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The Journal of Antibiotics Aug 2016Photorhabdus luminescens is a bioluminescent entomopathogenic bacterium that undergoes phenotypic variation and lives in mutualistic association with nematodes of the...
Photorhabdus luminescens is a bioluminescent entomopathogenic bacterium that undergoes phenotypic variation and lives in mutualistic association with nematodes of the family Heterorhabditidae. The pair infects and kills insects, and during their coordinated lifecycle, the bacteria produce an assortment of specialized metabolites to regulate its mutualistic and pathogenic roles. As part of our search for new specialized metabolites from the Photorhabdus genus, we examined organic extracts from P. luminescens grown in an amino-acid-rich medium based on the free amino-acid levels found in the circulatory fluid of its common insect prey, the Galleria mellonella larva. Reversed-phase HPLC/UV/MS-guided fractionation of the culture extracts led to the identification of two new pyrazinone metabolites, lumizinones A (1) and B (2), together with two N-acetyl dipeptides (3 and 4). The lumizinones were produced only in the phenotypic variant associated with nematode development and insect pathogenesis. Their chemical structures were elucidated by analysis of 1D and 2D NMR and high-resolution ESI-QTOF-MS spectral data. The absolute configurations of the amino acids in 3 and 4 were determined by Marfey's analysis. Compounds 1-4 were evaluated for their calpain protease inhibitory activity, and lumizinone A (1) showed inhibition with an IC50 (half-maximal inhibitory concentration) value of 3.9 μm.
Topics: Amino Acids; Animals; Chromatography, High Pressure Liquid; Inhibitory Concentration 50; Lepidoptera; Magnetic Resonance Spectroscopy; Mass Spectrometry; Photorhabdus; Protease Inhibitors; Pyrazines; Spectrometry, Mass, Electrospray Ionization
PubMed: 27353165
DOI: 10.1038/ja.2016.79 -
PloS One 2014We conducted a systematic review and meta-analysis to clarify the incidence and risk of cardiotoxicity associated with bortezomib in cancer patients. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We conducted a systematic review and meta-analysis to clarify the incidence and risk of cardiotoxicity associated with bortezomib in cancer patients.
METHODS
Databases from PubMed, Web of Science and abstracts presented at ASCO meeting up to July 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating bortezomib in cancer patients with adequate data on cardiotoxicity. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies.
RESULTS
A total of 5718 patients with a variety of malignancies from 25 clinical trials were included in our analysis. The incidence of all-grade and high-grade cardiotoxicity associated with bortezomib was 3.8% (95%CI: 2.6-5.6%) and 2.3% (1.6-3.5%), with a mortality of 3.0% (1.4-6.5%). Patients treated with bortezomib did not significantly increase the risk of all-grade (OR 1.15, 95%CI: 0.82-1.62, p=0.41) and high-grade (OR 1.13, 95%CI: 0.58-2.24, p=0.72) cardiotoxicity compared with patients treated with control medication. Sub-group analysis showed that the incidence of cardiotoxicity varied with tumor types, treatment regimens and phases of trials. No evidence of publication bias was observed.
CONCLUSIONS
The use of bortezomib does not significantly increase the risk of cardiotoxicity compared to control patients. Further studies are recommended to investigate this association and risk differences among different tumor types, treatment regimens and phases of trials.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Heart Diseases; Humans; Incidence; Neoplasms; Odds Ratio; Pyrazines; Risk
PubMed: 24489948
DOI: 10.1371/journal.pone.0087671 -
The Lancet. Respiratory Medicine May 2023
Topics: Humans; Amides; Antiviral Agents; COVID-19; Pyrazines; Treatment Outcome
PubMed: 36528037
DOI: 10.1016/S2213-2600(22)00479-9 -
Molecules (Basel, Switzerland) May 2015A series of N-alkyl-3-(alkylamino)pyrazine-2-carboxamides and their N-alkyl-3-chloropyrazine-2-carboxamide precursors were prepared. All compounds were characterized by...
