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JAMA Jul 2023Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4β2 nicotinic acetylcholine receptors, which mediate nicotine... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4β2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal.
OBJECTIVE
To evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo.
DESIGN, SETTING, AND PARTICIPANTS
A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021.
INTERVENTIONS
Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support.
MAIN OUTCOMES AND MEASURES
Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary).
RESULTS
Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred.
CONCLUSIONS AND RELEVANCE
Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04576949.
Topics: Humans; Middle Aged; Alkaloids; Azocines; Duration of Therapy; Quinolizines; Smoking Cessation; Tobacco Use Disorder; Smoking Cessation Agents; Double-Blind Method; Treatment Outcome; Male; Female; Quinolizidine Alkaloids; Nicotine; Receptors, Nicotinic; Cigarette Smoking
PubMed: 37432430
DOI: 10.1001/jama.2023.10042 -
Brazilian Journal of Biology = Revista... 2023The Amaryllidaceae family is widely distributed in the tropics, presenting biological activity attributed mostly to alkaloids, such as an important inhibitory activity... (Review)
Review
The Amaryllidaceae family is widely distributed in the tropics, presenting biological activity attributed mostly to alkaloids, such as an important inhibitory activity of acetylcholinesterase (AChE), antifungal, antibacterial, and cytotoxic activities. The present study aims to review the spectrum of action of the main biological activities and toxicity of secondary metabolites found in Amaryllidaceae through a literature review, using Prisma and the descriptors "Pharmacological effects of Amaryllidaceae" and "Amaryllidaceae family" and "Pharmacological actions of Amaryllidaceae", used in English and Portuguese. The literature search was done in March and May 2023. Original works published from 2012 to 2023, available in full, and presenting experimental and clinical studies were included. After the selection considering the inclusion and exclusion criteria, 60 articles fulfilled the defined criteria. From a pharmacological point of view, the highlight is due to the alkaloid galantamine, which has the potential- and is already used - for treating Alzheimer's. The toxicological aspect must be considered and evaluated carefully, as alkaloids have been associated with adverse effects such as nausea, vomiting, diarrhea, abdominal pain, and cardiovascular, neurological, and respiratory changes. Furthermore, some studies indicate that consuming these plants in significant quantities can lead to hepatic and renal toxicity. Therefore, the therapeutical use of this family's plant drugs and derivatives requires further studies to elucidate its effects and point out metabolites with therapeutic potential.
Topics: Alkaloids; Amaryllidaceae; Cholinesterase Inhibitors; Plant Extracts
PubMed: 38126586
DOI: 10.1590/1519-6984.277092 -
Molecules (Basel, Switzerland) Jun 2023Cepharanthine, a natural bisbenzylisoquinoline (BBIQ) alkaloid isolated from the plant , is the only bisbenzylisoquinoline alkaloid approved for human use and has been... (Review)
Review
Cepharanthine, a natural bisbenzylisoquinoline (BBIQ) alkaloid isolated from the plant , is the only bisbenzylisoquinoline alkaloid approved for human use and has been used in the clinic for more than 70 years. Cepharanthine has a variety of medicinal properties, including signaling pathway inhibitory activities, immunomodulatory activities, and antiviral activities. Recently, cepharanthine has been confirmed to greatly inhibit SARS-CoV-2 infection. Therefore, we aimed to describe the pharmacological properties and mechanisms of cepharanthine, mainly including antitumor, anti-inflammatory, anti-pathogen activities, inhibition of bone resorption, treatment of alopecia, treatment of snake bite, and other activities. At the same time, we analyzed and summarized the potential antiviral mechanism of cepharanthine and concluded that one of the most important anti-viral mechanisms of cepharanthine may be the stability of plasma membrane fluidity. Additionally, we explained its safety and bioavailability, which provides evidence for cepharanthine as a potential drug for the treatment of a variety of diseases. Finally, we further discuss the potential new clinical applications of cepharanthine and provide direction for its future development.
