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1.
PLoS One ; 8(9): e76011, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24098756

RESUMO

BACKGROUND: The formation of pyrrole adducts might be responsible for peripheral nerve injury caused by n-hexane. The internal dose of pyrrole adducts would supply more information for the neurotoxicity of n-hexane. The current study was designed to investigate the tissue distributions of 2, 5-hexanedione (2,5-HD) and pyrrole adducts in rats exposed to n-hexane, and analyze the correlation between pyrrole adducts and 2,5-HD in tissues. METHODS: Male Wistar rats were given daily dose of 500,1000, 2000, 4000 mg/kg bw n-hexane by gavage for 5 days. The rats were sacrificed 24 hours after the last administration. The levels of 2, 5-hexanedione and pyrrole adducts in tissues were measured by gas chromatography and Ehrlich's reagent, respectively. The correlations between 2, 5-hexanedione and pyrrole adducts were analyzed by linear regression. RESULTS: Dose-dependent effects were observed between the dosage of n-hexane and 2, 5-hexanedione, and pyrrole adducts in tissues. The highest level of 2, 5-hexanedione was found in urine and the lowest in sciatic nerve, while the highest level of pyrrole adducts was seen in liver and the lowest in serum. There were significant correlations among the free 2, 5-hexanedione, total 2, 5-hexanedione and pyrrole adducts within the same tissues. Pyrrole adducts in serum showed the most significant correlation with free 2, 5-hexanedione or pyrrole adducts in tissues. CONCLUSION: The findings suggested that pyrrole adducts in serum might be a better indicator for the internal dose of free 2, 5-hexanedione and pyrrole adducts in tissues.


Assuntos
Biomarcadores/sangue , Hexanos/toxicidade , Hexanonas/metabolismo , Pirróis/metabolismo , Animais , Benzaldeídos , Cromatografia Gasosa , Relação Dose-Resposta a Droga , Hexanos/administração & dosagem , Hexanonas/farmacocinética , Hexanonas/urina , Modelos Lineares , Fígado/metabolismo , Masculino , Pirróis/sangue , Pirróis/farmacocinética , Ratos , Ratos Wistar
2.
Cancer Chemother Pharmacol ; 69(4): 1039-49, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22186884

RESUMO

PURPOSE: Preclinical studies evaluated the anti-tumor activity and mechanism of action of AMP423, a naphthyl derivative of 2-cyanoaziridine-1-carboxamide with structural similarity to the pro-oxidant anti-tumor agent imexon. METHODS: The cytotoxic potency was evaluated in vitro against a variety of human cancer cell lines. Mechanism-of-action studies were performed in the human 8226/S myeloma cell line and its imexon-resistant variant, 8226/IM10. In vivo activity was evaluated against human myeloma and lymphoma xenografts in SCID mice. Pharmacokinetics and toxicology were investigated in non-tumor-bearing mice. RESULTS: The 72-h IC(50)s for all cell types ranged from 2 to 36 µM, across a wide variety of human cancer cell lines. AMP423 was active in SCID mice bearing 8226/S myeloma and SU-DHL-6 B-cell lymphoma tumors, with a median tumor growth delay (T-C) of 21 days (P = 0.0002) and 5 days (P = 0.004), respectively, and a median tumor growth inhibition (T/C) of 33.3% (P = 0.03) and 82% (P = 0.01), respectively. In non-tumor-bearing mice, AMP423 was not myelosuppressive. Mechanistic studies show that AMP423's mode of cell death is a mixture of necrosis and apoptosis, with generation of reactive oxygen species, inhibition of protein synthesis, and a decrease in reduced sulfhydryl levels, but no alkylation of nucleophiles. Unlike its structural analog imexon, which causes cell cycle arrest in G(2)/M, AMP423 induces the accumulation of cells in S-phase. CONCLUSIONS: AMP423 has pro-oxidant effects similar to imexon, has greater cytotoxic potency in vitro, and has anti-tumor activity in hematologic tumors in vivo.


