ABSTRACT
Androgen deprivation induces vascular dysfunction in which altered release and action of prostanoids has been extensively studied. On the other hand, the vascular organ-culture system has been reported as a valid model for phenotypic changes that occur in several cardiovascular pathologies. Since there are no studies analyzing the impact of androgenic loss on vascular vulnerability during induced vascular damage, the objective of this study was to analyze the possible preventive role of male sex hormones on the organ culture-induced vascular damage in rat aorta. The link to possible changes in gross structure was also analyzed. For this purpose, fresh and 20 h-cultured aortic arterial segments from intact and orchidectomized rats were used to analyze: (i) the release and vasomotor effect of the thromboxane A2 (TXA2), prostaglandin (PG) E2, PGF2α and PGI2; (ii) the vasodilator response induced by acetylcholine (ACh) as well as the involvement of prostanoids, in particular TXA2, in the ACh-induced response; (iii) the effect of activation of thromboxane/prostaglandin (TP) receptors on the ACh-induced response; and (iv) the vascular structure. The results showed that organ culture: i) increased production of prostanoids; ii) increased prostanoids-induced vasomotor responses; iii) decreased ACh-induced relaxation after incubation with indomethacin, a blocker of cyclooxygenases; iv) increased the ACh-induced relaxation after incubation with the TXA2 synthase inhibitor, furegrelate, more in arteries from orchidectomized rats than in those of intact rats; v) diminished ACh-induced relaxation after U-46619 incubation only in arteries from orchidectomized rats; and vi) preserved the integrity of the different vascular layers. These results showed the protective role of male sex hormones against the induced vascular damage, since a decreased deleterious effect of prostanoids, in particular that of TXA2, was observed in arteries from rats with intact gonadal function.
Subject(s)
Androgens/pharmacology , Aorta/drug effects , Endothelium, Vascular/drug effects , Orchiectomy/methods , Organ Culture Techniques/methods , Prostaglandins/toxicity , Thromboxane A2/toxicity , Animals , Aorta/metabolism , Aorta/pathology , Blood Pressure , Cyclooxygenase 2/chemistry , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Male , Models, Animal , Rats , Rats, Sprague-Dawley , Thromboxane-A Synthase/antagonists & inhibitorsABSTRACT
Cyclopentenone prostaglandins (CyPGs), such as 15-deoxy-Δ(12,14)-prostaglandin J2 (15dPGJ2), are reactive prostaglandin metabolites exerting a variety of biological effects. CyPGs are produced in ischemic brain and disrupt the ubiquitin-proteasome system (UPS). Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a brain-specific deubiquitinating enzyme that has been linked to neurodegenerative diseases. Using tandem mass spectrometry (MS) analyses, we found that the C152 site of UCH-L1 is adducted by CyPGs. Mutation of C152 to alanine (C152A) inhibited CyPG modification and conserved recombinant UCH-L1 protein hydrolase activity after 15dPGJ2 treatment. A knock-in (KI) mouse expressing the UCH-L1 C152A mutation was constructed with the bacterial artificial chromosome (BAC) technique. Brain expression and distribution of UCH-L1 in the KI mouse was similar to that of wild type (WT) as determined by western blotting. Primary cortical neurons derived from KI mice were resistant to 15dPGJ2 cytotoxicity compared with neurons from WT mice as detected by the WST-1 cell viability assay and caspase-3 and poly ADP ribose polymerase (PARP) cleavage. This protective effect was accompanied with significantly less ubiquitinated protein accumulation and aggregation as well as less UCH-L1 aggregation in C152A KI primary neurons after 15dPGJ2 treatment. Additionally, 15dPGJ2-induced axonal injury was also significantly attenuated in KI neurons as compared with WT. Taken together, these studies indicate that UCH-L1 function is important in hypoxic neuronal death, and the C152 site of UCH-L1 has a significant role in neuronal survival after hypoxic/ischemic injury.
