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Molecules (Basel, Switzerland) Sep 2022Lobeline is an alkaloid derived from the leaves of an Indian tobacco plant (), which has been prepared by chemical synthesis. It is classified as a partial nicotinic...
Lobeline is an alkaloid derived from the leaves of an Indian tobacco plant (), which has been prepared by chemical synthesis. It is classified as a partial nicotinic agonist and has a long history of therapeutic usage ranging from emetic and respiratory stimulant to tobacco smoking cessation agent. The presence of both and isomers in lobeline is well known, and many studies on the relationship between the structure and pharmacological activity of lobeline and its analogs have been reported. However, it is a remarkable fact that no studies have reported the differences in pharmacological activities between the two isomers. In this article, we found that different degrees of isomerization of lobeline injection have significant differences in respiratory excitatory effects in pentobarbital sodium anesthetized rats. Compared with -lobeline injections, the respiratory excitatory effect was significantly reduced by 50.2% after administration of injections which contained 36.9% -lobeline. The study on the influencing factors of isomerization between two isomers shown that this isomerization was a one-way isomerism and only converted from to , where temperature was the catalytic factor and pH was the key factor. This study reports a new discovery. Despite the widespread use of ventilators, first-aid medicines such as nikethamide and lobeline has retired to second line, but as a nonselective antagonist with high affinity for a4b2 and a3b2 nicotinic acetylcholine receptors (nAChRs). In recent years, lobeline has shown great promise as a therapeutic drug for mental addiction and nervous system disorders, such as depression, Alzheimer disease and Parkinson disease. Therefore, we suggest that the differences between two isomers should be concerned in subsequent research papers and applications.
Topics: Alkaloids; Animals; Emetics; Isomerism; Lobelia; Lobeline; Nicotinic Agonists; Nikethamide; Pentobarbital; Rats; Receptors, Nicotinic; Respiratory System Agents
PubMed: 36234790
DOI: 10.3390/molecules27196253 -
Signal Transduction and Targeted Therapy Sep 2022Mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of acute respiratory distress syndrome (ARDS). However, there is significant...
Mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of acute respiratory distress syndrome (ARDS). However, there is significant heterogeneity in their therapeutic efficacy, largely owing to the incomplete understanding of the mechanisms underlying the therapeutic activities of MSCs. Here, we hypothesize that the cholinergic anti-inflammatory pathway (CAP), which is recognized as a neuroimmunological pathway, may be involved in the therapeutic mechanisms by which MSCs mitigate ARDS. Using lipopolysaccharide (LPS) and bacterial lung inflammation models, we found that inflammatory cell infiltration and Evans blue leakage were reduced and that the expression levels of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in lung tissue were significantly increased 6 hours after MSC infusion. When the vagus nerve was blocked or α7 nicotinic acetylcholine (ACh) receptor (α7nAChR)-knockout mice were used, the therapeutic effects of MSCs were significantly reduced, suggesting that the CAP may play an important role in the effects of MSCs in ARDS treatment. Our results further showed that MSC-derived prostaglandin E2 (PGE2) likely promoted ACh synthesis and release. Additionally, based on the efficacy of nAChR and α7nAChR agonists, we found that lobeline, the nicotinic cholinergic receptor excitation stimulant, may attenuate pulmonary inflammation and alleviate respiratory symptoms of ARDS patients in a clinical study (ChiCTR2100047403). In summary, we reveal a previously unrecognized MSC-mediated mechanism of CAP activation as the means by which MSCs alleviate ARDS-like syndrome, providing insight into the clinical translation of MSCs or CAP-related strategies for the treatment of patients with ARDS.