Assuntos
Antineoplásicos/farmacologia , Aziridinas/farmacologia , Linfoma de Células B/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Naftalenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Aziridinas/química , Aziridinas/farmacocinética , Pontos de Checagem do Ciclo Celular , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Hexanonas/química , Hexanonas/farmacocinética , Hexanonas/farmacologia , Humanos , Linfoma de Células B/metabolismo , Masculino , Camundongos , Camundongos SCID , Mieloma Múltiplo/metabolismo , Naftalenos/química , Naftalenos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 31(9): 2781-5, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21868520

RESUMO

AIM: We evaluated mechanisms of interaction between the alkyating agent dacarbazine (DTIC) and the pro-oxidant, imexon, in the human A375 melanoma cell line. MATERIALS AND METHODS: The effect of DTIC and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Pharmacokinetic and antitumor effects were evaluated in mice. RESULTS: Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo. CONCLUSION: Imexon and dacarbazine show additive effects in vitro but not in vivo in human A375 melanoma cells.


Assuntos
Antineoplásicos/farmacologia , Dacarbazina/farmacologia , Hexanonas/farmacologia , Melanoma/patologia , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Área Sob a Curva , Linhagem Celular Tumoral , Ensaio Cometa , Dacarbazina/sangue , Dacarbazina/farmacocinética , Interações Medicamentosas , Ensaios de Seleção de Medicamentos Antitumorais , Hexanonas/sangue , Hexanonas/farmacocinética , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos SCID
4.
Anticancer Drugs ; 21(7): 708-15, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20571355

RESUMO

Imexon [AOP99.0001 (4-imino-1,3-diazobicyclo[3. 1. 0]-hexan-2-one)] belongs to a novel class of promising anticancer agents that induce tumor apoptosis through oxidative stress. Clinical experience since the late 1960s has provided initial evidence for a clinical antitumor activity. Our open-label, multicenter phase I clinical trial was designed to further investigate the adverse event (AEs) profile and pharmacokinetics of AOP99.0001 in pretreated myeloma patients and collect initial data on the potential clinical efficacy in this indication. Thirty-six patients with relapsed or refractory myeloma, who had been pretreated with at least two lines of therapy earlier, were included. Imexon was applied intravenously on 5 consecutive days for 2 weeks (d1-5 and d8-12) for a 3-week cycle. The plasma half-life of AOP99.0001 and its active metabolite AOP99.0002 was found to be approximately 1.2 and 2.6 h, respectively. The mean duration of treatment with Imexon was 6.8 weeks in a dose range between 50 and 1000 mg/m without reaching dose-limiting toxicity. Drug-related AEs occurring with a frequency of greater than 10% were fatigue, nausea, constipation, headache, asthenia, anemia, thrombocytopenia, leukopenia and creatinine increase. A total of nine severe adverse events occurred in three patients. No mortality was encountered when patients were on treatment with Imexon. Preliminary antimyeloma efficacy of AOP99.0001 was observed with 1 minimal response, 12 (36%) stable disease responses, and all other evaluable patients had progressive disease. Remarkably, the patient with minimal response also experienced a complete clinical resolution of myeloma-associated polyneuropathy. Overall, Imexon was safe and well tolerated in the dose range investigated. Imexon showed minor clinical activity as a single agent in heavily pretreated myeloma patients. On account of its unique mechanism of action, favorable toxicity profile, initial clinical evidence for antimyeloma activity, and its known synergistic activity in combination with approved agents for myeloma treatment, AOP99.0001 is recommended for future clinical studies in combination regimens in multiple myeloma.


Assuntos
Antineoplásicos/uso terapêutico , Hexanonas/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Apoptose , Relação Dose-Resposta a Droga , Feminino , Hexanonas/efeitos adversos , Hexanonas/farmacocinética , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estresse Oxidativo , Recidiva , Resultado do Tratamento
5.
J Clin Oncol ; 25(13): 1779-84, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17470869

RESUMO

PURPOSE: Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers. PATIENTS AND METHODS: Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays. RESULTS: There were 13 dose levels evaluated, from 20 mg/m2/d to 1,000 mg/m2/d. The MTD recommended for phase II studies was 875 mg/m2/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m2/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve-dependent decrease in cystine levels 8 hours after dosing at 750 mg/m2/d. CONCLUSION: The phase II recommended dose of imexon is 875 mg/m2/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.


