Статті в журналах: "THERAPEUTICS ACTION"

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Lenz, Kiersten D., Katja E. Klosterman, Harshini Mukundan, and Jessica Z. Kubicek-Sutherland. "Macrolides: From Toxins to Therapeutics." Toxins 13, no. 5 (May 12, 2021): 347. http://dx.doi.org/10.3390/toxins13050347.

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Macrolides are a diverse class of hydrophobic compounds characterized by a macrocyclic lactone ring and distinguished by variable side chains/groups. Some of the most well characterized macrolides are toxins produced by marine bacteria, sea sponges, and other species. Many marine macrolide toxins act as biomimetic molecules to natural actin-binding proteins, affecting actin polymerization, while other toxins act on different cytoskeletal components. The disruption of natural cytoskeletal processes affects cell motility and cytokinesis, and can result in cellular death. While many macrolides are toxic in nature, others have been shown to display therapeutic properties. Indeed, some of the most well known antibiotic compounds, including erythromycin, are macrolides. In addition to antibiotic properties, macrolides have been shown to display antiviral, antiparasitic, antifungal, and immunosuppressive actions. Here, we review each functional class of macrolides for their common structures, mechanisms of action, pharmacology, and human cellular targets.

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Cattley, Russell C., and Bert R. Radinsky. "Cancer Therapeutics: Understanding the Mechanism of Action." Toxicologic Pathology 32, no. 1_suppl (January 2004): 116–21. http://dx.doi.org/10.1080/01926230490426507.

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Cefalu, William T., and David Ribnicky. "Modulation of Insulin Action by Botanical Therapeutics." Obesity and Weight Management 5, no. 6 (December 2009): 277–81. http://dx.doi.org/10.1089/obe.2009.0604.

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Eidelman, Cristy, Tracy Sandritter, and Jennifer Lowry. "Individualized Pediatric Therapeutics Clinic: Action in Practice." Pediatrics 142, no. 1_MeetingAbstract (May 1, 2018): 798. http://dx.doi.org/10.1542/peds.142.1ma8.798.

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Cronstein, Bruce N. "Molecular therapeutics. Methotrexate and its mechanism of action." Arthritis & Rheumatism 39, no. 12 (December 1996): 1951–60. http://dx.doi.org/10.1002/art.1780391203.

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Alves de Souza, Stephanny Miranda, Blanca Hernández-Ledesma, and Theo Luiz Ferraz de Souza. "Lunasin as a Promising Plant-Derived Peptide for Cancer Therapy." International Journal of Molecular Sciences 23, no. 17 (August 23, 2022): 9548. http://dx.doi.org/10.3390/ijms23179548.

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Cancer has become one of the main public health problems worldwide, demanding the development of new therapeutic agents that can help reduce mortality. Lunasin is a soybean peptide that has emerged as an attractive option because its preventive and therapeutic actions against cancer. In this review, we evaluated available research on lunasin’s structure and mechanism of action, which should be useful for the development of lunasin-based therapeutic products. We described data on its primary, secondary, tertiary, and possible quaternary structure, susceptibility to post-translational modifications, and structural stability. These characteristics are important for understanding drug activity and characterizing lunasin products. We also provided an overview of research on lunasin pharmacokinetics and safety. Studies examining lunasin’s mechanisms of action against cancer were reviewed, highlighting reported activities, and known molecular partners. Finally, we briefly discussed commercially available lunasin products and potential combination therapeutics.

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7

Chaney, Sarah. "The action of the imagination." History of the Human Sciences 30, no. 2 (April 2017): 17–33. http://dx.doi.org/10.1177/0952695116687225.

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Histories of dynamic psychotherapy in the late 19th century have focused on practitioners in continental Europe, and interest in psychological therapies within British asylum psychiatry has been largely overlooked. Yet Daniel Hack Tuke (1827–95) is acknowledged as one of the earliest authors to use the term ‘psycho-therapeutics’, including a chapter on the topic in his 1872 volume, Illustrations of the Influence of the Mind upon the Body in Health and Disease. But what did Tuke mean by this concept, and what impact did his ideas have on the practice of asylum psychiatry? At present, there is little consensus on this topic. Through in-depth examination of what psycho-therapeutics meant to Tuke, this article argues that late-19th-century asylum psychiatry cannot be easily separated into somatic and psychological strands. Tuke’s understanding of psycho-therapeutics was extremely broad, encompassing the entire field of medical practice (not only psychiatry). The universal force that he adopted to explain psychological therapies, ‘the Imagination’, was purported to show the power of the mind over the body, implying that techniques like hypnotism and suggestion might have an effect on any kind of symptom or illness. Acknowledging this aspect of Tuke’s work, I conclude, can help us better understand late-19th-century psychiatry – and medicine more generally – by acknowledging the lack of distinction between psychological and somatic in ‘psychological’ therapies.

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Jerome, Christopher P., and Rogely Boyce. "Bone Therapeutics: Safety Considerations, Session Summary." Toxicologic Pathology 45, no. 7 (October 2017): 855–58. http://dx.doi.org/10.1177/0192623317737231.

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This session was a series of presentations focused on safety considerations for late stage or currently marketed bone therapeutic agents. The first presentation was an overview of a major regulatory requirement in the nonclinical filing package for bone therapeutics, studies designed to assess the impact of an agent on bone quality. Two presentations focused on safety issues associated with drugs whose primary mechanism of action is inhibition of bone resorption. Typical findings associated with this class of agents in general and reproductive toxicology studies were reviewed, highlighting INHAND (International Harmonization of Nomenclature and Diagnostic Criteria) nomenclature. This was followed by an overview of safety issues that have been identified largely through clinical experience. Similar presentations followed emphasizing safety and regulatory issues associated with classes of drugs whose primary mechanism of action is stimulation of bone formation known broadly as bone anabolic agents. The major focus of these discussions was carcinogenicity risk assessment. The final presentation was an introduction to a rapidly evolving area in bone therapeutics, treatment of rare genetic bone diseases, and the developmental challenges associated with these indications and novel therapeutic modalities.

