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International Journal of Molecular... Jan 2023A unique combinatorial bioluminescence (BL) imaging system was developed for determining molecular events in mammalian cells with various colors and BL intensity...
A unique combinatorial bioluminescence (BL) imaging system was developed for determining molecular events in mammalian cells with various colors and BL intensity patterns. This imaging system consists of one or multiple reporter luciferases and a series of novel coelenterazine (CTZ) analogues named "S-series". For this study, ten kinds of novel S-series CTZ analogues were synthesized and characterized concerning the BL intensities, spectra, colors, and specificity of various marine luciferases. The characterization revealed that the S-series CTZ analogues luminesce with blue-to-orange-colored BL spectra with marine luciferases, where the most red-shifted BL spectrum peaked at 583 nm. The colors completed a visible light color palette with those of our precedent C-series CTZ analogues. The synthesized substrates , , , and were found to have a unique specificity with marine luciferases, such as R86SG, NanoLuc (shortly, NLuc), and ALuc16. They collectively showed unique BL intensity patterns to identify the marine luciferases together with colors. The marine luciferases, R86SG, NLuc, and ALuc16, were multiplexed into multi-reporter systems, the signals of which were quantitatively unmixed with the specific substrates. When the utility was applied to a single-chain molecular strain probe, the imaging system simultaneously reported three different optical indexes for a ligand, i.e., unique BL intensity and color patterns for identifying the reporters, together with the ligand-specific fold intensities in mammalian cells. This study directs a new combinatorial BL imaging system to specific image molecular events in mammalian cells with multiple optical indexes.
Topics: Animals; Ligands; Luciferases; Imidazoles; Pyrazines; Luminescent Measurements; Mammals
PubMed: 36674934
DOI: 10.3390/ijms24021420 -
Medical Science Monitor : International... Nov 2017BACKGROUND To explore the theoretical basis for protecting the brain from ischemic stroke with tetramethylpyrazine, we studied whether and how tetramethylpyrazine could...
BACKGROUND To explore the theoretical basis for protecting the brain from ischemic stroke with tetramethylpyrazine, we studied whether and how tetramethylpyrazine could protect neurons against the oxygen-glucose deprivation (OGD)-induced death and whether transient receptor potential cation channel, subfamily C, member 6 (TRPC6) was involved. MATERIAL AND METHODS Primary rat cortical neurons were cultured and an OGD model was established in the presence or absence of tetramethylpyrazine. Neuronal death was assessed by measuring the uptake of membrane-impermeable PI. Western blot analysis was used to determine the protein expressions of TRPC6 and caspase-3. The involvement of TRPC6 was tested via RNAi against TRPC6. RESULTS OGD-induced neuronal death was decreased by tetramethylpyrazine in a concentration-dependent manner. The expression of TRPC6 protein was decreased by OGD. Furthermore, downregulating TRPC6 by RNA interfering mimicked the effect of OGD in neuronal death. Tetramethylpyrazine attenuated OGD-induced TRPC6 downregulation in a tetramethylpyrazine concentration-dependent manner. However, these effects of tetramethylpyrazine on attenuating OGD-induced neuronal death were abolished by TRPC6 RNAi. CONCLUSIONS Tetramethylpyrazine can protect neurons from oxygen-glucose deprivation-induced death, possibly via TRPC6.
Topics: Animals; Apoptosis; Down-Regulation; Glucose; Neuroprotective Agents; Oxygen; Pyrazines; RNA Interference; Rats, Sprague-Dawley; TRPC Cation Channels
PubMed: 29104282
DOI: 10.12659/msm.904554 -
European Journal of Obstetrics,... Jan 2022COVID-19 is a rapidly spreading disease and many people have been infected in a short time. Favipiravir is under investigation for the treatment of COVID-19 and given to...
OBJECTIVE
COVID-19 is a rapidly spreading disease and many people have been infected in a short time. Favipiravir is under investigation for the treatment of COVID-19 and given to patients in many countries following emergency use approval. Based on data from animal studies, favipiravir use is contraindicated during pregnancy. Currently, there is no human data except for a single case report on use of favipiravir in pregnancy.
STUDY DESIGN
This article includes the outcomes of 29 pregnancies reported to the Clinical Pharmacology and Toxicology Unit regarding favipiravir use in pregnancy. For drug risk assessment, maternal characteristics were obtained at first contact. After the expected day of delivery, follow-up is conducted by phone call and all relevant data regarding pregnancy and newborn outcome were documented.
RESULTS
Of the 29 pregnancies exposed to favipiravir, 5 were electively terminated and 24 resulted in live birth. There were no miscarriages or no stillbirths. There were 25 live births including one pair of twins. Three children were born premature, and one infant had patent foramen ovale. Birth weights, lengths and head circumferences of all infants were within normal range.
CONCLUSION
The results of the study indicate that favipiravir is unlikely to be a major human teratogen, but experience is still limited for a well-grounded risk assessment. Although these findings may be useful for the physicians and patients, larger studies are needed due to small number of cases.
