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The Neurodegenerative Characteristics of Alzheimer’s Disease and Related Multi-Target Drug Design Studies
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Hayrettin Ozan Gülcan, Ilkay Erdogan Orhan
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.
Pharmacological Strategies for Uterine Relaxation
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
Michael Hollingsworth, Sandra J. Downing, Josephine M. S. Cheuk, Ian T. Piper, Sarah J. Hughes
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.
Physiology of Hearing
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
Soumit Dasgupta, Michael Maslin
Otoprotective endogenous compounds play an important role in preserving the delicate cochlear structures and influence the biochemical cascade, although in a rather heterogeneous way. These include heat shock factors (HSFs) and heat shock proteins (HSPs), both abundantly expressed in the cochlea, which can modify the apoptosis response;84downregulation of some growth factors;85 neurotrophin, mainly glial cell-derived neurotrophic factor (GDNF) regulation,86 to modify the end result of apoptosis for recovery of function and the coenzymes Q9 and Q10.87
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.
Targeting coagulation to unlock antitumor immunity?
Published in OncoImmunology, 2022
Antoine Galmiche, Zuzana Saidak, François Ghiringhelli
Coagulation is a vital biochemical cascade that is almost systematically activated in human tumors.1 As a consequence of this hypercoagulant state, solid tumors often induce systemic complications, such as venous thromboembolism, that account for significant mortality and morbidity (especially in glioblastoma, lung carcinoma or pancreatic adenocarcinoma).1 The role of the coagulation cascade as a source of hemostatic complications has motivated the development of pharmacological anticoagulant agents, such as low-molecular weight heparins or direct oral anticoagulants (DOAC). Despite an attractive preclinical rationale, preventing thomboembolic accidents in cancer patients has proven difficult and current anticoagulation protocols have failed to broadly extend the survival of ambulatory cancer patients.1 Lack of personalization and the intrinsic narrow therapeutic window of the available treatments (that target the common effectors of coagulation, thus inducing hemorrhage and bleeding), could explain this.1
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].