Protection of rat gastric mucosa against ethanol injury by the new synthetic prostaglandin MDL 646

Oral administration to fasted rats of absolute ethanol produces extensive necrotic lesions of gastric mucosa as well as a massive leakage of proteins and mucus glycoproteins into gastric lumen. When the new synthetic prostaglandin MDL 646, belonging to the PGE1 series, is administered intragastrically (2 or 10 micrograms/kg) 30 min before ethanol administration, a significant protection of rat gastric mucosa against alcohol injury is observed.     

Dexamethasone suppression of ovulation in PMS-treated immature rats

Summary A single injection of 2.0 mg/kg dexamethasone (DXM) administered at 51 h after pregnant mare serum gonadatropin (PMS) treatment inhibited both ovulation and luteinization. S.c. injection of human chorionic gonadotropin (HGG) caused ovulation ond luteinization in DXM-PMS-treated rats, whereas treatment with ACTH failed to overcome the DXM inhibitory effect. These findings are interpreted to indicate that DXM inhibits ovulation through a mechanism which might involve the central nervous system.     

Dexamethasone suppression of ovulation in PMS-treated immature rats.

A single injection of 2.0 mg/kg dexamethasone (DXM) administered at 51 h after pregnant mare serum gonadatropin (PMS) treatment inhibited both ovulation and luteinization. S.c. injection of human chorionic gonadotropin (HGG) caused ovulation and luteinization in DXM-PMS-treated rats, whereas treatment with ACTH failed to overcome the DXM inhibitory effect. These findings are interpreted to indicate that DXM inhibits ovulation through a mechanism which might involve the central nervous system.     

Protection of rat gastric mucosa against ethanol injury by the new synthetic prostaglandin MDL 646

Summary Oral administration to fasted rats of absolute ethanol produces extensive necrotic lesions of gastric mucosa as well as a massive leakage of proteins and mucus glycoproteins into gastric lumen. When the new synthetic prostaglandin MDL 646, belonging to the PGE₁ series, is administered intragastrically (2 or 10 g/kg) 30 min before ethanol administration, a significant protection of rat gastric mucosa against alcohol injury is observed.This work was supported in part by a contribution from Ministero della Pubblica Istruzione (MPI), Rome, Italy.     

Effect of ethanol on toxicity and metabolism of amphetamine in the mouse.

Ethanol, 3 g/kg i.p., did not significantly alter the acute toxicity of amphetamine in the mouse. However, the urinary metabolite pattern was changed, suggesting that ethanol suppressed metabolism of the stimulant during the initial 6 h period. After 24 h, the mouse metabolized the same fraction of a given dose of amphetamine, whether it was given as amphetamine alone or amphetamine mixed with 2,3 or 4 g/kg ethanol.     

Effect of azimexon (BM 12.531) on mouse granulocyte-macrophage and monocyte-macrophage progenitor cells

Summary Treatment of mice with 25 mg/kg azimexon (BM 12.531) resulted in an increase in granulocyte-macrophage colony-forming cells (GM-CFC) in spleen and bone marrow after a transient depression in the cell populations. Bone marrow monocyte-macrophage colony-forming cells (MM-CFC) increased at 7 days after treatment, and splenic MM-CFC were least affected by azimexon treatment. The increase in granulocytic and monocytic colony-forming cells may play a role in the previously reported protection by azimexon against radiation and drug-induced toxicity.Supported by the Armed Forces Radiobiology Research Institute, Defense Nuclear Agency, under Research Work Unit MJ 00026.     

Radioprotection conferred by Corynebacterium parvum against the lethality caused by X irradiation at sublethal and lethal doses in the mouse]

Intraperitoneal injection of Corynebacterium parvum (C. parvum) into Balb/c mice produces a protection against toxicity or lethality provoked by ionizing radiation (750 R and 950 R). Survivals reaching nearly 90 days have been recorded.     

Dexamethasone-induced neutrophilia. Negative correlation with increased plasma adrenaline concentrations

Maximal increments in adrenaline and dexamethasone (DXM) plasma concentrations were observed c15 (T50 40 min) and 30 (T50 210-240 min) minutes after an i.v. DXM dose (6 mg/m2 BSA) in man. There appears, however, to be no direct interaction between these agents in the development of induced neutrophilia, which occurs c240 min postinjection.     