Assuntos
Antineoplásicos/uso terapêutico , Hexanonas/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Feminino , Meia-Vida , Hexanonas/efeitos adversos , Hexanonas/farmacocinética , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade
6.
Anticancer Drugs ; 17(10): 1179-84, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17075317

RESUMO

Imexon, a novel pro-oxidant, thiol-binding agent, is currently in phase I/II clinical trials in patients with advanced solid tumors. The aim of this study was to characterize the preclinical pharmacology of imexon in vivo. We investigated the anticancer activity of imexon in several cancer cell lines grown as xenografts in severe combined immunodeficient mice. Imexon was active against both hematologic and solid tumor types. The maximally tolerated dose, at the selected dosing schedule, was 150 mg/kg. Using the maximally tolerated dose of imexon, we sought to identify a potential pharmacodynamic biomarker to monitor the mechanistic effect systemically. As imexon binds cellular thiols in vitro, thiol depletion by imexon in vivo was evaluated as a potential biomarker. Following a single 150 mg/kg dose of imexon by intraperitoneal injection, glutathione levels decreased by 40% at 3 h in mouse erythrocytes. In mouse plasma, imexon treatment led to a significant decrease in cystine levels 2-4 h after drug administration. Notably, by this time, free imexon plasma levels were nondetectable. By investigating the pharmacokinetics of imexon, we also found that imexon undergoes rapid clearance from plasma in a dose-independent fashion with a half-life of 12-15 min. In summary, imexon is active against several cancer types in vivo. Imexon also decreases circulating thiols and exhibits dose-independent pharmacokinetics in mice. Plasma cystine levels may represent a biomarker of imexon activity in vivo.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Hexanonas/farmacologia , Hexanonas/farmacocinética , Animais , Biomarcadores Tumorais/análise , Cistina/análise , Cistina/sangue , Relação Dose-Resposta a Droga , Eritrócitos/química , Feminino , Glutationa/análise , Glutationa/sangue , Humanos , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Modelos Biológicos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Arch Toxicol ; 75(11-12): 643-52, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11876497

RESUMO

Co-exposure to methyl ethyl ketone (MEK) potentiates the neurotoxicity of n-hexane in humans as well as in animals. This effect is associated with increased persistence of 2,5-hexanedione (2,5-HD) in blood, probably due to inhibition of 2,5-HD phase II biotransformation by MEK. There is no previous quantitative toxicokinetic model to describe this interaction. In this study we constructed a toxicokinetic model to depict the inhibition of 2,5-HD metabolism and elimination by MEK. Experimental data on 2,5-HD blood concentrations in rats from a published study were used to estimate model parameters. Three different inhibition mechanisms were evaluated: competitive, uncompetitive, and noncompetitive inhibition. Extrapolation from high to low doses was made to assess the interactive effects of MEK on 2,5-HD beyond experimental conditions. The models developed successfully described the toxicokinetic behavior of 2,5-HD when inhibited by MEK. The competitive inhibition model yielded a much lower estimate for the constant (65.5 mg/l) of 2,5-HD inhibition by MEK than did the uncompetitive and noncompetitive models (403 and 440 mg/l, respectively). The apparent half-life of 2,5-HD appeared to be a linear function of the Michaelis-Menten constant, and 2,5-HD and MEK concentrations in rats. The area under the curve of 2,5-HD in blood of rats was a nonlinear function of 2,5-HD and MEK concentrations in the blood. This study highlights the importance of the interactive effect of MEK on deactivation and elimination of 2,5-HD, and further illustrates the advantage of toxicokinetic modeling to investigate chemical interactions associated with exposure to multiple chemical agents.


Assuntos
Butanonas/farmacocinética , Hexanonas/farmacocinética , Neurotoxinas/farmacocinética , Animais , Área Sob a Curva , Relação Dose-Resposta a Droga , Interações Medicamentosas , Meia-Vida , Masculino , Modelos Biológicos , Ratos , Ratos Wistar
8.
Toxicol Lett ; 119(1): 39-47, 2001 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-11275420

