Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 34
Filter
1.
Gastroenterology ; 161(5): 1423-1432.e4, 2021 11.
Article in English | MEDLINE | ID: mdl-34273347

ABSTRACT

BACKGROUND & AIMS: Diet may contribute to the increasing incidence of colorectal cancer (CRC) before age 50 (early-onset CRC). Microbial metabolism of dietary sulfur produces hydrogen sulfide (H2S), a gastrointestinal carcinogen that cannot be easily measured at scale. As a result, evidence supporting its role in early neoplasia is lacking. METHODS: We evaluated long-term adherence to the sulfur microbial diet, a dietary index defined a priori based on increased abundance of 43 bacterial species involved with sulfur metabolism, with risk of CRC precursors among 59,013 individuals who underwent lower endoscopy in the Nurses' Health Study II (1991-2015), a prospective cohort study with dietary assessment every 4 years through validated food frequency questionnaires and an assessment of dietary intake during adolescence in 1998. The sulfur microbial diet was characterized by intake high in processed meats, foods previously linked to CRC development, and low in mixed vegetables and legumes. Multivariable logistic regression for clustered data was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We documented 2911 cases of early-onset adenoma. After adjusting for established risk factors, higher sulfur microbial diet scores were associated with increased risk for early-onset adenomas (ORquartile [Q]4 vs Q1, 1.31; 95% CI, 1.10-1.56, Ptrend = .02), but not serrated lesions. Compared with the lowest, women in the highest quartile of sulfur microbial diet scores had significantly increased risk of early-onset adenomas with greater malignant potential (ORQ4 vs Q1, 1.65 for villous/tubulovillous histology; 95% CI, 1.12-2.43; Ptrend = .04). Similar trends for early-onset adenoma were observed based on diet consumed during adolescence. In contrast, no clear association for adenomas was identified after age 50. CONCLUSIONS: Our findings in a cohort of young women support a role for dietary interactions with gut sulfur-metabolizing bacteria in early-onset colorectal carcinogenesis, possibly beginning in adolescence.


Subject(s)
Adenomatous Polyps/epidemiology , Bacteria/metabolism , Colonic Polyps/epidemiology , Colorectal Neoplasms/epidemiology , Diet/adverse effects , Gastrointestinal Microbiome , Precancerous Conditions/epidemiology , Sulfur Compounds/adverse effects , Adenomatous Polyps/diagnosis , Adult , Age of Onset , Colonic Polyps/diagnosis , Colorectal Neoplasms/diagnosis , Female , Humans , Hydrogen Sulfide/adverse effects , Hydrogen Sulfide/metabolism , Middle Aged , Precancerous Conditions/diagnosis , Prospective Studies , Risk Assessment , Risk Factors , Sulfur Compounds/administration & dosage , Sulfur Compounds/metabolism , Time Factors , United States/epidemiology
2.
Food Chem Toxicol ; 149: 112031, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33529679

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most common fatal malignant tumors. Glycosmis pentaphylla is used by traditional medical practitioners worldwide to treat various diseases. We isolated and identified a chemical component with potential anti-hepatocellular carcinoma (HCC) effects. Methylgerambullin is a sulfur containing amine and has significant antihepatoma activity in vitro and in vivo. Methylgerambullin was significantly cytotoxic to HCC cells and induces apoptosis in HCC cells. In addition, methylgerambullin is able to inhibit the growth of transplanted tumors in nude mice without significant toxicity. Regarding the anti-cancer mechanism of methylgerambullin, treatment with methylgerambullin increased the expression of caspase-3, caspase-9 and Bax in vitro and in vivo and reduce the expression of B-cell lymphoma-2 (Bcl-2). Simultaneously, methylgerambullin can also affect ERS-related proteins, inhibit Protein Kinase B (Akt) activity, cause dephosphorylation of downstream Bad, and inhibit the expression of the Signal Transducer and Activator of Transcription 3 (STAT3) protein to inhibit HCC cells proliferation. Overall, these results suggest that methylgerambullin can inhibit HCC cells proliferation by inducing mitochondrial apoptosis, activating ERS signaling pathways and inhibiting the Akt and STAT3 pathways.


