Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Toxicity model”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources
PubMed1996

Ribavirin potentiates the efficacy and toxicity of 2',3'- dideoxyinosine in the murine acquired immunodeficiency syndrome model.

The efficacy and toxicity of ribavirin (25 or 125 mg/kg/day), 2',3'-dideoxyinosine (ddI) (200 mg/kg/day) and a combination of both drugs at these doses given for 6 weeks were investigated in the murine acquired immunodeficiency syndrome model. Our results showed a significant protection against splenomegaly, lymphadenopathy and hypergammaglobulinemia in mice treated with ribavirin at 25 mg/kg/day alone or in combination with ddI at 200 mg/kg/day. A good synergistic effect was observed with the drug combination, whereas ddI alone (200 mg/kg/day) did not give any protection. Ribavirin/ddI combination protected against the loss of CD8 T cells in spleen and restored the capacity of splenocytes to proliferate after activation with a mitogenic agent. Moreover, the drug combination resulted in a protection of the spleen and cervical lymph node architectures and a regression of germinal centers. Hematotoxicity appeared at a dose of 125 mg/kg of ribavirin alone and increased when used concomitantly with ddI. In conclusion, ribavirin and ddI at low doses are synergistic and effective in the murine acquired immunodeficiency disease model, but at high doses they are toxic.

Animals↗
PubMed2006

Gastric mucosal cell model for estimating relative gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.

The study objective was to characterize the AGS human gastric mucosal cell line as a model for estimating gastrointestinal toxicity of COX-inhibiting compounds. Rofecoxib, celecoxib, nimesulide, ibuprofen, indomethacin, aspirin, salicylic acid, naproxen and acetaminophen were tested for inhibition of COX-2-mediated prostaglandin E2 synthesis in A549 and AGS cells. The IC50 ratio AGS/A549 was calculated as an estimate of the therapeutic index (TI) for gastrointestinal toxicity. Calculated IC50 values of non-steroidal anti-inflammatory drugs (NSAIDs) in A549 cells were in excellent agreement with published values (r = 0.996; P < 0.005). Calcium ionophore induction of arachidonic acid release in AGS cells provided TI similar to those using platelets and A549 cells (r = 0.918; P < 0.01). The AGS/A549 model exhibited lower TI than the platelet/A549 model. Spearman ranking correlated clinical NSAID gastropathy with lower AGS TI values. The AGS cell line has excellent potential to serve as a model for assessing the gastrointestinal effects of COX-inhibiting compounds.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Dose response and toxicity of doxorubicin microspheres in a rat tumor model.

The therapeutic response and toxic effects of chemotherapy using several doses of doxorubicin in conventional solution form or bound to an ion-exchange resin were compared in a rat tumor model, to assess the relationship of drug dose to therapeutic efficacy and associated toxicity. Single bolus injections of 3.0, 4.5, 6.0, 7.5 and 9.0 mg/kg were administered via the abdominal aorta to rats bearing hindlimb tumors. Tumor size was measured serially and the growth rates of treated groups were compared with a control growth curve. In addition, the effect of empty microspheres on tumor growth rate was assessed. The levels of circulating white blood cells were measured and compared to control levels to provide an indication of the severity of bone marrow toxicity experienced by each form of treatment. Finally, any difference in the distribution of doxorubicin to tumor, hindlimb and cardiac tissue following administration of doxorubicin as free drug or on microspheres was ascertained. Empty ion-exchange resin exerted a small although significant detrimental effect on tumor growth which may be explained by the embolization of microspheres in the precapillary blood vessels of the tumor resulting in a transient delay in tumor growth rate. The lowest dose of doxorubicin produced a significantly better therapeutic response when administered in the free drug form, but higher doses elicited an equivalent delay in tumor growth for both drug microsphere and free drug groups in a dose-dependent manner, with the maximum anti-tumor response occurring at the highest dose. Treatment with free doxorubicin at high doses resulted in significant reductions of circulating white blood cells suggesting the occurrence of bone marrow toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1998

Interleukin 15 offers selective protection from irinotecan-induced intestinal toxicity in a preclinical animal model.

Irinotecan (CPT-11) is a chemotherapeutic agent that is active in the treatment of a variety of solid tumor malignancies. Diarrhea represents the most common dose-limiting toxicity that is independent of the schedule of administration. A rat model with dose-limiting toxicity profiles that are similar to those observed in patients treated with CPT-11 was developed and used to evaluate the role of interleukin 15 (IL-15) in the modulation of the therapeutic selectivity of CPT-11 in normal rats and rats bearing advanced colorectal cancer. The maximum tolerated dose and lethal dose (LD) of CPT-11 by i.v. push daily x 3 were 150 and 200 mg/kg/day, respectively. CPT-11 at the LD induced a 93-100% incidence of severe diarrhea and an 86-100% incidence of lethality in treated animals. IL-15, a cytokine with multiple mechanisms of action, was used at a 100 or 400 microg/kg/dose with different schedules of administration (3, 8, and 11 doses, i.p.) to protect against CPT-11-induced toxicity. IL-15 offered complete and sustained selective protection against CPT-11-induced delayed diarrhea and lethality. IL-15 also moderately potentiated the antitumor activity of CPT-11 in rats bearing advanced colorectal cancer. Morphological examination of rat intestinal tissues after treatment with LD of CPT-11 revealed dramatic protection of duodenal and colonic tissue architecture by IL-15. CPT-11 alone produced serious damage to duodenal villi and colonic crypts. The results clearly demonstrated the ability of IL-15 to provide significant protection from CPT-11-induced intestinal toxicity with maintenance of antitumor activity, resulting in an increase in the therapeutic index of CPT-11. The clinical relevance of the results obtained in this model system needs to be confirmed.

Animals↗
PubMed2003

Quantification of joint effect for hydrogen bond and development of QSARs for predicting mixture toxicity.

A QSAR model is successfully proposed to predict the toxicity effect on Photobacterium phosphoreum by nonpolar-narcotic-chemical mixtures and/or polar-narcotic-chemical mixtures. For nonpolar-narcotic-chemical mixtures and polar-narcotic-chemical mixtures, their corresponding hydrophobicity-based QSAR models are derived from regression analysis. Comparison of these two QSAR models make us believe that it is the joint effect of hydrogen bond in polar-narcotic-chemical mixture that leads to the difference between these two models. Such joint effect of hydrogen bond can be quantified as AMH and BMH by using the different partition coefficients of mixtures in various organic phase/water systems. And the regression analysis results convinced us that the introduction of AMH does improve the quality of the QSAR model with r2=0.948, S.E.=0.166 and F=745.201 at P=0.000 for total 84 mixtures.

Drug Synergism↗
PubMed1983

Isolated intestinal cells of guinea pig: a suitable model for assessing direct toxic effects of ethanol on the mucosa of the upper small intestine.

The effects of acute ethanol (1-10%) on membrane transport and respiration in isolated jejunal cells of guinea pig were investigated. Three substrates with different transport mechanisms were employed: uridine (active, Na+-dependent transport), choline (saturable, Na+-independent transport), and chenodeoxycholate (simple diffusion). Uridine and choline transport were half-maximally inhibited by 3% ethanol; this inhibition was paralleled by a similar decrease in mitochondrial respiration and ATP production. Chenodeoxycholate uptake in contrast was virtually unaffected by up to 10% ethanol. It is concluded that acute ethanol inhibits active carrier-mediated absorption, but has no effect on transcellular diffusion of lipophilic compounds.

Adenosine Triphosphate↗
PubMed1992

Skin organ culture model to test the toxicity of polyoxyethylene networks.

