RESUMO
4-Hexen-1-ol, 5-methyl-2-(1-methylethenyl)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)- is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)- is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from read-across analog 3-methylbut-3-en-1-ol (CAS # 763-32-6) show that there are no safety concerns for 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)- for skin sensitization under the current declared levels of use. The photoirritation/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)- is not expected to be photoirritating/photoallergenic. The environmental endpoints were evaluated; 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Assuntos
Perfumes , Animais , Humanos , Hexanóis/toxicidade , Hexanóis/química , Testes de Mutagenicidade , Odorantes , Perfumes/toxicidade , Perfumes/química , Medição de Risco , Testes de ToxicidadeRESUMO
The existing information supports the use of this material as described in this safety assessment. 2-Methyl-4-phenylbutyraldehyde was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog ß-methyl-benzenepentanal (CAS # 55,066-49-4) show that 2-methyl-4-phenylbutyraldehyde is not expected to be genotoxic and provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity endpoint. Data on read-across analog phenylacetaldehyde (CAS # 122-78-1) provide a calculated MOE >100 for the reproductive toxicity endpoint. Data show that there are no safety concerns for 2-methyl-4-phenylbutyraldehyde for skin sensitization under the current declared levels of use. The photoirritation/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 2-methyl-4-phenylbutyraldehyde is not expected to be photoirritating/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to 2-methyl-4-phenylbutyraldehyde is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; 2-methyl-4-phenylbutyraldehyde was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
RESUMO
The existing information supports the use of this material as described in this safety assessment. This material has not been fully evaluated for photoallergenic potential. 2,4,6-Cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for reactive materials (64 µg/cm2); exposure is below the DST. Based on data, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- is a photoirritant but is not a concern under the current declared use levels. 2,4,6-Cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was not evaluated for photoallergenicity. The environmental endpoints were evaluated; for the hazard assessment based on the screening data, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Assuntos
Odorantes , Perfumes , Testes de Mutagenicidade , Perfumes/toxicidade , Bioacumulação , Clima , Medição de RiscoRESUMO
BACKGROUND: Carboplatin and cisplatin, alone or in combination with paclitaxel, have similar efficacies against ovarian cancer (OVCA) yet exhibit different toxicity profiles. We characterised the common and unique cellular pathways that underlie OVCA response to these drugs and analyse whether they have a role in OVCA survival. METHODS: Ovarian cancer cell lines (n=36) were treated with carboplatin, cisplatin, paclitaxel, or carboplatin-paclitaxel (CPTX). For each cell line, IC(50) levels were quantified and pre-treatment gene expression analyses were performed. Genes demonstrating expression/IC(50) correlations (measured by Pearson; P<0.01) were subjected to biological pathway analysis. An independent OVCA clinico-genomic data set (n=142) was evaluated for clinical features associated with represented pathways. RESULTS: Cell line sensitivity to carboplatin, cisplatin, paclitaxel, and CPTX was associated with the expression of 77, 68, 64, and 25 biological pathways (P<0.01), respectively. We found three common pathways when drug combinations were compared. Expression of one pathway ('Transcription/CREB pathway') was associated with OVCA overall survival. CONCLUSION: The identification of the Transcription/CREB pathway (associated with OVCA cell line platinum sensitivity and overall survival) could improve patient stratification for treatment with current therapies and the rational selection of future OVCA therapy agents targeted to these pathways.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Carboplatina/administração & dosagem , Linhagem Celular Tumoral/imunologia , Cisplatino/administração & dosagem , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Feminino , Humanos , Neoplasias Ovarianas/mortalidade , Paclitaxel/administração & dosagem , Transdução de Sinais , Resultado do TratamentoRESUMO
The existing information supports the use of this material as described in this safety assessment. 2-Tridecanone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 2-heptanone (CAS # 110-43-0) show that 2-tridecanone is not expected to be genotoxic and provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and reproductive toxicity endpoints. Data from read-across analog 2-heptanone (CAS # 110-43-0) show that there are no safety concerns for 2-tridecanone for skin sensitization under the current declared levels of use. The photoirritation/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 2-tridecanone is not expected to be photoirritating/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class II material, and the exposure to 2-tridecanone is below the TTC (0.47 mg/day). The environmental endpoints were evaluated; 2-Tridecanone was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Assuntos
Odorantes , Perfumes , Testes de Toxicidade , Testes de Mutagenicidade , Perfumes/toxicidade , Sistema de Registros , Medição de RiscoRESUMO
Therefore, the phenethyl formate MOE for the fertility endpoint can be calculated by dividing the phenethyl alcohol NOAEL in mg/kg/day by the total systemic exposure to phenethyl formate, 1000/0.00062 or 1612903.