Subject(s)
Amides/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Rutaceae/chemistry , Sulfur Compounds/pharmacology , Amides/administration & dosage , Amides/chemistry , Animals , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Dose-Response Relationship, Drug , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Plant Leaves , Random Allocation , Sulfur Compounds/administration & dosage , Sulfur Compounds/chemistry
3.
Sci Rep ; 10(1): 17074, 2020 10 13.
Article in English | MEDLINE | ID: mdl-33051479

ABSTRACT

GYNOPHILUS (Lcr REGENERANS) is a live biotherapeutic product (LBP) aimed at restoring the vaginal microbiome and contains the live biotherapeutic microorganism Lactobacillus rhamnosus Lcr35. In this study, the LBP formulation and manufacturing process significantly enhanced the anti-Candida activity of L. rhamnosus Lcr35, with a complete loss of viability of the yeast after 48 h of coincubation. Sodium thiosulfate (STS), one excipient of the product, was used as a potentiator of the anti-Candida spp. activity of Lactobacilli. This contact-independent phenomenon induced fungal cell disturbances, as observed by electron microscopy observations. Nonverbal sensory experiments showed clear odor dissimilarities between cocultures of L. rhamnosus Lcr35 and C. albicans in the presence and absence of STS, suggesting an impact of odor-active metabolites. A volatolomic approach allowed the identification of six odor-active compounds, including one sulfur compound that was identified as S-methyl thioacetate (MTA). MTA was associated with the antifungal effect of Lcr35, and its functional link was established in vitro. We show for the first time that the LBP GYNOPHILUS, which is a highly active product in the reduction of vulvovaginal candidiasis, requires the presence of a sulfur compound to fully achieve its antifungal effect.


Subject(s)
Antifungal Agents/administration & dosage , Candidiasis, Vulvovaginal/microbiology , Candidiasis, Vulvovaginal/therapy , Lacticaseibacillus rhamnosus/physiology , Probiotics/administration & dosage , Sulfur Compounds/administration & dosage , Acetates/administration & dosage , Candida albicans/pathogenicity , Candida albicans/physiology , Candida albicans/ultrastructure , Coculture Techniques , Female , Humans , In Vitro Techniques , Lacticaseibacillus rhamnosus/ultrastructure , Microbiota , Microscopy, Electron , Odorants , Thiosulfates/administration & dosage , Vagina/drug effects , Vagina/microbiology
4.
Angew Chem Int Ed Engl ; 59(37): 16218-16224, 2020 09 07.
Article in English | MEDLINE | ID: mdl-32484601

ABSTRACT

In the present study, we investigated the biotransformation of the neonicotinoid pesticide sulfoxaflor and the metabolic responses in Sprague-Dawley rats. Sulfoxaflor transformation was catalyzed by cytochrome P450 while five phase I and four phase II metabolites were identified for the first time in vivo. The experimental results demonstrated that sulfoxaflor brought about the metabolic profiling disturbances in liver and bile. Exposure to sulfoxaflor caused dysregulation of bile acid synthesis and reabsorption by the expression of farnesoid X receptor (FXR). Our data provided insights into biotransformation of chemicals while enabling the implementation of a new toolbox for the design of sulfoximine compounds.


Subject(s)
Pesticides/pharmacokinetics , Pyridines/pharmacokinetics , Sulfur Compounds/pharmacokinetics , Animals , Bile/metabolism , Biocatalysis , Biotransformation , Dose-Response Relationship, Drug , Liver/metabolism , Metabolomics , Pyridines/administration & dosage , Rats , Rats, Sprague-Dawley , Sulfur Compounds/administration & dosage
5.
Curr Gastroenterol Rep ; 20(11): 53, 2018 Sep 28.
Article in English | MEDLINE | ID: mdl-30267281

ABSTRACT

PURPOSE OF REVIEW: The increased use of biologic agents over the past two decades has led to a reappraisal of the role of the immunomodulators (thiopurines and methotrexate) in the treatment of inflammatory bowel disease. The purpose of this review is to summarize recent data on the use of thiopurines and methotrexate either as monotherapy or as part of combination therapy with biologic agents. RECENT FINDINGS: Recent studies have addressed the need for concomitant immunomodulatory therapy in treatment-naïve patients starting anti-TNF-α therapy, the appropriate dose of the immunomodulator in this setting, the minimum duration of combination therapy, and the possible mechanisms by which immunomodulators enhance the effectiveness of anti-TNF-α agents. Little is known about the role of immunomodulators in combination with agents belonging to other classes of biologic therapies. Recent studies have shown that methotrexate is not effective in inducing or maintaining remission in ulcerative colitis. Finally, several studies have broadened our understanding of the infection and malignancy risks of the immunomodulators. Immunomodulators continue to have a place in the treatment of inflammatory bowel disease. However, with the ever-increasing list of biologic agents, properly positioning the immunomodulators within the overall therapeutic scheme is a complicated task. In order to optimize outcomes, each patient requires an individualized approach, which takes into account risks, benefits, cost, alternatives, and patient preferences.