Films of polyoxyethylene network were prepared from two types of triethoxysilane-terminated prepolymers. In this way, films of polyoxyethylene network with possible applications in the biomedical field could be made easier. To test their biocompatibility, these networks were added to organ cultures of adult human skin and embryonic chicken skin. A rapid toxic effect was observed, especially with the urethane-linked network. Enzymatical degradation of the network by enzymes in the culture medium might be responsible for the formation of toxic metabolites. Testing of related chemical compounds in our in vitro assay suggested that the formation of a silane group with an amino terminal is most likely to be responsible for the toxic effects observed.

Adult↗
PubMedDate not supplied

Freshly isolated hepatocytes as a model for studying the toxicity of paracetamol.

The toxicity of paracetamol has been investigated in freshly isolated hamster hepatocytes. Two phases of toxicity have been identified. In phase 1, metabolic activation of paracetamol occurs with depletion of glutathione. In phase 2, there is progressive morphological damage, leading ultimately to cell death. This occurs even in the absence of further exposure to paracetamol. The thiol reductant, dithiothreitol, added at the start of phase 2, prevents and reverses the toxicological damage that would otherwise occur. Thus, it is most likely that paracetamol causes hepatotoxicity through oxidation of SH groups in key enzymes. N-Acetylcysteine, but not methionine, has an effect similar to that of dithiothreitol. This difference is probably due to oxidation of the enzymes involved in the conversion of methionine to cysteine, whereas N-acetylcysteine can still serve as a precursor of glutathione. The glutathione can act both by adduct formation with the metabolite of paracetamol and as a thiol reductant. Species differences in sensitivity to paracetamol toxicity were shown to be due to differences in the rate of oxidation of the drug to its toxic metabolite. Most people are relatively poor activators of paracetamol, but in few subjects the reaction proceeds quite rapidly, rendering such individuals more sensitive to the hepatotoxic effects of the drug.

Acetaminophen↗
PubMed2006

Peripheral inflammation and neuroprotection: systemic pretreatment with complete Freund's adjuvant reduces 6-hydroxydopamine toxicity in a rodent model of Parkinson's disease.

Complete Freund's adjuvant (CFA), a pro-inflammatory agent, was inoculated, subcutaneously, to Sprague-Dawley rats prior to the intrastriatal injection of 6-hydroxydopamine (6-OHDA). Animals were sacrificed 7 and 28 days following 6-OHDA injection; neuronal damage, glial activation and cytokine levels, within the nigrostriatal system, were then investigated. Nigrostriatal degeneration induced by 6-OHDA was accompanied by early microglial and astroglial activation, which preceded the onset of dopaminergic cell loss, in the SNc, without significant changes in cytokine levels. CFA pretreatment markedly reduced the SNc neuronal loss and associated microglial activation, as well as the rotational response to apomorphine. These changes were associated with moderate, transient increases in the nigrostriatal levels of glial-cell-derived neurotrophic factor (GDNF) and pro-inflammatory cytokines, including interleukin (IL)-1alpha, IL-1beta and IL-6. Our results show that prior delivery of a peripheral, pro-inflammatory stimulus induces neuroprotection, in a rodent model of Parkinson's disease, possibly through the modulation of cytokine production at the nigrostriatal level.

Adjuvants, Immunologic↗
PubMed2000

Yeasts as a model for assessing the toxicity of the fungicides Penconazol, Cymoxanil and Dichlofluanid.

In the present work the sensitivity of yeast strains of Kluyveromyces marxianus, Pichia anomala, Candida utilis, Schizosaccharomyces pombe and Saccharomyces cerevisiae, to the fungicides cymoxanil, penconazol, and dichlofluanid, was evaluated. Dichlofluanid induced the most negative effects, whereas penconazol in general was not very toxic. Overall, our results show that the parameters IC50 for specific respiration rates of C. utilis and S. cerevisiae and C(D) for cell viability of S. cerevisiae can be applied to quantify the toxicity level of the above compounds in yeast. Hence, could be explored as an alternative or at least as a complementary test in toxicity studies and, therefore, its potential for inclusion in a tier testing toxicity test battery merits further research.

Acetamides↗
PubMed1999

Cyclodextrin inclusion complexes of antimycotics intended to act in the oral cavity--drug supersaturation, toxicity on TR146 cells and release from a delivery system.

