Pharmacological Strategies for Uterine Relaxation
Robert E. Garfield, Thomas N. Tabb in Control of Uterine Contractility, 2019
There is substantial support for the idea that agonist-receptor interaction is linked to functional inhibition of contractions mainly via a G-protein-mediated stimulation of adenylyl cyclase.17 A number of studies have shown that agonists at β2-adrenoceptors can increase the concentration of cyclic 3’,5’ adenosine monophosphate (cAMP) in myometria.11,17–21 It is suggested that there is in turn increased activity of protein kinase A leading to phosphorylation of membrane proteins resulting in decreased calcium ion (Ca2+) entry into and increased Ca2+ efflux from myometrial cells.18,22 The oxytocin-induced formation of inositol trisphosphates is decreased by agonists at β-adrenoceptors.22,23,23a These events will reduce the rise in intracellular Ca2+ concentrations produced by spasmogens, decrease the affinity of Ca2+ to bind to calmodulin, and reduce the activity of myosin light chain kinase; these are essential final stages in the biochemical cascade necessary for contraction. This purported biochemical cascade will explain why agonists at β2-adrenoceptors will functionally oppose spontaneous contractions and a wide range of spasmogens.
The Neurodegenerative Characteristics of Alzheimer’s Disease and Related Multi-Target Drug Design Studies
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
The pathogenesis of Alzheimer’s disease is still very complex. The majority of the attention is focused on the amyloidogenic pathway, since it is the main identified neurodegenerative biochemical cascade induced throughout the development of the disease. Besides, other mechanisms leading to oxidative stress are also considered as alternative targets for the treatment of the disease. Some of the phase trials employing drug candidates purely designed to target one of these neurodegenerative mechanisms (e.g., amyloidogenic pathway) have provided promising results in terms of the prevention of toxic mechanisms. However, none of them has been found validated in terms of the improvement of cognition that is gradually lost throughout the development of AD. Therefore, for the last two decades, a multi-target drug design approach is mainly followed for molecule design in AD research studies. Based on the targets that have been found critical, at least two of them are selected. Among those approaches, the employment of cholinesterase inhibition as the main constituent is still valid, since, besides NMDA receptor partial antagonism, cholinesterase inhibition is the only alternative providing cognitive enhancement. The near future will display the outcomes of the clinical results of these multi-target oriented drug candidates.
Bioscience indications for chronic disease management and neuromedical interventions following traumatic brain injury
Mark J. Ashley, David A. Hovda in Traumatic Brain Injury, 2017
Focal damage can be expected to impact certain motor, sensory, or cognitive functions, depending upon the neural structures or systems involved. Diffuse axonal injury (DAI) is recognized as a primary component of neurophysiological dysfunction in 40% to 50% of all brain injury of traumatic etiology.33 DAI tends to affect specific regions of the human brain, such as the parasagittal white matter of the cerebral cortex, the corpus callosum, and the pontine–mesencephalic junction adjacent to the superior cerebellar peduncles.34 At the cellular level, direct forces of sufficient magnitude breach the cellular membrane, initiating a cytotoxic, biochemical cascade of events, which impacts neuronal health and function in the immediate vicinity of the primary damage (Figure 1.1).35 The damage inflicted by this cytotoxic biochemical cascade, however, may not be restricted to the locality of the primary site of damage and may reach far distant cellular structures within the central nervous system (CNS).36
Where do we go next in antidepressant drug discovery? A new generation of antidepressants: a pivotal role of AMPA receptor potentiation and mGlu2/3 receptor antagonism
Published in Expert Opinion on Drug Discovery, 2022
Andrzej Pilc, Agata Machaczka, Paweł Kawalec, Jodi L. Smith, Jeffrey M. Witkin
Skolnick originally hypothesized that AMPA receptor potentiators would be antidepressant as early as 2001 [134] based upon the ability of these compounds to induce BDNF signaling like other antidepressant mechanisms (Figure 3) [114,115]. The potential for AMPA receptor potentiators to produce rapid-acting antidepressant effects was suggested later [39,115]. Alt et al., (2006) [46] provided a heuristic model of antidepressant action based upon AMPA receptor potentiation as a key launching point for triggering the antidepressant biochemical cascade for both conventional and rapid acting ADDs. As seen in Figure 3, this part of the antidepressant machinery is still recognized as pivotal [132,133]. Preclinical studies have demonstrated antidepressant-like effects of this class of compounds, and they are also able to synergize with the antidepressant-like effects of standard of care ADDs of broad pharmacological classes [135]. These later findings further reinforce the key role of AMPA receptor facilitation in antidepressant pharmacology and suggest the use of these compounds as adjunct ADD therapies. Few studies have been disclosed in depressed patients treated with AMPAkines [136,137]. For example, a Phase 1b study in depressed patients showed improvements in depressed symptoms and enhancement in executive function with Org 26,576 (Figure 6) [138]. Clinical differentiation, classification, and utilization of populations of depressed patients is important in clinical trials of ADDs and may be an issue with the clinical trial literature in this area as well [139].
Platelet-rich plasma outcomes do not correlate with patient satisfaction or perceived cost-effectiveness
Published in The Physician and Sportsmedicine, 2023
Edward S. Mojica, Charles C. Lin, Noah Kirschner, Paola F. Ortega, Eoghan T. Hurley, Kirk A. Campbell, Michael J. Alaia, Laith M. Jazrawi
Osteoarthritis (OA) is a common clinical problem in the field of orthopedics, presenting in about 10% of people over the age of 60 with the potential to severely reduce quality of life [1–3]. OA is defined by destruction of the articular cartilage and the remodeling of subchondral bone to compensate [4]. While OA can typically be slowed through lifestyle modification, the inflammatory biochemical cascade ultimately contributes to the progression of disease and the eventual need for arthroplasty [4–6]. The knee is the most common site of OA, comprising 80% of OA diagnoses [7]. Intra-articular injections have become a mainstay in conservative therapy for OA as they have relatively few risks and have the potential to provide short-term pain reduction and improve joint function [8–11]. Of the various injection therapies available, there is increasing interest in platelet-rich plasma (PRP) as an innovative biological therapeutic to a long-standing clinical challenge.
Predicting functional outcomes after stroke: an observational study of acute single-channel EEG
Published in Topics in Stroke Rehabilitation, 2020
Jeffrey Rogers, Sandy Middleton, Peter H. Wilson, Stuart J. Johnstone
Stroke is associated with immediate brain changes resulting from the suppression of oxygen and glucose supply, including a biochemical cascade that can lead to cell death and cerebral infarction.1–3 Electroencephalography (EEG) is sensitive to the effects of these acute changes in cerebral blood flow4,5 and neural metabolism.6,7 Such changes can be identified through the disruption or deterioration of normal electrical activity within the four classical frequency bands: delta, theta, alpha, and beta. Delta and theta are primarily associated with a low state of arousal, and a prominence of these slow frequency waves is reported in individuals with neurological disease or injury.8 Faster frequency alpha waves are associated with a state of relaxation and readiness, while beta waves mainly occur when an individual is actively engaged in mental effort.8 In particular, EEG obtained in the acute stage after stroke (i.e. <72 h) is often associated with the rapid appearance of slow delta frequency waves and attenuation of faster alpha frequency activity.9–13
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