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Profiles of Drug Substances,... 2024Duvelisib (DUV) is chemically named as (S)-3-(1-((9H-Purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. It is a novel drug with a small molecular weight and... (Review)
Review
Duvelisib (DUV) is chemically named as (S)-3-(1-((9H-Purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. It is a novel drug with a small molecular weight and characterized by dual phosphoinositide-3-kinase (PI3K)- and PI3K-inhibitory activity. The Food and Drug Administration (FDA) recently approved DUV for the management of small lymphocytic lymphoma (SLL) and relapsed or refractory chronic lymphocytic leukemia (CLL) in adult patients. DUV is marketed under the brand name of Copiktra® (Verastem, Inc., Needham, MA, USA). This chapter provides a critical extensive review of the literature, the description of DUV in terms of its names, formulae, elemental composition, appearance, and use in the treatment of CLL, SLL, and follicular lymphoma. The chapter also describes the methods for preparation of DUV, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.
Topics: Adult; Humans; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Phosphatidylinositol 3-Kinases; Purines
PubMed: 38423708
DOI: 10.1016/bs.podrm.2023.11.002 -
Current Opinion in Pulmonary Medicine Jan 2018Metabolomics has been used to uncover the metabolic signatures of asthma, both for biomarker identification and pathophysiologic mechanisms research. We aimed to review... (Review)
Review
PURPOSE OF REVIEW
Metabolomics has been used to uncover the metabolic signatures of asthma, both for biomarker identification and pathophysiologic mechanisms research. We aimed to review recent advances in this field, published since 2016, and discuss these findings implications to future research and application into clinical practice.
RECENT FINDINGS
Experimental asthma models and clinical studies in both children and adults supported independent metabolic signatures of asthma. Common reported pathways included purine, glycerophospholipid, glutathione, fatty acids, and arginine and proline metabolism. Metabolomics-based studies identified candidate biomarkers related to asthma severity and corticosteroid resistance, and supported the definition of the obesity-related phenotype at the molecular level. A systematic review with meta-analysis and recent prospective studies favored exhaled volatile organic compounds as one of the most promising biomarkers in asthma diagnosis and monitoring.
SUMMARY
Metabolomics has provided unique and novel insights into asthma profiling at the molecular level. Current challenges include procedures standardization and control of potentially confounding variables for external validation. Point-of-care technology developments bring metabolomics closer to clinical practice. In addition to biomarkers identification, relating metabolites to their biologic role will serve as critical foundations for understanding the biology underpinning asthma heterogeneity and for specific-targeted therapies. VIDEO ABSTRACT.
Topics: Adrenal Cortex Hormones; Asthma; Biomarkers; Exhalation; Humans; Metabolomics; Obesity; Phenotype; Predictive Value of Tests; Purines; Volatile Organic Compounds
PubMed: 29059088
DOI: 10.1097/MCP.0000000000000437 -
Purinergic Signalling Dec 2019Extracellular purines (ATP and adenosine) are ubiquitous intercellular messengers. During tissular damage, they function as damage-associated molecular patterns (DAMPs).... (Review)
Review
Extracellular purines (ATP and adenosine) are ubiquitous intercellular messengers. During tissular damage, they function as damage-associated molecular patterns (DAMPs). In this context, purines announce tissue alterations to initiate a reparative response that involve the formation of the inflammasome complex and the recruitment of specialized cells of the immune system. The present review focuses on the role of the purinergic system in liver damage, mainly during the onset and development of fibrosis. After hepatocellular injury, extracellular ATP promotes a signaling cascade that ameliorates tissue alterations to restore the hepatic function. However, if cellular damage becomes chronic, ATP orchestrates an aberrant reparative process that results in severe liver diseases such as fibrosis and cirrhosis. ATP and adenosine, their receptors, and extracellular ectonucleotidases are mediators of unique processes that will be reviewed in detail.
Topics: Adenosine; Adenosine Triphosphate; Animals; Humans; Liver; Liver Diseases; Purines; Receptors, Purinergic
PubMed: 31576486
DOI: 10.1007/s11302-019-09680-3 -
Archives of Physiology and Biochemistry Feb 2022To find the association between purine metabolites and diabetic complications in rats.