Topics: Amides; COVID-19; Female; Humans; Pregnancy; Pregnancy Outcome; Pyrazines; SARS-CoV-2
PubMed: 34902747
DOI: 10.1016/j.ejogrb.2021.12.001 -
Molecular Cancer Therapeutics Oct 2021PTC596 is an investigational small-molecule tubulin-binding agent. Unlike other tubulin-binding agents, PTC596 is orally bioavailable and is not a P-glycoprotein...
PTC596 is an investigational small-molecule tubulin-binding agent. Unlike other tubulin-binding agents, PTC596 is orally bioavailable and is not a P-glycoprotein substrate. So as to characterize PTC596 to position the molecule for optimal clinical development, the interactions of PTC596 with tubulin using crystallography, its spectrum of preclinical anticancer activity, and its pharmacokinetic-pharmacodynamic relationship were investigated for efficacy in multiple preclinical mouse models of leiomyosarcomas and glioblastoma. Using X-ray crystallography, it was determined that PTC596 binds to the colchicine site of tubulin with unique key interactions. PTC596 exhibited broad-spectrum anticancer activity. PTC596 showed efficacy as monotherapy and additive or synergistic efficacy in combinations in mouse models of leiomyosarcomas and glioblastoma. PTC596 demonstrated efficacy in an orthotopic model of glioblastoma under conditions where temozolomide was inactive. In a first-in-human phase I clinical trial in patients with cancer, PTC596 monotherapy drug exposures were compared with those predicted to be efficacious based on mouse models. PTC596 is currently being tested in combination with dacarbazine in a clinical trial in adults with leiomyosarcoma and in combination with radiation in a clinical trial in children with diffuse intrinsic pontine glioma.
Topics: Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Benzimidazoles; Cell Proliferation; Female; Glioblastoma; Humans; Leiomyosarcoma; Male; Maximum Tolerated Dose; Mice; Mice, Nude; Middle Aged; Prognosis; Pyrazines; Tissue Distribution; Tubulin Modulators; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 34315764
DOI: 10.1158/1535-7163.MCT-20-0774 -
Revista Espanola de Quimioterapia :... Apr 2017Favipiravir (T-705) is a new antiviral drug with strong inhibitory activity on RNA-dependent RNA polymerase of most RNA virus genome. All the influenza viruses have been... (Review)
Review
Favipiravir (T-705) is a new antiviral drug with strong inhibitory activity on RNA-dependent RNA polymerase of most RNA virus genome. All the influenza viruses have been shown fully sensitive to this new antiviral, including genetic strains to neuraminidase inhibitors (oseltamivir) resistance. Its mechanism of action lies in blocking viral replication and induction of lethal mutagenesis which determines the loss of infective activity of influenza viruses. Its activity is particularly intense in the respiratory tract, decreasing the viral load to non-infectious levels. Clinical trials in humans have not yet completed but have very favourable results. It seems that the best therapy would be the combination of favipiravir with oseltamivir; both antivirals are synergistic and avoid the emergence of resistance.
Topics: Amides; Animals; Antiviral Agents; Humans; Influenza, Human; Orthomyxoviridae; Pyrazines
PubMed: 28176519
DOI: No ID Found -
Haematologica Sep 2014
Topics: Amyloidosis; Boronic Acids; Bortezomib; Cardiomyopathies; Cyclophosphamide; Dexamethasone; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Pyrazines
PubMed: 25176981
DOI: 10.3324/haematol.2014.113464 -
Molecules (Basel, Switzerland) Jun 2021In the current work, a simple, economical, accurate, and precise HPLC method with UV detection was developed to quantify Favipiravir (FVIR) in spiked human plasma using...
In the current work, a simple, economical, accurate, and precise HPLC method with UV detection was developed to quantify Favipiravir (FVIR) in spiked human plasma using acyclovir (ACVR) as an internal standard in the COVID-19 pandemic time. Both FVIR and ACVR were well separated and resolved on the C18 column using the mobile phase blend of methanol:acetonitrile:20 mM phosphate buffer (pH 3.1) in an isocratic mode flow rate of 1 mL/min with a proportion of 30:10:60 %, . The detector wavelength was set at 242 nm. Maximum recovery of FVIR and ACVR from plasma was obtained with dichloromethane (DCM) as extracting solvent. The calibration curve was found to be linear in the range of 3.1-60.0 µg/mL with regression coefficient (r) = 0.9976. However, with acceptable r, the calibration data's heteroscedasticity was observed, which was further reduced using weighted linear regression with weighting factor 1/x. Finally, the method was validated concerning sensitivity, accuracy (Inter and Intraday's % RE and RSD were 0.28, 0.65 and 1.00, 0.12 respectively), precision, recovery (89.99%, 89.09%, and 90.81% for LQC, MQC, and HQC, respectively), stability (% RSD for 30-day were 3.04 and 1.71 for LQC and HQC, respectively at -20 °C), and carry-over US-FDA guidance for Bioanalytical Method Validation for researchers in the COVID-19 pandemic crisis. Furthermore, there was no significant difference for selectivity when evaluated at LLOQ concentration of 3 µg/mL of FVIR and relative to the blank.
Topics: Acyclovir; Amides; Antiviral Agents; Biological Assay; COVID-19; Calibration; Chromatography, High Pressure Liquid; Drug Stability; Freezing; Humans; Liquid-Liquid Extraction; Pyrazines; Reference Standards; Reproducibility of Results; Solvents; COVID-19 Drug Treatment
PubMed: 34206357
DOI: 10.3390/molecules26133789 -
Clinical Pharmacokinetics Oct 2020Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib.
METHODS
The pharmacokinetic profile of gilteritinib was assessed from five clinical studies.
RESULTS
Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20-450 mg). Median maximum concentration was reached 2-6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function.
CONCLUSIONS
Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment.
CLINICAL TRIAL REGISTRATION
NCT02014558, NCT02456883, NCT02571816.
Topics: Aniline Compounds; Drug Interactions; Female; Humans; Male; Protein Kinase Inhibitors; Pyrazines
PubMed: 32304015
DOI: 10.1007/s40262-020-00888-w -
The Journal of Physical Chemistry. A Jun 2022Coelenterazine and other imidazopyrazinones are important bioluminescent substrates widespread in marine species and can be found in eight phyla of luminescent...
Coelenterazine and other imidazopyrazinones are important bioluminescent substrates widespread in marine species and can be found in eight phyla of luminescent organisms. Light emission from these systems is caused by the formation and subsequent thermolysis of a dioxetanone intermediate, whose decomposition allows for efficient chemiexcitation to singlet excited states. Interestingly, some studies have also reported the involvement of unexpected dioxetane intermediates in the chemi- and bioluminescent reactions of Coelenterazine, albeit with little information on the underlying mechanisms of these new species. Herein, we have employed a theoretical approach based on density functional theory to study for the first time the thermolysis reaction and chemiexcitation profile of two Coelenterazine dioxetanes. We have found that the thermolysis reactions of these species are feasible but with relevant energetic differences. More importantly, we found that the singlet chemiexcitation profiles of these dioxetanes are significantly less efficient than the corresponding dioxetanones. Furthermore, we identified triplet chemiexcitation pathways for the Coelenterazine dioxetanes. Given this, the chemiexcitation of these dioxetanes should lead only to minimal luminescence. Thus, our theoretical investigation of these systems indicates that the thermolysis of these dioxetanes should only provide "dark" pathways for the formation of nonluminescent degradation products of the chemi- and bioluminescent reactions of Coelenterazine and other imidazopyrazinones.
Topics: Imidazoles; Luminescent Measurements; Models, Theoretical; Pyrazines
PubMed: 35612291
DOI: 10.1021/acs.jpca.2c01835 -
Medical Science Monitor : International... Nov 2015BACKGROUND In the past decades, a large number of randomized controlled trials (RCTs) on the efficacy of ligustrazine injection combined with conventional antianginal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND In the past decades, a large number of randomized controlled trials (RCTs) on the efficacy of ligustrazine injection combined with conventional antianginal drugs for angina pectoris have been reported. However, these RCTs have not been evaluated in accordance with PRISMA systematic review standards. The aim of this study was to evaluate the efficacy of ligustrazine injection as adjunctive therapy for angina pectoris. MATERIAL AND METHODS The databases PubMed, Medline, Cochrane Library, Embase, Sino-Med, Wanfang Databases, Chinese Scientific Journal Database, Google Scholar, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and the Chinese Science Citation Database were searched for published RCTs. Meta-analysis was performed on the primary outcome measures, including the improvements of electrocardiography (ECG) and the reductions in angina symptoms. Sensitivity and subgroup analysis based on the M score (the refined Jadad scores) were also used to evaluate the effect of quality, sample size, and publication year of the included RCTs on the overall effect of ligustrazine injection. RESULTS Eleven RCTs involving 870 patients with angina pectoris were selected in this study. Compared with conventional antianginal drugs alone, ligustrazine injection combined with antianginal drugs significantly increased the efficacy in symptom improvement (odds ratio [OR], 3.59; 95% confidence interval [CI]: 2.39 to 5.40) and in ECG improvement (OR, 3.42; 95% CI: 2.33 to 5.01). Sensitivity and subgroup analysis also confirmed that ligustrazine injection had better effect in the treatment of angina pectoris as adjunctive therapy. CONCLUSIONS The 11 eligible RCTs indicated that ligustrazine injection as adjunctive therapy was more effective than antianginal drugs alone. However, due to the low quality of included RCTs, more rigorously designed RCTs were still needed to verify the effects of ligustrazine injection as adjunctive therapy for angina pectoris.
Topics: Angina Pectoris; Chemotherapy, Adjuvant; Drugs, Chinese Herbal; Humans; Platelet Aggregation Inhibitors; Pyrazines; Randomized Controlled Trials as Topic
PubMed: 26615387
DOI: 10.12659/msm.895362