RESUMO

The interaction of zinc(II) on the toxicokinetics of 2,5-hexanedione (2,5-HD), the ultimate toxic metabolite of n-hexane, was performed by quantifying the changes of two urinary biomarkers, free 2,5-HD and pyrrole derivatives, in rats exposed to 2,5-HD and to 2,5-HD plus zinc acetate. Eight groups of Wistar rats were exposed for 4 days (dietary and intraperitoneally) to 2,5-HD, zinc acetate and 2,5-HD plus zinc acetate and the 24 h urine was used to determine the excretion of these biomarkers. On comparing the results obtained by the two routes of exposure with different doses of 2,5-HD and zinc acetate, it was observed that there was a significant decrease (P<0.05) in the excretion of free 2,5-HD and pyrroles derivatives in rats exposed to the chemical mixture, when compared with the excretion of these biomarkers in rats exposed to 2,5-HD alone. To evaluate the mechanism of this interaction, further experiments were performed using one group of rat dietary pre-exposed to zinc acetate followed by 2,5-HD exposure. The results of our experiment suggest that zinc protect proteins of pyrrolization by coordination to amino groups, with the subsequent inhibition of protein cross-linking responsible by 2,5-HD neurotoxicity.


Assuntos
Hexanonas/farmacocinética , Hexanonas/toxicidade , Neurotoxinas/farmacocinética , Neurotoxinas/toxicidade , Acetato de Zinco/farmacologia , Administração Oral , Animais , Biomarcadores/urina , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hexanonas/urina , Injeções Intraperitoneais , Masculino , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/prevenção & controle , Neurotoxinas/urina , Pirróis/urina , Ratos , Ratos Wistar
9.
J Appl Toxicol ; 20(3): 211-4, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10797474

RESUMO

The protective role of zinc against the toxic effects of 2, 5-hexanedione (2,5-HD), the main neurotoxic metabolite of n-hexane, was investigated by studying the interference of zinc on the toxicokinetics of 2,5-HD. Six groups of Wistar rats were exposed for 3 days to diets containing 2,5-HD, zinc chloride and 2,5-HD+zinc chloride. The amounts of pyrroles and free and total 2,5-HD in urine were determined using Ehrlichs's reagent and gas chromatography/flame ionization detection, respectively. The results show that after the first day of co-exposure (ZnCl(2)+2,5-HD) there was a significant decrease in the excretion of pyrroles and free 2, 5-HD in rats exposed to the chemical mixture when compared to the pyrroles and free 2,5-HD excreted in rats exposed to 2,5-HD alone. However, no significant decrease was observed in the urinary excretion of total 2,5-HD (free 2,5-HD + preformed 2,5-HD). Suggestions are made about the role played by this metal ion in inhibiting pyrrole formation.


Assuntos
Cloretos/uso terapêutico , Hexanonas/antagonistas & inibidores , Síndromes Neurotóxicas/prevenção & controle , Compostos de Zinco/uso terapêutico , Animais , Hexanonas/farmacocinética , Hexanonas/toxicidade , Masculino , Pirróis/urina , Ratos , Ratos Wistar , Espectrofotometria Atômica
10.
Arch Toxicol ; 72(9): 597-600, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9806432

RESUMO

Exposure to 2,5-hexanedione (2,5-HD), a major n-hexane metabolite, can cause loss of photoreceptor cells, particularly when combined with light energy. The aims of this study were to document the levels of 2,5-HD reached in relation to time in retina, aqueous humor, and serum of the Sprague-Dawley albino rat after: (1) a single oral administration of 2,5-HD (0.04 g/ kg body wt.) by tube feeding; and (2) after subchronic oral administration of 2,5-HD. In addition, morphometric analysis of the retina was carried out to evaluate cell loss at the end of administration and after various periods of recovery. The 2,5-HD concentration in retinal tissue, aqueous humor, and serum reached a peak within 1 h after exposure to a single dose of 2,5-HD. Twenty four hours after the exposure, only a minor amount of 2,5-HD could be detected in the retina and aqueous humor. When 2,5-HD was administered subchronically (0.04 g/kg body wt. per day, for 35 days) no loss of photoreceptor cells was seen immediately after the end of exposure or at the end of a 4-week recovery period. Rats exposed to 0.60 g/kg body wt. per day for 11 days showed no significant loss of photoreceptor cells immediately after the end of exposure but there was a substantial loss of photoreceptor cells after 2 and 4 weeks of recovery. The results demonstrate that 2,5-HD reaches the aqueous humor and retina, and penetrates blood-aqueous humor/retina barriers after oral administration. Moreover, retinal degeneration seen in the animals may be directly caused by 2,5-HD and these changes are dose dependent.


