Advances in Pharmacology

Synthetic cathinone derivatives comprise a family of psychoactive compounds structurally related to amphetamine. Over the last decade, clandestine chemists have synthesized a consistent stream of innovative cathinone derivatives to outpace governmental regulatory restrictions. Many of these unregulated substances are produced and distributed as designer drugs. Two of the principal chemical scaffolds exploited to expand the synthetic cathinone family are methcathinone and α-pyrrolidinopentiophenone (or α-pyrrolidinovalerophenone, α-PVP)...

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...

Nicotine use disorder remains a major public health emergency despite years of trumpeting the consequences of smoking. This is likely due to the complex interplay of genetics and nicotine exposure across the lifespan of these individuals. Genetics influence all aspects of life, including complex disorders such as nicotine use disorder. This review first highlights the critical neurocircuitry underlying nicotine dependence and withdrawal, and then describes the cellular signaling mechanisms involved. Finally, current genetic, genomic, and transcriptomic evidence for new drug development of smoking cessation aids is discussed, with a focus on the Neuregulin 3 Signaling Pathway...

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.

The dopamine transporter (DAT) is a key site of action for cocaine and amphetamines. Dysfunctional DAT is associated with aberrant synaptic dopamine transmission and enhanced drug-seeking and taking behavior. Studies in cultured cells and ex vivo suggest that DAT function is sensitive to membrane cholesterol content. Although it is largely unknown whether psychostimulants alter cholesterol metabolism in the brain, emerging evidence indicates that peripheral cholesterol metabolism is altered in patients with psychostimulant use disorder and circulating cholesterol levels are associated with vulnerability to relapse...

This review discusses the diverse effects of nicotine on the various nicotinic acetylcholine receptors of the central and peripheral nervous system and how those effects may promote the usage and addiction to tobacco products.

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...

In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of d-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release d-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents...

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...

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...

Methamphetamine (METH) is the most commonly misused amphetamine-type stimulant throughout the globe. METH is very rewarding, and its misuse can lead to a diagnosis of METH use disorder (MUD). Although METH use is observed in both sexes, there are, however, reported differences in the clinical manifestations of METH use and its consequences. These observations indicate the need for more research on the long-term sex-dependent consequences of METH taking in both preclinical and clinical settings. In effect, sex is a biological variable that can impact conclusions drawn from various basic and clinical studies...

Use of amphetamines during adolescence, a critical period of brain development and reorganization, may lead to particularly adverse outcomes that are long-lasting. Similarly, female users may be uniquely vulnerable to certain aspects of drug use. A recognition of the role of use during adolescence and sex on outcomes of amphetamine and methamphetamine exposure are of critical importance in understanding and treating substance use disorders. This chapter highlights what human research, which has been largely epidemiological, suggests about sex and age differences in drug use patterns and outcomes...

The availability of monoamine neurotransmitters in the brain is under the control of dopamine, norepinephrine, and serotonin transporters expressed on the plasma membrane of monoaminergic neurons. By regulating transmitter levels these proteins mediate crucial functions including cognition, attention, and reward, and dysregulation of their activity is linked to mood and psychiatric disorders of these systems. Amphetamine-based transporter substrates stimulate non-exocytotic transmitter efflux that induces psychomotor stimulation, addiction, altered mood, hallucinations, and psychosis, thus constituting a major component of drug neurochemical and behavioral outcomes...

Macrolide compounds, many of which are derived from natural sources, all share a lactone ring structure, but of varying sizes. Their biological activities differ with structure and size but tend to overlap. Marketed macrolide drugs include immunosuppressives and antibiotics. Some of the latter have been shown to exert anti-inflammatory activities, due to direct effects on inflammatory cells and processes when used for respiratory infections. Consequently, azithromycin is included in clinical guidelines for COPD and asthma treatment, though it has the disadvantage, as an antibiotic, of increasing bacterial resistance...

Phosphodiesterase enzymes (PDE) have long been known as regulators of cAMP and cGMP, second messengers involved in various signaling pathways and expressed in a variety of cell types implicated in respiratory diseases such as airway smooth muscle and inflammatory cells making them a key target for the treatment of lung diseases as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and pulmonary hypertension (PH). The first reported PDE inhibitor was the xanthine, theophylline, described as a non-specific PDE inhibitor and whilst this drug is effective, it also has a range of unwanted side effects...

Severe or refractory asthma is seen in approximately 5% of asthmatic subjects who have unsatisfactory symptom control despite adherence to high-dose inhaled glucocorticoid therapies resulting in significant morbidity, reduced quality of life with attendant implications for healthcare costs. Marked heterogeneity in symptoms and at the molecular phenotypic level are hallmarks of asthma resulting in the requirement of specifically targeted treatments to block the key pathways of the disease. Monoclonal antibody (mAb)-based biologics targeted at inhibition of the type 2 cytokines IL-4, IL-5 and IL-13 have become established as effective treatments for severe asthma, with significant clinical benefit seen in carefully selected patient populations that take asthma phenotypes and endotypes into account...

Inhaled therapy is the cornerstone of the management of asthma and chronic obstructive pulmonary disease (COPD). Drugs such as bronchodilators and corticosteroids are administered directly to the airways for local effect and rapid onset of action while systemic exposure and side effects are minimized. There are four major types of inhaler devices used clinically to generate aerosols for inhalation, namely, pressurized metered-dose inhalers (pMDIs), nebulizers, Soft Mist™ inhalers (SMIs) and dry powder inhalers (DPIs)...

Increasing evidence suggests that there is acceleration of lung ageing in chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), with the accumulation of senescent cells in the lung. Senescent cells fail to repair tissue damage and release an array of inflammatory proteins, known as the senescence-associated secretory phenotype, which drive further senescence and disease progression. This suggests that targeting cellular senescence with senotherapies may treat the underlying disease process in COPD and IPF and thus reduce disease progression and mortality...

Chronic obstructive pulmonary disease (COPD) is a major cause of death and reduces quality of life that contributes to a health problem worldwide. Chronic airway inflammation is a hallmark of COPD, which occurs in response to exposure of inhaled irritants like cigarette smoke. Despite accessible to the most up-to-date medications, none of the treatments is currently available to decrease the disease progression. Therefore, it is believed that drugs which can reduce airway inflammation will provide effective disease modifying therapy for COPD...

Idiopathic pulmonary fibrosis (IPF) results from the dysregulated process of injury and repair, which promotes scarring of the lung tissue and deposition of collagen-rich extracellular matrix (ECM) components, that make the lung unphysiologically stiff. IPF presents a serious concern as its pathogenesis remains elusive, and current anti-fibrotic treatments are only effective in slowing rather than halting disease progression. The IPF disease pathogenesis is incompletely defined, complex and incorporates interplay between different fibrogenesis signaling pathways...