Cancer is the second leading cause of mortality, only overcome by cardiovascular diseases, and has caused more than 8.7 million deaths in 2015 all over the world. This figure is expected to rise to ...about 13.1 million by 2030. In order to prevent or cure this fatal illness, substantial efforts have been devoted to develop and discover new anticancer drugs with same or better antitumor activity but lesser toxicity. Matrine is an alkaloid isolated from Sophora flavescens Ait. For decades, matrine and its derivatives have been studied as antineoplastic agents which predominantly work by inhibiting proliferation and inducing apoptosis of cancer cells. The mechanism responsible for the anticancer activity of matrine can be recognized via up-regulating or down-regulating expression of the cancer related molecules, eventually causing tumor cell death. This review summarizes research developments of matrine and its derivatives as anticancer agents. A few possible research directions, suggestions and clues for future work on the development of novel matrine-based anticancer agents with improved expected activities and lesser toxicity have also been provided.
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•Cancer is the second leading cause of mortality worldwide, only overcome by cardiovascular diseases.•Cancer-related deaths are expected to increase to 13.1 million by 2030.•Matrine (C15H24N2O) is an alkaloid found in plants from the genus Sophora.•Matrine and its derivatives have been studied as antineoplastic agents which predominantly work by inhibiting proliferation and inducing apoptosis of cancer cells.•Matrine synergistically enhance the efficacy of chemotherapy when it is used in combination with other anticancer drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and ...reducing smoking satisfaction (acting as an antagonist).
Objectives
To review the efficacy of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.
Search methods
We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or , or as keywords. The register is compiled from searches of MEDLINE, EMBASE, and PsycINFO using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in May 2015, although we have included a few key trials published after this date. We also searched online clinical trials registers.
Selection criteria
We included randomised controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow‐up period of six months from start of treatment.
Data collection and analysis
We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomisation procedure, concealment of allocation, and completeness of follow‐up.
The main outcome measured was abstinence from smoking at longest follow‐up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel‐Haenszel fixed‐effect model.
Main results
Two trials of cytisine (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow‐up, with a pooled risk ratio (RR) of 3.98 (95% confidence interval (CI) 2.01 to 7.87; low‐quality evidence). One recent trial comparing cytisine with NRT in 1310 people found a benefit for cytisine at six months (RR 1.43, 95% CI 1.13 to 1.80).
One trial of dianicline (602 people) failed to find evidence that it was effective (RR 1.20, 95% CI 0.82 to 1.75). This drug is no longer in development.
We identified 39 trials that tested varenicline, 27 of which contributed to the primary analysis (varenicline versus placebo). Five of these trials also included a bupropion treatment arm. Eight trials compared varenicline with nicotine replacement therapy (NRT). Nine studies tested variations in varenicline dosage, and 13 tested usage in disease‐specific subgroups of patients. The included studies covered 25,290 participants, 11,801 of whom used varenicline.
The pooled RR for continuous or sustained abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.24 (95% CI 2.06 to 2.43; 27 trials, 12,625 people; high‐quality evidence). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.08 (95% CI 1.56 to 2.78; 4 trials, 1266 people). The pooled RR for varenicline versus bupropion at six months was 1.39 (95% CI 1.25 to 1.54; 5 trials, 5877 people; high‐quality evidence). The RR for varenicline versus NRT for abstinence at 24 weeks was 1.25 (95% CI 1.14 to 1.37; 8 trials, 6264 people; moderate‐quality evidence). Four trials which tested the use of varenicline beyond the 12‐week standard regimen found the drug to be well‐tolerated during long‐term use. The number needed to treat with varenicline for an additional beneficial outcome, based on the weighted mean control rate, is 11 (95% CI 9 to 13). The most commonly reported adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Our analysis of reported serious adverse events occurring during or after active treatment suggests there may be a 25% increase in the chance of SAEs among people using varenicline (RR 1.25; 95% CI 1.04 to 1.49; 29 trials, 15,370 people; high‐quality evidence). These events include comorbidities such as infections, cancers and injuries, and most were considered by the trialists to be unrelated to the treatments. There is also evidence of higher losses to follow‐up in the control groups compared with the intervention groups, leading to a likely underascertainment of the true rate of SAEs among the controls. Early concerns about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation led to the addition of a boxed warning to the labelling in 2008. However, subsequent observational cohort studies and meta‐analyses have not confirmed these fears, and the findings of the EAGLES trial do not support a causal link between varenicline and neuropsychiatric disorders, including suicidal ideation and suicidal behaviour. The evidence is not conclusive, however, in people with past or current psychiatric disorders. Concerns have also been raised that varenicline may slightly increase cardiovascular events in people already at increased risk of those illnesses. Current evidence neither supports nor refutes such an association, but we await the findings of the CATS trial, which should establish whether or not this is a valid concern.
Authors' conclusions
Cytisine increases the chances of quitting, although absolute quit rates were modest in two recent trials. Varenicline at standard dose increased the chances of successful long‐term smoking cessation between two‐ and three‐fold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion or with NRT. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The most frequently recorded adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Early reports of possible links to suicidal ideation and behaviour have not been confirmed by current research.
Future trials of cytisine may test extended regimens and more intensive behavioural support.
A 810 nm STED nanoscopy setup and an appropriate combination of two fluorescent dyes (Si-rhodamine 680SiR and carbopyronine 610CP) have been developed for near-IR live-cell super-resolution imaging. ...Vimentin endogenously tagged using the CRISPR/Cas9 approach with the SNAP tag, together with a noncovalent tubulin label, provided reliable and cell-to-cell reproducible dual-color confocal and STED imaging of the cytoskeleton in living cells.
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“Dogel ebs” was known as Sophora flavescens Ait., which has been widely utilized in the clinical practice of traditional Chinese Mongolian herbal medicine for thousands of years. Shen Nong's Materia ...Medica (Shen Nong Ben Cao Jing in Chinese pinyin) recorded that it is bitter in taste and cold in nature with the effect of clearing heat and eliminating dampness, insecticide, diuresis. Due to its extensive application in the fields of ethnopharmacological utilization, the pharmaceutical researches of Sophora flavescens Ait.s keeps deepening. Modern pharmacological studies have exhibited that matrine, which is rich in this traditional herbal medicine, mediates its main biological properties.
This review aimed at summarizing the latest and comprehensive information of matrine on the pharmacology, pharmacokinetics, toxicity, clinical application and preparation researches to explore the therapeutic potential of this natural ingredient. In addition, outlooks and perspective for possible future researches that related are also discussed.
Related information concerning matrine was gathered from the internet database of Google scholar, Pubmed, ResearchGate, Web of Science and Wiley Online Library with the keywords including “matrine”, “pharmacology”, “toxicology” and “pharmacokinetics”, “clinical application”, etc.
Based on literatures, matrine has a variety of pharmacological effects, including anti-cancer, anti-inflammatory, anti-microbial, detoxification and so on. Nevertheless, there are still some doubts about it due to the toxicity and questionable bioavailability that does exist.
Future researches directions probably include elucidate the mechanism of its toxicity and accurately tracing the in vivo behavior of its drug delivery system. Without doubt, integration of toxicity and efficiency and structure modification based on it are also pivotal methods to enhance pharmacological activity and bioavailability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•First report of development an UPLC-MS/MS method for the determination of N-methylcytisine in rat plasma.•First report of pharmacokinetic study of N-methylcytisine after oral and intravenous ...administration.•First report of the bioavailability of N-methylcytisine.