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Kordus, Shannon L., Audrey K. Thomas, and D. Borden Lacy. "Clostridioides difficile toxins: mechanisms of action and antitoxin therapeutics." Nature Reviews Microbiology 20, no. 5 (November 26, 2021): 285–98. http://dx.doi.org/10.1038/s41579-021-00660-2.

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Guo, Haitao, Justin B. Callaway, and Jenny P.-Y. Ting. "Inflammasomes: mechanism of action, role in disease, and therapeutics." Nature Medicine 21, no. 7 (June 29, 2015): 677–87. http://dx.doi.org/10.1038/nm.3893.

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11

Cines, Douglas B., Steven E. McKenzie, and Don L. Siegel. "Mechanisms of Action of Therapeutics in Idiopathic Thrombocytopenic Purpura." Journal of Pediatric Hematology/Oncology 25, Supplement 1 (December 2003): S52—S56. http://dx.doi.org/10.1097/00043426-200312001-00012.

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Szlachcic, Anna, Malgorzata Zakrzewska, and Jacek Otlewski. "Longer action means better drug: Tuning up protein therapeutics." Biotechnology Advances 29, no. 4 (July 2011): 436–41. http://dx.doi.org/10.1016/j.biotechadv.2011.03.005.

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13

Kwekkeboom, Rick F. J., Zhiyong Lei, Pieter A. Doevendans, René J. P. Musters, and Joost P. G. Sluijter. "Targeted delivery of miRNA therapeutics for cardiovascular diseases: opportunities and challenges." Clinical Science 127, no. 6 (May 21, 2014): 351–65. http://dx.doi.org/10.1042/cs20140005.

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Dysregulation of miRNA expression has been associated with many cardiovascular diseases in animal models, as well as in patients. In the present review, we summarize recent findings on the role of miRNAs in cardiovascular diseases and discuss the opportunities, possibilities and challenges of using miRNAs as future therapeutic targets. Furthermore, we focus on the different approaches that can be used to deliver these newly developed miRNA therapeutics to their sites of action. Since siRNAs are structurally homologous with the miRNA therapeutics, important lessons learned from siRNA delivery strategies are discussed that might be applicable to targeted delivery of miRNA therapeutics, thereby reducing costs and potential side effects, and improving efficacy.

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Blier, Pierre, and Mostafa El Mansari. "Serotonin and beyond: therapeutics for major depression." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1615 (April 5, 2013): 20120536. http://dx.doi.org/10.1098/rstb.2012.0536.

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The serotonin (5-HT, 5-hydroxytryptamine) system has been implicated in the pathogenesis of major depressive disorder (MDD). The case for its contribution to the therapeutic efficacy of a wide variety of antidepressant treatments is, however, much stronger. All antidepressant strategies have been shown to enhance 5-HT transmission in the brain of laboratory animals. Catecholamines, norepinephrine (NE) and dopamine (DA) can also play a pivotal role in the mechanism of action of certain antidepressant strategies. The enhancement of 5-HT transmission by selective serotonin reuptake inhibitors, which leads to a dampening of the activity of NE and DA neurons, may account in part for the low remission rate achieved with these medications and/or the residuals symptoms after remission is achieved. The functional connectivity between the 5-HT, NE and DA systems can be used to understand the mechanism of action of a wide variety of augmentation strategies in treatment-resistant MDD. Proof-of-concept studies have shown that antidepressant medications with complementary mechanisms of action on monoaminergic systems can double the remission rate achieved in a trial of standard duration. Novel approaches are also being used to treat MDD, which also appear to involve the monoaminergic system(s) to a varying extent.

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15

Bose, Debopriya, Laboni Roy, and Subhrangsu Chatterjee. "Peptide therapeutics in the management of metastatic cancers." RSC Advances 12, no. 33 (2022): 21353–73. http://dx.doi.org/10.1039/d2ra02062a.

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Karagiannis, Dimitris, and Theodoros Rampias. "HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity." Cancers 13, no. 14 (July 16, 2021): 3575. http://dx.doi.org/10.3390/cancers13143575.

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Intra-tumoral heterogeneity presents a major obstacle to cancer therapeutics, including conventional chemotherapy, immunotherapy, and targeted therapies. Stochastic events such as mutations, chromosomal aberrations, and epigenetic dysregulation, as well as micro-environmental selection pressures related to nutrient and oxygen availability, immune infiltration, and immunoediting processes can drive immense phenotypic variability in tumor cells. Here, we discuss how histone deacetylase inhibitors, a prominent class of epigenetic drugs, can be leveraged to counter tumor heterogeneity. We examine their effects on cellular processes that contribute to heterogeneity and provide insights on their mechanisms of action that could assist in the development of future therapeutic approaches.

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17

Bhutani, Jaikrit, Asfandyar Sheikh, and Asfandyar Niazi. "Akt inhibitors: mechanism of action and implications for anticancer therapeutics." Infectious Agents and Cancer 8, no. 1 (2013): 49. http://dx.doi.org/10.1186/1750-9378-8-49.

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18

Whitebay, E. A., K. A. M. Gasem, B. J. Neely, and J. D. Ramsey. "In Silico Prediction of Mechanism of Action for Cancer Therapeutics." Molecular Informatics 32, no. 8 (July 11, 2013): 735–41. http://dx.doi.org/10.1002/minf.201300039.

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19

Dcona, M. Michael, Koushambi Mitra, and Matthew C. T. Hartman. "Photocontrolled activation of small molecule cancer therapeutics." RSC Medicinal Chemistry 11, no. 9 (2020): 982–1002. http://dx.doi.org/10.1039/d0md00107d.

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Photosensitive molecules that mimic existing cancer drugs can potentially improve specificity of drug action. Here, we highlight examples of photocages and photoswitches that can be used in disease treatment with high spatio-temporal control.

