Advances in pharmacology最新文献

Inflammatory bowel disease (IBD) is a collective term for chronic inflammatory diseases of the intestinal tract. The term IBD encompasses two main forms, Crohn's disease (CD) and Ulcerative colitis (UC). CD is characterized by inflammation throughout the length of the gut, especially the ileum and colon, and is often complicated with fistulae and/or intestinal strictures. Ulcerative colitis (UC) is inflammatory disease restricted to the colon and rectum. In practice however, IBD is a heterogenous disease with CD and UC representing the extremes of a continuum of diseases with varied clinical presentation, including disease location, severity, and manifestation of extraintestinal diseases. This disease heterogeneity poses a challenge to successful and efficacious therapeutic treatment as the etiology driving disease in individual patients is unknown and likely to be multifactorial, including genetic predisposition, environmental factors such as the microbiota, as well as social behaviors such as smoking and diet. Precision medicine provides a strategy to account for disease heterogeneity and diverse etiology to select for patients most likely to respond to a given therapeutic. In this chapter we present an example of the development of a novel antibody therapeutic, Tulisokibart, as a model for a Precision Medicine approach to the successful treatment of patients with IBD.

Nicotine has been well-characterized for its ability to alter neurophysiology to promote rewarding and reinforcing properties. However, several exogenous chemicals possess properties that modulate or enhance nicotine's ability to alter neurophysiology. This chapter focuses on nicotine's impact on behavior through changes in neurophysiology and several chemical entities that in-turn modulate nicotine's ability to act as a neuromodulator.

Methamphetamine (METH) regulation of the dopamine transporter (DAT) and central nervous system (CNS) dopamine transmission have been extensively studied. However, our understanding of how METH influences neuroimmune communication and innate and adaptive immunity is still developing. Recent studies have shed light on the bidirectional communication between the CNS and the peripheral immune system. They have established a link between CNS dopamine levels, dopamine neuronal activity, and peripheral immunity. Akin to dopamine neurons in the CNS, a majority of peripheral immune cells also express DAT, implying that in addition to their effect in the CNS, DAT ligands such as methamphetamine may have a role in modulating peripheral immunity. For example, by directly influencing DAT-expressing peripheral immune cells and thus peripheral immunity, METH can trigger a feed-forward cascade that impacts the bidirectional communication between the CNS and peripheral immune system. In this review, we aim to discuss the current understanding of how METH modulates both innate and adaptive immunity and identify areas where knowledge gaps exist. These gaps will then be considered in guiding future research directions.

The long-term remission rates achieved with current treatment options for Crohn's disease with perianal fistula (CD-PAF)-including antibiotics, biologics, immunomodulators, and Janus kinase inhibitors, often combined with advanced surgical interventions-remain unsatisfactory. This chapter explores several innovative biomaterials-based solutions, such as plugs, adhesives, fillers, and stem cell-based therapies. The key approaches and treatment outcomes of these advanced therapies are examined, focusing on their ability to modulate the immune response, promote tissue healing, and improve patient outcomes. Additionally, the chapter discusses future directions, including the optimization of biomaterial designs, enhancement of delivery and retention of regenerative therapies, and a deeper understanding of the underlying mechanisms of healing.

The synthetic cathinones are man-made compounds derived from the naturally occurring drug cathinone, which is found in the khat plant. The drugs in this pharmacological class that will be the focus of this chapter include mephedrone, MDPV, methcathinone and methylone. These drugs are colloquially known as "bath salts". This misnomer suggests that these drugs are used for health improvement or that they have legitimate medical uses. The synthetic cathinones are dangerous drugs with powerful pharmacological effects that include high abuse potential, hyperthermia and hyperlocomotion. These drugs also share many of the pharmacological effects of the amphetamine class of drugs including methamphetamine, amphetamine and MDMA and therefore have high potential to cause damage to the central nervous system. The synthetic cathinones are frequently taken in combination with other psychoactive drugs such as alcohol, marijuana and the amphetamine-like stimulants, creating a situation where heightened pharmacological and neurotoxicological effects are likely to occur. Despite the structural features shared by the synthetic cathinones and amphetamine-like stimulants, including their actions at monoamine transporters and receptors, the effects of the synthetic cathinones do not always match those of the amphetamines. In particular, the synthetic cathinones are far less neurotoxic than their amphetamine counterparts, they produce a weaker hyperthermia, and they cause less glial activation. This chapter will briefly review the pharmacology and neurotoxicology of selected synthetic cathinones with the aim of delineating key areas of agreement and disagreement in the literature particularly as it relates to neurotoxicological outcomes.

