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1.
J Vet Pharmacol Ther ; 32(4): 329-37, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19614837

RESUMO

Although non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing pain and inflammation, these agents have adverse effects. Selective inhibitors of COX-2 are an alternative to traditional NSAIDs. Deramaxx [Novartis Animal Health US, Inc. (NAH), Greensboro, NC, USA] contains the selective COX-2 inhibitor, deracoxib, and is approved for the relief of pain and inflammation associated with orthopedic surgery and osteoarthritis in dogs. The safety of Deramaxx was evaluated in two target animal safety studies: 40 dogs (four dogs/sex/group) received 0, 4, 6, 8, or 10 mg/kg/day deracoxib once daily for 21 days; and 60 dogs (five dogs/sex/group) received 0, 2, 4, 6, 8, or 10 mg/kg/day deracoxib once daily for 6 months. There was a dose-dependent trend towards increased blood urea nitrogen (BUN) in treated dogs, however mean BUN values remained within the reference range at the labeled doses. In both trials, histopathology revealed focal renal tubular degeneration/regeneration in some dogs receiving >or=6 mg/kg/day deracoxib. Focal renal papillary necrosis was seen in one dog treated with 8 mg/kg/day and in three dogs receiving 10 mg/kg/day deracoxib on the 6-month study. No other parameters of renal function were adversely affected for either study. Results show that Deramaxx is safe and well-tolerated in dogs when administered as directed.


Assuntos
Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/normas , Cães/sangue , Sulfonamidas/administração & dosagem , Sulfonamidas/normas , Análise de Variância , Animais , Nitrogênio da Ureia Sanguínea , Inibidores de Ciclo-Oxigenase 2/toxicidade , Cães/urina , Relação Dose-Resposta a Droga , Eutanásia Animal , Feminino , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Testes de Função Hepática/veterinária , Masculino , Placebos/administração & dosagem , Sulfonamidas/toxicidade , Comprimidos
2.
Int J Cosmet Sci ; 24(4): 217-24, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18498513

RESUMO

Toxicity assessment of new cosmetic ingredients is often relegated to the end of the research and development (R&D) cycle. This is an inefficient development scheme, since toxicity concerns often lead to restrictions on the type of cosmetic applications the ingredient can go into and can even lead to abandoning the ingredient. This paper presents a tiered approach for integrating toxicology into cosmetic ingredient R&D. The tiered approach is flexible allowing a company to make cost-efficient use of readily available resources. Integrating toxicity assessment of new cosmetic ingredients early in the R&D cycle would help avoid developing ingredients with limited or no market potential due to toxicity concerns.

3.
Food Chem Toxicol ; 39(8): 759-86, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11434984

RESUMO

Inorganic phosphate salts are widely used as food ingredients and in a variety of commercial applications. The United States Food and Drug Administration (FDA) considers inorganic phosphates "Generally Recognized As Safe" (GRAS) (FDA, 1973a, 1979) [FDA: Food and Drug Administration 1973a. GRAS (Generally Recognized as Safe) food ingredients-phosphates. NTIS PB-221-224, FDA, Food and Drug Administration, 1979. Phosphates; Proposed Affirmation of and Deletion From GRAS Status as Direct and Human Food Ingredients. Federal Register 44 (244). 74845-74857, 18 December (1979)] and the European Union (EU) allows inorganic phosphates to be added directly to food (EU Directive 95/2/EC as amended by 98/72/EC). In this review, data on the acute, subchronic and chronic toxicity, genotoxicity, teratogenicity and reproductive toxicity from the published literature and from unpublished studies by the manufacturers are reviewed. Based on the toxicity data and similar chemistry, the inorganic phosphates can be separated into four major classes, consisting of monovalent salts, divalent salts, ammonium salts and aluminum salts. The proposed classification scheme supports the use of toxicity data from one compound to assess the toxicity of another compound in the same class. However, in the case of eye and skin irritation, the proposed classification scheme cannot be used because a wide range of responses exists within each class. Therefore, the eye and skin hazards associated with an individual inorganic phosphate should be assessed on a chemical-by-chemical basis. A large amount of toxicity data exists for all four classes of inorganic phosphates. The large and comprehensive database allows an accurate assessment of the toxicity of each class of inorganic phosphate. Overall, all four classes of inorganic phosphates exhibit low oral, inhalation and dermal toxicities. Based on these data, humans are unlikely to experience adverse effects when the daily phosphorus consumption remains below 70 mg/kg/day (JECFA, 1964, 1982a) [JECFA (Joint FAO/WHO Expert Committee on Food Additives 1964. Specifications for the Identity and Purity of Food Additives and their Toxicological Evaluation) Emulsifiers, Stabilizers, Bleaching, and Maturing Agents. Technical Report Series of the World Health Organization 281; ECFA (Joint FAO/WHO Expert Committee on Food Additives 1982a. Phosphoric Acid and Phosphate Salts. ICS/FA/82)].