Subject(s)
Brain Ischemia/genetics , Cyclopentanes/toxicity , Neurons/drug effects , Neurons/physiology , Point Mutation , Prostaglandins/toxicity , Ubiquitin Thiolesterase/genetics , Animals , Binding Sites , Brain Ischemia/enzymology , Brain Ischemia/pathology , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/enzymology , Neurons/metabolism , Rats , Ubiquitin Thiolesterase/biosynthesisABSTRACT
Prostaglandins are endogenous mediators formed from arachidonic acid by cyclooxygenases and prostaglandin synthases during inflammatory processes. The five-membered ring can be dehydrated, and α,ß-unsaturated cyclopentenone PGs (cyPGs) are generated. Recent studies have been focused on their potential pharmacological use against inflammation and cancer. However, little is known so far about possible adverse health effects of cyPGs. We addressed the question whether selected cyPGs at a concentration range of 0.1-10 µM exhibit mutagenic and genotoxic properties in the hamster lung fibroblast V79 cell line and whether these effects are accompanied by a depletion of intracellular glutathione (GSH). The cyPGs 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) and prostaglandin A2 (PGA2) significantly induced DNA damage in V79 cells after 1 h of incubation. Furthermore, a more pronounced increase in formamidopyrimidine-DNA glycosylase (FPG) sensitive sites, indicative of oxidative DNA-damage, was observed. The findings on DNA-damaging properties were supported by our results that 15dPGJ(2) acts as an aneugenic agent which induces the amount of kinetochore positive micronuclei associated with an increase of apoptosis. The strong potency of cyPGs to rapidly bind GSH measured in a chemical assay and to significantly reduce the GSH level after only 1 h of incubation may contribute to the observed oxidative DNA strand breaks, whereas directly induced oxidative stress via reactive oxygen species could be excluded. However, after an extended incubation time of 24 h no genotoxicity could be measured, this may contribute to the lack of mutagenicity in the hypoxanthine phosphorybosyltransferase (HPRT) assay. In conclusion, potential in vitro genotoxicity of cyPG and a strong impact on GSH homeostasis have been demonstrated, which may be involved in carcinogenesis mediated by chronic inflammation.
Subject(s)
Cyclopentanes/toxicity , Fibroblasts/drug effects , Glutathione/metabolism , Mutagens/toxicity , Prostaglandins/toxicity , Animals , Cell Line , Cricetinae , DNA Breaks/drug effects , Fibroblasts/metabolism , Oxidative Stress/drug effectsABSTRACT
Chemical investigation of the AcOEt/MeOH extract of Clavularia viridis collected in Taiwan has afforded four new prostanoids, named claviridins A-D (1-4, resp.). The structures of compounds 1-4 were determined on the basis of 1D- and 2D-NMR techniques, including COSY, HMQC, HMBC, and NOESY experiments. Pharmacological studies revealed that compounds 1-4 exhibited potent cytotoxicity against human cancer cells.
Subject(s)
Anthozoa/chemistry , Prostaglandins/chemistry , Animals , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Molecular Conformation , Prostaglandins/isolation & purification , Prostaglandins/toxicity , TaiwanABSTRACT
We have shown that nanoparticle inhalation impairs endothelium-dependent vasodilation in coronary arterioles. It is unknown whether local reactive oxygen species (ROS) contribute to this effect. Rats were exposed to TiO(2) nanoparticles via inhalation to produce a pulmonary deposition of 10 microg. Coronary arterioles were isolated from the left anterior descending artery distribution, and responses to acetylcholine, arachidonic acid, and U46619 were assessed. Contributions of nitric oxide synthase and prostaglandin were assessed via competitive inhibition with N(G)-Monomethyl-L-Arginine (L-NMMA) and indomethacin. Microvascular wall ROS were quantified via dihydroethidium (DHE) fluorescence. Coronary arterioles from rats exposed to nano-TiO(2) exhibited an attenuated vasodilator response to ACh, and this coincided with a 45% increase in DHE fluorescence. Coincubation with 2,2,6,6-tetramethylpiperidine-N-oxyl and catalase ameliorated impairments in ACh-induced vasodilation from nanoparticle exposed rats. Incubation with either L-NMMA or indomethacin significantly attenuated ACh-induced vasodilation in sham-control rats, but had no effect in rats exposed to nano-TiO(2). Arachidonic acid induced vasoconstriction in coronary arterioles from rats exposed to nano-TiO(2), but dilated arterioles from sham-control rats. These results suggest that nanoparticle exposure significantly impairs endothelium-dependent vasoreactivity in coronary arterioles, and this may be due in large part to increases in microvascular ROS. Furthermore, altered prostanoid formation may also contribute to this dysfunction. Such disturbances in coronary microvascular function may contribute to the cardiac events associated with exposure to particles in this size range.