In this work, a sensitive and selective UPLC-MS/MS method for determination of N-methylcytisine in rat plasma is developed. After addition of hordenine as an internal standard (IS), protein precipitation by acetonitrile-methanol (9:1, v/v) was used to prepare samples. Chromatographic separation was achieved on a UPLC BEH HILIC (2.1 mm×100mm, 1.7μm) with acetonitrile (containing 10mM ammonium formate) and water (containing 0.1% formic acid and 10mM ammonium formate) as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reaction monitoring (MRM) mode was used for quantification using target fragment ions m/z 205.1→58.0 for N-methylcytisine, and m/z 166.1→121.0 for IS. Calibration plots were linear throughout the range 2-2000ng/mL for N-methylcytisine in rat plasma. Mean recoveries of N-methylcytisine in rat plasma ranged from 86.1% to 94.8%. RSD of intra-day and inter-day precision were both<13%. The accuracy of the method was between 94.5% and 109.4%. The method was successfully applied to pharmacokinetic study of N-methylcytisine after either oral or intravenous administration. For the first time, the absolute bioavailability of N-methylcytisine was reported as high as 55.5%.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This review covers the isolation, structure determination, synthesis, chemical transformations and biological activity of indolizidine and quinolizidine alkaloids. Included in the review are the ...hydroxylated indolizidines lentiginosine, swainsonine, castanospermine and their analogues; alkaloids from animal sources, including arthropods and amphibians; alkaloids from the genera Polygonatum, Prosopis and Poranthera; phenanthroindolizidine and phenanthroquinolizidine alkaloids; Nuphar alkaloids; lupine alkaloids; and alkaloids from marine sources. 130 references are cited.
Three new matrine-type alkaloids, (+)-5α-hydroxyoxysophocarpine (1), (−)-12β-hydroxyoxysophocarpine (2), and (+)-5α-hydroxylemannine (3), along with 14 known analogues, (−)-sophocarpine (4), ...(−)-5α-hydroxysophocarpine (5), (−)-9α-hydroxysophocarpine (6), (+)-12α-hydroxysophocarpine (7), (−)-12β-hydroxysophocarpine (8), (+)-oxysophocarpine (9), (+)-matrine (10), (+)-sophoranol (11), (+)-9α-hydroxymatrine (12), (−)-14β-hydroxymatrine (13), (+)-oxymatrine (14), (+)-5α-hydroxyoxymatrine (15), (−)-14β-hydroxyoxymatrine (16), and (+)-sophoramine (17), were isolated from the rhizomes of Sophora tonkinensis. Their structures were elucidated via spectrometric data analyses, and the absolute configurations were established by single-crystal X-ray diffraction and ECD data. Alkaloids 2, 6, 11, and 13 exhibited antiviral activity against the Coxsackie virus B3 (CVB3), with IC50 values of 26.62–252.18 μM, and alkaloids 7, 8, and 17 inhibited influenza virus A/Hanfang/359/95 (H3N2) replication with IC50 values of 63.07–242.46 μM.
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Cytisine, a natural bioactive compound that is mainly isolated from plants of the Leguminosae family (especially the seeds of Laburnum anagyroides), has been marketed in central and eastern Europe as ...an aid in the clinical management of smoking cessation for more than 50 years. Its main targets are neuronal nicotinic acetylcholine receptors (nAChRs), and pre-clinical studies have shown that its interactions with various nAChR subtypes located in different areas of the central and peripheral nervous systems are neuroprotective, have a wide range of biological effects on nicotine and alcohol addiction, regulate mood, food intake and motor activity, and influence the autonomic and cardiovascular systems. Its relatively rigid conformation makes it an attractive template for research of new derivatives. Recent studies of structurally modified cytisine have led to the development of new compounds and for some of them the biological activities are mediated by still unidentified targets other than nAChRs, whose mechanisms of action are still being investigated. The aim of this review is to describe and discuss: 1) the most recent pre-clinical results obtained with cytisine in the fields of neurological and non-neurological diseases; 2) the effects and possible mechanisms of action of the most recent cytisine derivatives; and 3) the main areas warranting further research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against ...at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone
, through a 1,2-disubstituted quinolizinone
to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone
. Compound
has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound
also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound
qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.
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