Topics: Animals; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Knockout; Neuroimmunomodulation; Respiratory Distress Syndrome; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 36064538
DOI: 10.1038/s41392-022-01124-6 -
The Cochrane Database of Systematic... May 2013Smoking is the leading preventable cause of illness and premature death worldwide. Some medications have been proven to help people to quit, with three licensed for this... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Smoking is the leading preventable cause of illness and premature death worldwide. Some medications have been proven to help people to quit, with three licensed for this purpose in Europe and the USA: nicotine replacement therapy (NRT), bupropion, and varenicline. Cytisine (a treatment pharmacologically similar to varenicline) is also licensed for use in Russia and some of the former socialist economy countries. Other therapies, including nortriptyline, have also been tested for effectiveness.
OBJECTIVES
How do NRT, bupropion and varenicline compare with placebo and with each other in achieving long-term abstinence (six months or longer)? How do the remaining treatments compare with placebo in achieving long-term abstinence? How do the risks of adverse and serious adverse events (SAEs) compare between the treatments, and are there instances where the harms may outweigh the benefits?
METHODS
The overview is restricted to Cochrane reviews, all of which include randomised trials. Participants are usually adult smokers, but we exclude reviews of smoking cessation for pregnant women and in particular disease groups or specific settings. We cover nicotine replacement therapy (NRT), antidepressants (bupropion and nortriptyline), nicotine receptor partial agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid receptor antagonists (rimonabant), clonidine, lobeline, dianicline, mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, and silver acetate. Our outcome for benefit is continuous or prolonged abstinence at least six months from the start of treatment. Our outcome for harms is the incidence of serious adverse events associated with each of the treatments. We searched the Cochrane Database of Systematic Reviews (CDSR) in The Cochrane Library, for any reviews with 'smoking' in the title, abstract or keyword fields. The last search was conducted in November 2012. We assessed methodological quality using a revised version of the AMSTAR scale. For NRT, bupropion and varenicline we conducted network meta-analyses, comparing each with the others and with placebo for benefit, and varenicline and bupropion for risks of serious adverse events.
MAIN RESULTS
We identified 12 treatment-specific reviews. The analyses covered 267 studies, involving 101,804 participants. Both NRT and bupropion were superior to placebo (odds ratios (OR) 1.84; 95% credible interval (CredI) 1.71 to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively). Varenicline increased the odds of quitting compared with placebo (OR 2.88; 95% CredI 2.40 to 3.47). Head-to-head comparisons between bupropion and NRT showed equal efficacy (OR 0.99; 95% CredI 0.86 to 1.13). Varenicline was superior to single forms of NRT (OR 1.57; 95% CredI 1.29 to 1.91), and to bupropion (OR 1.59; 95% CredI 1.29 to 1.96). Varenicline was more effective than nicotine patch (OR 1.51; 95% CredI 1.22 to 1.87), than nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and than 'other' NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75 to 1.48). Combination NRT also outperformed single formulations. The four categories of NRT performed similarly against each other, apart from 'other' NRT, which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01 to 1.46). Cytisine (a nicotine receptor partial agonist) returned positive findings (risk ratio (RR) 3.98; 95% CI 2.01 to 7.87), without significant adverse events or SAEs. Across the 82 included and excluded bupropion trials, our estimate of six seizures in the bupropion arms versus none in the placebo arms was lower than the expected rate (1:1000), at about 1:1500. SAE meta-analysis of the bupropion studies demonstrated no excess of neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 0.77; 95% CI 0.37 to 1.59). SAE meta-analysis of 14 varenicline trials found no difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to 1.55), and subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56). Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 1.48 to 2.78). Neither nortriptyline nor bupropion were shown to enhance the effect of NRT compared with NRT alone. Clonidine increased the chances of quitting (RR 1.63; 95% CI 1.22 to 2.18), but this was offset by a dose-dependent rise in adverse events. Mecamylamine in combination with NRT may increase the chances of quitting, but the current evidence is inconclusive. Other treatments failed to demonstrate a benefit compared with placebo. Nicotine vaccines are not yet licensed for use as an aid to smoking cessation or relapse prevention. Nicobrevin's UK license is now revoked, and the manufacturers of rimonabant, taranabant and dianicline are no longer supporting the development or testing of these treatments.