Topics: Humans; COVID-19; SARS-CoV-2; Benzylisoquinolines; Alkaloids; Antiviral Agents
PubMed: 37446681
DOI: 10.3390/molecules28135019 -
Toxins Dec 2023Piperine is a plant-derived promising piperamide candidate isolated from the black pepper ( L.). In the last few years, this natural botanical product and its... (Review)
Review
Piperine is a plant-derived promising piperamide candidate isolated from the black pepper ( L.). In the last few years, this natural botanical product and its derivatives have aroused much attention for their comprehensive biological activities, including not only medical but also agricultural bioactivities. In order to achieve sustainable development and improve survival conditions, looking for environmentally friendly pesticides with low toxicity and residue is an extremely urgent challenge. Fortunately, plant-derived pesticides are rising like a shining star, guiding us in the direction of development in pesticidal research. In the present review, the recent progress in the biological activities, mechanisms of action, and structural modifications of piperine and its derivatives from 2020 to 2023 are summarized. The structure-activity relationships were analyzed in order to pave the way for future development and utilization of piperine and its derivatives as potent drugs and pesticides for improving the local economic development.
Topics: Alkaloids; Benzodioxoles; Polyunsaturated Alkamides; Pesticides; Biology
PubMed: 38133200
DOI: 10.3390/toxins15120696 -
Phytochemistry Sep 2023Medicinal plants constitute a source for designing clinically useful drugs targeting diseases through various mechanisms. Plant secondary metabolites can be used as lead... (Review)
Review
Medicinal plants constitute a source for designing clinically useful drugs targeting diseases through various mechanisms. Plant secondary metabolites can be used as lead compounds of drugs. Corynanthe alkaloids are highly abundant natural bioactive substances of various core structures possessing important properties such as nerve excitation and antimalarial and analgesic effects. In this review, we summarize and review the state-of-the-art corynanthe-type alkaloid research focusing on phytochemistry, pharmacology, and structural chemistry. Approximately 120 articles reporting 231 alkaloids classified into simple corynanthe, yohimbine, oxindole corynanthe, mavacurane, sarpagine, akuammiline, strychnos, and ajmaline-type groups were compiled. Relevant biological properties discussed include antiviral, antibacterial, anti-inflammatory, antimalarial, muscle-relaxant, vasorelaxant, and analgesic activities and activities affecting the main nervous and cardiac systems, as well as NF-κB inhibitory and Na-glucose cotransporter inhibitory properties. This review provides insights and a reference for future studies, thus paving the way for the discovery of drugs based on corynanthe alkaloids.
Topics: Pausinystalia; Antimalarials; Alkaloids; Plants, Medicinal; Analgesics; Phytochemicals; Plant Extracts
PubMed: 37422009
DOI: 10.1016/j.phytochem.2023.113786 -
Nature Metabolism Mar 2024Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD) levels are hallmarks of skeletal muscle ageing and sarcopenia, but it is unclear whether these...
Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD) levels are hallmarks of skeletal muscle ageing and sarcopenia, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid, NAD levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD pool and increases NAD levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD-boosting strategy with therapeutic potential for age-associated muscle decline.
Topics: Humans; Male; Mice; Animals; Sarcopenia; NAD; Caenorhabditis elegans; Aging; Muscle, Skeletal; Alkaloids
PubMed: 38504132
DOI: 10.1038/s42255-024-00997-x -
Phytotherapy Research : PTR Nov 2023Central nervous system (CNS) disease is one of the most important causes of human death. Because of their complex pathogenesis, more and more attention has been paid to... (Review)
Review
Central nervous system (CNS) disease is one of the most important causes of human death. Because of their complex pathogenesis, more and more attention has been paid to them. At present, drug treatment of the CNS is the main means; however, most drugs only relieve symptoms, and some have certain toxicity and side effects. Natural compounds derived from plants can provide safer and more effective alternatives. Alkaloids are common nitrogenous basic organic compounds found in nature, which exist widely in many kinds of plants and have unique application value in modern medicine. For example, Galantamine and Huperzine A from medicinal plants are widely used drugs on the market to treat Alzheimer's disease. Therefore, the main purpose of this review is to provide the available information on natural alkaloids with the activity of treating central nervous system diseases in order to explore the trends and perspectives for the further study of central nervous system drugs. In this paper, 120 alkaloids with the potential effect of treating central nervous system diseases are summarized from the aspects of sources, structure types, mechanism of action and structure-activity relationship.
Topics: Humans; Alkaloids; Plant Extracts; Alzheimer Disease; Plants, Medicinal; Central Nervous System Diseases
PubMed: 37455555
DOI: 10.1002/ptr.7955 -
The New Phytologist Oct 2023Mitragynine, an analgesic alkaloid from the plant Mitragyna speciosa (kratom), offers a safer alternative to clinical opioids such as morphine, owing to its more...