Prostaglandin analogue protects pancreatic B-cells against cyclosporin A toxicity

Cyclosporin A toxicity on pancreatic B-cells and its prevention by rioprostil, a prostaglandin E1 analogue, were studied in the model of the isolated perfused pancreas of rats treated with both compounds for 8 days. At toxic doses of cyclosporin (10 and 20 mg/kg b.wt), the B-cells showed severe hydropic degeneration of the endoplasmatic reticulum and slight degranulation of the B-cells. Accordingly, the insulin secretion was markedly impaired. Administration of rioprostil ameliorated the insulin secretion significantly, but not the ultrastructural changes. At therapeutic levels of cyclosporin (5 mg/kg b.wt), the hydropic degeneration and the drop in insulin secretion were completely prevented by rioprostil. This observation might have therapeutic implications in the treatment of patients, in particular those undergoing pancreatic transplantation.     

Prostaglandin analogue protects pancreatic B-cells against cyclosporin A toxicity

Summary Cyclosporin A toxicity on pancreatic B-cells and its prevention by rioprostil, a prostaglandin E₁ analogue, were studied in the model of the isolated perfused pancreas of rats treated with both compounds for 8 days. At toxic doses of cyclosporin (10 and 20 mg/kg b.wt), the B-cells showed severe hydropic degeneration of the endoplasmatic reticulum and slight degranulation of the B-cells. Accordingly, the insulin secretion was markedly impaired. Administration of rioprostil ameliorated the insulin secretion significantly, but not the ultrastructural changes. At therapeutic levels of cyclosporin (5 mg/kg b.wt), the hydropic degeneration and the drop in insulin secretion were completely prevented by rioprostil. This observation might have therapeutic implications in the treatment of patients, in particular those undergoing pancreatic transplantation.     

Effect of ethanol intake on phenytoin metabolism in volunteers.

Ingestion of ethanol, 1 g/kg, did not influence the phenytoin half-life in 5 volunteers after single i.v. administration of 3 mg/kg phenytoin. The control phenytoin half-life was 12.4 h (SD +/- 4.4); with ethanol ingestion it was 12.3 h (SD +/- 5.2).     

Teratogenicity screening in standardized chick embryo culture: effects of dexamethasone and diphenylhydantoin

Teratogenic and toxic effects of DXM and DPH were tested using a standardized chick embryo culture. Survival, growth and malformations were scored with respect to the drug concentrations used. DXM (greater than 10(-8) mol/l) inhibited the differentiation of the extraembryonic blood circulation and induced craniofacial anomalies. DPH (greater than 1.5 10(-5) mol/l) induced cardiomegaly, craniofacial and somitic anomalies. Both drugs were lethal at 10(-3) mol/l. Comparison of results obtained with 8 drugs shows that the method has a good discriminative power and specificity and that it can be used as a simple, reliable and economical primary screening test, making it possible to reduce the use of animals in toxicological studies.     

The effects of naloxone on the analgesic activities of general anaesthetics

Summary Inhaled concentrations of nitrous oxide (80%), halothane (0.5%), trichloroethylene (0.5%) and s.c. ethanol (1 ml/kg) caused similar degrees of excitation and ataxia in mice. Nitrous oxide, tricholoroethylene and ethanol caused analgesia (hot plate and writhing tests), but only that caused by nitrous oxide was antagonized by naloxone (20 mg/kg). Halothane lacked analgesic activity.     

Electrocardiographic and behavioral effects ofl-DOPA in the guinea-pig

Conclusions The effects ofl-DOPA administered per os on conditioning, spontaneous behavior and the electrocardiogram of the guinea-pig are reported and compared.l-DOPA is able to inhibit the conditioned behavior in doses per os without any effect on spontaneous behavior or motility. Moreoverl-DOPA in doses up to 15 times higher than the average therapeutic daily dose pro kg used in man (TDD), does not alter the ECG of the guinea-pig. We did not observe ECG changes even after a total dose pro kg 60 times higher than TDD, which induced behavioral alterations in the 4 treated animals and one death.The present results may indicate psychotropic properties forl-DOPA and do confirm the low toxicity and cardiotoxicity of the drug, when supplied in a pure preparation of quality 12.