AUTHORS' CONCLUSIONS
NRT, bupropion, varenicline and cytisine have been shown to improve the chances of quitting. Combination NRT and varenicline are equally effective as quitting aids. Nortriptyline also improves the chances of quitting. On current evidence, none of the treatments appear to have an incidence of adverse events that would mitigate their use. Further research is warranted into the safety of varenicline and into cytisine's potential as an effective and affordable treatment, but not into the efficacy and safety of NRT.
Topics: Adult; Alkaloids; Antidepressive Agents, Second-Generation; Azocines; Benzazepines; Bupropion; Humans; Nicotinic Agonists; Nortriptyline; Quinolizines; Quinoxalines; Randomized Controlled Trials as Topic; Review Literature as Topic; Smoking; Smoking Cessation; Tobacco Use Cessation Devices; Varenicline
PubMed: 23728690
DOI: 10.1002/14651858.CD009329.pub2 -
Frontiers in Pharmacology 2021In this work, we reviewed the progress in the phytochemical and biological investigations of bioactive components derived from medicinally valuable species. In the last... (Review)
Review
In this work, we reviewed the progress in the phytochemical and biological investigations of bioactive components derived from medicinally valuable species. In the last 60 years, has garnered significant attention from the phytochemist from around the world, majorly due to the discovery of bioactive piperidine alkaloids (e.g., lobinaline and lobeline) in the early 1950s. Later, lobeline underwent clinical trials for several indications including the treatment of attention deficit hyperactivity disorder and a multicenter phase three trial for smoking cessation. Subsequently, several other alkaloids derived from different species of were also investigated for their pharmacological characteristics. However, in the last few years, the research focus has started shifting to the characterization of the other novel chemical classes. The major shift has been noticed due to the structurally similar alkaloid components, which essentially share similar pharmacological, physicochemical, and toxicological profiles. In this review, we present an up-to-date overview of their progress with special attention to understanding the molecular mechanisms of the novel bioactive components.
PubMed: 33762957
DOI: 10.3389/fphar.2021.638210 -
The Cochrane Database of Systematic... Feb 2012Lobeline is a partial nicotine agonist, which has been used in a variety of commercially available preparations to help stop smoking. (Review)
Review
BACKGROUND
Lobeline is a partial nicotine agonist, which has been used in a variety of commercially available preparations to help stop smoking.
OBJECTIVES
The objective of this review was to assess the effects of lobeline on long term smoking cessation.
SEARCH METHODS
We searched the Cochrane Tobacco Addiction Group trials register (most recent search December 2011).
SELECTION CRITERIA
Randomized trials comparing lobeline to placebo or an alternative therapeutic control, which reported smoking cessation with at least six months follow-up.
DATA COLLECTION AND ANALYSIS
We extracted data in duplicate on the type of subjects, the dose and form of lobeline, the outcome measures, method of randomisation, and completeness of follow-up.
MAIN RESULTS
We identified no trials meeting the full inclusion criteria including long term follow-up. One large trial failed to detect any effect on short-term abstinence.
AUTHORS' CONCLUSIONS
There is no evidence available from long term trials that lobeline can aid smoking cessation, and the short-term evidence suggests there is no benefit.