Assuntos
Aditivos Alimentares/toxicidade , Fosfatos/toxicidade , Animais , Cricetinae , Bases de Dados Factuais , Aditivos Alimentares/classificação , Cobaias , Humanos , Camundongos , Testes de Mutagenicidade , Fosfatos/classificação , Política Pública , Ratos , Teratogênicos/toxicidade , Testes de Toxicidade
4.
Regul Toxicol Pharmacol ; 33(1): 37-59, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11259178

RESUMO

We used the benchmark dose (BMD) methodology devised by Crump (Fundam. Appl. Toxicol. 4, 854-871, 1984) to estimate BMDs for 90-day toxicological data and several fabricated data sets. From a toxicological perspective, dose-response modeling offers certain advantages over using a point estimate, such as the currently used no-observable-adverse-effect level (NOAEL) approach. However, there are many variables associated with the BMD that could be set to produce unreasonable BMD estimates. Some of these variables and decisions are examined in this study. BMDs were calculated for discrete and continuous endpoints using a variety of different variables (e.g., maximum likelihood estimates [MLEs], lower-confidence limits [LCLs], and different risk levels). In addition, the fabricated data sets were manipulated (i.e., dose groups eliminated) and the BMDs recalculated. This process tested how the BMD estimates varied using different forms of the data. For the 90-day toxicological studies, the BMDs were typically within an order of magnitude of the NOAEL for discrete endpoints. For the discrete endpoints, the MLEs were typically greater than the NOAEL and the LCLs were typically less than the NOAEL. The BMD was insensitive to changes in the data points one to two dose groups beyond the NOAEL/LOAEL. With the continuous data, the ratios of MLEs and LCLs to the NOAEL were highly variable, and no general trend could be determined. The BMD methodology offers potential improvements in the risk assessment process since dose-response characteristics are used to calculate the BMD. Depending upon how the BMD is defined, i.e., the form of the dose-response model, and how the BMD is used in the risk assessment process, BMD estimates may produce reference doses/concentrations that are more or less conservative than the NOAEL approach. Active involvement in discussions with regulatory agencies is needed to ensure that inappropriate models and unreasonable BMDs are not used. In addition, further discussions on how BMDs should be used in the risk assessment process are needed.


Assuntos
Testes de Toxicidade/métodos , Xenobióticos/toxicidade , Animais , Relação Dose-Resposta a Droga , Determinação de Ponto Final , Humanos , Nível de Efeito Adverso não Observado , Medição de Risco
5.
J Pharmacol Exp Ther ; 286(1): 519-24, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9655897

RESUMO

It was previously shown that a necrogenic dose of acetaminophen (APAP) induced the 25- and 70-kDa heat shock proteins (hsp25 and hsp70i) in mouse liver, whereas nonnecrogenic doses failed to alter the level of either hsp. A strong correlation between the intralobular sites of APAP arylation of protein and hsp induction suggested that APAP-induced protein denaturation may play a role in triggering hsp induction. This study was conducted to determine whether APAP arylation of protein without concurrent toxicity could cause hsp induction. APAP (250 mg/kg i.p.) hepatotoxicity was eliminated using N-acetylcysteine (NAC, 300 mg/kg i.p.) or the cytochrome P-450 inhibitor diallyl sulfide (200 mg/kg p.o.). NAC did not inhibit APAP arylation of protein when administered 1 or 3 hr after the APAP dose but decreased binding by approximately 50% when administered at the same time as the APAP dose. Even though APAP hepatotoxicity was blocked by NAC administered 0 or 1 hr after the APAP dose, NAC did not inhibit the induction of hsp25 or hsp70i, indicating that APAP arylation of protein may play a key role in triggering hsp induction. Diallyl sulfide blocked APAP arylation of protein, hepatotoxicity, and induction of both hsps. These data are consistent with the hypothesis that toxicant adduction of protein triggers hsp induction.