Subject(s)
Coronary Vessels/physiology , Nanoparticles/toxicity , Reactive Oxygen Species/metabolism , Administration, Inhalation , Animals , Arachidonic Acid/metabolism , Arachidonic Acid/pharmacology , Arterioles/drug effects , Body Weight/physiology , Capillaries/physiology , Coronary Circulation/drug effects , Heart/drug effects , In Vitro Techniques , Male , Nanoparticles/administration & dosage , Nitric Oxide/physiology , Organ Size/drug effects , Oxidative Stress/drug effects , Prostaglandins/toxicity , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/adverse effects , Signal Transduction/drug effects , Thromboxanes/pharmacology , Titanium/toxicity , Vasoconstriction/drug effects , Vasodilation/drug effectsABSTRACT
Two prostaglandins, PGA2 and PGB2, were isolated from the Okinawan zoanthid, Palythoa kochii, during a search for paclitaxel-like neurite-degenerating compounds from natural sources using a cell-based assay method. In the presence of PGA2 at 30 microM, the neuronal processes induced in PC12 cells by the nerve growth factor (NGF) degenerated over 24 h, whereas PGB2 had no effect on the neuronal processes of PC12 cells. This activity of PGA2 was similar to that of the microtubule-stabilizing agents, paclitaxel (Taxol) and epothilone A, unlike the microtubule-depolymerizing agent, colchicine, which brought about quick neurite degeneration within 3 h. PGA2 stimulated tubulin polymerization, although less potently than paclitaxel. An examination of structure-activity relationships across several PGs suggests that the cyclopentenone ring structure and the orientation of its dipolar moment played an important role in the paclitaxel-like neurite-degenerating activity. These results suggest that the cyclopentenone-type PGs can interact with microtubules to inhibit their function like paclitaxel.
Subject(s)
Anthozoa/chemistry , Microtubules/drug effects , Microtubules/metabolism , Neurites/drug effects , Neurites/metabolism , Prostaglandins/chemistry , Prostaglandins/pharmacology , Animals , Epothilones/pharmacology , Molecular Structure , Nerve Growth Factor/pharmacology , PC12 Cells , Paclitaxel/pharmacology , Prostaglandins/isolation & purification , Prostaglandins/toxicity , Rats , Structure-Activity RelationshipABSTRACT
Durante dos siglos las preparaciones de bismuto han sido útiles en una variedad de desórdenes gastrointestinales. Una renovada atención sobre la terapia con bismuto surgió cuando se demostró que los compuestos de bismuto son efectivos contra la infección por Helicobacter pylori. La necesidad de su erradicación total ha potenciado el uso del subcitrato de bismuto coloidal (SBC). En este sentido, parece actuar por varios mecanismos. El presente trabajo de revisión describe la farmacología del SBC en el tratamiento de descontroles gastrointestinales. El uso prolongado de compuestos de bismuto a dosis elevadas, que se produjo en el pasado, dio lugar a la aparición de efectos adversos serios. Los estudios sobre la administración oral de SBC sugieren que, utilizado en las dosis recomendadas, ha sido efectivo y seguro. No obstante, la posible toxicidad de las preparaciones de bismuto debe tenerse presente. En el presente trabajo se muestra una descripción de absorción, distribución, eliminación y toxicidad del SBC. Años atrás no había ningún estudio sistemático sobre las relaciones de estructura-actividad del SBC. Sin embargo, recientemente se ha producido un importante progreso en esta área. Así que, otro aspecto interesante de esta revisión es que resume, discute y describe las principales propiedades físicas, químicas y estructurales de SBC
Bismuth preparations have been useful in a variety of gastrointestinal disorders for two centuries. A renewed attention in bismuth therapy arose when it was shown that bismuth preparations are effective against Helicobacter pylori infection. The need for its total eradication has resulted in the use colloidal bismuth subcitrate (CBS). In this sense, it appears to act via several mechanisms. Present review describes CBS pharmacology in the treatment of gastrointestinal disorders. The prolonged use of high dose bismuth compounds in the past has shown some serious side effects. The studies on CBS oral administration suggests that, utilized in recommended dosages, it has been effective and safe. Nevertheless, the possible toxicity of bismuth preparations should be kept in mind. A description about CBS absorption, distribution, elimination and toxicity are shown in the present review. In the past, there had been no systematic study of the structure-activity relationships of CBS. Recently, however, there has been important progress in this area. So, another interesting aspect of this review is that summarizes, discusses and describes the main physical, chemical and structural properties of CBS