Assuntos
Olho/efeitos dos fármacos , Olho/metabolismo , Hexanonas/farmacologia , Hexanonas/farmacocinética , Neurotoxinas/farmacologia , Neurotoxinas/farmacocinética , Administração Oral , Animais , Humor Aquoso/metabolismo , Peso Corporal/efeitos dos fármacos , Hexanonas/administração & dosagem , Masculino , Neurotoxinas/administração & dosagem , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Fatores de Tempo
11.
Int Arch Occup Environ Health ; 71(4): 236-44, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9638479

RESUMO

OBJECTIVE: To clarify changes in the serum, nerve, and urinary levels of 2,5-hexanedione (2,5-HD) in rats on coadministration with methyl ethyl ketone (MEK), acetone (AC), and toluene (TO). METHOD: 2,5-HD alone or combined with MEK, AC, and TO was injected subcutaneously into a total of 306 male Wistar rats. The rats were divided as follows into 7 groups: (1) 2.6 mmol/kg 2,5-HD alone (HD) and (2) 2.6 mmol/ kg 2,5-HD combined with 2.6 mmol/kg MEK (HD + MEK), (3) with 2.6 mmol/kg AC (HD + AC), (4) with 2.6 mmol/kg TO (HD + TO), (5) with 13.0 mmol/kg MEK (HD + 5MEK), (6) with 13.0 mmol/kg AC (HD + 5AC), and (7) with 13.0 mmol/kg TO (HD + 5TO). 2,5-HD concentrations in the serum, sciatic nerve, and urine of rats were determined within 16 h of the injections and pharmacokinetic parameters were estimated. RESULTS: It was observed that (1) the 2,5-HD concentration and AUC value (area under concentration versus time curve) determined in the serum and nerve increased significantly in the cotreated groups as compared with the HD group; (2) the effect MEK had in elevating the 2,5-HD concentration and AUC in the serum and nerve was stronger than that of AC, and the effect AC had was stronger than that of TO; (3) a. dose increase from 2.6 to 13.0 mmol/kg for MEK and AC induced further increases in the 2,5-HD concentration and AUC determined in the serum and nerve; (4) elimination constants recorded for 2,5-HD (Ke) from the serum and nerve decreased in all the cotreated groups, and the degree of the decrease correlated inversely with the elevation in 2,5-HD concentration and AUC in the serum and nerve; and (5) urinary 2,5-HD concentrations measured in the 13.0-mmol/kg cotreated groups increased in parallel with the elevation in serum 2,5-HD concentrations. CONCLUSION: Coadministration of 2,5-HD with MEK, AC, or TO can increase the concentration and AUC of 2,5-HD in serum and the sciatic nerve, and these increases can be further enhanced by an increase in the concomitant doses of MEK and AC.


Assuntos
Acetona/farmacologia , Butanonas/farmacologia , Inibidores da Colinesterase/farmacocinética , Hexanonas/farmacocinética , Neurotoxinas/farmacocinética , Nervo Isquiático/efeitos dos fármacos , Solventes/farmacologia , Tolueno/farmacologia , Animais , Área Sob a Curva , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hexanonas/farmacologia , Injeções Subcutâneas , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Neurotoxinas/farmacologia , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo
12.
Int Arch Occup Environ Health ; 71(4): 284-8, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9638486

RESUMO

OBJECTIVE: Determination of the urinary levels of 2.5-hexanedione (2,5-HD) was performed in subjects belonging to the Italian general population to define the reference value for this metabolite. MATERIALS AND METHODS: Urine samples were collected from 123 healthy Italian subjects who had not been occupationally exposed to n-hexane or methyl-n-butyl ketone (60 men and 63 women; 53 living in urban areas and 70 living in rural areas; 36 smokers and 87 nonsmokers; 65 aged above 35 years and 58 aged below 35 years). The determinations were performed by a gas chromatography method using a flame ionization detector (FID). A quality-control step was realized by analysis of 78 of these samples by high-performance liquid chromatography (HPLC) with UV detection. RESULTS AND DISCUSSION: The distribution of 2,5-HD concentration was log-normal and the corresponding centiles at the 95% confidence interval were as follows: the 50th centile, 0.270 mg/l for men and 0.191 mg/l for women; the 75th centile, 0.352 and 0.330 mg/l, respectively, for men and women; and the 95th centile, 0.762 and 0.582 mg/l, respectively, for men and women. The reference value, calculated as the upper unilateral 95% tolerance interval at 95% of confidence, was 0.795 mg/l for men and 0.627 for women.