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20

Mehta, M., O. A. Branford, and K. J. Rolfe. "The evidence for natural therapeutics as potential anti-scarring agents in burn-related scarring." Burns & Trauma 4 (May 4, 2016): 1–12. http://dx.doi.org/10.1186/s41038-016-0040-1.

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Abstract Though survival rate following severe thermal injuries has improved, the incidence and treatment of scarring have not improved at the same speed. This review discusses the formation of scars and in particular the formation of hypertrophic scars. Further, though there is as yet no gold standard treatment for the prevention or treatment of scarring, a brief overview is included. A number of natural therapeutics have shown beneficial effects both in vivo and in vitro with the potential of becoming clinical therapeutics in the future. These natural therapeutics include both plant-based products such as resveratrol, quercetin and epigallocatechin gallate as examples and includes the non-plant-based therapeutic honey. The review also includes potential mechanism of action for the therapeutics, any recorded adverse events and current administration of the therapeutics used. This review discusses a number of potential ‘treatments’ that may reduce or even prevent scarring particularly hypertrophic scarring, which is associated with thermal injuries without compromising wound repair.

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21

Patterson, Jacoby. "Small interfering RNA (siRNA)-based therapeutics." Drug and Therapeutics Bulletin 61, no. 5 (April 25, 2023): 72–76. http://dx.doi.org/10.1136/dtb.2023.000004.

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In early studies in simple organisms and mammalian cell lines, small interfering RNA (siRNA) molecules were found to allow experimental cleavage of intracellular messenger RNA (mRNA; the transcription product of a cell gene), reducing the levels of the proteins that would otherwise be formed by the action of the mRNA, thereby ‘silencing’ a specific gene. Researchers subsequently assessed the effects of this class of molecule in patients with various genetic conditions (eg, hereditary amyloidosis) that could benefit from reductions in the excessive quantities of harmful proteins (eg, amyloid). Due to the hydrophilic (non-fat-soluble) nature of the molecules, they have been formulated as lipid nanoparticles to aid transport into cells or conjugated to molecules with an ability to target certain cells in the body (eg, hepatocytes) to aid specificity of action. Their intracellular effects may last up to several months before they are broken down and inactivated. As they need to be composed of an exact complementary sequence to be able to cleave the target mRNA, they are thought to have few unwanted effects apart from infusion or injection site reactions. Several siRNA medicines have been licensed and many other products are in development for genetic hepatic, cardiovascular and ocular conditions.

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Hargreaves, Alexander, Caolann Brady, Jack Mellors, Tom Tipton, Miles W. Carroll, and Stephanie Longet. "Filovirus Neutralising Antibodies: Mechanisms of Action and Therapeutic Application." Pathogens 10, no. 9 (September 16, 2021): 1201. http://dx.doi.org/10.3390/pathogens10091201.

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Filoviruses, especially Ebola virus, cause sporadic outbreaks of viral haemorrhagic fever with very high case fatality rates in Africa. The 2013–2016 Ebola epidemic in West Africa provided large survivor cohorts spurring a large number of human studies which showed that specific neutralising antibodies played a key role in protection following a natural Ebola virus infection, as part of the overall humoral response and in conjunction with the cellular adaptive response. This review will discuss the studies in survivors and animal models which described protective neutralising antibody response. Their mechanisms of action will be detailed. Furthermore, the importance of neutralising antibodies in antibody-based therapeutics and in vaccine-induced responses will be explained, as well as the strategies to avoid immune escape from neutralising antibodies. Understanding the neutralising antibody response in the context of filoviruses is crucial to furthering our understanding of virus structure and function, in addition to improving current vaccines & antibody-based therapeutics.

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Bhakta, Minoti, Trang Vuong, Tetsuya Taura, David S. Wilson, Jennifer R. Stratton, and Kimberly D. Mackenzie. "Migraine therapeutics differentially modulate the CGRP pathway." Cephalalgia 41, no. 5 (February 24, 2021): 499–514. http://dx.doi.org/10.1177/0333102420983282.

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Background The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP – fremanezumab, galcanezumab and eptinezumab – and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature. Methods To gain insights into the potential differences between these CGRP pathway therapeutics, we compared the effect of a CGRP ligand antibody (fremanezumab), a CGRP receptor antibody (erenumab) and a CGRP receptor small molecule antagonist (telcagepant) using a combination of binding, functional and imaging assays. Results Erenumab and telcagepant antagonized CGRP, adrenomedullin and intermedin cAMP signaling at the canonical human CGRP receptor. In contrast, fremanezumab only antagonized CGRP-induced cAMP signaling at the human CGRP receptor. In addition, erenumab, but not fremanezumab, bound and internalized at the canonical human CGRP receptor. Interestingly, erenumab also bound and internalized at the human AMY1 receptor, a CGRP receptor family member. Both erenumab and telcagepant antagonized amylin-induced cAMP signaling at the AMY1 receptor while fremanezumab did not affect amylin responses. Conclusion The therapeutic effect of agents targeting the CGRP ligand versus receptor for migraine prevention (antibodies) or acute treatment (gepants) may involve distinct mechanisms of action. These findings suggest that differing mechanisms could affect efficacy, safety, and/or tolerability in migraine patients.

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A, Abdelmoktader. "A Holistic Review on Chloroquine/Hydroxychloroquine the AntiParasitic Therapeutics." Virology & Immunology Journal 4, no. 1 (January 28, 2020): 1–12. http://dx.doi.org/10.23880/vij-16000233.

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Hydroxychloroquine and chloroquine have driven attention as potential anti-parasitic therapeutics with extended influences against other various medical conditions. Recently, these drugs were presented against the pandemic of COVID-19. In addition, there is a growing data concerning the resistance to the traditional anti-parasitic regimens. Here, we introduce a general descriptive review to demonstrate (1) a rapid historical view for these drugs, (2) their pharmacokinetics, (3) mode of action and how this affected malaria and whether it can applied in other parasitic diseases or not, and (4) their medical manipulations in other medical conditions involving COVID-19 in the top of the list. The review also tried to introduce their limitations of usage in accordance to previous in vitro and clinical settings. We call for further development in their formula for less toxic and more effective pharmaceutical versions.

