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Biomedicine & Pharmacotherapy =... Jun 2022Ligusticum chuanxiong Hort (known as Chuanxiong in China, CX) is one of the most widely used and long-standing medicinal herbs in China. Tetramethylpyrazine (TMP) is an... (Review)
Review
Ligusticum chuanxiong Hort (known as Chuanxiong in China, CX) is one of the most widely used and long-standing medicinal herbs in China. Tetramethylpyrazine (TMP) is an alkaloid and one of the active components of CX. Over the past few decades, TMP has been proven to possess several pharmacological properties. It has been used to treat a variety of diseases with excellent therapeutic effects. Here, the pharmacological characteristics and molecular mechanism of TMP in recent years are reviewed, with an emphasis on the signal-regulation mechanism of TMP. This review shows that TMP has many physiological functions, including anti-oxidant, anti-inflammatory, and anti-apoptosis properties; autophagy regulation; vasodilation; angiogenesis regulation; mitochondrial damage suppression; endothelial protection; reduction of proliferation and migration of vascular smooth muscle cells; and neuroprotection. At present, TMP is used in treating cardiovascular, nervous, and digestive system conditions, cancer, and other conditions and has achieved good curative effects. The therapeutic mechanism of TMP involves multiple targets, multiple pathways, and bidirectional regulation. TMP is, thus, a promising drug with great research potential.
Topics: Antineoplastic Agents; Autophagy; Ligusticum; Pyrazines
PubMed: 35483189
DOI: 10.1016/j.biopha.2022.113005 -
International Journal of Molecular... Jan 2021Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe... (Review)
Review
Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxidative stress, and alterations of transcriptional programs in both the peripheral and central nervous systems. Moreover, we describe the necessity of advancing studies that identify the potential efficacy of approved drugs on the basis of pathological mechanisms, as this is a convincing strategy for rapid translation to patients with cancer and BIPN.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Humans; Peripheral Nervous System Diseases; Proteasome Inhibitors; Pyrazines
PubMed: 33477371
DOI: 10.3390/ijms22020888 -
Accounts of Chemical Research Aug 2021Pyrazinacenes are a class of nitrogen-containing heteroacene molecules composed of linearly fused pyrazine units, which might also include dihydropyrazine groups leading... (Review)
Review
Pyrazinacenes are a class of nitrogen-containing heteroacene molecules composed of linearly fused pyrazine units, which might also include dihydropyrazine groups leading to different reduced states of the compounds. While they are structurally similar to hydrocarbon acenes (e.g., pentacene) the presence of increasing numbers of N-heteroatoms introduces several different additional features of the compounds so that they can be considered for investigations beyond those suggested for acenes (i.e., organic field-effect transistors, solar cell components). Pyrazinacenes are in several ways complementary to C-H-only acenes based on the increasing stability of reduced states of the compounds with increasing numbers of fused pyrazine rings, although an acene-like electronic structure persists in the compounds so far studied. However, the introduction of multiple N atoms leads to properties that depart from C-H-only acenes. In particular, the compounds exhibit a delocalization of NH protons in extended reduced compounds and oxidation state switchability in solution and at interfaces. The presence of NH groups also allows an easy introduction of solubilizing groups at the pyrazinacene chromophore. In this Account, we will describe the preparation of extended pyrazinacenes from dipyrazino[2,3-b:2',3'-e]pyrazine (1,4,5,8,9,10-hexaazaanthracene; ) derivatives up to 1,4,5,6,7,8,9,12,13,14,15,16,17,18-tetradecaazaheptacene () and also assess structures of the relevant compounds based on X-ray crystallographic studies. Emergent properties of the molecules include highly unusual linear tautomeric processes based on a delocalization of protons (and the corresponding formation of orbitals based on multiple adjacent N lone electron pair interactions), which suggest special transport properties based on molecular protonics. Molecules such as decazapentacene () exhibit multistability of oxidation state, and this is predicted to promote the redox catalytic properties of the compounds. The oxidation-state switching of on-surface processes is also described and has been investigated using scanning tunneling microscopy. The longest known pyrazinacene chromophore () exhibits amphiprotism with its state of protonation being strongly coupled to its fluorescence emission properties in the near-infrared region indicating possible uses in pH-coupled bioimaging applications. The synthesis of the pyrazinacenes is flexible and allows the preparation of symmetrically or unsymmetrically substituted derivatives for the development of more complex molecules and for control of the electronic structure of the acene unit. Overall, the pyrazinacenes represent an emerging class of highly nitrogenous heteroacenes with unique properties and excellent potential for development in different applications based on their special supramolecular properties including guest binding or interactions in biological systems.
