIon Slatineanu, 22, 71137 Bucharest,
Romania The vectoring of the drugs by intermediate systems which are capable to release active substances only to affected area is a challenging issue for researches world wide. The aim of the present study were the synthesis of zeolit-Cu, -Cyclophosphamide and the analyses of its performance. The interpretation was done on groups of rats, healthy and with tumor which showed the change of their anatomo-pathological, hematological and biochemical parameters. The obtained results allow us to consider that administration of Cyclophosphamide though the zeolit-Cu,-Cyclophosphamide system is an advantage, especially in the case of long treatment.
IP2D1041
FORMULATION OF INSOLUBLE TESTSUBSTANCES FORLONGTERMORALADMINISTRATION IN TOXICOLOGY INVESTIGATIONS
T. Smith *, J. Kelly. Covance Laboratories (Europe), Harrogate, North Yorkshire, England An increasing proportion of pharmaceutical and chemical entities under development are either insoluble or difficult to suspend in standard media To achieve a suitable formulation for administration to laboratory animals the physical properties of the formulation and any potential effects of the vehicle on the test system must be considered Due to the large number of toxicological studies performed at this laboratory various different strategies for handling insoluble test materials have been established for oral gavage administration Knowledge of the physical properties of vehicles and practical experience with the formulations can achieve increased exposure of the test system through increased achievable dose concentrations and bioavailability. The administration of many suspension media are associated with adverse effects, for example skin disorders associated with administration of oil based suspensions, kidney disorders associated with administration of polyethylene glycol. The physical properties of non-aqueous media may also present practical problems, for example the viscosity of the vehicle or formulation at room temperature. Reference to background findings associated with a vehicle can provide important information on the snitability of the vehicle for long term exposure, allowing an evaluation of
119
IP2D234 I SAFETYPHARMACOLOGICAL STUDIES OF DRUGS K. Vertes*, M. Kovacs, Gy. Sebestyen, Pharmaceutical Control and Developing Laboratory Co.Ltd. Budapest, Hungary Increased demands can be found on safety pharmacological evaluation prior to registration or introduction of new drugs but no effective guideline has known yet. This new experimental requirement can be reasoned that side effects can't be estimated correctly by traditional toxicological methods. A set of methods to study side effects of new drugs on different organ systems was chosen as follows: Generalsigns: Irwin test CNS: locomotor activity, proconvulsant (pentetrazol), anticonvulsant (writhing, t-f1ick), body temperature, hexobarbital, pentobarbital sleeping time Circulation, respiration: blood pressure, heart rate, EKG, tidal volume, respiratory rate Autonomicnervoussystemand smoothmuscle: isolated guinea-pig ileum
Gastro-intestinal system (GI transittime) Water and electrolyte excretion (Na", K', cr ) Drug interaction (zoxazolamine paralysis) Negative and positive controls (as reference substances) were applied. Dose levels were selected on the basis of previously performed routine repeated dose toxicological studies. The studies were performed under GLP conditions. All important organ systems were investigated and no any sideeffects of the tested drugs were found under the applied test conditions. The results obtained by the aforementioned study package were accepted by the German authorities.
P2E. Drugs of Abuse
IP2E1051
MECHANISMS OF NEUROTOXICITY OF SUBSTITUTED AMPHETAMINES
R. Laverty *, B.R. Russell, Y. Zheng. Departmentof Pharmacology,
University of OtagoMedical School, Dunedin, New Zealand While the occurrence of neurotoxicity from high doses of substituted amphetamine derivatives has been known for some time, the mechanism(s) which cause this long-term damage, particularly to serotonin-containing nerves, remains indefinite. We have studied in rats the effects of several specific antagonists on the ability of, particularly, MDMA (methylenedioxymethamphetamine) and fenf1urarnine to produce persisting depletion of brain serotonin. The glycine-site specific antagonist at the NMDA receptor, ACEA 1021 (4 * 30 mglkg 2-hourly) and the specific DI antagonist, SCH 23390 (4 * 0.1 mglkg 2-hourly) both prevented the serotonin neurotoxicity due to MDMA (4 * 10 mglkg 2-hourly), but did not affect the depletion due to fenfluramine (4 * 10 rug/kg 2-hourly). Inhibition of nitric oxide synthase (NOS) by nitroarginine had a partially protective effect on neurotoxicity induced by MDMA; there was no protection against repeated doses of fenfluramine. MDMA causes an increase in NOS activity in several brain regions, but fenfluramine had a less pronounced effect, causing a significant increase only in cerebellum. The neuroprotective effects did not appear to be related to acute effects of the drugs on amine release or on body temperature. It would appear that several mechanisms combine to produce the destruction of serotonin nerves by substituted amphetamines, and that different compounds may produce the same end result by different mechanisms.