Subject(s)
Gastrointestinal Agents/administration & dosage , Immunologic Factors/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Methotrexate/administration & dosage , Purines/administration & dosage , Sulfur Compounds/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Azathioprine/administration & dosage , Biological Factors/administration & dosage , Biological Factors/therapeutic use , Drug Therapy, Combination , Gastrointestinal Agents/therapeutic use , Humans , Immunologic Factors/administration & dosage , Mercaptopurine/administration & dosage , Mercaptopurine/therapeutic use , Methotrexate/therapeutic use , Purines/therapeutic use , Sulfur Compounds/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors
6.
Nature ; 561(7721): 109-112, 2018 09.
Article in English | MEDLINE | ID: mdl-30111837

ABSTRACT

Intensive agriculture currently relies on pesticides to maximize crop yield1,2. Neonicotinoids are the most widely used insecticides globally3, but increasing evidence of negative impacts on important pollinators4-9 and other non-target organisms10 has led to legislative reassessment and created demand for the development of alternative products. Sulfoximine-based insecticides are the most likely successor11, and are either licensed for use or under consideration for licensing in several worldwide markets3, including within the European Union12, where certain neonicotinoids (imidacloprid, clothianidin and thiamethoxam) are now banned from agricultural use outside of permanent greenhouse structures. There is an urgent need to pre-emptively evaluate the potential sub-lethal effects of sulfoximine-based pesticides on pollinators11, because such effects are rarely detected by standard ecotoxicological assessments, but can have major impacts at larger ecological scales13-15. Here we show that chronic exposure to the sulfoximine-based insecticide sulfoxaflor, at dosages consistent with potential post-spray field exposure, has severe sub-lethal effects on bumblebee (Bombus terrestris) colonies. Field-based colonies that were exposed to sulfoxaflor during the early growth phase produced significantly fewer workers than unexposed controls, and ultimately produced fewer reproductive offspring. Differences between the life-history trajectories of treated and control colonies first became apparent when individuals exposed as larvae began to emerge, suggesting that direct or indirect effects on a small cohort may have cumulative long-term consequences for colony fitness. Our results caution against the use of sulfoximines as a direct replacement for neonicotinoids. To avoid continuing cycles of novel pesticide release and removal, with concomitant impacts on the environment, a broad evidence base needs to be assessed prior to the development of policy and regulation.


Subject(s)
Bees/drug effects , Bees/physiology , Insecticides/adverse effects , Pyridines/adverse effects , Sulfur Compounds/adverse effects , Animals , Female , Insecticides/administration & dosage , Male , Population Dynamics , Pyridines/administration & dosage , Reproduction/drug effects , Sulfur Compounds/administration & dosage
7.
Photodiagnosis Photodyn Ther ; 24: 7-14, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30144532

ABSTRACT

Due to their many unique properties, graphene quantum dots (GQDs) have attracted much attention and are a promising material with potential applications in many fields. One application of GQDs is as a photodynamic therapy agent that generates singlet oxygen. In this work, GQDs were grown by focusing nanosecond laser pulses into benzene and then were later combined with methylene blue (MB) and used to eradicate the Gram-negative bacteria, Escherichia coli, and Gram-positive bacteria, Micrococcus luteus. Theoretical calculation of pressure evolution was calculated using the standard finite difference method. Detailed characterization was performed with transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier-transform infrared (FTIR), UV-vis (UV-vis), and photoluminescence (PL) spectra. Furthermore, MB-GQD singlet oxygen generation was investigated by measuring the rate of 9,10-anthracenediyl-bis(methylene) dimalonic acid photobleaching. Combining MB with GQDs caused enhanced singlet oxygen generation. Our results show that the MB-GQD combination efficiently destroys bacteria. The (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay was used to determine if GQDs in dark conditions caused human cellular side-effects and affected cancer and noncancer cellular viability. We found that even high concentrations of GQDs do not alter viability under dark conditions. These results suggest that the MB-GQD combination is a promising form of photodynamic therapy.