Assuntos
Inibidores da Colinesterase/farmacocinética , Monitoramento Ambiental , Poluentes Ambientais/farmacocinética , Hexanonas/farmacocinética , Neurotoxinas/farmacocinética , Adulto , Inibidores da Colinesterase/efeitos adversos , Intervalos de Confiança , Poluentes Ambientais/efeitos adversos , Feminino , Hexanonas/efeitos adversos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Neurotoxinas/efeitos adversos , Valores de Referência , Fumar/urina
13.
Neurochem Res ; 22(1): 27-32, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9021758

RESUMO

The same total dose (1.2 g/kg/week) of 2,5-hexanedione (2,5-HD) was administered subcutaneously at 100 mg/kg/12 hr, 200 mg/kg/24 hr, and 400 mg/kg/48 hr to three groups of Donryu rats. The peripheral neuropathy induced by 2,5-HD was confirmed by clinical observation every day, and neurophysiological measurements every 4 weeks. During the 15th week of this experiment, 2,5-HD concentrations in plasma 0.5 to 24 hours after injection were determined. It was found that the greater the dose of 2,5-HD per treatment injected, the earlier peripheral neuropathy developed. Toxicokinetic analysis showed that both the values of the area under the plasma concentration versus time curve and the half life of 2,5-HD were increased, but the excretion parameters (Ke) were decreased, in animals treated with 200 mg/kg/24 hr and 400 mg/kg/48 hr 2,5-HD.


Assuntos
Hexanonas/toxicidade , Neurotoxinas/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esquema de Medicação , Hexanonas/administração & dosagem , Hexanonas/farmacocinética , Masculino , Condução Nervosa/efeitos dos fármacos , Neurotoxinas/administração & dosagem , Neurotoxinas/farmacocinética , Ratos , Ratos Endogâmicos
14.
Toxicol Appl Pharmacol ; 137(2): 141-8, 1996 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8661338

RESUMO

2,5-hexanedione (2,5-HD) is a Sertoli cell toxicant which causes germ cell loss and testicular atrophy in the rat. The mechanism of germ cell death over the course of 2,5-HD treatment is not known nor is the reason why residual germ cells do not repopulate the seminiferous epithelium following toxicant withdrawal. In the current study, the role of apoptosis in germ cell loss was studied. Male Fischer rats were treated for up to 5 weeks with 1% 2,5-HD in the drinking water and killed between 0 and 12 weeks after the start of toxicant exposure. Apoptosis was assessed in control and treated animals by (1) DNA fragmentation detected by gel electrophoresis, (2) cellular morphology on plastic sections, and (3) DNA fragmentation in situ by terminal deoxy-nucleotidyl transferase-mediated digoxigenin-UTP nick end label (TUNEL) staining of testis cross sections. All three indices demonstrated a substantial increase in apoptosis which peaked at 5 weeks of 2,5-HD treatment. Morphological analysis determined that apoptosis occurred in germ cells of the seminiferous epithelium. DNA fragmentation determined by gel electrophoresis was barely detectable until 5-6 weeks of toxicant exposure. However, TUNEL staining of testis cross sections indicated that germ cell apoptosis increased after as early as 2 weeks of toxicant exposure, providing a highly sensitive biological marker of toxicant-induced testicular injury. These data also suggested a differential sensitivity of germ cells to toxicant exposure with spermatid apoptosis occurring first at 4-5 weeks of treatment followed by apoptosis of spermatocytes and spermatogonia between 6 and 12 weeks. Together, these data demonstrate that apoptosis is the mechanism of germ cell loss in 2,5-HD-induced testicular injury.