A series of N-alkyl-3-(alkylamino)pyrazine-2-carboxamides and their N-alkyl-3-chloropyrazine-2-carboxamide precursors were prepared. All compounds were characterized by analytical methods and tested for antimicrobial and antiviral activity. The antimycobacterial MIC values against Mycobacterium tuberculosis H37Rv of the most effective compounds, 3-(hexylamino)-, 3-(heptylamino)- and 3-(octylamino)-N-methyl-pyrazine-2-carboxamides 14‒16, was 25 μg/mL. The compounds inhibited photosystem 2 photosynthetic electron transport (PET) in spinach chloroplasts. This activity was strongly connected with the lipophilicity of the compounds. For effective PET inhibition longer alkyl chains in the 3-(alkylamino) substituent in the N-alkyl-3-(alkylamino)pyrazine-2-carboxamide molecule were more favourable than two shorter alkyl chains.
Topics: Antitubercular Agents; Bacterial Proteins; Chloroplasts; Electron Transport; Fatty Acid Synthases; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Pyrazines; Spinacia oleracea; Structure-Activity Relationship
PubMed: 26007174
DOI: 10.3390/molecules20058687 -
Molecules (Basel, Switzerland) Nov 2017This study examined the efficacy of the percutaneous delivery of a tetramethylpyrazine-loaded microemulsion (TMP-ME) on skin pretreated with microneedles (MN). The...
This study examined the efficacy of the percutaneous delivery of a tetramethylpyrazine-loaded microemulsion (TMP-ME) on skin pretreated with microneedles (MN). The TMP-ME formulation was optimized in vitro with skin permeation experiments, using a uniform experimental design, guided by a pseudo-ternary phase diagram, in which the TMP skin permeation level and mean particle size were indices. The effects of MN pretreatment on skin permeation by TMP-ME were assessed using in vitro skin permeation, in vivo skin microdialysis, and pharmacokinetic studies in rats. The influence of MN pretreatment on the skin barrier function was evaluated by measuring the electrical resistance of rat skin before and after MN insertion. In the optimal formulation of TMP-ME, the weight percentages of Maisine 35-1 (oil phase), Labrasol (surfactant), and Transcutol P (co-surfactant) were 7%, 30% and 10%, respectively, with 1.5% TMP loading. In the in vitro skin permeation study, MN-assisted TMP-ME exhibited a two-fold increase in a 24-h cumulative TMP permeation compared with TMP-ME alone ( < 0.05). In the skin microdialysis study, TMP in MN-assisted TMP-ME exhibited a 1.25-fold increase in C, a 0.93-fold decrease in T, and a 0.88-fold increase in AUC ( < 0.05). Similarly, in the pharmacokinetic study, TMP in MN-assisted TMP-ME exhibited a 2.11-fold increase in C, a 0.67-fold decrease in T, and a 1.07-fold increase in AUC ( < 0.05). The percutaneous electrical resistance of rat skin before and after MN insertion was 850 ± 50 Ω/cm² and 283 ± 104 Ω/cm² respectively, indicating that MN dramatically compromises the skin barrier. These results suggest that MN assistance increases the skin permeation rate and the extent of percutaneous absorption of TMP-ME, and that the mechanism may involve the reversible barrier perturbation effect. The rate and extent of percutaneous absorption of TMP-ME can be significantly enhanced by MN assistance, possibly because MN causes a reversible barrier perturbation effect on skin.
