Treatment of nicotine addiction: present therapeutic options and pipeline developments.
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ABSTRACT:
SUBMITTER: Polosa R
PROVIDER: S-EPMC5564372 | biostudies-other | 2011 May
REPOSITORIES: biostudies-other
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Project description:Advances in neuroimaging and genomics provide an unprecedented opportunity to accelerate medication development for nicotine dependence and other addictions. Neuroimaging studies have begun to elucidate the functional neuroanatomy and neurochemistry underlying effects of nicotine and nicotine abstinence. In parallel, genetic studies, including both candidate gene and genome-wide association approaches, are identifying key neurobiological targets and pathways important in addiction to nicotine. To date, only a few neuroimaging studies have explored effects of nicotine or abstinence on brain activity as a function of genotype. Most analyses of genotype are retrospective, resulting in small sample sizes for testing effects of the minor alleles for candidate genes. The purpose of this review is to provide an outline of the work in neuroimaging, genetics, and nicotine dependence, and to explore the potential for increased integration of these approaches to improve nicotine dependence treatment.
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Project description:Pustular psoriasis is an unusual form of psoriasis that frequently presents clinical challenges for dermatologists. The condition presents with pustules on an erythematous background and has two distinct subtypes: localized disease on the palms and soles, called palmoplantar pustulosis (PPP), and generalized pustular psoriasis (GPP). The involvement of the fingers, toes, and nails is defined as a separate localized variant, acrodermatitis continua of Hallopeau, and is now thought to be a subset of PPP. The rarity of pustular psoriasis frequently makes the correct diagnosis problematic. In addition, treatment is limited by a relative lack of evidence-based therapeutic options. Current management is often based on existing therapies for standard plaque psoriasis. However, there remains a need for treatments with high, sustained efficacy and a rapid onset of action in pustular psoriasis. Recent advances in understanding of the pathogenesis of pustular psoriasis have provided insights into potential therapies. Treatment of pustular psoriasis is generally determined by the extent and severity of disease, and recent years have seen an increasing use of newer agents, including biologic therapies. Current classes of biologic therapies with US Food and Drug Administration and European Medicines Agency approval for treatment of moderate-to-severe plaque psoriasis in the USA (and elsewhere) include tumor necrosis factor alpha inhibitors (adalimumab, certolizumab pegol, etanercept, infliximab), interleukin (IL)-17 inhibitors (brodalumab, ixekizumab, secukinumab), an IL-12/23 inhibitor (ustekinumab), and IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab). Recently, specific inhibitors of the IL-36 pathway have been evaluated in GPP and PPP, including spesolimab, an IL-36 receptor inhibitor which has shown promising results in GPP. The emerging drugs for pustular psoriasis offer the possibility of rapid and effective treatment with lower toxicities than existing therapies. Further research into agents acting on the IL-36 pathway and other targeted therapies has the potential to transform the future treatment of patients with pustular psoriasis. This article reviews the clinical features of PPP and GPP, and current understanding of the genetics and immunopathology of these conditions; it also provides an update on emerging treatments.
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Project description:BACKGROUND:Smoking and tobacco use continue to be the largest preventable causes of death globally. A novel therapeutic approach has recently been proposed: administration of an enzyme that degrades nicotine, the main addictive component of tobacco, minimizing brain exposure and reducing its reinforcing effects. Pre-clinical proof of concept has been previously established through dosing the amine oxidase NicA2 from Pseudomonas putida in rat nicotine self-administration models of addiction. RESULTS:This paper describes efforts towards optimizing NicA2 for potential therapeutic use: enhancing potency, improving its pharmacokinetic profile, and attenuating immunogenicity. Libraries randomizing residues located in all 22 active site positions of NicA2 were screened. 58 single mutations with 2- to 19-fold enhanced catalytic activity compared to wt at 10??M nicotine were identified. A novel nicotine biosensor assay allowed efficient screening of the many primary hits for activity at nicotine concentrations typically found in smokers. 10 mutants with improved activity in rat serum at or below 250?nM were identified. These catalytic improvements translated to increased potency in vivo in the form of further lowering of nicotine blood levels and nicotine accumulation in the brains of Sprague-Dawley rats. Examination of the X-ray crystal structure suggests that these mutants may accelerate the rate limiting re-oxidation of the flavin adenine dinucleotide cofactor by enhancing molecular oxygen's access. PEGylation of NicA2 led to prolonged serum half-life and lowered immunogenicity observed in a human HLA DR4 transgenic mouse model, without impacting nicotine degrading activity. CONCLUSIONS:Systematic mutational analysis of the active site of the nicotine-degrading enzyme NicA2 has yielded 10 variants that increase the catalytic activity and its effects on nicotine distribution in vivo at nicotine plasma concentrations found in smokers. In addition, PEGylation substantially increases circulating half-life and reduces the enzyme's immunogenic potential. Taken together, these results provide a viable path towards generation of a drug candidate suitable for human therapeutic use in treating nicotine addiction.