Assuntos
Acetaminofen/toxicidade , Acetilcisteína/farmacologia , Analgésicos não Narcóticos/farmacologia , Proteínas de Choque Térmico HSP70/biossíntese , Proteínas de Choque Térmico , Fígado/efeitos dos fármacos , Proteínas de Neoplasias/biossíntese , Acetaminofen/metabolismo , Animais , Fígado/metabolismo , Masculino , Camundongos , Chaperonas Moleculares , Ligação Proteica
6.
Cell Stress Chaperones ; 3(2): 130-41, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9672248

RESUMO

The heat shock protein (Hsp) response is induced by heat shock and a large variety of different chemicals. Searching for a common denominator of these different inducers, we and others developed the notion that all inducers may generate abnormally folded, i.e. non-native, proteins, and that such non-native proteins may trigger the Hsp response. Experimentation prompted by this notion resulted, for example, in the demonstration that chemically denatured proteins, introduced in cells by microinjection, can activate the response. Based on the chemical nature of inducers and on results reported from several studies, we hypothesized that inducers of the Hsp response may be generally capable of triggering oxidation of non-protein thiols, particularly glutathione. Such oxidation is known to lead to formation of glutathione-protein mixed disulfides and protein-protein disulfides. Presumably, thiol adduction and cross-linking would affect the structure of proteins involved, resulting in unfolding of a fraction of these proteins, causing heat shock factor (Hsf) activation. To test the feasibility of this hypothesis, thirteen different inducers were selected, and it was shown that all chemical inducers as well as heat shock cause drastic oxidation of glutathione under conditions under which they induce HSE DNA-binding activity. Under the same conditions, all chemical inducers and heat shock also cause trimerization of Hsf1. For several inducers, it was also shown that they enhance thiol oxidation of proteins. Finally, in vitro experiments support the notion that activation of Hsf1 does not require oxidation of the factor itself or of its coregulators. These results are in complete agreement with the above hypothesis.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Glutationa/metabolismo , Arsenitos/farmacologia , Azetidinas/farmacologia , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/isolamento & purificação , Dissulfeto de Glutationa/metabolismo , Células HeLa , Fatores de Transcrição de Choque Térmico , Proteínas de Choque Térmico/biossíntese , Temperatura Alta , Humanos , Peróxido de Hidrogênio/farmacologia , Iodoacetamida/farmacologia , Cinética , Substâncias Macromoleculares , Oxirredução , Puromicina/farmacologia , Fatores de Transcrição
7.
Drug Metab Dispos ; 26(3): 267-71, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9492391

RESUMO

The hepatotoxicity of the analgesic acetaminophen is believed to be mediated by covalent binding to critical proteins. Radiolabeled 3'-hydroxyacetanilide, a regioisomer of acetaminophen, covalently binds to proteins at levels similar to those of acetaminophen, but without toxicity. Covalent binding has recently been detected by Western blot to a 50-kDa microsomal protein that comigrated with CYP2E1 and was accompanied by a loss of the CYP2E1 activity. However, radiolabel studies previously indicated that a significant amount of the radiolabel is lost during electrophoresis. In the present study, 3'-hydroxyacetanilide covalent binding was detected immunohistochemically in liver using an anti-acetaminophen antiserum. 3'-Hydroxyacetanilide (1000 mg/kg, ip) administration to mice resulted in panlobular immunostaining in liver, with the single layer of hepatocytes surrounding the central veins having the greatest intensity of staining. Staining was most intense at 1 hr and somewhat decreased at 3 and 6 hr. In contrast, immunochemical staining indicated that covalent binding of acetaminophen (250 mg/kg, ip) was confined to the centrilobular hepatocytes, the area of the ensuing necrosis. Cobaltous chloride pretreatment decreased the total intensity of the panlobular immunostaining following 3'-hydroxyacetanilide. The CYP2E1 inhibitor diallyl sulfide decreased the intensity of immunostaining in the central vein area only. Western blot analysis indicated diallyl sulfide also eliminated binding to the microsomal 50-kDa protein. These data are consistent with centrilobular binding of 3'-hydroxyacetanilide, mediated in part by CYP2E1, and panlobular binding, mediated by other P450 enzymes.