Subject(s)
Graphite/chemistry , Low-Level Light Therapy/methods , Methylene Blue/therapeutic use , Quantum Dots/therapeutic use , Singlet Oxygen/agonists , Sulfur Compounds/therapeutic use , Cell Survival/radiation effects , Lasers, Solid-State , Methylene Blue/administration & dosage , Quantum Dots/administration & dosage , Sulfur Compounds/administration & dosage
8.
J Econ Entomol ; 110(6): 2436-2442, 2017 12 05.
Article in English | MEDLINE | ID: mdl-29029168

ABSTRACT

Pest-induced changes in plant reflectance are crucial for the development of pest management programs using remote sensing. However, it is unknown if plant reflectance data is also affected by foliar insecticides applied for pest management. Our study assessed the effects of foliar insecticides on leaf reflectance of soybean. A 2-yr field trial and a greenhouse trial were conducted using randomized complete block and completely randomized designs, respectively. Treatments consisted of an untreated check, a new systemic insecticide (sulfoxaflor), and two representatives of the most common insecticide classes used for soybean pest management in the north-central United States (i.e., λ-cyhalothrin and chlorpyrifos). Insecticides were applied at labeled rates recommended for controlling soybean aphid; the primary insect pest in the north-central United States. Leaf-level reflectance was measured using ground-based spectroradiometers. Sulfoxaflor affected leaf reflectance at some red and blue wavelengths but had no effect at near-infrared or green wavelengths. Chlorpyrifos affected leaf reflectance at some green, red, and near-infrared wavelengths but had no effect at blue wavelengths. λ-cyhalothrin had the least effect on spectral reflectance among the insecticides, with changes to only a few near-infrared wavelengths. Our results showing immediate and delayed effects of foliar insecticides on soybean reflectance indicate that application of some insecticides may confound the use of remote sensing for detection of not only insects but also plant diseases, nutritional and water deficiencies, and other crop stressors.


Subject(s)
Glycine max/drug effects , Insecticides/administration & dosage , Light , Pest Control , Chlorpyrifos/administration & dosage , Nitriles/administration & dosage , Plant Leaves/drug effects , Plant Leaves/physiology , Pyrethrins/administration & dosage , Pyridines/administration & dosage , Random Allocation , Glycine max/physiology , Spectrum Analysis , Sulfur Compounds/administration & dosage
9.
Heart Lung Circ ; 26(11): 1183-1190, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28256403

ABSTRACT

BACKGROUND: The uptake of bone-seeking radiotracers in the amyloid heart is well recognised. 99mTc-DPD has been shown to be highly sensitive for cardiac transthyretin (ATTR) amyloid in an overseas population, but is not registered for use in Australia. We explored its utility as a diagnostic tool within our population. METHODS: Patients diagnosed with AL and ATTR (wild-type and inherited) cardiac amyloidosis were prospectively recruited from the Princess Alexandra Hospital Amyloidosis Centre. Patients underwent injection with 99mTc-DPD then planar whole body imaging was performed at 5 minutes post-injection (soft tissue phase) and 3 hours (bone phase). A myocardial SPECT and low amperage CT were acquired after the late whole-body scan. Scans were analysed by two nuclear imaging specialists. Intensity of cardiac 99mTc-DPD uptake was graded as 0 to 3 in accordance with previous criteria, and semiquantitative analysis was performed using a heart to whole body ratio (H:WB) on the 3-hour scan. Patients also underwent electrocardiography and transthoracic echocardiography, and blood samples were taken for troponin I and brain natriuretic peptide levels, to assess for any correlation with DPD uptake. RESULTS: Twenty-one patients (8 AL and 13 ATTR) completed the study. Median age was 58 and 70 years for AL and ATTR patients respectively, and 19 (90.5%) were male. 99mTc-DPD scintigraphy was positive in 2 (25%) of AL, and 13 (100%) of ATTR patients. Grade of cardiac uptake, and mean H:WB (0.1249 v. 0.0794) was greater in the ATTR cohort (p-value<0.001 and 0.001 respectively). No statistically significant correlation was identified between H:WB and echocardiographic parameters. There was a significant positive correlation between H:WB and the PR interval on ECG (p=0.026). CONCLUSIONS: 99mTc-DPD scintigraphy is highly sensitive for the diagnosis of cardiac ATTR amyloid, but less so for AL amyloid.


Subject(s)
Amyloid Neuropathies, Familial , Cardiomyopathies , Echocardiography , Electrocardiography , Organotechnetium Compounds/administration & dosage , Sulfur Compounds/administration & dosage , Tomography, Emission-Computed , Aged , Amyloid Neuropathies, Familial/blood , Amyloid Neuropathies, Familial/diagnostic imaging , Amyloid Neuropathies, Familial/physiopathology , Australia , Cardiomyopathies/blood , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/physiopathology , Female , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Troponin I/blood
10.
Cutis ; 96(2): 128-30, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26367751

ABSTRACT

Sodium sulfacetamide is effective in the management of a variety of inflammatory facial dermatoses and often is used in combination with sulfur for a synergistic effect. Adverse effects from sodium sulfacetamide are rare and generally are limited to mild application-site reactions. This agent is contraindicated in any patient with known hypersensitivity to sulfonamides.