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Project description:BackgroundDamage to the insula disrupts nicotine-induced cravings and is associated with greater odds of cessation. The role of laterality in regulating these changes is unclear. Neuroimaging studies in cigarette smokers show left hemispheric activation during a period of forced withdrawal and right hemispheric activation after having just smoked. Among current smokers hospitalized for stroke involving their insula, we compared left versus right insular damage and its effect on smoking outcomes.MethodsA total of 37 smokers hospitalized with unilateral insular strokes (14 right, 23 left) were administered questionnaires to assess urge (Questionnaire on Smoking Urges) before (retrospectively) and during hospitalization and 3 months post-stroke, withdrawal during hospitalization (Wisconsin Smoking Withdrawal Scale), and prolonged abstinence at 3 months post-stroke. Crude and adjusted linear regression models were performed controlling for baseline covariates.ResultsRight and left insular-damaged smokers experienced a significant decrease in urge from baseline to hospitalization and three-month follow-up (p < 0.01). Smokers with left-sided insular infarcts relative to right-sided experienced a larger decrease in acute urge (adjusted β=-1.16, 95% CI: -2.59, 0.27, p = 0.11) but not chronically (adjusted β=-0.06, 95% CI: -1.53, 1.40, p = 0.93). Left-sided insular damage was also associated with significantly fewer and less severe withdrawal symptoms during hospitalization (adjusted β=-3.52, 95% CI: -7.01, -0.04, p = 0.05). No differences were noted between groups for prolonged abstinence (p = 0.50).ConclusionsLeft insular adaptations are suggestive to have an impact on acute changes in urge and withdrawal more so than the right insula, however lateral asymmetries did not exist for long-term changes.
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Project description:Neurodevelopmental disorders are a large family of conditions of genetic or environmental origin that are characterized by deficiencies in cognitive and behavioral functions. The therapeutic management of individuals with these disorders is typically complex and is limited to the treatment of specific symptoms that characterize each disorder. The neurodevelopmental disorder Rett syndrome (RTT) is the leading cause of severe intellectual disability in females. Mutations in the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MECP2), located on the X chromosome, have been confirmed in more than 95% of individuals meeting diagnostic criteria for classical RTT. RTT is characterized by an uneventful early infancy followed by stagnation and regression of growth, motor, language, and social skills later in development. This review will discuss the genetics, pathology, and symptoms that distinguish RTT from other neurodevelopmental disorders associated with intellectual disability. Because great progress has been made in the basic and clinical science of RTT, the goal of this review is to provide a thorough assessment of current pharmacotherapeutic options to treat the symptoms associated with this disorder. Furthermore, we will highlight recent discoveries made with novel pharmacological interventions in experimental preclinical phases, and which have reversed pathological phenotypes in mouse and cell culture models of RTT and may result in clinical trials.