Assuntos
Acetaminofen/metabolismo , Acetanilidas/metabolismo , Compostos Alílicos , Fígado/fisiologia , Acetanilidas/toxicidade , Animais , Cobalto/farmacologia , Inibidores do Citocromo P-450 CYP2E1 , Imuno-Histoquímica , Fígado/citologia , Masculino , Camundongos , Camundongos Endogâmicos , Microssomos/química , Microssomos/metabolismo , Ligação Proteica , Ratos , Sulfetos/farmacologia
8.
J Pharmacol Exp Ther ; 282(3): 1533-40, 1997 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9316869

RESUMO

The effect of acetaminophen (APAP) and 3'-hydroxyacetanilide (AMAP) on heat shock protein (hsp) induction in mouse liver was examined using Western blotting and immunohistochemistry. Western blots from APAP (200 mg/kg i.p.)-treated mice showed increased hsp25 levels at 6 and 24 hr and increased hsp70i levels at 3, 6 and 24 hr. No apparent induction was observed for other hsps (hsp60, hsc70, or hsp90). No increase in the levels of any of the hsps was apparent in Western blots from AMAP (1000 mg/kg i.p.)-treated mice. Immunohistochemical localization of hsp25 and hsp70i in the liver after APAP treatment showed increases in the levels of both hsps within the zone of affected cells at early time points (3 and 6 hr), but at 24 hr, elevated hsp25 levels were observed primarily in cells on the periphery of the lesions. Hepatocytes with increased hsp25 or hsp70i levels also had detectable reactive metabolite binding from APAP, as determined using immunostaining. No hepatotoxicity was observed in liver sections from AMAP treated mice, even though immunostaining indicated widespread reactive metabolite binding. Immunostaining for hsps confirmed that no increase in hsp25 or hsp70i levels occurred in response to this binding. Differences in hsp expression after APAP vs. AMAP may be due to differences in protein targets adducted by their respective reactive metabolites, in the concentrations of adducted proteins or perhaps in some other differential effect necessary for hsp upregulation.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Narcóticos/toxicidade , Proteínas de Choque Térmico/biossíntese , Fígado/efeitos dos fármacos , Acetaminofen/metabolismo , Animais , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Estereoisomerismo
9.
Hepatology ; 25(5): 1147-53, 1997 May.
Artigo em Inglês | MEDLINE | ID: mdl-9141432

RESUMO

The effect of cocaine on heat shock protein (hsp) induction in murine liver was examined using Western blotting and immunohistochemistry. A single dose of cocaine (50 mg/kg, intraperitoneal [i.p.]) was administered to naive, phenobarbital (PB)-induced or beta-naphthoflavone (betaNF)-induced mice, and the level of hsps in the liver analyzed 3, 6, and 24 hours after the cocaine dose. As measured by Western blotting, hsp70i levels were increased at all time points, and hsp25 levels at the 6- and 24-hour time points. Levels of hsp60, hsc70, and hsp90 remained unchanged. Pretreatment of mice with the cytochrome P-450 inhibitor SKF-525A eliminated both cocaine hepatotoxicity and the induced accumulation of hsp25 and hsp70i. Immunohistochemical localization of hsp25 and hsp70i in the liver showed that concentrations of both hsps were elevated only in cells with altered morphology. As has been observed previously, hepatic enzyme induction with PB or betaNF shifted the location of the necrotic lesion within the lobule from zone 2, as observed in naive mice of this strain, toward zone 1 (PB) or zone 3 (betaNF), respectively. Localization of induced accumulation of hsp25 and hsp70i was found to shift within the lobule in parallel with the necrotic lesion in these animals. Immunostaining of cocaine reactive metabolites bound to proteins was superimposable on the areas with hsp accumulation and cells with altered morphology. Our observations indicate a strong spatial correlation within the lobule between cocaine reactive metabolite formation, induced accumulation of hsp25 and hsp70i, and cytotoxicity (necrosis).