Subject(s)
Dermatologic Agents/administration & dosage , Skin Diseases/drug therapy , Sulfacetamide/administration & dosage , Administration, Cutaneous , Dermatologic Agents/adverse effects , Dermatologic Agents/therapeutic use , Drug Synergism , Humans , Skin Diseases/pathology , Sulfacetamide/adverse effects , Sulfacetamide/therapeutic use , Sulfur Compounds/administration & dosage , Sulfur Compounds/therapeutic use
11.
Ann Nutr Metab ; 66(2-3): 168-181, 2015.
Article in English | MEDLINE | ID: mdl-26045206

ABSTRACT

BACKGROUND/AIMS: The prevalence of cardiovascular diseases (CVD) is rising and it is the prime cause of death in all developed countries. Bioactive compounds (BACs) can play a role in CVD prevention and treatment. To examine the scientific evidence supporting BACs groups' efficacy in CVD prevention and treatment, we conducted a systematized review. METHODS: All available information on Medline, LILACS and EMBASE; all randomized controlled trials (RCTs) with prospective, parallel or crossover designs in humans in which the BACs effect was compared with that of placebo/control. Vascular homeostasis, blood pressure, endothelial function, oxidative stress and inflammatory biomarkers were considered primary outcomes. RESULTS: We selected 26 articles, verifying their quality based on the Scottish Intercollegiate Guidelines Network, establishing diverse quality levels of scientific evidence according to the design and bias risk of a study. Grades of recommendation were included, depending on the evidence strength of antecedents. CONCLUSIONS: Evidence shows that certain BACs' derivative from active lipids and nitrogen compounds, mainly from horse chestnut seed extract, sterol plants, allium derivatives, and certain doses of beta-glucans, can be helpful in decreasing the prevalence of CVD risk factors. However, further rigorous evidence is necessary to support and prove BACs' effect on CVD prevention and treatment.


Subject(s)
Cardiovascular Diseases/prevention & control , Phytochemicals/administration & dosage , Phytosterols/administration & dosage , Diet , Dietary Carbohydrates/administration & dosage , Dietary Fiber/administration & dosage , Flavonoids/administration & dosage , Humans , MEDLINE , Nitrogen Compounds/administration & dosage , Polysaccharides/administration & dosage , Randomized Controlled Trials as Topic , Sulfur Compounds/administration & dosage , beta-Glucans/administration & dosage
12.
Chem Commun (Camb) ; 50(80): 11788-805, 2014 Oct 14.
Article in English | MEDLINE | ID: mdl-25019301

ABSTRACT

Hydrogen sulfide (H2S) is a newly recognized signaling molecule with very potent cytoprotective actions. The fields of H2S physiology and pharmacology have been rapidly growing in recent years, but a number of fundamental issues must be addressed to advance our understanding of the biology and clinical potential of H2S in the future. Hydrogen sulfide releasing agents (also known as H2S donors) have been widely used in these fields. These compounds are not only useful research tools, but also potential therapeutic agents. It is therefore important to study the chemistry and pharmacology of exogenous H2S and to be aware of the limitations associated with the choice of donors used to generate H2S in vitro and in vivo. In this review we summarized the developments and limitations of currently available donors including H2S gas, sulfide salts, garlic-derived sulfur compounds, Lawesson's reagent/analogs, 1,2-dithiole-3-thiones, thiol-activated donors, photo-caged donors, and thioamino acids. Some biological applications of these donors were also discussed.


Subject(s)
Hydrogen Sulfide/administration & dosage , Hydrogen Sulfide/pharmacology , Protective Agents/administration & dosage , Protective Agents/pharmacology , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Drug Liberation , Garlic/chemistry , Humans , Hydrogen Sulfide/chemistry , Organothiophosphorus Compounds/administration & dosage , Organothiophosphorus Compounds/chemistry , Organothiophosphorus Compounds/pharmacology , Protective Agents/chemistry , Sulfur Compounds/administration & dosage , Sulfur Compounds/chemistry , Sulfur Compounds/pharmacology
14.
Environ Toxicol Pharmacol ; 36(2): 675-679, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23892072

ABSTRACT

A comprehensive pharmacokinetic profiling of novel drugs and therapeutics is a definite prerequisite of drug discovery and development. The present study expedites the in vivo and in vitro pharmacokinetic properties of colloidal sulfur nanoparticles (SNPs). In vitro dissolution properties of SNPs have been demonstrated and compared with the in vivo pharmacokinetic parameters of rabbit (Oryctolagus cuniculus) serum sample. The present study was also aimed at developing levels of correlation between in vitro and in vivo pharmacokinetic parameters. Cumulative results of the proposed study also suggest good in vitro-in vivo correlation of these novel nanocolloids and suggest their immediate profiling as an antimicrobial drug.