Assuntos
Apoptose/efeitos dos fármacos , Hexanonas/toxicidade , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Testículo/efeitos dos fármacos , Testículo/patologia , Animais , Atrofia/induzido quimicamente , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , DNA/análise , DNA/efeitos dos fármacos , DNA/metabolismo , DNA Nucleotidilexotransferase , Digoxigenina , Eletroforese em Gel de Ágar , Hexanonas/farmacocinética , Masculino , Ratos , Ratos Endogâmicos F344 , Coloração e Rotulagem/métodos , Uridina Trifosfato
15.
Invest New Drugs ; 13(2): 113-6, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8617572

RESUMO

Imexon is an aziridine compound originally studied for immune-enhancing effects on lymphocytes. The drug was well-tolerated in humans and was shown to be active in a variety of animal tumor models. Recently, imexon has demonstrated antitumor activity in human multiple myeloma cell lines in vitro. The pharmacokinetics of the compound using normal phase HPLC assay were studied in normal mice and in dogs with mast cell tumors. Doses of 100 mg/kg given intraperitoneally produced peak plasma levels over 100 micrograms/ml in mice and the drug was rapidly eliminated with half lives of 8 minutes (alpha phase) and 29 minutes (beta phase). Only 20% of an oral imexon dose was absorbed in the mouse. In dogs, the alpha and beta phase half lives ranged from 18-26 minutes and 91-110 minutes, respectively. Peak levels over 100 micrograms/ml were obtained following intravenous doses of 12.5 mg/kg and 25 mg/kg. Imexon was active in mice bearing either P-388 or L-1210 leukemia, but not in mice with B-16 melanoma. These results suggest that cytotoxic drug concentrations can be obtained in vivo and that imexon is active in lymphoproliferative tumors.


Assuntos
Antineoplásicos/farmacocinética , Drogas em Investigação/farmacocinética , Hexanonas/farmacocinética , Leucemia L1210/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Drogas em Investigação/administração & dosagem , Drogas em Investigação/uso terapêutico , Meia-Vida , Hexanonas/administração & dosagem , Hexanonas/uso terapêutico , Injeções Intraperitoneais , Injeções Intravenosas , Leucemia L1210/patologia , Leucemia P388/patologia , Masculino , Sarcoma de Mastócitos/tratamento farmacológico , Sarcoma de Mastócitos/metabolismo , Melanoma Experimental/patologia , Camundongos , Células Tumorais Cultivadas
16.
Environ Health Perspect ; 102 Suppl 9: 133-7, 1994 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7698075

RESUMO

Chemical mixtures and multiple routes of exposure are frequently difficult problems for exposure and risk assessors. Chemicals can interact synergistically or antagonistically at a variety of physiologic and biochemical loci within target cells. Many of these interactions can be accounted for with a thorough understanding of the pharmacokinetics of the compounds in the mixture. Many pharmacokinetic processes such as metabolism and absorption can be impacted by the presence of other chemicals in the environment and diet and as a result of medication. In addition, variations between responses as a result of different exposure scenarios (route of exposure, frequency, magnitude) can sometimes result from the impacts upon the pharmacokinetics. Pharmacokinetic models, when properly formulated and tested, can be useful tools to describe and predict the magnitude of the impact of multichemical and multiroute exposures. Several examples will be used to demonstrate this potentially powerful tool and how it can impact the risk assessment process.


Assuntos
Poluentes Atmosféricos/farmacocinética , Poluentes Atmosféricos/metabolismo , Clorofórmio/metabolismo , Clorofórmio/farmacocinética , Hexanonas/metabolismo , Hexanonas/farmacocinética , Humanos , Fígado/metabolismo , Medição de Risco
17.
Int Arch Occup Environ Health ; 65(1): 71-4, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8354578

RESUMO

Occupational exposure to n-hexane in shoe factory workers was monitored by measuring urinary 2,5-hexanedione, the major metabolite of this solvent and the probable cause of peripheral neuropathy in exposed workers. Solvent pollution was monitored in the work environments of 189 employees, of whom 123 (65%) worked in Alicante, Spain, and 66 (35%) in Veneto, Italy. 2,5-Hexanedione was measured in spot urine samples collected from workers at the end of the shift. Information on working conditions was obtained from a previous study. A significant linear correlation was found between mean environmental concentration of n-hexane and urinary concentration of 2,5-hexanedione. The variability in the correlation may have been due to the variable use of protective clothing (gloves), and to variations in exposure during the working week. In numerous workers, percutaneous absorption of n-hexane represented as much as 50% of the total absorbed dose. Urinary concentrations of 2,5-hexanedione tended to increase during the working week. Simultaneous exposure to n-hexane and toluene tended to reduce urinary excretion of 2,5-hexanedione, whereas exposure to n-hexane and methyl ethyl ketone tended to increase excretion of the metabolite.