Topics: Humans; Lobeline; Nicotinic Antagonists; Smoking Cessation; Smoking Prevention
PubMed: 22336780
DOI: 10.1002/14651858.CD000124.pub2 -
Respiratory Care Dec 2003Cigarette smoking is the primary cause of chronic obstructive pulmonary disease, and smoking cessation is the most effective means of stopping the progression of chronic... (Review)
Review
Cigarette smoking is the primary cause of chronic obstructive pulmonary disease, and smoking cessation is the most effective means of stopping the progression of chronic obstructive pulmonary disease. Worldwide, approximately a billion people smoke cigarettes and 80% reside in low-income and middle-income countries. Though in the United States there has been a substantial decline in cigarette smoking since 1964, when the Surgeon General's report first reviewed smoking, smoking remains widespread in the United States today (about 23% of the population in 2001). Nicotine is addictive, but there are now effective drugs and behavioral interventions to assist people to overcome the addiction. Available evidence shows that smoking cessation can be helped with counseling, nicotine replacement, and bupropion. Less-studied interventions, including hypnosis, acupuncture, aversive therapy, exercise, lobeline, anxiolytics, mecamylamine, opioid agonists, and silver acetate, have assisted some people in smoking cessation, but none of those interventions has strong research evidence of efficacy. To promote smoking cessation, physicians should discuss with their smoking patients "relevance, risk, rewards, roadblocks, and repetition," and with patients who are willing to attempt to quit, physicians should use the 5-step system of "ask, advise, assess, assist, and arrange." An ideal smoking cessation program is individualized, accounting for the reasons the person smokes, the environment in which smoking occurs, available resources to quit, and individual preferences about how to quit. The clinician should bear in mind that quitting smoking can be very difficult, so it is important to be patient and persistent in developing, implementing, and adjusting each patient's smoking-cessation program. One of the most effective behavioral interventions is advice from a health care professional; it seems not to matter whether the advice is from a doctor, respiratory therapist, nurse, or other clinician, so smoking cessation should be encouraged by multiple clinicians. However, since respiratory therapists interact with smokers frequently, we believe it is particularly important for respiratory therapists to show leadership in implementing smoking cessation.
Topics: Adult; Antidepressive Agents, Second-Generation; Behavior Therapy; Bupropion; Humans; Nicotine; Prevalence; Respiratory Therapy; Smoking; Smoking Cessation; Smoking Prevention; Tobacco Use Disorder; Treatment Outcome; United States
PubMed: 14651764
DOI: No ID Found -
British Medical Journal Oct 1953
Topics: Air Pollution; Humans; Lobeline; Smoke; Nicotiana
PubMed: 13082128
DOI: No ID Found -
Evidence-based Complementary and... 2021Parkinson's disease is a common neurodegenerative disorder marked by the accumulation of the protein alpha synuclein. Studies have indicated the role of prolyl...
Parkinson's disease is a common neurodegenerative disorder marked by the accumulation of the protein alpha synuclein. Studies have indicated the role of prolyl oligopeptidase (POP), a serine protease, in alpha synuclein accumulation. Therefore, POP emerges as an attractive medicinal target. Traditionally, most of the early medicines have been plant-based owing to their ready availability and negligible side effects. Alkaloids owing to their neurotransmitter modulatory, anti-amyloid, anti-oxidant, and anti-inflammatory activities have shown potential in neurodegenerative disease. In this work, we computationally evaluated alkaloid class of phytochemicals for their therapeutic efficacy against POP. Alkaloids were retrieved from the publically available database, Chemical Entities of Biological Interest (ChEBI), and screened for their drug likeness (Lipinski's rule of 5) and absorption, distribution, metabolism, and excretion, and toxicity (ADMET) in Discovery Studio by ensuring parameters suitable for a central nervous system disease such as blood-brain barrier (BBB) level set to ≤2, absorption level set to 0 and solubility level permitted set to 2, 3, or 4. Next, molecular docking was performed to learn about the affinity of the filtered alkaloids with the POP. Subsequently, molecular dynamic simulations were conducted to assess the reliability and stability of the alkaloid-protein complex. Our study identified metergoline, pipercallosine, celacinnine, lobeline, cystodytin G, lycoperine A, hookerianamide J, and martefragin A as putative lead compounds against POP. Among these, metergoline, pipercallosine, hookerianamide J, and lobeline showed the most promising results. These compounds demonstrated better or equivalent molecular docking scores in comparison to three POP inhibitors that had reached clinical trials, i.e., Z-321, S-17092, and JTP-4819. MD simulations indicated that these compounds remained intact at the active site while adhering to the binding mode and interaction patterns as that of the reported inhibitors. The research conducted here, therefore, provides evidence for conducting in vitro POP inhibitory studies of these newly identified plant-based POP inhibitors.