Subject(s)
Anti-Infective Agents/pharmacokinetics , Nanoparticles , Sulfur Compounds/pharmacokinetics , Administration, Oral , Animals , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/blood , Anti-Infective Agents/chemistry , Biological Availability , Chemistry, Pharmaceutical , Colloids , Female , Models, Biological , Rabbits , Solubility , Sulfur Compounds/administration & dosage , Sulfur Compounds/blood , Sulfur Compounds/chemistry , Technology, Pharmaceutical/methods
15.
Toxicol Appl Pharmacol ; 270(2): 164-73, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23607986

ABSTRACT

Registration of new plant protection products (e.g., herbicide, insecticide, or fungicide) requires comprehensive mammalian toxicity evaluation including carcinogenicity studies in two species. The outcome of the carcinogenicity testing has a significant bearing on the overall human health risk assessment of the substance and, consequently, approved uses for different crops across geographies. In order to understand the relevance of a specific tumor finding to human health, a systematic, transparent, and hypothesis-driven mode of action (MoA) investigation is, appropriately, an expectation by the regulatory agencies. Here, we describe a novel approach of prospectively generating the MoA data by implementing additional end points to the standard guideline toxicity studies with sulfoxaflor, a molecule in development. This proactive MoA approach results in a more robust integration of molecular with apical end points while minimizing animal use. Sulfoxaflor, a molecule targeting sap-feeding insects, induced liver effects (increased liver weight due to hepatocellular hypertrophy) in an initial palatability probe study for selecting doses for subsequent repeat-dose dietary studies. This finding triggered the inclusion of dose-response investigations of the potential key events for rodent liver carcinogenesis, concurrent with the hazard assessment studies. As predicted, sulfoxaflor induced liver tumors in rats and mice in the bioassays. The MoA data available by the time of the carcinogenicity finding supported the conclusion that the carcinogenic potential of sulfoxaflor was due to CAR/PXR nuclear receptor activation with subsequent hepatocellular proliferation. This MoA was not considered to be relevant to humans as sulfoxaflor is unlikely to induce hepatocellular proliferation in humans and therefore would not be a human liver carcinogen.


Subject(s)
Insecticides/toxicity , Liver/drug effects , Pyridines/toxicity , Sulfur Compounds/toxicity , Toxicity Tests/methods , Animals , Cell Proliferation/drug effects , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP2B1/metabolism , Dose-Response Relationship, Drug , Female , Insecticides/administration & dosage , Liver/enzymology , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Knockout , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Prospective Studies , Pyridines/administration & dosage , RNA/chemistry , RNA/genetics , Rats , Rats, Inbred F344 , Real-Time Polymerase Chain Reaction , Sulfur Compounds/administration & dosage
16.
Thromb Res ; 130(4): e222-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22795218

ABSTRACT

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen that is activated by thrombin in plasma. In fibrinolytic processes, carboxy-terminal lysine (Lys) residues in partially degraded fibrin are important sites for plasminogen binding and activation, and an active form of TAFI (TAFIa) inhibits fibrinolysis by eliminating these residues proteolytically. We synthesized DD2 [7-Amino-2-(sulfanylmethyl)heptanoic acid], a Lys analogue containing sulfur, as an inhibitor of TAFIa and investigated its pharmacological profile and pathophysiological role in thrombolysis via in vitro and in vivo studies. DD2 specifically inhibited plasma TAFIa activity with an apparent IC(50) (50% inhibitory concentration) value of 3.4×10(-8)M under the present experimental condition and enhanced tissue plasminogen activator-mediated clot lysis in a concentration-dependent manner. In order to study tissue factor (TF)-induced microthrombosis in an animal model, rats were given intravenous injection (2.5mg/kg and higher) or oral administration (10mg/kg and higher) of DD2. This attenuated TF-induced glomerular fibrin deposition and increased the plasma levels of fibrin degradation products and D-dimer in a dose-dependent manner. A DD2 dose approximately 4X higher than the dose used in intravenous injections was required to achieve an equivalent thrombolytic effect to that seen following oral administration. Moreover, the oral absorption efficiency of DD2 into the vasculature was 29.8%. These results indicate that both intravenous and oral administration of DD2 enhanced endogenous fibrinolysis and reduced thrombi in a TF-induced microthrombosis model.