The dissolution rate, the toxicity and the release from chewing gum of miconazole and econazole cyclodextrin products and complexes were investigated. The dissolution rate studies showed that an amorphous miconazole hydroxypropyl-beta-cyclodextrin product gave drug supersaturation, whereas drug supersaturation was not present during dissolution rate testing of an econazole hydroxypropyl-beta-cyclodextrin product. The miconazole hydroxypropyl-beta-cyclodextrin product and genuine cyclodextrin inclusion complexes of miconazole, econazole and clotrimazole were toxic on a human TR146 buccal cell culture model. The toxicity was probably due to drug supersaturation, thereby increasing the bioavailability of the antimycotics. The econazole hydroxypropyl-beta-cyclodextrin product and physical mixtures of miconazole or econazole and beta-cyclodextrin did not give supersaturation and were not as toxic as the above-mentioned compounds. Neat econazole and miconazole, a genuine econazole beta-cyclodextrin complex and the miconazole hydroxypropyl-beta-cyclodextrin product were incorporated in chewing gum. The miconazole hydroxypropyl-beta-cyclodextrin gum had a much higher drug release in vitro than the neat miconazole gum. The genuine econazole beta-cyclodextrin complex only increased the drug release moderately when compared with the release from the neat econazole gum. The release studies were performed on a mastication device.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1995

Cultured proximal cells derived from transgenic mouse provide a model to study drug toxicity.

The effects of gentamicin on N-acetyl-beta-D-glucosaminidase (NAG) and acid phosphatase (AcP), two lysosomal enzymes present in proximal renal tubule cells, were studied in the PKSV-PCT cell line derived from proximal convoluted tubules from the kidney of a transgenic mouse carrying SV40 large T antigen under the control of the L-type pyruvate kinase gene. Gentamicin (400 micrograms/ml for 72 hr) did not alter cell viability, but significantly reduced cell growth and favored the formation of myeloid bodies. Gentamicin (50 to 800 micrograms/ml for 72 hr) decreased in a dose-dependent manner the cellular NAG in PKSV-PCT cells and stimulated its secretion by 20 to 60%. Chloroquine (50 to 100 microns) and ammonium chloride (NH4Cl, 30mM), two lysosomotropic amines known to stimulate the secretion of lysosomal enzymes in fibroblasts and macrophages, also stimulated secreted NAG in PKSV-PCT cells. However, the effect of chloroquine was less marked in PKSV-PCT cells than in cultured mouse 3T3 fibroblasts. Gentamicin induced lysosomal alkalinization but, in contrast to chloroquine and NH4Cl, the aminoside strongly stimulated the secretion of AcP. The secretion induced by gentamicin was nonpolarized, since the percentage of secreted NAG significantly increased from both the apical and basal sides of PKSV-PCT cells grown on permeable filters. Thus, these data suggest that gentamicin alters the secretion of NAG and AcP by a non-specific pathway and indicate that the PKSV-PCT cell line is a suitable system to examine the cellular action of drugs in kidney proximal tubule cells.

Acetylglucosaminidase↗
PubMed2001

Chronic aristolochic acid toxicity in rabbits: a model of Chinese herbs nephropathy?