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Alaithan, Haitham, Nirbhay Kumar, Mohammad Z. Islam, Angelike P. Liappis, and Victor E. Nava. "Novel Therapeutics for Malaria." Pharmaceutics 15, no. 7 (June 23, 2023): 1800. http://dx.doi.org/10.3390/pharmaceutics15071800.

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Malaria is a potentially fatal disease caused by protozoan parasites of the genus Plasmodium. It is responsible for significant morbidity and mortality in endemic countries of the tropical and subtropical world, particularly in Africa, Southeast Asia, and South America. It is estimated that 247 million malaria cases and 619,000 deaths occurred in 2021 alone. The World Health Organization’s (WHO) global initiative aims to reduce the burden of disease but has been massively challenged by the emergence of parasitic strains resistant to traditional and emerging antimalarial therapy. Therefore, development of new antimalarial drugs with novel mechanisms of action that overcome resistance in a safe and efficacious manner is urgently needed. Based on the evolving understanding of the physiology of Plasmodium, identification of potential targets for drug intervention has been made in recent years, resulting in more than 10 unique potential anti-malaria drugs added to the pipeline for clinical development. This review article will focus on current therapies as well as novel targets and therapeutics against malaria.

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26

Schneider, Jay S. "GM1 Ganglioside as a Disease-Modifying Therapeutic for Parkinson’s Disease: A Multi-Functional Glycosphingolipid That Targets Multiple Parkinson’s Disease-Relevant Pathogenic Mechanisms." International Journal of Molecular Sciences 24, no. 11 (May 24, 2023): 9183. http://dx.doi.org/10.3390/ijms24119183.

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting millions of patients worldwide. Many therapeutics are available for treating PD symptoms but there is no disease-modifying therapeutic that has been unequivocally shown to slow or stop the progression of the disease. There are several factors contributing to the failure of many putative disease-modifying agents in clinical trials and these include the choice of patients and clinical trial designs for disease modification trials. Perhaps more important, however, is the choice of therapeutic, which for the most part, has not taken into account the multiple and complex pathogenic mechanisms and processes involved in PD. This paper discusses some of the factors contributing to the lack of success in PD disease-modification trials, which have mostly investigated therapeutics with a singular mechanism of action directed at one of the many PD pathogenic processes, and suggests that an alternative strategy for success may be to employ multi-functional therapeutics that target multiple PD-relevant pathogenic mechanisms. Evidence is presented that the multi-functional glycosphingolipid GM1 ganglioside may be just such a therapeutic.

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Brady, Daniel, Alessandro Grapputo, Ottavia Romoli, and Federica Sandrelli. "Insect Cecropins, Antimicrobial Peptides with Potential Therapeutic Applications." International Journal of Molecular Sciences 20, no. 23 (November 22, 2019): 5862. http://dx.doi.org/10.3390/ijms20235862.

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The alarming escalation of infectious diseases resistant to conventional antibiotics requires urgent global actions, including the development of new therapeutics. Antimicrobial peptides (AMPs) represent potential alternatives in the treatment of multi-drug resistant (MDR) infections. Here, we focus on Cecropins (Cecs), a group of naturally occurring AMPs in insects, and on synthetic Cec-analogs. We describe their action mechanisms and antimicrobial activity against MDR bacteria and other pathogens. We report several data suggesting that Cec and Cec-analog peptides are promising antibacterial therapeutic candidates, including their low toxicity against mammalian cells, and anti-inflammatory activity. We highlight limitations linked to the use of peptides as therapeutics and discuss methods overcoming these constraints, particularly regarding the introduction of nanotechnologies. New formulations based on natural Cecs would allow the development of drugs active against Gram-negative bacteria, and those based on Cec-analogs would give rise to therapeutics effective against both Gram-positive and Gram-negative pathogens. Cecs and Cec-analogs might be also employed to coat biomaterials for medical devices as an approach to prevent biomaterial-associated infections. The cost of large-scale production is discussed in comparison with the economic and social burden resulting from the progressive diffusion of MDR infectious diseases.

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Kline, Christina, and Wafik El-Deiry. "Personalizing Colon Cancer Therapeutics: Targeting Old and New Mechanisms of Action." Pharmaceuticals 6, no. 8 (August 21, 2013): 988–1038. http://dx.doi.org/10.3390/ph6080988.

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Rovis, Tihana, and Giuseppe Legname. "Prion Protein-Specific Antibodies-Development, Modes of Action and Therapeutics Application." Viruses 6, no. 10 (October 1, 2014): 3719–37. http://dx.doi.org/10.3390/v6103719.

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Jefferis, Royston. "Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action." Trends in Pharmacological Sciences 30, no. 7 (July 2009): 356–62. http://dx.doi.org/10.1016/j.tips.2009.04.007.

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Ray, Arghya, Yan Song, Ting DU, Clifton C. Mo, Arturo Olguin, Janice Chen, Christopher Brooks, et al. "A High Throughput Quantitative Seroproteomics Analysis of Multiple Myeloma Patients on Tagraxofusp Therapy Identifies Novel Cytokine-Assisted Mechanism of Action." Blood 136, Supplement 1 (November 5, 2020): 34. http://dx.doi.org/10.1182/blood-2020-141571.