Subject(s)
Amino Acids/therapeutic use , Carboxypeptidase B2/antagonists & inhibitors , Fibrinolysis/drug effects , Fibrinolytic Agents/therapeutic use , Thrombosis/drug therapy , Administration, Intravenous , Administration, Oral , Amino Acids/administration & dosage , Amino Acids/chemistry , Animals , Carboxypeptidase B2/blood , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/chemistry , Humans , Lysine/administration & dosage , Lysine/analogs & derivatives , Lysine/therapeutic use , Male , Rats , Sulfur Compounds/administration & dosage , Sulfur Compounds/chemistry , Sulfur Compounds/therapeutic use , Thromboplastin , Thrombosis/chemically induced , Thrombosis/pathology
17.
Int J Pharm ; 421(1): 53-62, 2011 Dec 12.
Article in English | MEDLINE | ID: mdl-21963468

ABSTRACT

We investigated the enhancement effect of chemical enhancers and iontophoresis on the in vitro transdermal and transbuccal delivery of lidocaine HCl (LHCl), nicotine hydrogen tartrate (NHT), and diltiazem HCl (DHCl) using porcine skin and buccal tissues. Dodecyl 2-(N,N-dimethylamino) propionate (DDAIP), dodecyl-2-(N,N-dimethylamino) propionate hydrochloride (DDAIP HCl), N-(4-bromobenzoyl)-S,S-dimethyliminosulfurane (Br-iminosulfurane), and azone (laurocapram) were used as chemical enhancers. The study results showed that the application of iontophoresis at either 0.1 mA or 0.3 mA significantly enhanced transdermal and transmucosal delivery of LHCl, NHT and DHCl. It was also demonstrated that iontophoresis had a more pronounced enhancement effect on transdermal delivery than on transbuccal delivery of LHCl, NHT and DHCl. In addition, DDAIP HCl was found to be the most effective enhancer for transbuccal delivery of LHCl and NHT.


Subject(s)
Diltiazem/administration & dosage , Iontophoresis , Lidocaine/administration & dosage , Nicotine/administration & dosage , Skin Absorption , Administration, Buccal , Administration, Cutaneous , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/chemistry , Animals , Azepines/administration & dosage , Azepines/chemistry , Diltiazem/pharmacokinetics , Drug Delivery Systems , In Vitro Techniques , Lidocaine/pharmacokinetics , Mouth Mucosa/metabolism , Nicotine/pharmacokinetics , Skin/metabolism , Sulfur Compounds/administration & dosage , Sulfur Compounds/chemistry , Swine
18.
Int J Pharm ; 421(1): 34-44, 2011 Dec 12.
Article in English | MEDLINE | ID: mdl-21959104

ABSTRACT

In this study, microemulsion microstructures, key formulation variables, and their relationship to drug transdermal permeation enhancement were investigated. A microemulsion system with high water soluble capacity was developed, using isopropyl myristate, Labrasol, and Cremophor EL as oil, surfactant, and co-surfactant, respectively. The microstructures of the microemulsions were characterized by a combination of techniques including electrical conductivity measurement (EC), differential scanning calorimetry (DSC), electro-analytical cyclic voltammetry (CV), dynamic light scattering (DLS). Three microemulsion formulations with the model drugs at water contents of 20%, 40%, and 70% representing the microstructures of W/O, Bi-continuous, and O/W were prepared along the water dilution line of oil to surfactant ratio of 1/9. Skin permeation of hydrophobic and hydrophilic model drugs, ketoprofen, lidocaine, and caffeine in the microemulsion formulations was studied using Franz-cells and dermatomed porcine skin. Permeation of all drugs from microemulsions was enhanced significantly compared with the control propylene glycol formulation. The drug permeation flux and the cumulative permeation amount after 24h increased with water content in the microemulsions, thus correlated to the formulation microstructures of W/O, Bi-continuous, and O/W. The permeation of lipophilic drugs ketoprofen and lidocaine increased with water content in a more pronounced manner, which seemed to follow an exponential growth trend, while the permeation of hydrophilic drug caffeine appeared to increase linearly. Additionally, at the same water content, increasing oil content led to higher ketoprofen permeation.