Mitragynine, an analgesic alkaloid from the plant Mitragyna speciosa (kratom), offers a safer alternative to clinical opioids such as morphine, owing to its more favorable side effect profile. Although kratom has been traditionally used for stimulation and pain management in Southeast Asia, the mitragynine biosynthesis pathway has remained elusive. We embarked on a search for mitragynine biosynthetic genes from the transcriptomes of kratom and other members of the Rubiaceae family. We studied their functions in vitro and in vivo. Our investigations led to the identification of several reductases and an enol methyltransferase that forms a new clade within the SABATH methyltransferase family. Furthermore, we discovered a methyltransferase from Hamelia patens (firebush), which catalyzes the final step. With the tryptamine 4-hydroxylase from the psychedelic mushroom Psilocybe cubensis, we accomplished the four-step biosynthesis for mitragynine and its stereoisomer, speciogynine in both yeast and Escherichia coli when supplied with tryptamine and secologanin. Although we have yet to pinpoint the authentic hydroxylase and methyltransferase in kratom, our discovery completes the mitragynine biosynthesis. Through these breakthroughs, we achieved the microbial biosynthesis of kratom opioids for the first time. The remarkable enzyme promiscuity suggests the possibility of generating derivatives and analogs of kratom opioids in heterologous systems.
Topics: Analgesics, Opioid; Mitragyna; Plant Extracts; Tryptamines; Secologanin Tryptamine Alkaloids; Mixed Function Oxygenases
PubMed: 37518950
DOI: 10.1111/nph.19162 -
Natural Product Reports Oct 2023Covering: marine indole alkaloids ( = 2048) and their reported bioactivities up to the end of 2021Despite increasing numbers of marine natural products (MNPs) reported... (Meta-Analysis)
Meta-Analysis Review
Covering: marine indole alkaloids ( = 2048) and their reported bioactivities up to the end of 2021Despite increasing numbers of marine natural products (MNPs) reported each year, most have only been examined for cytotoxic, antibacterial, and/or antifungal biological activities with the majority found to be inactive in these assays. In this context, why are natural products continuing to be examined in assays they are unlikely to show significant activity in, and what targets might be more useful for expanding knowledge of their biologically relevant chemical space? We have undertaken a meta-analysis of the biological activities for 2048 marine indole alkaloids (MIAs), a diverse sub-class of MNPs reported up to the end of 2021, and this has highlighted that the bioactivity potentials for up to 86% of published MIAs remains underexplored and/or undefined. Although most published MIAs are not cytotoxic or antimicrobial, there is a continued focus on using these assays to evaluate new structurally related analogues. Using cheminformatics analyses, the chemical diversity of the 2048 MIAs were clustered using fragment based fingerprints and their reported bioactivity potency towards specific disease targets was assessed for structure activity trends. These analyses showed that there are groups of MIAs that possess potent and diverse activities and that many analogues, previously tested only in cellular toxicity assays, could be better exploited to generate structure activity relationships associated with leads to treat emerging diseases. A collection of indole drug and drug-lead structures from non-natural sources were also incorporated into the dataset providing complementary bioactivity profiles that were further used to predict underexplored areas of potential new activity and to better direct future testing of MIAs. Our findings clearly suggest the biological evaluation of MIAs continues to be conducted on a narrow range of bioassays and disease targets, and that shifting the focus to non-toxic disease targets should provide expanded knowledge of biologically relevant chemical space aimed at maximising the potential of MIAs for drug discovery.
Topics: Indole Alkaloids; Antineoplastic Agents; Anti-Infective Agents; Biological Products; Antifungal Agents
PubMed: 36790012
DOI: 10.1039/d2np00085g -
Natural Product Reports Feb 2024Covering: 2016 to 2023The synthetic chemistry community is always in pursuit of efficient routes to natural products. Among the many available general strategies,... (Review)
Review
Covering: 2016 to 2023The synthetic chemistry community is always in pursuit of efficient routes to natural products. Among the many available general strategies, skeletal reorganization, which involves the formation, cleavage, and migration of C-C and C-heteroatom bonds, stands out as a particularly useful approach for the efficient assembly of molecular skeletons. In addition, it allows for late-stage modification of natural products for quick access to other family members or unnatural derivatives. This review summarizes efficient syntheses of steroid, terpenoid, and alkaloid natural products that have been achieved by means of this strategy in the past eight years. Our goal is to illustrate the strategy's potency and reveal the spectacular human ingenuity demonstrated in its use and development.
Topics: Humans; Biological Products; Alkaloids; Terpenes
PubMed: 38291905
DOI: 10.1039/d3np00066d