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Project description:Tobacco smoking results in more than five million deaths each year and accounts for ∼90% of all deaths from lung cancer.3 Nicotine, the major reinforcing component of tobacco smoke, acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are allosterically regulated, ligand-gated ion channels consisting of five membrane-spanning subunits. Twelve mammalian α subunits (α2-α10) and three β subunits (β2-β4) have been cloned. The predominant nAChR subtypes in mammalian brain are those containing α4 and β2 subunits (denoted as α4β2* nAChRs). The α4β2* nAChRs mediate many behaviors related to nicotine addiction and are the primary targets for currently approved smoking cessation agents. Considering the large number of nAChR subunits in the brain, it is likely that nAChRs containing subunits in addition to α4 and β2 also play a role in tobacco smoking. Indeed, genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the α5, α3, and β4 nAChR subunits, respectively, has been shown to increase vulnerability to tobacco dependence and smoking-associated diseases including lung cancer. Moreover, mice, in which expression of α5 or β4 subunits has been genetically modified, have profoundly altered patterns of nicotine consumption. In addition to the reinforcing properties of nicotine, the effects of nicotine on appetite, attention, and mood are also thought to contribute to establishment and maintenance of the tobacco smoking habit. Here, we review recent insights into the behavioral actions of nicotine, and the nAChR subtypes involved, which likely contribute to the development of tobacco dependence in smokers.
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Project description:Carbapenem-resistant Enterobacterales (CRE) are included in the list of the most threatening antibiotic resistance microorganisms, being responsible for often insurmountable therapeutic issues, especially in hospitalized patients and immunocompromised individuals and patients in intensive care units. The enzymatic resistance to carbapenems is encoded by different β-lactamases belonging to A, B or D Ambler class. Besides compromising the activity of last-resort antibiotics, CRE have spread from the clinical to the environmental sectors, in all geographic regions. The purpose of this review is to present present and future perspectives on CRE-associated infections treatment.
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Project description:Nicotine, primary component of tobaco produces craving and withdrawal effect both in humans and animals. Nicotine shows a close resemblance to other addictive drugs in molecular, neuroanatomical and pharmacological, particularly the drugs which enhances the cognitive functions. Nicotine mainly shows its action through specific nicotinic acetylcholine receptors located in brain. It stimulates presynaptic acetylcholine receptors thereby enhancing Ach release and metabolism. Dopaminergic system is also stimulated by it, thus increasing the concentration of dopamine in nuclear accumbens. This property of nicotine according to various researchers is responsible for reinforcing behavioral change and dependence of nicotine. Various researchers have also depicted that some non dopaminergic systems are also involved for rewarding effect of nicotinic withdrawal. Neurological systems such as GABAergic, serotonergic, noradrenergic, and brain stem cholinergic may also be involved to mediate the actions of nicotine. Further, the neurobiological pathway to nicotine dependence might perhaps be appropriate to the attachment of nicotine to nicotinic acetylcholine receptors, peruse by stimulation of dopaminergic system and activation of general pharmacological changes that might be responsible for nicotine addiction. It is also suggested that MAO A and B both are restrained by nicotine. This enzyme helps in degradation dopamine, which is mainly responsible for nicotinic actions and dependence. Various questions remain uninsurable to nicotine mechanism and require more research. Also, various genetic methods united with modern instrumental analysis might result for more authentic information for nicotine addiction.
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Project description:Even though smoking rates have long been on the decline, nicotine addiction still affects 20% of the US population today. Moreover, nicotine dependence shows high comorbidity with many mental illnesses including, but are not limited to, attention deficit hyperactivity disorder, anxiety disorders, and depression. The reason for the high rates of smoking in patients with mental illnesses may relate to attempts to self-medicate with nicotine. While nicotine may alleviate the symptoms of mental disorders, nicotine abstinence has been shown to worsen the symptoms of these disorders. In this chapter, we review the studies from animal and human research examining the bidirectional relationship between nicotine and attention deficit hyperactivity disorder, anxiety disorders, and depression as well as studies examining the roles of specific subunits of nicotinic acetylcholine receptors (nAChRs) in the interaction between nicotine and these mental illnesses. The results of these studies suggest that activation, desensitization, and upregulation of nAChRs modulate the effects of nicotine on mental illnesses.
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