Subject(s)
Caffeine/chemistry , Ketoprofen/chemistry , Lidocaine/chemistry , Administration, Cutaneous , Animals , Azepines/administration & dosage , Azepines/chemistry , Caffeine/pharmacokinetics , Calorimetry, Differential Scanning , Electric Conductivity , Emulsions , Glycerides , Glycerol/analogs & derivatives , Glycerol/chemistry , Hydrophobic and Hydrophilic Interactions , In Vitro Techniques , Ketoprofen/pharmacokinetics , Lidocaine/pharmacokinetics , Myristates/chemistry , Organic Chemicals/chemistry , Permeability , Skin/metabolism , Sulfur Compounds/administration & dosage , Sulfur Compounds/chemistry , Surface-Active Agents/chemistry , Swine , Water/administration & dosage , Water/chemistry
19.
Rhinology ; 48(1): 71-6, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20502739

ABSTRACT

INTRODUCTION: The aim of this study was to evaluate the efficiency of sulphurous thermal water in the treatment of chronic rhinosinusitis (CRS). METHODS: Eighty patients with CRS were included and randomly assigned into two groups. Patients underwent a 12-day course of warm vapour inhalations and nasal irrigations with sulphurous thermal water in group A, and a physiological solution in group B. RESULTS: Compared with group B, in group A the results were as follows: serum concentration of IgE was significantly lower (p<0.05) 12 days (76.27+26.3 mg/dl vs. 97.44±45.4) and 3 months after the beginning of the treatment (75.48+26.1 mg/dl vs. 98.37±41.4); IgA titers were not significantly higher 12 days (231.09±120.3 mg/dl vs. 220.44+114.4 mg/dl) and 3 months after the beginning of the treatment (235.44±118.5 mg/dl vs. 214.51±111.8 mg/dl); VAS scores were significantly (p<0.05) improved at 12 days (1.7+0.18 vs. 6.9±0.51) and 3 months after the start (1.8+0.22 vs. 7.1±0.59); NMIT was normal at 12 days (11.54±1.59 min vs. 17.38+1.83 min) and 3 months after the beginning of the treatment (11.46+2.07 min vs. 17.43±2.01 min); total nasal resistances were significantly (p<0.05) decreased at 12 days and 3 months. CONCLUSION: Our results indicate the efficiency and applicability of sulphurous thermal water in the treatment of CRS.


Subject(s)
Mineral Waters/administration & dosage , Rhinitis/therapy , Sinusitis/therapy , Sulfur Compounds/administration & dosage , Administration, Inhalation , Chronic Disease , Double-Blind Method , Female , Humans , Male , Middle Aged , Pain Measurement , Rhinomanometry , Therapeutic Irrigation , Volatilization , Water/chemistry
20.
Food Sci Technol Int ; 16(6): 463-503, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21339165

ABSTRACT

An inventory of the most part of sulfur-containing volatile compounds (SCVCs) present in seafood was carried out. These molecules constitute key compounds to understand and improve seafood quality. According to their nature, concentration and environmental parameters (temperature), they can move the overall seafood odor from desirable to rotten. Sulfury odors can also indicate problems in sanitary quality. Thus, it is essential to monitor the generation of these compounds to better control the organoleptic and sanitary quality of seafood. SCVC were divided in two categories: aliphatic compounds and cyclic compounds. Among cyclic SCVC, several families of compounds can be distinguished as thiophenes, thiazoles and their respective derivatives. The main pathways of formation of SCVC in seafood are investigated in order to better understand their presence in seafood aroma. Microbial mediated enzymatic reactions are mainly implied in the generation of aliphatic SCVC whereas Maillard reactions are involved in the generation of cyclic SCVC. A small part of SCVC could also derive from the environment by direct bioaccumulation of S-containing molecules or precursors. Then, the occurrence of SCVC in seafood is discussed according to the extraction methods, analysis methods - sometimes olfactometric methods and the species - the state and the average biochemical composition of the seafood matrix in which they were recovered. Finally, among the identified SCVC, the odorant properties of odor-active volatile compounds were investigated. Aromatic notes and odorant thresholds for odorant SCVC of seafood aroma are listed. Both pathways of formation and lists of SCVC linked to their odorant properties constitute important indicators to optimise seafood quality from an organoleptic and sanitary point of view.


Subject(s)
Seafood/analysis , Sulfur Compounds , Volatile Organic Compounds , Animals , Crustacea/metabolism , Fishes/metabolism , Mollusca/metabolism , Odorants , Quality Control , Sulfur Compounds/administration & dosage , Sulfur Compounds/analysis , Sulfur Compounds/chemistry , Sulfur Compounds/metabolism , Volatile Organic Compounds/administration & dosage , Volatile Organic Compounds/analysis , Volatile Organic Compounds/chemistry , Volatile Organic Compounds/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...