Assuntos
Monitoramento Ambiental/métodos , Hexanos/análise , Hexanonas/urina , Exposição Ocupacional/análise , Solventes/análise , Adolescente , Adulto , Biotransformação , Butanonas/metabolismo , Interações Medicamentosas , Feminino , Hexanos/farmacocinética , Hexanonas/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Sapatos , Absorção Cutânea , Solventes/farmacocinética , Tolueno/análise , Tolueno/metabolismo
18.
Int Arch Occup Environ Health ; 65(4): 275-8, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8144240

RESUMO

To compare two methods of biological monitoring for the evaluation of risk of occupational exposure to n-hexane, we analyze the relationship between environmental exposure to this solvent and urinary excretion of 2,5-hexanedione and n-hexane in exhaled air in 69 workers employed in the shoe industry. Environmental exposure to the solvent was monitored with personal diffusive samplers, which were desorbed with carbon sulfide and analyzed by gas chromatography. To measure 2,5-hexanedione, urine was subjected to acid hydrolysis, separation in octadecyl silane columns, elution with 5% aqueous acetonitrile solution and extraction with dichloromethane, followed by gas chromatography. In exhaled air, n-hexane was measured with a sampling system that permitted concentration of aliquots of end-exhaled air (alveolar air) from one or more exhalations in a tube packed with activated charcoal, which was then desorbed with carbon sulfide and analyzed by gas chromatography. Concentrations of n-hexane in breathing zone air were significantly correlated with urinary concentrations of 2,5-hexanedione (r = 0.88) and with exhaled air n-hexane (r = 0.86); in addition, the two biological indicators correlated significantly (r = 0.70). Analyses in both exhaled air and urine were thus considered useful for biological monitoring of the risk of exposure to n-hexane.


Assuntos
Adesivos , Testes Respiratórios , Monitoramento Ambiental/métodos , Hexanos/farmacocinética , Exposição Ocupacional , Adolescente , Adulto , Relação Dose-Resposta a Droga , Feminino , Hexanos/efeitos adversos , Hexanonas/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Sapatos
19.
Toxicol Appl Pharmacol ; 108(3): 390-6, 1991 May.
Artigo em Inglês | MEDLINE | ID: mdl-2020966

RESUMO

Fast anterograde axonal transport has been advanced as a potential site of action of acrylamide (ACR) and the neurotoxic gamma-diketones in producing nerve degeneration. The segmental analysis method of axonal transport was used to measure the rate and quantity of protein transport in the rat sciatic nerve from 1 to 24 hr after a single injection of 50 mg/kg (0.7 mmol/kg) ACR or 4 mmol/kg 2,5-hexanedione (2,5-HD). The single injection of ACR or 2,5-HD resulted in an immediate reduction in transport quantity of 48 and 43%, respectively. Transport remained depressed for 16 hr; recovery occurred from 16 to 24 hr reaching control levels at 24 hr postinjection for both toxicants. Protein transport, measured immediately after the 2nd, 4th, 7th, and 10th injections, was reduced 36-38% by 50 mg/kg ACR and 30-43% by 4 mmol/kg 2,5-HD. Therefore, both ACR and 2,5-HD produce a transient and repeated compromise of fast anterograde transport during the dosing regimen which results in distal nerve degeneration. Assuming a rate of recovery after each subsequent dose similar to the first, the protein delivery to the axon was calculated to be reduced 29% by ACR and 22% by 2,5-HD. Current evidence supports the hypothesis that a toxicant-induced reduction in protein delivery to the axon by ACR and 2,5-HD contributes to development of axonal degeneration.


Assuntos
Acrilamidas/toxicidade , Axônios/efeitos dos fármacos , Hexanonas/toxicidade , Filamentos Intermediários/efeitos dos fármacos , Acrilamida , Acrilamidas/farmacocinética , Animais , Axônios/patologia , Transporte Biológico , Hexanonas/farmacocinética , Filamentos Intermediários/patologia , Ratos , Ratos Endogâmicos
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