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Zusammenfassung Verabreicht manl-Dopa (1000 mg/kg per os) an Meerschweinchen, so kann dadurch das konditionierte Verhalten gehemmt werden, während das Spontanverhalten und die Motilität unverändert bleiben. Es sind keine Modifikationen des Elektrokardiogramms festzustellen, selbst dann nicht, wenn die 60fache mittlere therapeutische Tagesdosis gegeben wird.

     

Nitric oxide inhibition intensifies cold-restraint induced gastric ulcers in rats

Treatment 20 min beforehand with an inhibitor of nitric oxide (NO) synthesis, N^W-nitro-l-arginine methyl ester (L-NAME) (12.5, 25, 50 or 100 mg/kg, s.c.), dose-dependently intensified gastric glandular mucosal ulceration produced by cold-restraint stress. Hexamethonium (20 mg/kg) or atropine (1 mg/kg) pretreatment s.c. 20 min before stress strongly antagonised stress-evoked ulceration, as well as the ulcer-potentiating effects of L-NAME when either cholinoceptor antagonist was given concurrently with the NO inhibitor. Stress-induced mast cell degranulation was not worsened by L-NAME pretreatment. The findings suggest that NO could confer partial protection against stress-induced gastric ulcer formation; its activity is triggered off by the ulcerogenic mechanism of stress.     

Enhancement of ethanol-induced sleep by whole oil of nutmeg

In young chickens, the whole oil of nutmeg (200 mg/kg) increased the duration of sleep induced by ethanol (1--4 g/kg), particularly deep sleep. Iproniazid (50-400 mg/kg), a monoamine oxidase inhibitor, did not mimic this effect.     

Teratogenicity screening in standardized chick embryo culture: Effects of dexamethasone and diphenylhydantoin

Summary Teratogenic and toxic effects of DXM and DPH were tested using a standardized chick embryo culture. Survival, growth and malformations were scored with respect to the drug concentrations used. DXM (>10^–8 mol/l) inhibited the differentiation of the extraembryonic blood circulation and induced craniofacial anomalies. DPH (>1.5 10^–5 mol/l) induced cardiomegaly, craniofacial and somitic anomalies. Both drugs were lethal at 10^–3 mol/l. Comparison of results obtained with 8 drugs shows that the method has a good discriminative power and specificity and that it can be used as a simple, reliable and economical primary screening test, making it possible to reduce the use of animals in toxicological studies.Supported by the grant 4.790.0.84.17 from the Swiss National Science Foundation.     

Dexamethasone-induced neutrophilia. Negative correlation with increased plasma adrenaline concentrations

Summary Maximal increments in adrenaline and dexamethasone (DXM) plasma concentrations were observed c15 (T₅₀ 40 min) and 30 (T₅₀ 210–240 min) minutes after an i.v. DXM dose (6 mg/m² BSA) in man. There appears, however, to be no direct interaction between these agents in the development of induced neutrophilia, which occurs c240 min postinjection.Acknowledgments. The authors wish to thank Mrs C. Ditzler, Merck Sharp & Dohme Research Laboratories, USA, for determining the plasma dexamethasone concentrations J. M. M. is currently on sabbatical leave from McGaw Laboratories, USA. C. R. B. is a Rhodes scholar.     

Diurnal rhythm of ethanol metabolism in the rat

Male Sprague-Dawley rats injected with 2.0 g/kg of ethanol and analyzed 1 h later at 8 specific times of the day showed diurnal rhythms for alcohol concentrations in the blood, urine, brain and liver tissues. The circadian fluctuation noted for the concentrations of blood and tissue ethanol might indicate a diurnal variation in the enzymatic metabolism of ethanol.     

Plant thionins – the structural perspective

Thionins belong to a rapidly growing family of biologically active peptides in the plant kingdom. Thionins are small (∼5 kDA), cysteine-rich peptides with toxic and antimicrobial properties. They show a broad cellular toxicity against wide range of organisms and eukaryotic cell lines; while possessing some selectivity. Thionins are believed to be involved in protection against plant pathogens, including bacteria and fungi, by working directly at the membrane. The direct mechanism of action is still surrounded by controversy. Here the results of structural studies are reviewed and confronted with recent results of biophysical studies aimed at defining the function of thionins. The proposed toxicity mechanisms are reviewed and the attempt to reconcile competing hypotheses with a wealth of structural and functional studies is made. Received 3 December 2005; received after revision 6 February 2006; accepted 18 March 2006