Subject(s)
Bismuth/chemistry , Bismuth/pharmacology , Bismuth/therapeutic use , Gastrointestinal Diseases/therapy , Gastrointestinal Agents/therapeutic use , Helicobacter pylori/chemistry , Helicobacter pylori , Anti-Ulcer Agents/chemical synthesis , Anti-Ulcer Agents/pharmacology , Prostaglandins/pharmacology , Bismuth/toxicity , Anti-Ulcer Agents/toxicity , Prostaglandins/biosynthesis , Prostaglandins/pharmacokinetics , Prostaglandins/toxicity , Bismuth/adverse effects , Anti-Ulcer Agents/therapeutic use , 35528ABSTRACT
Chronic inflammatory reactions in the brain appear to be one of the primary etiological factors in the pathogenesis of Alzheimer's disease (AD). This is supported by the fact that the secretory products of inflammatory reactions, which include cytokines, complement proteins, adhesion molecules, and free radicals, are neurotoxic. We have recently reported that prostaglandins (PGs), which are also released during inflammatory reactions, cause rapid degenerative changes in differentiated murine neuroblastoma cells (NB) in culture. PGA1 is more effective than PGE1. Similar observations were made in a primary culture of fetal rat hippocampal cells. Epidemiological and clinical studies on AD also support the involvement of PGs in neuronal degeneration. Thus, we propose a hypothesis that PGs are one of the major extracellular signals that initiate neuronal degeneration, which is mediated by intracellular signals such as the beta-amyloid peptide (Abeta) and ubiquitin, since the levels of these proteins are increased by PG treatment. We further suggest that adenosine 3', 5'-cyclic monophosphate (cAMP) is one of the factors that regulate the levels of both Abeta and ubiquitin in NB cells. Increases in the level of Abeta in NB cells following an elevation of intracellular cAMP levels appear to be due to an increase in the rate of processing of the amyloid precursor protein (APP) rather than an increase in the expression of APP. The mechanisms underlying Abeta-induced neuronal degeneration have been under intense investigation, and several mechanisms of action have been proposed. We postulate that PG-induced elevation of Abeta may lead to an increased binding of Abeta to the 20S proteasome, resulting in a reduction of 20S proteasome-mediated degradation of ubiquitin-conjugated proteins. This is predicted to lead to an increase in an accumulation of abnormal proteins, which ultimately contribute to neuronal degeneration and death. Based on our hypothesis and on studies published by others, we propose that a combination of nonsteroidal anti-inflammatory drugs, which inhibit the synthesis of PGs, and antioxidant vitamins, which quench free radicals and both of which have been recently reported to be of some value in AD treatment when used-individually, may be much more effective in the prevention and treatment of AD than the individual agents alone.
Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , Brain/pathology , Neurotoxins/metabolism , Prostaglandins/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Animals , Cells, Cultured , Humans , Inflammation/metabolism , Neurons/drug effects , Neurons/pathology , Neurotoxins/toxicity , Prostaglandins/toxicity , RatsSubject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/toxicity , Colonic Neoplasms/drug therapy , Iodized Oil , Liver Neoplasms/drug therapy , Melanoma/drug therapy , Prostaglandins/administration & dosage , Prostaglandins/therapeutic use , Animals , Cell Division/drug effects , Cell Survival/drug effects , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Cisplatin/toxicity , Colonic Neoplasms/pathology , Drug Carriers , Female , HeLa Cells , Humans , Injections, Intra-Arterial , Liver Neoplasms/pathology , Male , Melanoma/pathology , Mice , Mice, Inbred Strains , Mice, Nude , Microspheres , Prostaglandins/toxicity , Rabbits , Rats , Rats, Sprague-Dawley , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