PubMed: 33897801
DOI: 10.1155/2021/6687572 -
BioRxiv : the Preprint Server For... Feb 2024Plant secondary metabolites pose a challenge for generalist herbivorous insects because they are not only potentially toxic, they also may trigger aversion. On the...
Plant secondary metabolites pose a challenge for generalist herbivorous insects because they are not only potentially toxic, they also may trigger aversion. On the contrary, some highly specialized herbivorous insects evolved to use these same compounds as 'token stimui' for unambiguous determination of their host pants. Two questions that emerge from these observations are how recently derived herbivores evolve to overcome this aversion to plant secondary metabolites and the extent to which they evolve increased attraction to these same compounds. In this study, we addressed these questions by focusing on the evolution of bitter taste preferences in the herbivorous drosophilid , which is phylogenetically nested deep in the paraphyletic . We measured behavioral and neural responses of and a set of non-herbivorous species representing a phylogenetic gradient (, , and ) towards host- and non-host derived bitter plant compounds. We observed that evolved a shift in bitter detection, rather than a narrow shift towards glucosinolates, the precursors of mustard-specific defense compounds. In a dye-based consumption assay, exhibited shifts in aversion toward the non-mustard bitter, plant-produced alkaloids caffeine and lobeline, and reduced aversion towards glucosinolates, whereas the non-herbivorous species each showed strong aversion to all bitter compounds tested. We then examined whether these changes in bitter preferences of could be explained by changes in sensitivity in the peripheral nervous system and compared electrophysiological responses from the labellar sensilla of , , and . Using scanning electron microscopy, we also created a map of labellar sensilla in and We assigned each sensillum to a functional sensilla class based on their morphology and initial response profiles to bitter and sweet compounds. Despite a high degree of conservation in the morphology and spatial placement of sensilla between , electrophysiological studies revealed that had reduced sensitivity to glucosinolates to varying degrees. We found this reduction only in I type sensilla. Finally, we speculate on the potential role that evolutionary genetic changes in gustatory receptors between and may play in driving these patterns. Specifically, we hypothesize that the evolution of bitter receptors expressed in I type sensilla may have driven the reduced sensitivity observed in , and ultimately, its reduced bitter aversion. The system showcases the importance of reduced aversion to bitter defense compounds in relatively young herbivorous lineages, and how this may be achieved at the molecular and physiological level.
PubMed: 38464294
DOI: 10.1101/2024.02.27.582299 -
Frontiers in Neuroscience 2014Alcohol and drug dependence are serious public health problems worldwide. The prevalence of alcohol and drug dependence in the United States and other parts of the world... (Review)
Review
Alcohol and drug dependence are serious public health problems worldwide. The prevalence of alcohol and drug dependence in the United States and other parts of the world is significant. Given the limitations in the efficacy of current pharmacotherapies to treat these disorders, research in developing alternative pharmacotherapies continues. Preclinical and clinical evidence thus far has indicated that brain nicotinic acetylcholine receptors (nAChRs) are important pharmacological targets for the development of medications to treat alcohol and drug dependence. The nAChRs are a super family of ligand gated ion channels, and are expressed throughout the brain with twelve neuronal nAChR subunits (α2-α10 and β2-β4) identified. Here, we review preclinical and clinical evidence involving a number of nAChR ligands that target different nAChR subtypes in alcohol and nicotine addiction. The important ligands include cytisine, lobeline, mecamylamine, varenicline, sazetidine A and others that target α4β2(*) nAChR subtypes as small molecule modulators of the brain nicotinic cholinergic system are also discussed. Taken together, both preclinical and clinical data exist that support nAChR-based ligands as promising therapeutic agents for the treatment of alcohol and drug dependence.
PubMed: 25642160
DOI: 10.3389/fnins.2014.00426