Assuntos
Odorantes , Perfumes , Qualidade de Produtos para o Consumidor , Formiatos , Perfumes/toxicidade , Fenilacetatos , Sistema de Registros , Medição de Risco , Testes de ToxicidadeRESUMO
In addition, the total systemic exposure to α-irone (1.1 µg/kg/day) is below the TTC (30 µg/kg/day; Kroes et al., 2007) for the repeated dose toxicity endpoint of a Cramer Class I material at the current level of use.
Assuntos
Odorantes , Perfumes , Testes de Mutagenicidade , Norisoprenoides , Perfumes/toxicidade , Sistema de Registros , Medição de Risco , Testes de ToxicidadeRESUMO
The MOE is greater than 100. Without adjustment for specific uncertainty factors related to inter-species and intra-species variation, the material exposure by inhalation at 0.0040 mg/day is deemed to be safe under the most conservative consumer exposure scenario.
Assuntos
Perfumes , Testes de Toxicidade , Acetatos , Compostos de Benzil , Qualidade de Produtos para o Consumidor , Dano ao DNA , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Determinação de Ponto Final , Nível de Efeito Adverso não Observado , Odorantes , Perfumes/toxicidade , Sistema de Registros , Medição de RiscoRESUMO
The existing information supports the use of this material as described in this safety assessment. Geraniol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that geraniol is not genotoxic. Data on geraniol provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and reproductive toxicity endpoints. Data provided geraniol a No Expected Sensitization Induction Level (NESIL) of 11000 µg/cm2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; geraniol is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to geraniol is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; geraniol was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Assuntos
Odorantes , Perfumes , Monoterpenos Acíclicos , Testes de Mutagenicidade , Perfumes/toxicidade , Sistema de Registros , Medição de RiscoRESUMO
The existing information supports the use of this material as described in this safety assessment. 3-Cyclohexene-1-carboxaldehyde, 1-ethenyl- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 3-cyclohexene-1-carboxaldehyde, 1-ethenyl- is not genotoxic. Data on 3-cyclohexene-1-carboxaldehyde, 1-ethenyl- provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity endpoint. The reproductive and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to 3-cyclohexene-1-carboxaldehyde, 1-ethenyl-is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). Data provided 3-cyclohexene-1-carboxaldehyde, 1-ethenyl- a No Expected Sensitization Induction Level (NESIL) of 1000 µg/cm2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 3-cyclohexene-1-carboxaldehyde, 1-ethenyl- is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 3-cyclohexene-1-carboxaldehyde, 1-ethenyl- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Assuntos
Odorantes , Perfumes , Cicloexenos/toxicidade , Testes de Mutagenicidade , Perfumes/toxicidade , Sistema de Registros , Medição de RiscoRESUMO
The existing information supports the use of this material as described in this safety assessment. Octyl isobutyrate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog hexyl isobutyrate (CAS # 2349-07-7) show that octyl isobutyrate is not expected to be genotoxic. Data on analog propyl (2S)-2-(1,1-dimethylpropoxy)-propanoate (CAS # 319002-92-1) provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose and reproductive toxicity endpoints. Data from analog hexyl 2-methylbutyrate (CAS # 10032-15-2) provided octyl isobutyrate a No Expected Sensitization Induction Level (NESIL) of 7000 µg/cm2 for the skin sensitization endpoint. Octyl isobutyrate is not expected to be phototoxic/photoallergenic based on ultraviolet/visible (UV/Vis) spectra. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material; exposure to is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; octyl isobutyrate was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Assuntos
Isobutiratos/toxicidade , Odorantes , Humanos , Testes de Mutagenicidade , Testes de ToxicidadeRESUMO
BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Pontuação de Propensão , Estudos Retrospectivos , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
BACKGROUND: There is no clear consensus on the recommended second-line treatment for patients with metastatic pancreatic cancer who have disease progression following gemcitabine-based therapy. We retrospectively evaluated the clinical outcomes of liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (FL) and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) in patients who had failed on the first-line gemcitabine-based therapy. PATIENTS AND METHODS: From January 2015 to August 2019, 378 patients with MPC who had received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as second-line treatment across 11 institutions were included in this retrospective study. RESULTS: There were no significant differences in baseline characteristics between groups, except age and first-line regimens. With a median follow-up of 6 months, the median progression-free survival (PFS) was 3.7 months with nal-IRI/FL versus 4.6 months with FOLFIRINOX (P = 0.44). Median overall survival (OS) was 7.7 months with nal-IRI/FL versus 9.7 months with FOLFRINOX (P = 0.13). There was no significant difference in PFS and OS between the two regimens in the univariate and multivariate analyses. The subgroup analysis revealed that younger age (<70 years) was associated with better OS with FOLFIRINOX. In contrast, older age (≥70 years) was associated with better survival outcomes with nal-IRI/FL. Adverse events were manageable with both regimens; however, the incidence of grade 3 or higher neutropenia and peripheral neuropathy was higher in patients treated with FOLFIRINOX than with nal-IRI/FL. CONCLUSIONS: Second-line nal-IRI/FL and FOLFIRINOX showed similar effectiveness outcomes after progression following first-line gemcitabine-based therapy. Age could be the determining factor for choosing the appropriate second-line therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fluoruracila/efeitos adversos , Humanos , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , República da Coreia , Estudos RetrospectivosRESUMO
When spin label is added to Chlamydomonas the organism is apparently unaffected, but the paramagnetic resonance signal of the spin label decreases. Irradiation with visible light greatly accelerates this decrease, which is partially reversible. If the cells are grown in the presence of the spin label and washed well, no spin label signal is detectable. However, such cells can no longer catalyze the destruction of added spin label in the light. This finding sug- gests that the molecule is bound to a specific site, which undergoes a change in conformation with illumination.
RESUMO
AIMS: The objective of this study was to investigate the ability of specific bacterial components of Lactobacillus plantarum KFCC11389P to induce anti-inflammatory mediators in cell cultures of the murine macrophage cell line, RAW 264.7. METHODS AND RESULTS: The RAW 264.7 cells were stimulated with viable bacterial cells (VC), heat-killed (HK) cells, cell walls (CW) or ultrafiltrates of metabolic products (UF). An increase in the levels of tumour necrosis factor (TNF)-alpha was observed in VC, HK and CW, but this effect was much lower in UF. VC stimulated higher levels of interleukin (IL)-6 releases as well as nitric oxide production than HK. In contrast, UF and its separated molecule, fraction 4, were much strong IL-10 inducers. Fraction 4 (8.1 kDa), especially, inhibited the production of pro-inflammatory cytokines, IL-6 (89% decrease) and TNF-alpha (55% decrease), in lipopolysaccharide (LPS)-stimulated murine macrophages. CONCLUSIONS: The results of this study indicate that metabolic products of Lact. plantarum KFCC11389P could influence the immune-modulating activity via IL-10, and pretreatment with this specific molecule could inhibit LPS-induced release of IL-6 and TNF-alpha. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings suggest that the specific molecules of Lact. plantarum KFCC11389P may be useful for the treatment of acute inflammatory responses such as Crohn's disease or ulcerative colitis.