Prostaglandins (PGs) with antiproliferative activity against tumor cells consist of the cyclopentenone PGs and the alkylidene cyclopentenone PGs. Such PGs are PGD2, PGJ2, delta 12-PGJ2, PGA1, delta 7-PGA1, and PGA2. Both PGJ2 and delta 12-PGJ2 are ultimate metabolites of PGD2 and have potent antiproliferative activity on tumor cells. delta 12-PGJ2 was identified in human urine, whereas delta 7-PGA1 has not been found in the human body. One important characteristic of both delta 7-PGA1 and delta 12-PGJ2 is that they have little cross resistance with cisplatin and adriamycin in vitro and in vivo. delta 7-PGA1 has 5-fold greater antitumor activity than delta 12-PGJ2. Methyl ester-delta 7PGA1 (methyl-delta 7-PGA1) is stable chemically and can be easily synthesized in large amounts. All four isomers of methyl-delta 7-PGA1 showed the same antiproliferative activities on ovarian carcinoma cells. In addition, methyl-delta 7-PGA1 integrated in lipid microspheres (lipo-methyl-delta 7-PGA1) is more soluble in water than methyl-delta 7-PGA1 alone. Hence, lipo-methyl-delta 7-PGA1 was selected for extensive preclinical studies. Intravenous administration of lipo-methyl-delta 7-PGA1 could inhibit the growth of both HeLa S3 and Lovo colon cancer cells transplanted subcutaneously in nude mice. Lipo-methyl-delta 7-PGA1 by intraperitoneal administration could prolong the survival of scid mice bearing 2008C/13* cells resistant to cisplatin. The combined administration of cisplatin and lipo-methyl-delta 7-PGA1 prolonged the survival of nude mice bearing HRA cells compared with each single agent alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Antineoplastic Agents/therapeutic use , Prostaglandins/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , Cell Division/drug effects , Humans , Mice , Prostaglandins/pharmacology , Prostaglandins/toxicity , Tumor Cells, CulturedABSTRACT
We examined an in vitro system to screen for diarrheagenic chemicals using an established intestinal cell line (T84 human colonic carcinoma). The cells were grown on Millicell-PCF (polycarbonate membrane) wells. The cells were seeded at approximately 5 x 10(6) cells/30mm well and incubated for 9-11 days in a 5% CO2 incubator saturated with water at 37 degrees C. The culture medium was a 1:1 mixture of Ham's F12 and Dulbecco's MEM with 5% fetal bovine serum and 25 micrograms/ml gentamicin sulfate. The well containing cells was removed from the incubator and mounted in a modified Ussing chamber for measurement of short-circuit current (ISC). Chemical-induced increases in ISC are usually indicative of electrogenic epithelial Cl- secretion, which is associated with diarrheagenic effects in animals and humans. T84 cells grown on Millicell-PCF membrane responded with an increase in ISC after basolateral addition of the cholinergic (muscarinic) agonist carbachol, prostaglandin E2, 16,16-dimethylprostaglandin E2, and forskolin, while non-diarrheagenic prostaglandin D2 did not affect ISC. Based on our results, this in vitro system has the potential to be adapted as a rapid screen for detecting diarrheagenic chemicals.
Subject(s)
Diarrhea/chemically induced , Drug Evaluation, Preclinical/methods , Intestines/drug effects , Carbachol/toxicity , Colforsin/toxicity , Electrophysiology , Humans , Intestines/physiopathology , Prostaglandins/toxicity , Tumor Cells, CulturedABSTRACT
A monomeric derivative and several oligomeric derivatives were synthesized from prostaglandin B2. Their lipid solubility was studied by measuring their octanol-water partition coefficients. With EPR spectroscopy, the oligomeric derivatives were shown to have g = 2 signal, indicating these compounds have intrinsic free radicals. Measuring the rate of adenochrome formation, it was shown that these derivatives could scavenge superoxide anions. Using a spin-trapping technique employing DMPO, we found that these oligomers could also scavenge hydroxyl radicals. The calcium chelating activity of these compounds were also studied. In an in vitro rat model, these compounds inhibited lipid peroxidation as measured by the production of thiobarbituric acid reacting substances. Other prostaglandin oligomeric derivatives synthesized from PGE1 were also studied, and their properties were compared with these new compounds. Results suggest that both the water solubility and the chelating activity for calcium ions may not be related to their protective effects in ischemic or traumatic injury.