BACKGROUND: Chinese herbs nephropathy (CHN) is a new type of subacute interstitial nephritis that is attributed to aristolochic acid (AA), which inadvertently has been included in slimming pills. The contribution of other simultaneously prescribed drugs remains disputed. In the present study, the effects of a chronic intake of AA given as a single drug was evaluated through renal histology and function in rabbits. METHODS: Female New Zealand White rabbits were injected intraperitoneally with either 0.1 mg AA/kg or with saline 5 days a week for 17 to 21 months. Body weight, renal function, and urinary excretion of glucose and low molecular weight proteins were monitored prior to sacrifice at the end of the study period. RESULTS: All animals given AA developed renal hypocellular interstitial fibrosis, which was classified into three patterns. Fibrosis was confined to medullary rays (MRs) in pattern I (N = 3), extended to the outer cortical labyrinth (OCL) in pattern II (N = 2), and eventually to the inner cortical labyrinth (ICL) in pattern III (N = 6). Fibrosis in MR and OCL was associated with mainly proximal tubular epithelial cell flattening. All treated animals displayed urothelial atypia. Three of them also developed tumors of the urinary tract. No significant pathologic changes were found in control rabbits. AA-treated animals differed from controls by an impaired growth, increased serum creatinine, glucosuria, tubular proteinuria, and anemia. CONCLUSION: The observed pattern of renal histopathological lesions and disorders of the renal function, as well as urothelial atypia and malignancy, are very reminiscent of CHN. Our observations therefore support a causal role of AA alone in the genesis of this new nephropathy.

Animals↗
PubMedDate not supplied

Failure of intravitreal dexamethasone to diminish inflammation or retinal toxicity in an experimental model of Bacillus cereus endophthalmitis.

PURPOSE: To determine whether the usual clinical dose of intravitreal dexamethasone can attenuate intraocular inflammation and retinal necrosis in a rabbit model of fulminant Bacillus cereus endophthalmitis induced by crude exotoxins. METHODS: Thirty-six eyes from pigmented mongrel rabbits received intravitreal injections of varying concentrations of crude B. cereus exotoxins with or without concomitant injections of 400 microg of dexamethasone sodium phosphate (0.1% solution). After ophthalmoscopic examination at 4 or 18 hr postinjection, the animals were killed and histopathologic findings graded. RESULTS: Intraocular inflammation and retinal necrosis scores in eyes receiving both exotoxins and dexamethasone did not differ significantly from eyes receiving exotoxins alone for any exotoxin dose at 4 or 18 hr. The severity of retinal necrosis increased with toxin dose and was nearly maximal after 4 hr. Intraocular inflammation also generally increased with dose, but continued to increase until 18 hr. CONCLUSIONS: Standard clinical doses of intravitreal dexamethasone do not appear to attenuate the intraocular inflammatory or tissue response to secreted B. cereus exotoxins. Other treatment modalities including vitrectomy, to decrease exotoxin load, and exotoxin inhibitors may be necessary for the effective treatment of B. cereus endophthalmitis.

Animals↗
PubMed1998

2-Hydroxy-4-glutathion-S-yl-17beta-estradiol and 2-hydroxy-1-glutathion-S-yl-17beta-estradiol produce oxidative stress and renal toxicity in an animal model of 17beta-estradiol-mediated nephrocarcinogenicity.

Chronic exposure of male Syrian hamsters to a variety of estrogens has been linked with a high incidence of renal carcinoma. The basis of this species and tissue specificity remains to be resolved. We have recently shown that (i) 17beta-estradiol is nephrotoxic in the hamster in a manner dependent upon the activity of gamma-glutamyl transpeptidase and (ii) 17beta-estradiol is metabolized to a variety of catechol estrogen glutathione conjugates (Butterworth et al., Carcinogenesis, 18, 561-567, 1997). We report that the catechol estrogen glutathione conjugates exhibit redox properties similar to those of the catechol estrogens, and maintain the ability to generate superoxide radicals. Administration of 2-hydroxy-4-glutathion-S-yl-17beta-estradiol or 2-hydroxy-1-glutathion-S-yl-17beta-estradiol (0.27-5.0 micromol/kg) to Syrian hamsters, produces mild nephrotoxicity. Repeated daily administration of 2-hydroxy-4-glutathion-S-yl-17beta-estradiol causes a sustained elevation in urinary markers of renal damage and in the concentration of renal protein carbonyls and lipid hydroperoxides. Catechol estrogen oxidation and conjugation of glutathione in the liver, followed by the selective uptake of the redox active conjugates in tissues rich in gamma-glutamyl transpeptidase may contribute to 17beta-estradiol-induced renal tumors in the hamster.

Animals↗