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Background We showed a tumor-promoting and immunosuppressive role of plasmacytoid dendritic cells (pDCs; CD123/IL-3Rα+) in multiple myeloma (MM) pathogenesis (Chauhan et al. Cancer Cell, 2009;Ray et al, Leukemia, 2018). Importantly, tagraxofusp, an FDA-approved (for patients with blastic plasmacytoid dendritic cell neoplasm) novel targeted therapy directed against CD123, triggers anti-MM activity by reducing the viability of MM-promoting pDCs. These observations led to a recently completed phase 1 clinical trial of tagraxofusp and pomalidomide/dexamethasone in relapsed and refractory MM patients (NCT02661022). The treatment regimen demonstrated preliminary safety and efficacy, with 5 of 9 heavily pretreated patients achieving durable partial response (PR) (ASH 2019). Here, we report the initial results of our correlative science studies using bone marrow (BM), peripheral blood (PB), and serum from the study cohort. Materials and Methods Tagraxofusp is a bioengineered therapeutic protein developed by fusing human IL-3 to the catalytic translocation domain of truncated diphtheria toxin (DT) via a Met-His linker (Stemline Therapeutics, NY). pDCs and patient MM cells were purified from BM/PB samples after informed consent, and quantified using FACS, as described (Ray et al, Leukemia, 2018). A novel high-throughput seroproteomics platform SOMAscan was utilized to analyze 1,310 protein analytes in serum samples from MM patients (n = 9). SOMAscan data were subjected to meta-analysis to generate heatmaps, followed by hierarchical cluster analysis. SOMAscan results were validated with ELISA using supernatants from MM patient pDCs cultured with or without tagraxofusp. Results Analysis of BM/PB samples from MM patients receiving tagraxofusp therapy showed a marked reduction in the frequency of viable pDCs [average 2% at screening vs 0.75% post-tagraxofusp; n = 6; p = 0.036]. pDCs isolated from tagraxofusp-treated patients showed decreased ability to trigger MM cell growth. Seroproteomics analysis of MM patient serum before and after tagraxofusp therapy showed alterations in the levels of 100 proteins [Median Fold Change in expression: 0.39 to 4.5; n = 6; 3 each; p < 0.05]. Importantly, tagraxofusp treatment reduced pDC-related soluble proteins including IFN-α (fold change: 0.8, treated vs untreated; p < 0.05). Our earlier study showed that pDC-MM interactions triggered secretion of IL-3, which in turn promotes both pDC survival and MM cell growth. Importantly, tagraxofusp decreased serum IL-3 (fold change 0.75, treated vs untreated; p < 0.05), consistent with tagraxofusp decreasing survival of tumor-promoting pDCs. Conclusions Our current correlative science studies validate target specificity of tagraxofusp against MM pDCs in relapsed and refractory MM patients enrolled in a phase 1 clinical trial and support further evaluation for this novel therapeutic to improve the clinical outcome of patients with MM. Further combination studies are planned. Disclosures Mo: Celgene/BMS: Membership on an entity's Board of Directors or advisory committees. Olguin:Stemline Therapeutics: Current Employment. Chen:Stemline Therapeutics: Current Employment. Brooks:Stemline: Current Employment. Mughal:Stemline: Current Employment. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Chauhan:consultant to Stemline Therapeutics, Inc., and Equity owner in C4 Therapeutics.: Consultancy, Other: Equity owner in C4 Therapeutics.; Oncopeptide AB: Consultancy. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees.

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Juliano, Rudolph L. "Chemical Manipulation of the Endosome Trafficking Machinery: Implications for Oligonucleotide Delivery." Biomedicines 9, no. 5 (May 5, 2021): 512. http://dx.doi.org/10.3390/biomedicines9050512.

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Antisense oligonucleotides (ASOs), siRNA and splice switching oligonucleotides (SSOs) all have immense potential as therapeutic agents, potential that is now being validated as oligonucleotides enter the clinic. However, progress in oligonucleotide-based therapeutics has been limited by the difficulty in delivering these complex molecules to their sites of action in the cytosol or nucleus of cells within specific tissues. There are two aspects to the delivery problem. The first is that most types of oligonucleotides have poor uptake into non-hepatic tissues. The second is that much of the oligonucleotide that is taken up by cells is entrapped in endosomes where it is pharmacologically inert. It has become increasingly recognized that endosomal trapping is a key constraint on oligonucleotide therapeutics. Thus, many approaches have been devised to address this problem, primarily ones based on various nanoparticle technologies. However, recently an alternative approach has emerged that employs small molecules to manipulate intracellular trafficking processes so as to enhance oligonucleotide actions. This review presents the current status of this chemical biology approach to oligonucleotide delivery and seeks to point out possible paths for future development.

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Gurram, Bhaskar, and Ashish S. Patel. "Recent advances in understanding and managing pediatric inflammatory bowel disease." F1000Research 8 (December 13, 2019): 2097. http://dx.doi.org/10.12688/f1000research.19609.1.

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The landscape of pediatric inflammatory bowel disease is rapidly evolving. The therapeutic advances seen in the adult arena are rapidly being adopted by pediatric gastroenterologists and evaluated in both controlled trials and real-world experience. Though anti-tumor necrosis factor agents have been the primary therapy over the last decade, recently there has been an expansion of therapeutic targets and alternative mechanism of action drugs with a focus on individualized and personalized therapy. By reviewing epidemiology, pathophysiology, and goals of treatment, we hope to frame the discussion of current and novel therapeutics for the pediatric gastroenterologist. As scientific discovery continues to push the envelope in defining our understanding of pediatric inflammatory bowel disease, the current era of therapeutics gives us hope that a cure may be realized soon.

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Bannister, Kirsty, Juliane Sachau, Ralf Baron, and Anthony H. Dickenson. "Neuropathic Pain: Mechanism-Based Therapeutics." Annual Review of Pharmacology and Toxicology 60, no. 1 (January 6, 2020): 257–74. http://dx.doi.org/10.1146/annurev-pharmtox-010818-021524.

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Neuropathic pain (NeP) can result from sources as varied as nerve compression, channelopathies, autoimmune disease, and incision. By identifying the neurobiological changes that underlie the pain state, it will be clinically possible to exploit mechanism-based therapeutics for maximum analgesic effect as diagnostic accuracy is optimized. Obtaining sufficient knowledge regarding the neuroadaptive alterations that occur in a particular NeP state will result in improved patient analgesia and a mechanism-based, as opposed to a disease-based, therapeutic approach to facilitate target identification. This will rely on comprehensive disease pathology insight; our knowledge is vastly improving due to continued forward and back translational preclinical and clinical research efforts. Here we discuss the clinical aspects of neuropathy and currently used drugs whose mechanisms of action are outlined alongside their clinical use. Finally, we consider sensory phenotypes, patient clusters, and predicting the efficacy of an analgesic for neuropathy.

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35

Vose, Julie M., Brian C. H. Chiu, Bruce D. Cheson, Janet Dancey, and John Wright. "Update on Epidemiology and Therapeutics for Non-Hodgkin’s Lymphoma." Hematology 2002, no. 1 (January 1, 2002): 241–62. http://dx.doi.org/10.1182/asheducation-2002.1.241.

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Abstract This chapter presents updated information on the trends and patterns of non-Hodgkin’s lymphoma (NHL) diagnoses as well as new information on chemotherapeutic and immunotherapeutic options for NHL treatment. In Section I, Dr. Brian Chiu summarizes the current knowledge regarding the etiologic factors and patterns of NHL as well as suggests future epidemiologic studies based on these preliminary results. In Section II, Dr. Bruce Cheson and colleagues outline new chemotherapeutic and small molecule antineoplastic agents with unique mechanisms of action such as protease inhibitors, farnesyl transferase or histone deacetylase inhibitors, and antisense oligonucleotides. In Section III, Dr. Julie Vose reviews the anti-lymphoma effects of monoclonal antibodies, radioimmunoconjugates, idiotype vaccines, and immunologic enhancing adjuvants with respect to mechanisms of action, clinical trials, and their potential for patient therapy.

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Harris, C. L., D. A. Fraser, and B. P. Morgan. "Tailoring anti-complement therapeutics." Biochemical Society Transactions 30, no. 6 (November 1, 2002): 1019–26. http://dx.doi.org/10.1042/bst0301019.

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Complement is a core component of the immune system, which performs vital roles in immune surveillance. However, the active products that enable complement to perform its physiological roles can inappropriately target self tissues and cause pathology. Complement-mediated inflammation and tissue destruction is an important drive to pathology in diseases as diverse as rheumatoid arthritis and dementia. Two decades ago there were no agents that could be used therapeutically to inhibit the activation of complement, but increased understanding of the natural control of complement in vivo has markedly changed this situation. The realization that drugs mimicking the action of the complement regulatory proteins present on self cells, and in plasma, could effectively control pathological activation of complement has opened the door to the use of anti-complement therapy in disease. Here we will review the development of anticomplement therapeutics from the first generation agents, which are unmodified recombinant forms of natural regulators, to recent strategies for making better drugs. We will describe strategies for targeting the anticomplement activity to the site of disease, and for extending the plasma half-life of the agent. Finally, we will illustrate a novel approach to the delivery of anticomplement agents, making prodrugs that are activated only at disease sites thus minimizing the deleterious effects of systemic complement inhibition.

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Vekaria, Mrudul Pravinbhai, and Pravin Tirgar. "Salicin a promising ER, PR and HER2 binding molecule proving lethal against Hormone + and triple negative breast cancer cells." International Journal of Ayurvedic Medicine 12, no. 1 (March 31, 2021): 73–83. http://dx.doi.org/10.47552/ijam.v12i1.1755.

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Therapeutics against breast cancer is a major research field, due to inefficiency or partial efficiency of existing therapeutics. An urge to discover better therapeutics always persists. Our objective is to study salicin against breast cancer cells, in order to find its therapeutic properties. To study the effect of salicin on breast cancer cells, we performed MTT assay on MCF-7 (hormone positive) and MDA-MB-231 (triple negative) breast cancer cell lines, we did brine shrimp lethality test (BSLT) assay to see the lethal effects of salicin. By the help of bioinformatics we tried to locate the targets that delineate salicin activity. Salicin was docked with estrogen receptor (ER), progesterone receptor (PR) and Human epidermal growth factor receptor 2 (HER2) to study its binding efficiency and possible targets of salicin. Salicin remarkably reduces cell viability both in MCF-7 and MDA-MB-231, along with being lethal to brine shrimps. These results together opine that salicin can be an effective therapeutics against breast cancer cells. The mechanism of action of salicin is probably through ER, PR and HER2 receptors because it can efficiently bind these receptors with minimum energy required for binding. This explains that salicin can easily bind to these receptors. These results together opine that salicin can be an effective therapeutics against breast cancer cells. The mechanism of action of salicin is probably through ER, PR and HER2 receptors because it can efficiently bind these receptors with minimum binding energy. ER, PR and HER2 are major reasons behind the disease pathogenicity depending on the type of breast cancer. According to our results salicin may either induce apoptosis or reduce cellular mitosis both via P53 dependent and independent pathway, which makes salicin a good choice of both hormone positive and negative breast cancer cells.

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Duvey, Brijesh Kumar, and Yogita Chowdhary. "A comprehensive list of plants used for anti-inflammatory action." Indian Journal of Pharmaceutical and Biological Research 4, no. 2 (June 30, 2016): 52–59. http://dx.doi.org/10.30750/ijpbr.4.2.7.

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Herbal medicines are important remedies in therapeutics for treatment of various diseases in India. The traditional health care system of India is Ayurveda [Ayus – Life, Veda – Knowledge, meaning – science of life] and it is one of the oldest therapeutic systems. India,with its great biodiversity, has a tremendous potential and advantage in the emerging field of herbal medicines. Medicinal plants as a group comprise approximately 7500 species and include representatives of about 17,000 species of higher flowering plants Use of natural product in the developments of drugs used in contemporary medicine is unsurpassed even when synthetic chemistry has been developed beyond expectations. Unlike synthetic substances the natural drug dose not gives symptomatic relief rather it provide complete cure of many diseases. Due to these salient feature herbal drugs has been realized seriously using all around the world. These day plant and their parts are extremely using in the treatment of various diseases such as respiratory problems, gastro-intestinal disorder, cardiac disease metabolic disorder and aging related problem. This review article is an effort of author to provide a comprehensive list of various plant and their parts used for the treatment in various therapeutic system.