AIM
To find the association between purine metabolites and diabetic complications in rats.
MATERIALS AND METHODS
Alloxan was administered to induce diabetes in rats. After 30 days, the levels of uric acid, inosine, xanthine, hypoxanthine and AMP were assessed in both plasma and liver tissues using HPLC technique.
RESULTS
A significant increase in xanthine, hypoxanthine, AMP levels ( < .001 and -value 2.78) and inosine in plasma and liver tissues ( < .05 and -value 2.11) with a concomitant increase in uric acid levels ( < .001 and -value 2.80) was observed in diabetic group.
CONCLUSION
Purine metabolites like uric acid and other intermediate products of purine metabolism are increased in diabetes. These results can be used in addition or separately in evaluating the progression of diabetes.
Topics: Animals; Diabetes Mellitus; Hypoxanthine; Purines; Rats; Uric Acid; Xanthine
PubMed: 31517540
DOI: 10.1080/13813455.2019.1663219 -
Xenobiotica; the Fate of Foreign... Jan 2020The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although... (Review)
Review
The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN) monitoring provides a basis for dose adjustment and the identification of patients with high levels of red cell methylmercaptopurine (MMP) and an increase in the MMP:TGN ratio. These patients are at risk for hepatotoxicity and where TGN levels are sub-therapeutic, non-response to therapy. Switching thiopurine hypermethylators to low-dose thiopurine and allopurinol combination therapy resolves hepatoxicity and increases sub-therapeutic TGN levels to regain clinical response. variants are a common cause of severe myelotoxicity in Asian populations where the frequency of TPMT deficiency is low. There is increasing evidence that testing for NUDT15 and TPMT deficiency in all populations prior to the start of thiopurine therapy is clinically useful and should be the first step in personalising thiopurine therapy.
Topics: Azathioprine; Drug Hypersensitivity; Erythrocytes; Female; Genotype; Humans; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine-Pyrimidine Metabolism, Inborn Errors; Purines
PubMed: 31682552
DOI: 10.1080/00498254.2019.1688424 -
Yeast (Chichester, England) Nov 2019Exploring new drug candidates or drug targets against many illnesses is necessary as "traditional" treatments lose their effectivity. Cancer and sicknesses caused by... (Review)
Review
Exploring new drug candidates or drug targets against many illnesses is necessary as "traditional" treatments lose their effectivity. Cancer and sicknesses caused by protozoan parasites are among these diseases. Cell purine metabolism is an important drug target. Theoretically, inhibiting purine metabolism could stop the proliferation of unwanted cells. Purine metabolism is similar across all eukaryotes. However, some medically important organisms or cell lines rely on their host purine metabolism. Protozoans causing malaria, leishmaniasis, or toxoplasmosis are purine auxotrophs. Some cancer forms have also lost the ability to synthesize purines de novo. Budding yeast can serve as an effective model for eukaryotic purine metabolism, and thus, purine auxotrophic strains could be an important tool. In this review, we present the common principles of purine metabolism in eukaryotes, effects of purine starvation in eukaryotic cells, and purine-starved Saccharomyces cerevisiae as a model for purine depletion-elicited metabolic states with applications in evolution studies and pharmacology. Purine auxotrophic yeast strains behave differently when growing in media with sufficient supplementation with adenine or in media depleted of adenine (starvation). In the latter, they undergo cell cycle arrest at G1/G0 and become stress resistant. Importantly, similar effects have also been observed among parasitic protozoans or cancer cells. We consider that studies on metabolic changes caused by purine auxotrophy could reveal new options for parasite or cancer therapy. Further, knowledge on phenotypic changes will improve the use of auxotrophic strains in high-throughput screening for primary drug candidates.
Topics: Adenine; Cell Cycle Checkpoints; Drug Development; Eukaryota; Humans; Neoplasms; Purines; Saccharomyces cerevisiae
PubMed: 31334866
DOI: 10.1002/yea.3434 -
Cell Metabolism Jan 2022Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of...
Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4 and CD8 T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation.
Topics: Autoimmunity; CD8-Positive T-Lymphocytes; Dendritic Cells; Lymphocyte Activation; Purines
PubMed: 34986329
DOI: 10.1016/j.cmet.2021.12.009 -
Molecular Psychiatry Jan 2018Psychiatric disorders are debilitating diseases, affecting >80 million people worldwide. There are no causal cures for psychiatric disorders and available therapies only... (Review)
Review
Psychiatric disorders are debilitating diseases, affecting >80 million people worldwide. There are no causal cures for psychiatric disorders and available therapies only treat the symptoms. The etiology of psychiatric disorders is unknown, although it has been speculated to be a combination of environmental, stress and genetic factors. One of the neurotransmitter systems implicated in the biology of psychiatric disorders is the purinergic system. In this review, we performed a comprehensive search of the literature about the role and function of the purinergic system in the development and predisposition to psychiatric disorders, with a focus on depression, schizophrenia, bipolar disorder, autism, anxiety and attention deficit/hyperactivity disorder. We also describe how therapeutics used for psychiatric disorders act on the purinergic system.
Topics: Animals; Causality; Humans; Mental Disorders; Purines; Receptors, Purinergic
PubMed: 28948971
DOI: 10.1038/mp.2017.188 -
Molecular Cell Sep 2021With the elucidation of myriad anabolic and catabolic enzyme-catalyzed cellular pathways crisscrossing each other, an obvious question arose: how could these networks... (Review)
Review
With the elucidation of myriad anabolic and catabolic enzyme-catalyzed cellular pathways crisscrossing each other, an obvious question arose: how could these networks operate with maximal catalytic efficiency and minimal interference? A logical answer was the postulate of metabolic channeling, which in its simplest embodiment assumes that the product generated by one enzyme passes directly to a second without diffusion into the surrounding medium. This tight coupling of activities might increase a pathway's metabolic flux and/or serve to sequester unstable/toxic/reactive intermediates as well as prevent their access to other networks. Here, we present evidence for this concept, commencing with enzymes that feature a physical molecular tunnel, to multi-enzyme complexes that retain pathway substrates through electrostatics or enclosures, and finally to metabolons that feature collections of enzymes assembled into clusters with variable stoichiometric composition. Lastly, we discuss the advantages of reversibly assembled metabolons in the context of the purinosome, the purine biosynthesis metabolon.
Topics: Animals; Humans; Metabolic Networks and Pathways; Metabolism; Metabolome; Multienzyme Complexes; Protein Interaction Maps; Purines
PubMed: 34547238
DOI: 10.1016/j.molcel.2021.08.030 -
Neuroscience May 2019Microglia are the main resident immune-competent cell type of the central nervous system (CNS); these cells are highly sensitive to subtle changes in the chemical... (Review)
Review
Microglia are the main resident immune-competent cell type of the central nervous system (CNS); these cells are highly sensitive to subtle changes in the chemical environment of the brain. Microglia are activated during diverse conditions, such as apoptosis, trauma, inflammation, and infection. The specific activities of microglia result from the confluence of environmental stimuli and the cellular state. It is likely that several signaling systems with different biological functions operate in competition and/or synergy, thus regulating similar microglial behaviors. The purinergic system is one of the fundamental signaling systems that establish microglial behavior in a wide spectrum of conditions. Adenosine tri-phosphate (ATP) belongs to the purinergic signaling system, which includes P2X, P2Y, and P1 receptors, as well as other proteins participating in ATP secretion and extracellular ATP degradation, and molecules that recognize purines as a ligand. In this review, we focus on the latest pre-clinical and basic purinergic system and microglial research, with particular attention to data collected in vivo and ex vivo. This chapter is divided into sections related to microglial ATP release, ATP degradation, and ATP-related actions mediated by P2X and P2Y receptor activation.
Topics: Adenosine Triphosphate; Animals; Calcium; Humans; Microglia; Purines; Receptors, Purinergic; Signal Transduction
PubMed: 30582977
DOI: 10.1016/j.neuroscience.2018.12.021