Topics: Crystallography, X-Ray; Heterocyclic Compounds; Molecular Structure; Oxidation-Reduction; Pyrazines; Spectrophotometry, Ultraviolet
PubMed: 34323462
DOI: 10.1021/acs.accounts.1c00315 -
Advances in Therapy Jan 2022In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag.
METHODS
Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019.
RESULTS
Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively.
CONCLUSIONS
These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen.
TRIAL REGISTRATION
ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306.
Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazines
PubMed: 34727317
DOI: 10.1007/s12325-021-01898-1 -
European Journal of Medicinal Chemistry Oct 2023Heterocycles are common in the structure of drugs used clinically to deal with diseases. Such drugs usually contain nitrogen, oxygen and sulfur, which possess... (Review)
Review
Heterocycles are common in the structure of drugs used clinically to deal with diseases. Such drugs usually contain nitrogen, oxygen and sulfur, which possess electron-accepting capacity and can form hydrogen bonds. These properties often bring enhanced target binding ability to these compounds when compared to alkanes. Pyrazine is a nitrogen-containing six-membered heterocyclic ring and many of its derivatives are identified as bioactive molecules. We review here the most active pyrazine compounds in terms of their structure, activity in vitro and in vivo (mainly antitumor activity) and the reported mechanisms of action. References have been downloaded through Web of Science, PubMed, Science Direct, Google Scholar and SciFinder Scholar. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. We found that compounds in which a pyrazine ring was fused into other heterocycles especially pyrrole or imidazole were the highly studied pyrazine derivatives, whose antineoplastic activity had been widely investigated. To the best of our knowledge, this is the first review of pyrazine derivatives and their bioactivity, especially their antitumor activity. This review should be useful for those engaged in development of medications based on heterocyclic compounds especially those based on pyrazine.
Topics: Pyrazines; Heterocyclic Compounds; Antineoplastic Agents; Nitrogen
PubMed: 37300915
DOI: 10.1016/j.ejmech.2023.115544 -
European Journal of Heart Failure Jan 2022
Topics: Acetamides; Heart Failure; Humans; Hypertension, Pulmonary; Pyrazines
PubMed: 34816552
DOI: 10.1002/ejhf.2387 -
Molecules (Basel, Switzerland) Jul 2022Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these... (Review)
Review
Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these heterocyclic ring systems are cyclizing a heterocyclic diamine with a nitrite or reacting hydrazine hydrate with dicarbonyl 1,2,3-triazoles. Several unique methods are known, particularly for the synthesis of 1,2,3-triazolo[1,5-]pyrazines and their benzo-fused quinoxaline and quinoxalinone-containing analogs. Recent applications detail the use of these heterocycles in medicinal chemistry (c-Met inhibition or GABA modulating activity) as fluorescent probes and as structural units of polymers.
Topics: Pyrazines; Pyridazines; Quinoxalines; Triazoles
PubMed: 35897857
DOI: 10.3390/molecules27154681 -
The Journal of the Association of... Aug 2020
Topics: Amides; Antiviral Agents; Pyrazines
PubMed: 32738849
DOI: No ID Found -
The Cochrane Database of Systematic... Feb 2024The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to challenge the health workforce and... (Review)
Review
BACKGROUND
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to challenge the health workforce and societies worldwide. Favipiravir was suggested by some experts to be effective and safe to use in COVID-19. Although this drug has been evaluated in randomized controlled trials (RCTs), it is still unclear if it has a definite role in the treatment of COVID-19.
OBJECTIVES
To assess the effects of favipiravir compared to no treatment, supportive treatment, or other experimental antiviral treatment in people with acute COVID-19.
SEARCH METHODS
We searched the Cochrane COVID-19 Study Register, MEDLINE, Embase, the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease, and three other databases, up to 18 July 2023.
SELECTION CRITERIA
We searched for RCTs evaluating the efficacy of favipiravir in treating people with COVID-19.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methodological procedures for data collection and analysis. We used the GRADE approach to assess the certainty of evidence for each outcome.
MAIN RESULTS
We included 25 trials that randomized 5750 adults (most under 60 years of age). The trials were conducted in Bahrain, Brazil, China, India, Iran, Kuwait, Malaysia, Mexico, Russia, Saudi Arabia, Thailand, the UK, and the USA. Most participants were hospitalized with mild to moderate disease (89%). Twenty-two of the 25 trials investigated the role of favipiravir compared to placebo or standard of care, whilst lopinavir/ritonavir was the comparator in two trials, and umifenovir in one trial. Most trials (24 of 25) initiated favipiravir at 1600 mg or 1800 mg twice daily for the first day, followed by 600 mg to 800 mg twice a day. The duration of treatment varied from five to 14 days. We do not know whether favipiravir reduces all-cause mortality at 28 to 30 days, or in-hospital (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.49 to 1.46; 11 trials, 3459 participants; very low-certainty evidence). We do not know if favipiravir reduces the progression to invasive mechanical ventilation (RR 0.86, 95% CI 0.68 to 1.09; 8 trials, 1383 participants; very low-certainty evidence). Favipiravir may make little to no difference in the need for admission to hospital (if ambulatory) (RR 1.04, 95% CI 0.44 to 2.46; 4 trials, 670 participants; low-certainty evidence). We do not know if favipiravir reduces the time to clinical improvement (defined as time to a 2-point reduction in patients' admission status on the WHO's ordinal scale) (hazard ratio (HR) 1.13, 95% CI 0.69 to 1.83; 4 trials, 721 participants; very low-certainty evidence). Favipiravir may make little to no difference to the progression to oxygen therapy (RR 1.20, 95% CI 0.83 to 1.75; 2 trials, 543 participants; low-certainty evidence). Favipiravir may lead to an overall increased incidence of adverse events (RR 1.27, 95% CI 1.05 to 1.54; 18 trials, 4699 participants; low-certainty evidence), but may result in little to no difference inserious adverse eventsattributable to the drug (RR 1.04, 95% CI 0.76 to 1.42; 12 trials, 3317 participants; low-certainty evidence).
AUTHORS' CONCLUSIONS
The low- to very low-certainty evidence means that we do not know whether favipiravir is efficacious in people with COVID-19 illness, irrespective of severity or admission status. Treatment with favipiravir may result in an overall increase in the incidence of adverse events but may not result in serious adverse events.
Topics: Adult; Humans; COVID-19; SARS-CoV-2; Amides; Pyrazines
PubMed: 38314855
DOI: 10.1002/14651858.CD015219.pub2 -
Neurotoxicity Research Oct 2021With the aging of the world population, neurodegenerative diseases are considered crippling diseases, which seriously affect the quality of life and are an increasing... (Review)
Review
With the aging of the world population, neurodegenerative diseases are considered crippling diseases, which seriously affect the quality of life and are an increasing burden on society and the economy. As a major alkaloid in Ligusticum chuanxiong Hort, tetramethylpyrazine (TMP) plays an increasingly significant role during neurodegenerative diseases, including roles as an anti-inflammatory, antioxidative, antiplatelet citatory poisoning, and anti-inflammation. This review focuses on the latest advances in the roles and mechanisms of action of TMP in neurodegenerative diseases to stimulate new concepts and methods for the prevention and treatment of neurodegenerative diseases.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Humans; Neurodegenerative Diseases; Pyrazines; Vasodilator Agents
PubMed: 34351568
DOI: 10.1007/s12640-021-00398-y