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Palihaderu, PADS, BILM Mendis, JMKJK Premarathne, WKRR Dias, Swee Keong Yeap, Wan Yong Ho, AS Dissanayake, et al. "Therapeutic Potential of miRNAs for Type 2 Diabetes Mellitus: An Overview." Epigenetics Insights 15 (January 2022): 251686572211300. http://dx.doi.org/10.1177/25168657221130041.

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MicroRNA(miRNA)s have been identified as an emerging class for therapeutic interventions mainly due to their extracellularly stable presence in humans and animals and their potential for horizontal transmission and action. However, treating Type 2 diabetes mellitus using this technology has yet been in a nascent state. MiRNAs play a significant role in the pathogenesis of Type 2 diabetes mellitus establishing the potential for utilizing miRNA-based therapeutic interventions to treat the disease. Recently, the administration of miRNA mimics or antimiRs in-vivo has resulted in positive modulation of glucose and lipid metabolism. Further, several cell culture-based interventions have suggested beta cell regeneration potential in miRNAs. Nevertheless, few such miRNA-based therapeutic approaches have reached the clinical phase. Therefore, future research contributions would identify the possibility of miRNA therapeutics for tackling T2DM. This article briefly reported recent developments on miRNA-based therapeutics for treating Type 2 Diabetes mellitus, associated implications, gaps, and recommendations for future studies.

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40

Bai, Zhiman, Jing Wei, Changmin Yu, Xisi Han, Xiaofei Qin, Chengwu Zhang, Wenzhen Liao, Lin Li, and Wei Huang. "Non-viral nanocarriers for intracellular delivery of microRNA therapeutics." Journal of Materials Chemistry B 7, no. 8 (2019): 1209–25. http://dx.doi.org/10.1039/c8tb02946f.

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MicroRNAs are small regulatory noncoding RNAs that regulate various biological processes. Herein, we will present the development of the strategies for intracellular miRNAs delivery, and specially focus on the rational designed routes, their mechanisms of action, as well as potential therapeutics used in the host cells orin vivostudies.

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41

Holz, Emily, Martine Darwish, Devin B. Tesar, and Whitney Shatz-Binder. "A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future." Pharmaceutics 15, no. 2 (February 10, 2023): 600. http://dx.doi.org/10.3390/pharmaceutics15020600.

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Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. As new mechanisms of action are uncovered, and as our understanding of existing mechanisms grows, the properties that are required and/or leveraged to enable therapeutic development continue to expand. One rapidly evolving area of interest is that of chemically enhanced peptide and protein therapeutics. While a variety of conjugate molecules such as antibody–drug conjugates, peptide/protein–PEG conjugates, and protein conjugate vaccines are already well established, others, such as antibody–oligonucleotide conjugates and peptide/protein conjugates using non-PEG polymers, are newer to clinical development. This review will evaluate the current development landscape of protein-based chemical conjugates with special attention to considerations such as modulation of pharmacokinetics, safety/tolerability, and entry into difficult to access targets, as well as bioavailability. Furthermore, for the purpose of this review, the types of molecules discussed are divided into two categories: (1) therapeutics that are enhanced by protein or peptide bioconjugation, and (2) protein and peptide therapeutics that require chemical modifications. Overall, the breadth of novel peptide- or protein-based therapeutics moving through the pipeline each year supports a path forward for the pursuit of even more complex therapeutic strategies.

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Pudlarz, Agnieszka, and Janusz Szemraj. "Nanoparticles as carriers of proteins, peptides and other therapeutic molecules." Open Life Sciences 13, no. 1 (October 31, 2018): 285–98. http://dx.doi.org/10.1515/biol-2018-0035.

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AbstractNanoparticles have many applications both in industry and medicine. Depending upon their physical and chemical properties, they can be used as carriers of therapeutic molecules or as therapeutics. Nanoparticles are made of synthetic or natural polymers, lipids or metals. Their use allows for faster transport to the place of action, thus prolonging its presence in the body and limiting side effects. In addition, the use of such a drug delivery system protects the drug from rapid disintegration and elimination from the body. In recent years, the use of proteins and peptides as therapeutic molecules has grown significantly. Unfortunately, proteins are subject to enzymatic digestion and can cause unwanted immune response beyond therapeutic action. The use of drug carriers can minimize undesirable side effects and reduce the dose of medication needed to achieve the therapeutic effect. The current study presents the use of several selected drug delivery systems for the delivery of proteins, peptides and other therapeutic molecules.

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43

Jena, N. R. "Drug targets, mechanisms of drug action, and therapeutics against SARS-CoV-2." Chemical Physics Impact 2 (June 2021): 100011. http://dx.doi.org/10.1016/j.chphi.2021.100011.

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Kuznietsova, Halyna, Natalia Dziubenko, Iryna Byelinska, Vasyl Hurmach, Andriy Bychko, Oksana Lynchak, Demyd Milokhov, Olga Khilya, and Volodymyr Rybalchenko. "Pyrrole derivatives as potential anti-cancer therapeutics: synthesis, mechanisms of action, safety." Journal of Drug Targeting 28, no. 5 (December 18, 2019): 547–63. http://dx.doi.org/10.1080/1061186x.2019.1703189.

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45

Peterson, Theresa C. "Therapeutic Potential for Cytokine Antagonists: Thalidomide and Pentoxifylline in Hansen’s Disease." Canadian Journal of Infectious Diseases 6, no. 1 (1995): 30–33. http://dx.doi.org/10.1155/1995/503276.

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Cytokine antagonists are a group of drugs defined by their actions on specific cytokines. Cytokine antagonists can inhibit action of cytokines by acting directly on receptors, by affecting production of cytokines or by binding to cytokines and preventing their subsequent action. Recent evidence suggests that Hansen’s disease, which is characterized by reactional states, is associated with elevated serum levels of tumour necrosis factor-α (tnf-α) and interleukin-1β during these reactional states. Thalidomide, a drug used to treat reactional states in Hansen’s disease, has been reported to enhance degradation oftnf-α mrna. Pentoxifylline has also been reported to altertnf-α mrnalevels by inhibitingtnf-a transcription. Combination of these two drugs as cytokine antagonists may prove to be beneficial as therapeutic agents in the treatment of reactional states in Hansen’s disease. Pentoxifylline may prove to be beneficial in the treatment of reactional states in Hansen’s disease patients who are female and of childbearing age. Cytokine antagonists alone or in combination will likely fill a niche in future therapeutics.

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P. Hardy, Matthew, Tony Rowe, and Sandra Wymann. "Soluble Complement Receptor 1 Therapeutics." Journal of Immunological Sciences 6, no. 4 (October 21, 2022): 1–17. http://dx.doi.org/10.29245/2578-3009/2022/4.1240.

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Human Complement Receptor 1 (CR1/CD35) is a potent negative regulator of the complement system. Its mechanism of action is through interaction with the complement activation fragments, C3b and C4b to mediate decay acceleration of the C3 and C5 convertase complexes as well as cleavage of both ligands into inactive fragments via cofactor activity. The result is inhibition of the classical, lectin, and alternative complement pathways. This article will focus on recombinant soluble forms of CR1 that have been generated as potential therapeutics for complement-mediated disorders. Specifically, we will review and contrast the in vitro and in vivo properties of: sCR1 (BRL55730/TP10/CDX-1135), the soluble full-length extracellular domain of human CR1; sCR1-sLex (TP20), a glyco-engineered version of sCR1 additionally targeted to activated endothelium; APT070 (Mirococept), a CR1 fragment conjugated to a myristoylated peptide to enhance tissue targeting; and CSL040, a soluble truncated version of the CR1 extracellular domain which exhibits altered potency and pharmacokinetic properties as compared to the parental molecule. The data obtained from studies on the effects of these CR1-based molecules in animal models of disease and their therapeutic applications will also be discussed.

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Allen, David B., Nadia Merchant, Bradley S. Miller, and Philippe F. Backeljauw. "Evolution and Future of Growth Plate Therapeutics." Hormone Research in Paediatrics 94, no. 9-10 (2021): 319–32. http://dx.doi.org/10.1159/000520812.

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Background: Longitudinal bone growth is regulated by multiple endocrine signals (e.g., growth hormone, insulin-like growth factor I, estrogen, and androgen) and local factors (e.g., fibroblast growth factors and their receptors and the C-natriuretic peptide/natriuretic peptide receptor-B pathway). Summary: Abnormalities in both endocrine and local regulation of growth plate physiology cause many disorders of human skeletal growth. Knowledge of these pathways creates therapeutic potential for sustaining or even augmenting linear growth. Key Message: During the past 4 decades, advances in understanding growth plate physiology have been accompanied by development and implementation of growth-promoting treatments that have progressed in both efficacy and specificity of action. This paper reviews the history and continuing evolution of growth plate therapeutics.

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Coler, Brahm Seymour, Oksana Shynlova, Adam Boros-Rausch, Stephen Lye, Stephen McCartney, Kelycia B. Leimert, Wendy Xu, et al. "Landscape of Preterm Birth Therapeutics and a Path Forward." Journal of Clinical Medicine 10, no. 13 (June 29, 2021): 2912. http://dx.doi.org/10.3390/jcm10132912.

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Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal corticosteroid administration for accelerating fetal lung maturity or to transfer patients to high-level care facilities. Globally, there is an unmet need for better tocolytic agents, particularly in low- and middle-income countries. Although most tocolytics, such as betamimetics and indomethacin, suppress downstream mediators of the parturition pathway, newer therapeutics are being designed to selectively target inflammatory checkpoints with the goal of providing broader and more effective tocolysis. However, the relatively small market for new PTB therapeutics and formidable regulatory hurdles have led to minimal pharmaceutical interest and a stagnant drug pipeline. In this review, we present the current landscape of PTB therapeutics, assessing the history of drug development, mechanisms of action, adverse effects, and the updated literature on drug efficacy. We also review the regulatory hurdles and other obstacles impairing novel tocolytic development. Ultimately, we present possible steps to expedite drug development and meet the growing need for effective preterm birth therapeutics.

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C. Moore, PharmD, BCPS, BCOP, DPLA, Donald. "2020–2021 Drug Updates: Investigational Therapeutics in the Pipeline." Journal of the Advanced Practitioner in Oncology 13, no. 3 (April 1, 2022): 286–91. http://dx.doi.org/10.6004/jadpro.2022.13.3.21.

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During JADPRO Live Virtual 2021, Donald C. Moore, PharmD, BCPS, BCOP, DPLA, discussed investigational therapeutic agents in the drug development pipeline. Dr. Moore highlighted agents that represent either a new drug class, a novel mechanism of action, a rethinking of how to approach treating a disease, or those that have recently received FDA Breakthrough Designation status that advanced practitioners should be aware of.

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C. Moore, PharmD, BCPS, BCOP, DPLA, FCCP, Donald. "2021–2022 Drug Updates: Investigational Therapeutics in the Pipeline." Journal of the Advanced Practitioner in Oncology 14, no. 3 (April 1, 2023): 237–40. http://dx.doi.org/10.6004/jadpro.2023.14.3.11.

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Анотація:

During JADPRO Live 2022, Donald C. Moore, PharmD, BCPS, BCOP, DPLA, FCCP, discussed investigational therapeutic agents in the drug development pipeline. Dr. Moore highlighted agents that represent either a new drug class, a novel mechanism of action, a rethinking of how to approach treating a disease, or those that have recently received FDA Breakthrough Designation status that advanced practitioners should be aware of.

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