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Neuropeptide Inactivation By Peptidases
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
Gerard O’Cuinn, Brendan O’Connor, Laura Gilmartin, Maria Smyth
Enkephalinase B was first identified when enkephalinase activity was solubilized from rat brain membranes and resolved into three distinct activities. These activities were identified as an aminopeptidase which released N-terminal tyrosine from enkephalin, an enkephalinase A which released Tyr-Gly-Gly and Phe-Leu and an enkephalinase B which released N-terminal Tyr-Gly127. A soluble dipeptidyl aminopeptidase III was subsequently described in rat brain which was also shown to release Tyr-Gly moieties from enkephalins. This activity, which was assayed using Arg-Arg-4-methyoxy-β-naphthylamide as substrate, was found to be 40% particulate and 60% soluble in most forebrain areas and to have a preference for enkephalins and angiotensins among the substrates tested with affinities in the micromolar range146. These findings raised the possibility that enkephalinase B might be a membrane bound form of dipeptidyl aminopeptidase III. Further support for this possibility came from angiotensin II degradation studies in cultured mouse spinal cord cells which showed release of Val3-Tyr4 from 3H-Tyr angiotensin II and of Tyr4-Ile5 from 3H-Tyr-angiotensin III147. These conversions were inhibited by Tyr-Tyr, a known inhibitor of dipeptidyl aminopeptidase III146.
The Thymus and Immunotherapy, Reconstructive Vs. Stimulatory or Suppressive Conceptions
Published in Marek P. Dabrowski, Barbara K. Dabrowska-Bernstein, Immunoregulatory Role of Thymus, 2019
Marek P. Dabrowski, Barbara K. Dabrowska-Bernstein
Enkephalins are small peptides composed of five amino acids and originate from much larger precursor proenkephalin A composed of 236 amino acids. Endorphins originate from proopiomelanocortin (264 amino acids) and usually represent sequence of 16 to 31 amino acids. The enkephalins can also be synthesized chemically. The methionine-enkephalin (Met-Enk) represents structure of Tyr-Gly-Gly-Phe-Met with molecular weight of 573.65, and when obtained sterilely as a lyophilized powder (Union Chemique Belge, UCB Bioproduct, Brussels, Belgium) can easily be reconstituted with saline for clinical purposes. Physiologically, enkephalins are destroyed within 90 s by serum enkephalinase and aminopeptidase. The specific action of Naloxane on the cellular opioid receptors antagonize the effects of enkephalings. Earlier studies revealed that the functions of enkephalins are involved in the perception of pain and are influencing some behavioral activities, including mood, feeding, and drinking desire and memory learning.132,133
Neuropharmacology Of Respiration
Published in Alan D. Miller, Armand L. Bianchi, Beverly P. Bishop, Neural Control of the Respiratory Muscles, 2019
Monique Denavit-Saubié, Arthur S. Foutz
In most cases, opioids, when applied locally on respiratory neurons, reduce their discharge frequency.20,62,63,80 However, this reduction of firing is not homogeneous throughout the duration of the respiratory cycle (as occurs with noradrenalin). In tonically discharging neurons, the higher frequency which gives its respiratory modulation to the pattern of discharge is more depressed than the basal frequency in the remaining part of the respiratory cycle.20,63 Consequently, the respiratory modulation of the neuron is reduced and even suppressed, since there is no longer any difference of firing frequency in relation to the respiratory cycle. This smoothing of the modulation of respiratory neurons, which has also been observed after local application of a mu receptor agonist levorphanol, is reversed by administration of naloxone.20 This is probably at the origin of the depression of the motor respiratory output observed under opiate intoxication. Moreover, this mechanism may occur under physiological conditions because an iontophoretic application of naloxone without a preceding administration of opioid slightly increases the modulation of respiratory neurons.63 This neuronal modulation is decreased after local administration of the enkephalinase inhibitor, kelatorphan, which induces a local accumulation of enkephalins.57
Evaluating the cost utility of racecadotril in addition to oral rehydration solution versus oral rehydration solution alone for children with acute watery diarrhea in four low middle-income countries: Egypt, Morocco, Philippines and Vietnam
Published in Journal of Medical Economics, 2022
Tamlyn Anne Rautenberg, Martin Downes, Pham Huy Tuan Kiet, Nermeen Ashoush, Antonio Rosete Dennis, Kyoo Kim
Racecadotril is an oral enkephalinase inhibitor used for the treatment of acute diarrhoea and authorised by the European Medicines Agency39,40. To date, no study has been done to evaluate the cost utility of racecadotril for the treatment of children with diarrhea in LMIC, although several studies have been published for high-income and upper-middle-income countries41–43. In view of the persistent challenge of diarrhoea, the growing importance of HTA in the countries in focus and the acceptability of leveraging on existing economic evaluations, this study has been undertaken. The objective is to evaluate R + ORS versus ORS alone in children under the age of five with acute watery diarrhoea in Egypt, Morocco, Philippines and Vietnam to support emerging HTA processes and inform public health funding bodies at country level.
Current strategies toward safer mu opioid receptor drugs for pain management
Published in Expert Opinion on Therapeutic Targets, 2019
Aliza T. Ehrlich, Brigitte L. Kieffer, Emmanuel Darcq
Another effort has been made to generate endogenous opioid peptide analogues [79]. This approach is appealing as it will use the naturally produced analgesic properties of endogenous opioids and improve at the same time their stability and bioavailability. Several methods have been used during the last few decades to make peptides druggable such as glycosylation, cyclization, modification of the C- and N-terminal and packaging of opioid peptides and are reviewed in detail in [79]. These strategies are still in their early stages, requiring a significant need of development due to the challenges in stabilizing peptides with short in-vivo half-life, and increasing their bioavailability making them capable of crossing the blood brain barrier. Another interesting approach consists of increasing peptide levels by inhibiting the enzyme(s) responsible for endogenous opioid peptide degradation [80]. The enzymes that degrade endogenous enkephalin opioid peptides are known as enkephalinases. The designed inhibitors of enkephalinases such as aminopeptidase N and neutral endopeptidase neprilysn (NEP), are called racecadotril, ubenimex (bestatin), and RB-101. Remarkably, preclinical observations support that these enkephalinase inhibitors are capable of producing efficient analgesia without respiratory depression, reward, tolerance and constipation [81]. This strategy is very appealing because it circumvents exogenous opioid use thereby avoiding dependency issues and lethal complications like respiratory depression, however until now enkephelinase inhibitors have not made it into the clinic to treat pain.
New concepts in opioid analgesia
Published in Expert Opinion on Investigational Drugs, 2018
Different strategies to obtain peripherally restricted opioids were pursued. A common approach is the development of hydrophilic substances with minimal capability to cross the blood–brain barrier. Among the first compounds were the mu-agonist loperamide and the kappa-agonist asimadoline. Peripheral restriction was also aimed for with glucuronidation, arylacetamide, morphinan-based, triazaspiro and peptidic compounds [10,30,38,99,101,116–118]. Several preclinical studies have described enkephalinase inhibitors with reduced barrier permeability, but clinical studies are lacking to date [8,13]. In collaboration with a group of chemists, we used a strategy applying a cleavable linker to attach morphine to a polyglycerol-based nanocarrier [119]. This conjugate (PG-M) was devised to selectively release morphine in inflamed tissue and to preclude blood–brain barrier permeation due to its high molecular weight and hydrophilicity. Preclinical experiments showed that this construct exclusively activated peripheral opioid receptors to produce analgesia in injured tissue without evoking sedation or constipation [119].