Assuntos
Cocaína/toxicidade , Proteínas de Choque Térmico/biossíntese , Fígado/metabolismo , Entorpecentes/toxicidade , Animais , Western Blotting , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR
10.
Toxicol Appl Pharmacol ; 147(2): 247-58, 1997 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9439720

RESUMO

Amphetamine has been shown previously to increase levels of the inducible 70-kDa heat shock protein (hsp70i) in mouse liver. In the present study, the hepatic concentrations of a variety of hsps in livers of mice pretreated with amphetamine (15 mg/kg, i.p.) were evaluated, and the time course of hsp induction was examined. Amphetamine treatment caused an acute rise in core body temperature to 40 degrees C for at least 1 hr and increased hsp25 and hsp70i levels, as measured by Western blotting, at 6, 24, 48, and 72 hr with no apparent induction of other hsps (hsp60, hsc70, or hsp90). A 72-hr amphetamine pretreatment lowered the hepatotoxicity of an acute dose of acetaminophen (350 mg/kg, i.p.) or bromobenzene (0.45 ml/kg, i.p.), but had no effect on the toxicity of carbon tetrachloride (0.04 ml/kg, i.p.) or cocaine (50 mg/kg, i.p.), as measured by serum alanine aminotransferase activity and histopathological analysis. No protection from acetaminophen or bromobenzene hepatotoxicity was observed when hepatotoxicant administration was delayed until hsp levels had returned to control values (144 hr after amphetamine pretreatment). Amphetamine pretreatment did not reduce in vivo covalent binding to proteins of radiolabeled [3H]acetaminophen, [14C]bromobenzene, [14C]carbon tetrachloride, or [3H]cocaine, indicating that the protective effects were not due to inhibition of reactive metabolite formation from these toxicants. These results suggest that elevated levels of hsp25 and hsp70i provide protection against acetaminophen and bromobenzene hepatotoxicity.


Assuntos
Anfetamina/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Proteínas de Choque Térmico/biossíntese , Hipertermia Induzida , Fígado/efeitos dos fármacos , Acetaminofen/toxicidade , Anfetamina/administração & dosagem , Animais , Bromobenzenos/toxicidade , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cocaína/toxicidade , Febre/induzido quimicamente , Febre/fisiopatologia , Imuno-Histoquímica , Fígado/patologia , Fígado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR
11.
Toxicol Appl Pharmacol ; 141(1): 117-23, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8917683

RESUMO

The objective of this study was to determine if a variety of hepatotoxicants could induce the level of heat shock protein 70I, and whether or not elevated levels of heat shock proteins (hsp's) could provide cytoprotection from those hepatotoxicants. Exposure of HepG2 cells to cytotoxic concentrations of bromobenzene, cadmium, cyclophosphamide, or diethylnitrosamine increased the level of hsp 70I protein and mRNA, while carbon tetrachloride and cocaine had no effect on hsp 70I or mRNA levels. To determine if induction of hsp 70I might afford protection against cytotoxicity, HepG2 cells were given a prior sublethal heat shock (sub-LHS) (43 degrees C for 1 hr) to induce hsp's and then challenged 24 hr later with the hepatotoxicants. Sub-LHS pretreatment diminished toxicity from bromobenzene, cadmium, cyclophosphamide, or diethyl-nitrosamine, but not carbon tetrachloride or cocaine. In cells treated with [14C]carbon tetrachloride or [3H]cocaine, no detectable covalent binding to proteins was observed; whereas, [14C]-bromobenzene treatment resulted in substantial covalent binding to cellular protein. The apparent absence of formation of reactive metabolite adducted proteins from cocaine and carbon tetrachloride may explain why no hsp 70I induction was observed with these agents. The correlation between hepatotoxicant induction of hsp 70I and cytoprotection afforded by sub-LHS pretreatment suggests that hsp 70I induction may represent an important cellular defense mechanism in the liver.


Assuntos
Bromobenzenos/toxicidade , Cádmio/toxicidade , Carcinógenos/toxicidade , Ciclofosfamida/toxicidade , Dietilnitrosamina/toxicidade , Proteínas de Choque Térmico HSP70/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Bromobenzenos/metabolismo , Tetracloreto de Carbono/metabolismo , Células Cultivadas , Cromatografia Gasosa , Cocaína/metabolismo , Eletroforese em Gel de Poliacrilamida , Humanos
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