Proliferating cell nuclear antigen (PCNA) is an essential scaffold protein in many cellular processes. It is best known for its role as a DNA sliding clamp and processivity factor during DNA replication, which has been extensively reviewed by others. However, the importance of PCNA extends beyond its DNA-associated functions in DNA replication, chromatin remodelling, DNA repair and DNA damage tolerance (DDT), as new non-canonical roles of PCNA in the cytosol have recently been identified. These include roles in the regulation of immune evasion, apoptosis, metabolism, and cellular signalling. The diverse roles of PCNA are largely mediated by its myriad protein interactions, and its centrality to cellular processes makes PCNA a valid therapeutic anticancer target. PCNA is expressed in all cells and plays an essential role in normal cellular homeostasis; therefore, the main challenge in targeting PCNA is to selectively kill cancer cells while avoiding unacceptable toxicity to healthy cells. This chapter focuses on the stress-related roles of PCNA, and how targeting these PCNA roles can be exploited in cancer therapy.

Modafinil is a central nervous system stimulant approved for the treatment of narcolepsy and sleep disorders. Due to its wide range of biochemical actions, modafinil has been explored for other potential therapeutic uses. Indeed, it has shown promise as a therapy for cognitive disfunction resulting from neurologic disorders like ADHD, and as a smart drug in non-medical settings. The mechanism(s) of actions underlying the therapeutic efficacy of this agent remains largely elusive. Modafinil is known to inhibit the dopamine transporter, thus decreasing dopamine reuptake following neuronal release, an effect shared by addictive psychostimulants. However, modafinil is unique in that only a few cases of dependence on this drug have been reported, as compared to other psychostimulants. Moreover, modafinil has been tested, with some success, as a potential therapeutic agent to combat psychostimulant and other substance use disorders. Modafinil has additional, but less understood, actions on other neurotransmitter systems (GABA, glutamate, serotonin, norepinephrine, etc.). These interactions, together with its ability to activate selected brain regions, are likely one of the keys to understand its unique pharmacology and therapeutic activity as a CNS stimulant. In this chapter, we outline the pharmacokinetics and pharmacodynamics of modafinil that suggest it has an "atypical" CNS stimulant profile. We also highlight the current approved and off label uses of modafinil, including its beneficial effects as a treatment for sleep disorders, cognitive functions, and substance use disorders.

Over the past decade, the zinc metalloenzyme glutamate carboxypeptidase (GCPII) has emerged as a novel therapeutic target for IBD. This enzyme is minimally expressed in healthy ileum or colon, but is profoundly upregulated in multiple IBD subtypes including: adult and pediatric Crohn's disease (CD), adult and pediatric ulcerative colitis (UC), and UC pouchitis. Encouragingly, small molecule GCPII inhibitors display promising efficacy in chemical and genetic preclinical colitis models. In this chapter we will: (1) review GCPII biology, (2) present the data confirming its upregulation in IBD patients at gene and protein levels, (3) discuss foundational pre-clinical studies that established the anti-colitis efficacy of small molecule GCPII inhibitors, and (4) introduce the rationale and development of a novel class of GCPII inhibitors, including lead compound (S)-IBD3540, which hold therapeutic promise for IBD.

Chronic intestinal inflammation in patients with inflammatory bowel disease (IBD) can lead to the development of fibrosis and the formation of strictures. Endoscopic balloon dilation and surgical resection are currently the only available treatments for fibrotic strictures. However, both strategies are associated with potential complications and high rates of stricture recurrence, necessitating additional procedures and/or multiple surgical resections. IBD therapeutic modalities aimed at inflammation, including anti-inflammatory agents, such as corticosteroids, biologics and small molecules, have shown limited efficacy in altering the natural history of strictures, ameliorating fibrosis progression, or preventing recurrences. New and innovative therapeutic approaches targeted at fibrosis are urgently needed. Herein, we provide an overview of emerging therapeutics, including novel drug delivery systems, for the management of intestinal fibrosis and strictures.

Parental exposure to drugs of abuse induces changes in the germline that can be transmitted across subsequent generations, resulting in enduring effects on gene expression and behavior. This transgenerational inheritance involves a dynamic interplay of environmental, genetic, and epigenetic factors that impact an individual's vulnerability to neuropsychiatric disorders. This chapter aims to summarize recent research into the mechanisms underlying the inheritance of gene expression and phenotypic patterns associated with exposure to drugs of abuse, with an emphasis on cocaine. We will first define the epigenetic modifications such as DNA methylation, histone post-translational modifications, and expression of non-coding RNAs that are impacted by parental cocaine use. We will then explore how parental cocaine use induces heritable epigenetic changes that are linked to alterations in neural circuitry and synaptic plasticity within reward-related circuits, ultimately giving rise to potential behavioral vulnerabilities. This discussion will consider phenotypic differences associated with gestational as well as both maternal and paternal preconception drug exposure and will emphasize differences based on offspring sex. In this context, we explore the complex interactions between genetics, epigenetics, environment, and biological sex. Overall, this chapter consolidates the latest developments in the multigenerational effects and long-term consequences of parental substance abuse.