Pharmacological Reviews

Type 2 diabetes mellitus (T2DM) is a complex disease that can lead to a variety of life-threatening secondary health conditions. Current treatment strategies primarily revolve around tight glucose control that is difficult to achieve and often turns out to be dangerous due to possible hypoglycemic events. Numerous long-term studies have demonstrated that complex pathways, including low-grade inflammation due to fluctuating glucose levels, are involved in the progression of the disease and the development of secondary health conditions...

Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described in organisms allover the phylogenetic tree. They catalyze the hydration of CO2 to bicarbonate and protons, and are involved in pH regulation, chemosensing and metabolism. The 15 α-CA isoforms present in humans are pharmacological drug targets known for decades, their inhibitors being used as diuretics, antiglaucoma, antiepileptic or antiobesity drugs, as well as for the management of acute mountain sickness, idiopathic intracranial hypertension and recently, as antitumor theragnostic agents...

The history of anti-obesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials...

Both pre-clinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurological and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilate oxidase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system...

Bitter perception plays a critical role for the detection of potentially harmful substances in food items for most vertebrates. The detection of bitter compounds is facilitated by specialized receptors located in taste buds of the oral cavity. This work focuses on the receptors, including their sensitivities, structure-function relationships, agonists and antagonists. Moreover, the existence of numerous bitter taste receptor variants in the human population and the fact that several of them affect individual bitter tasting profoundly, is discussed as well...

Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focussed primarily on the drug physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic and tissue-specific players in a range of biological and pathological processes, including within the intestine...

Hearing disorders pose significant challenges to individuals suffering them and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Current treatment options often focus on amplification devices, cochlear implants, or other rehabilitative therapies, leaving a substantial gap in effective pharmacological interventions. Advancements in our understanding of the molecular and cellular mechanisms involved in hearing disorders induced by noise, aging and ototoxicity have opened new avenues for drug development, some of which have led to a number of clinical trials with promising results...

α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease (PD), Dementia with Lewy Bodies and Multiple System Atrophy. Various factors, including post-translational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability...

Depression is a highly prevalent disorder and a leading cause of disability worldwide. It has a major impact on the affected individual and on society as a whole. Regrettably, current available treatments for this condition are insufficient in many patients. In recent years, the gut microbiome has emerged as a promising alternative target for treating and preventing depressive disorders. However, the microbes that form this ecosystem do not act alone, but are part of a complicated network connecting the gut and the brain that influences our mood...

Our knowledge of the roles of individual cytochrome P450 (P450, CYP) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" of metabolism reactions with new drug candidates. Endogenous biomarkers are being used for non-invasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions...

Over four decades of research support the link between Alzheimer's disease (AD) and somatostatin (somatotropin-releasing inhibitory factor, SRIF). SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-beta peptide (Aβ), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation...

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions...

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Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e., pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan, and North America and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies...

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity, and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), type-2 diabetes, and inflammatory bowel diseases (IBD)...

The class F of G protein-coupled receptors (GPCRs) consists of ten Frizzleds (FZD1-10 ) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched (PTCH). The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first class F GPCR IUPHAR nomenclature report, justifies an update...

Voltage-gated sodium (NaV ) channels are intimately involved in the generation and transmission of action potentials, and dysfunction of these channels may contribute to nervous system diseases such as epilepsy, neuropathic pain, psychosis, autism and cardiac arrhythmia. Many venom peptides selectively act on NaV channels. These include conotoxins, which are neurotoxins secreted by cone snails for prey capture or self-defense, but which are also valuable pharmacological tools for the identification and/or treatment of human diseases...

The purpose of this review is to summarize essential biological, pharmaceutical and clinical aspects in the field of topically applied medicines that may help scientists when trying to develop new topical medicines. After a brief history of topical drug delivery, a review of the structure and function of the skin, routes of drug absorption and their limitations is then provided. The most prevalent diseases and current topical treatment approaches are then detailed, the organization of which reflects the key disease categories of autoimmune and inflammatory, microbial infections, skin cancers and genetic skin diseases...

The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX1 and OX2 Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate...