Project description:Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure-biological activity relationship in fentanyl-related compounds and derivatives and their biological activity profiles. We discuss how changes in the scaffold structure can change biological and pharmacological activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.
Project description:Ketamine, a widely used anesthetic agent, is currently being investigated as a novel therapeutic for depression and suicidality. Ketamine has garnered substantial attention from researchers, clinicians, media outlets, and patients alike, but numerous questions remain. One of the compelling features of ketamine is the rapidity of its antidepressant effects, which peak just 24 h after infusion, setting it apart from other existing treatments. Ketamine's rapid time course has inspired research efforts to explore its potential as a life-saving therapy for patients at imminent risk of suicide. In this article, we review current evidence supporting the rapid effects of ketamine on suicidal ideation in the context of unipolar and bipolar depression. We then discuss several future directions that are necessary before ketamine can be considered a viable treatment option for suicidality in clinical settings. These include: testing for a specific anti-suicidal effect-separate from overall antidepressant effects-to ascertain whether ketamine might hold promise for a broader class of suicidal patients; ensuring that acute benefits of ketamine can be prolonged over a clinically meaningful timeframe; and developing a better understanding of the mechanisms by which ketamine might reduce suicide risk. Such efforts will enable the field to more accurately assess the potential of ketamine, as well as its limitations, allowing for appropriate placement within the context of comprehensive clinical care for suicide prevention.
Project description:Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments for MDD primarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant in MDD. We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with the NIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants.
Project description:Postpartum depression (PPD) is a serious health issue that can affect about 15% of the female population within after giving birth. It often conveys significant negative consequences to the offsprings. The symptoms and risk factors are somewhat similar to those found in non-postpartum depression. The main difference resides in the fact that PPD is triggered by postpartum specific factors, including especially biological changes in the hormone levels. Patients are usually diagnosed using a questionnaire onsite or in a clinic. Treatment of PPD often involves psychotherapy and antidepressant medications. In recent years, there have been more researches on the identification of biological markers for PPD. In this review, we will focus on the current research status of PPD, with an emphasis on the recent progress made on the identification of PPD biomarkers.
Project description:Discovering that the anesthetic drug ketamine has rapidly acting antidepressant effects in many individuals with major depression is one of the most important findings in clinical psychopharmacology in recent decades. The initial report of these effects in human subjects was based on a foundation of rodent preclinical studies carried out in the 1990s, and subsequent investigation has included both further studies in individuals with depression, as well as reverse translational experiments in animal models, especially rodents. While there is general agreement in the rodent literature that ketamine has rapidly-acting, and generally sustained, antidepressant-like properties, there are also points of contention across studies, including the precise mechanism of action of this drug. In this review, we briefly summarize prominent yet variable findings regarding the mechanism of action. We also discuss a combination of similarities and variances in the rodent literature in the antidepressant-like effects of ketamine as a function of dose, species and strain, test, stressor, and presumably sex of the experimenter. We then present previously unpublished mouse strain comparison data suggesting that subanesthetic ketamine does not have robust antidepressant-like properties in unstressed animals, and may actually promote depression-like behavior, in contrast to widely reported findings. We conclude that the data best support the notion of ketamine action principally via NMDA receptor antagonism, transiently boosting glutamatergic (and possibly other) signaling in diverse brain circuits. We also suggest that future studies should address in greater detail the extent to which antidepressant-like properties of this drug are stress-sensitive, in an effort to better model major depression present in humans.
Project description:Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine's use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression.
Project description:The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine's antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine's antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine's antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine's adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine's antidepressant effects.
Project description:In this review, we have attempted to describe all of the antibody-drug conjugates using a marine-derived compound as the "warhead", that are currently in clinical trials as listed in the current version of the NIH clinical trials database (clinicaltrials.gov). In searching this database, we used the beta-test version currently available, as it permitted more specific search parameters, since the regular version did not always find trials that had been completed in the past with some agents. We also added small discussion sections on candidates that are still at the preclinical stage, including a derivative of diazonamide that has an unusual interaction with tubulin (DZ-23840), which may also be a potential warhead in the future.
Project description:Human leukocyte antigen (HLA), also known as human major histocompatibility complex (MHC), is encoded by the HLA gene complex, and is currently known to have the highest gene density and the most polymorphisms among human chromosomal areas. HLA is divided into class I antigens, class II antigens, and class III antigens according to distribution and function. Classical HLA class I antigens include HLA-A, HLA-B, and HLA-C; HLA class II antigens include HLA-DP, HLA-DQ, and HLA-DR; nonclassical HLA class I and II molecules include HLA-F, E, H, X, DN, DO, and DM; and others, such as complement, are class III antigens. HLA is closely related to the body's immune response, regulation, and surveillance and is of great significance in the study of autoimmune diseases, tumor immunity, organ transplantation, and reproductive immunity. HLA is an important research topic that bridges immunology and clinical diseases. With the development of research methods and technologies, there will be more discoveries and broader prospects.
Project description:Ketamine is a fast-acting anesthetic with hypnotic properties. Moreover, could potentially improve affective symptoms in patients with refractory depressive disorder. Objective. explore the scientific literature available until December 10, 2021, about the efficacy and safety of ketamine in patients with treatment-refractory major depressive disorder. Material and methods. Scoping review that included PubMed and Scopus. Records of clinical trials and publications with empirical data in English and Spanish were included.