Topics: Administration, Cutaneous; Animals; Chemistry, Pharmaceutical; Emulsions; Male; Particle Size; Permeability; Pyrazines; Rats; Skin; Skin Absorption
PubMed: 29160824
DOI: 10.3390/molecules22112022 -
British Journal of Haematology Oct 2005
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Drug Eruptions; Glucocorticoids; Humans; Male; Methylprednisolone; Middle Aged; Multiple Myeloma; Pyrazines; Sweet Syndrome
PubMed: 16197442
DOI: 10.1111/j.1365-2141.2005.05636.x -
The AAPS Journal Jun 2008The leveraged use of biomarkers presents an opportunity in understanding target engagement and disease impact while accelerating drug development. For effective... (Review)
Review
The leveraged use of biomarkers presents an opportunity in understanding target engagement and disease impact while accelerating drug development. For effective integration in drug development, it is essential for biomarkers to aid in the elucidation of mechanisms of action and disease progression. The recent years have witnessed significant progress in biomarker selection, validation, and qualification, while enabling surrogate and clinical endpoint qualification and application. Biomarkers play a central role in target validation for novel mechanisms. They also play a central role in the learning/confirming paradigm, particularly when utilized in concert with pharmacokinetic/pharmacodynamic modeling. Clearly, these attributes make biomarker integration attractive for scientific and regulatory applications to new drug development. In this review, applications of proximal, or target engagement, and distal, or disease-related, biomarkers are highlighted using the example of the recent development of sitagliptin for type 2 diabetes, wherein elucidation of target engagement and disease-related biomarkers significantly accelerated sitagliptin drug development. Importantly, use of biomarkers as tools facilitated design of clinical efficacy trials while streamlining dose focus and optimization, the net impact of which reduced overall cycle time to filing as compared to the industry average.
Topics: Animals; Biomarkers; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Humans; Hypoglycemic Agents; Pyrazines; Sitagliptin Phosphate; Triazoles
PubMed: 18686043
DOI: 10.1208/s12248-008-9041-8 -
Journal of Evolutionary Biology Jul 2023Chemical defences often vary within and between populations both in quantity and quality, which is puzzling if prey survival is dependent on the strength of the defence....
Chemical defences often vary within and between populations both in quantity and quality, which is puzzling if prey survival is dependent on the strength of the defence. We investigated the within- and between-population variability in chemical defence of the wood tiger moth (Arctia plantaginis). The major components of its defences, SBMP (2-sec-butyl-3-methoxypyrazine) and IBMP (2-isobutyl-3-methoxypyrazine), are volatiles that deter bird attacks. We hypothesized that (1) variation in the chemical defences of male wood tiger moths reflects the local predation pressure; (2) observed differences in quantity and quality of defence among populations have a genetic basis; and (3) increasing concentrations of SBMP and IBMP will elicit greater aversive reactions in predators, with the two pyrazines having an additive effect on predators' avoidance. We found that (1) the chemical defence of wild moths partly reflects local predator selection: high predation pressure populations (Scotland and Georgia) had stronger chemical defences, but not lower variance, than the low-predation populations (Estonia and Finland). (2) Based on the common garden results, both genetic and environmental components seem to influence the strength of chemical defence in moth populations; and (3) IBMP alone did not provide protection against bird predators but worked against bird attacks only when combined with SBMP, and while SBMP was more effective at higher concentrations, IBMP was not. Altogether this suggests that, when it comes to pyrazine concentration, more is not always better, highlighting the importance of testing the efficacy of chemical defence and its components with relevant predators, as extrapolating from chemical data may be less than straightforward.
Topics: Animals; Male; Moths; Birds; Pyrazines; Predatory Behavior; Color
PubMed: 36546702
DOI: 10.1111/jeb.14142 -
Journal of Occupational and... Oct 2016An aircraft seat manufacturing company requested a NIOSH health hazard evaluation to help identify a strong odor that had persisted throughout the facility for over a...
An aircraft seat manufacturing company requested a NIOSH health hazard evaluation to help identify a strong odor that had persisted throughout the facility for over a year. Employees reported experiencing health effects thought to be related to the odor. We collected and analyzed area air samples for volatile organic compounds, endotoxin, bacterial and fungal metagenome, and metalworking fluid aerosol. Bulk metalworking fluid samples were analyzed for endotoxin, bacterial and fungal metagenome, and viable bacteria and fungus. We also evaluated the building ventilation systems and water diversion systems. Employees underwent confidential medical interviews about work practices, medical history, and health concerns. Based on our analyses, the odor was likely 2-methoxy-3,5-dimethylpyrazine. This pyrazine was found in air samples across the facility and originated from bacteria in the metalworking fluid. We did not identify bacteria known to produce the compound but bacteria from the same Proteobacteria order were found as well as bacteria from orders known to produce other pyrazines. Chemical and biological contaminants and odors could have contributed to health symptoms reported by employees, but it is likely that the symptoms were caused by several factors. We provided several recommendations to eliminate the odor including washing and disinfecting the metalworking machines and metalworking fluid recycling equipment, discarding all used metalworking fluid, instituting a metalworking fluid maintenance program at the site, and physically isolating the metalworking department from other departments.