Subject(s)
Alprostadil/analogs & derivatives , Antioxidants/chemistry , Prostaglandins, Synthetic/chemistry , Animals , Calcium/chemistry , Cell Membrane/drug effects , Chelating Agents/chemistry , Chemical Phenomena , Chemistry, Physical , Electron Spin Resonance Spectroscopy , Free Radical Scavengers , Hydroxylation , Lethal Dose 50 , Lipids , Mice , Nephelometry and Turbidimetry , Octanols , Prostaglandins/chemistry , Prostaglandins/toxicity , Prostaglandins B/chemistry , Solubility , Superoxides , WaterABSTRACT
The cytotoxic action of various prostanoids was examined on a transformed human epidermal cell line (HSC-1), and methyl(5S,6S,7Z)-5,6-diacetoxy-7-((2S)-4-chloro-2-hydroxy-2-((2 Z+ ++)-2-octenyl)-5-oxo-3-cyclopentenylidene)heptanoate (YM-11), which is a punaglandin compound, was found to be most active. YM-11 exerted a dose-dependent inhibition of HSC-1 cell growth over 0.03 microM (0.01 micrograms/ml), and at 0.3 microM (0.1 micrograms/ml) its growth was completely inhibited. The IC50 value of YM-11 on HSC-1 cell growth was calculated as 0.15 microM (0.05 micrograms/ml). Methyl(E)-7-(5-chloro-2-hydroxy-2-octyl-5-oxo-3-cyclopentenylidene )heptanoate (YM-3), which is also a punaglandin derivative, showed remarkable cytotoxicity on HSC-1 cells with an IC50 of 0.24 microM (0.08 micrograms/ml). Concerning other cytotoxic prostaglandins (PGs), the IC50 values of delta 7-PGA1, delta 12-PGJ2 and PGD2 were 1.5 microM (0.5 micrograms/ml), 2.1 microM (0.75 micrograms/ml) and 5.7 microM (2 micrograms/ml), respectively. On the basis of the present data and previous in vitro and in vivo evidence, punaglandin derivatives may be useful antineoplastic agents for skin cancer.
Subject(s)
Epidermis/drug effects , Prostaglandins/toxicity , Cell Division/drug effects , Cell Line, Transformed , Cell Survival/drug effects , Cell Transformation, Neoplastic , Epidermal Cells , HumansSubject(s)
Convulsants/analysis , Seizures/chemically induced , Amino Acids/toxicity , Animals , Carbolines/toxicity , Cats , Cerebral Cortex/drug effects , Convulsants/pharmacology , Cysteic Acid/toxicity , Cysteine/toxicity , Disease Models, Animal , Dogs , Estrogens/toxicity , Folic Acid/toxicity , Homocysteine/analogs & derivatives , Homocysteine/toxicity , Kynurenine/pharmacology , Methionine/toxicity , Mice , Neurotransmitter Agents/toxicity , Prostaglandins/toxicity , Pyridoxal Phosphate/toxicity , Quinolinic Acid , Quinolinic Acids/pharmacology , Rats , Spinal Cord/drug effectsSubject(s)
Leukemia L1210/drug therapy , Muscle Contraction/drug effects , Platelet Aggregation/drug effects , Prostaglandins D/pharmacology , Prostaglandins/pharmacology , Animals , Antineoplastic Agents , Colon/drug effects , Colon/physiology , Diarrhea/chemically induced , Guinea Pigs , Humans , Mice , Prostaglandin D2 , Prostaglandins/toxicity , Prostaglandins D/therapeutic useABSTRACT
Median lethal doses were estimated for PGBx administered to mice by the intraperitoneal and intravenous routes. The incidence of lethality (and therefore the LD50) was time dependent over a 96 hour period. The animals were active, were responsive and took nourishment during the 4-day post-injection period so that they apparently died from the direct effects of PGBx (or its metabolites) and not as a consequence of depression-induced dehydration or starvation.
Subject(s)
Polymers/toxicity , Prostaglandins B/toxicity , Prostaglandins/toxicity , Animals , Behavior, Animal/drug effects , Injections, Intraperitoneal , Injections, Intravenous , Lethal Dose 50 , Male , Mice , Mice, Inbred ICR , Nervous System Diseases/chemically induced , Oxidative Phosphorylation/drug effects , Time FactorsABSTRACT
Prostaglandin F2 alpha alone and in combination with sodium salicylate, was administered i.m. to pregnant CBA mice at various times on day 9 of gestation. A high frequency of rib malformations (90%) was recorded whereas the resorption rate was moderate (18%). When combining prostaglandin treatment (25 mg/kg i.m.) with sodium salicylate (500 mg/kg i.m.), the resorption rate increased. The malformation frequency remained unchanged except for the group with combined treatment at 10 a.m. (=maximum teratogenic period for salicylate induced rib malformations). This treatment resulted in a high frequency of maternal death; the resorption frequency was 75% and the surviving foetuses were malformed.