Topics: Air Pollutants, Occupational; Aircraft; Endotoxins; Environmental Monitoring; Genome, Bacterial; Genome, Fungal; Humans; Metallurgy; National Institute for Occupational Safety and Health, U.S.; Occupational Exposure; Odorants; Proteobacteria; Pyrazines; United States
PubMed: 27494786
DOI: 10.1080/15459624.2016.1183017 -
Antiviral efficacy of favipiravir against Ebola virus: A translational study in cynomolgus macaques.PLoS Medicine Mar 2018Despite repeated outbreaks, in particular the devastating 2014-2016 epidemic, there is no effective treatment validated for patients with Ebola virus disease (EVD)....
BACKGROUND
Despite repeated outbreaks, in particular the devastating 2014-2016 epidemic, there is no effective treatment validated for patients with Ebola virus disease (EVD). Among the drug candidates is the broad-spectrum polymerase inhibitor favipiravir, which showed a good tolerance profile in patients with EVD (JIKI trial) but did not demonstrate a strong antiviral efficacy. In order to gain new insights into the antiviral efficacy of favipiravir and improve preparedness and public health management of future outbreaks, we assess the efficacy achieved by ascending doses of favipiravir in Ebola-virus-infected nonhuman primates (NHPs).
METHODS AND FINDINGS
A total of 26 animals (Macaca fascicularis) were challenged intramuscularly at day 0 with 1,000 focus-forming units of Ebola virus Gabon 2001 strain and followed for 21 days (study termination). This included 13 animals left untreated and 13 treated with doses of 100, 150, and 180 mg/kg (N = 3, 5, and 5, respectively) favipiravir administered intravenously twice a day for 14 days, starting 2 days before infection. All animals left untreated or treated with 100 mg/kg died within 10 days post-infection, while animals receiving 150 and 180 mg/kg had extended survival (P < 0.001 and 0.001, respectively, compared to untreated animals), leading to a survival rate of 40% (2/5) and 60% (3/5), respectively, at day 21. Favipiravir inhibited viral replication (molecular and infectious viral loads) in a drug-concentration-dependent manner (P values < 0.001), and genomic deep sequencing analyses showed an increase in virus mutagenesis over time. These results allowed us to identify that plasma trough favipiravir concentrations greater than 70-80 μg/ml were associated with reduced viral loads, lower virus infectivity, and extended survival. These levels are higher than those found in the JIKI trial, where patients had median trough drug concentrations equal to 46 and 26 μg/ml at day 2 and day 4 post-treatment, respectively, and suggest that the dosing regimen in the JIKI trial was suboptimal. The environment of a biosafety level 4 laboratory introduces a number of limitations, in particular the difficulty of conducting blind studies and performing detailed pharmacological assessments. Further, the extrapolation of the results to patients with EVD is limited by the fact that the model is fully lethal and that treatment initiation in patients with EVD is most often initiated several days after infection, when symptoms and high levels of viral replication are already present.
CONCLUSIONS
Our results suggest that favipiravir may be an effective antiviral drug against Ebola virus that relies on RNA chain termination and possibly error catastrophe. These results, together with previous data collected on tolerance and pharmacokinetics in both NHPs and humans, support a potential role for high doses of favipiravir for future human interventions.
Topics: Amides; Animals; Antiviral Agents; Dose-Response Relationship, Drug; Ebolavirus; Female; Genome, Viral; Hemorrhagic Fever, Ebola; Humans; Macaca fascicularis; Mutagenesis; Pyrazines; RNA; Time Factors; Translational Research, Biomedical; Viral Load
PubMed: 29584730
DOI: 10.1371/journal.pmed.1002535