Neurokinin 1 receptor antagonist along with dexamethasone reduces the inflammation in COVID-19 patients: a novel therapeutic approach

Riffat Mehboob, Fridon Jawad Ahmad, Ahad Qayyum, Muhammad Asim Rana, Muhammad Akram Tariq, Shadi Tamur, Imran Shahid, Iman M Mirza, Amany Fathaddin, Samy A. Abusikkuen, Mohamed A Zayed

Abstract


Background: Corona virus infection is a respiratory infection, compromising the normal breathing in critical patients by damaging the lungs. The aim of this study was to evaluate the clinical outcomes of Substance P receptor Neurokinin 1 antagonist in COVID-19 patients against the usual treatments as controls.

Methods: It is a two-arm, open-label, randomized clinical trial that was carried out at Bahria International Hospital in Lahore, Pakistan. PCR-positive, hospitalized patients older than 18 years old, all sexes, and in the critical to life-threatening stage were included. 52 patients were placed in control group A and 67 patients were placed in intervention group B out of a total 119 patients who were randomly assigned to both arms. Before and after the intervention, lab tests were conducted in both groups. Aprepitant, a neurokinin-1 receptor antagonist, was additionally administered to the other arm while the other arm got standard therapy and care. Additionally, both groups received oral administration of the corticosteroid dexamethasone.

Results: Patients in group A were on average 56.05 years old, compared to 58.1 years old in group B. There were 24 women in group A and 28 in group B, while there were 28 men and 39 women in group A. Group A had three critical cases, but group B had six. The reduction in C-reactive protein in the intervention group, improvement in platelet count in group B, and normalization of ferritin and LDH levels in group B all indicated decreased inflammation in the biochemical and haematological parameters in both groups. However, because of the reduced sample size, it wasn't very significant.

Conclusion: The results of this recent trial provide a solid indication of Aprepitant's medicinal potential. Patients who got a combined therapy of dexamethasone and aprepitant had better clinical results, more favourable lab results, and lower levels of C-reactive protein, an inflammatory marker.


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References


Khan MA, Ho Y-S. Arsenic in drinking water: a review on Jia W, Wang W, Li R, Zhou Q, Qu Y, et al. Effect of Qinbai Qingfei Concentrated Pellets on substance P and neutral endopeptidase of rats with post-infectious cough. BMC Complementary Medicine and Therapies, (2020); 201-10.

Li M, Shang Y-x. Neurokinin-1 receptor antagonist decreases [Ca2+] i in airway smooth muscle cells by reducing the reverse-mode Na+/Ca2+ exchanger current. Peptides, (2019); 11569-74.

Mehboob R, Kurdi M, Bamaga A, Aldardeir N, Nasief H, Moshref LH, Alsinani T, Rayes AO, Jabbad RH. Substance P/ Neurokinin-1 Receptor, Trigeminal Ganglion, Latency, and Coronavirus Infection-Is There Any Link? Front Med (Lausanne). (2021); 18;8:727593.

Hökfelt T, Vincent S, Dalsgaard C, Skirboll L, Johansson O, et al. Distribution of substance P in brain and periphery and its possible role as a co-transmitter; 1982. pp. 84-106.

De Camilli P, Jahn R. Pathways to regulated exocytosis in neurons. Annual review of physiology, (1990); 52(1): 625-645.

Suvas S. Role of substance P neuropeptide in inflammation, wound healing, and tissue homeostasis. The Journal of Immunology, (2017); 199(5): 1543-1552.

Mashaghi A, Marmalidou A, Tehrani M, Grace PM, Pothoulakis C, et al. Neuropeptide substance P and the immune response. Cellular and molecular life sciences, (2016); 734249-4264.

Erdös EG, Skidgel RA. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones 1. The FASEB journal, (1989); 3(2): 145-151.

Rameshwar P, Oh H, Yook C, Gascon P, Chang V. Substance p-fibronectin-cytokine interactions in myeloproliferative disorders with bone marrow fibrosis. Acta haematologica, (2002); 109(1): 1-10.

Corbally N, Powell D, Tipton KF. The binding of endogenous and exogenous substance-P in human plasma. Biochemical pharmacology, (1990); 39(7): 1161-1166.

Otsuka K, Niimi A, Matsumoto H, Ito I, Yamaguchi M, et al. Plasma substance P levels in patients with persistent cough. Respiration, (2011); 82(5): 431-438.

Lavezzi AM, Mehboob R, Matturri L. Developmental alterations of the spinal trigeminal nucleus disclosed by substance P immunohistochemistry in fetal and infant sudden unexplained deaths. Neuropathology, (2011); 31(4): 405-413.

Mehboob R, Tanvir I, Warraich RA, Perveen S, Yasmeen S, et al. Role of neurotransmitter Substance P in progression of oral squamous cell carcinoma. Pathology-Research and Practice, (2015); 211(3): 203-207.

Mehboob R. Substance P/Neurokinin 1 and Trigeminal System: A Possible Link to the Pathogenesis in Sudden Perinatal Deaths. Front Neurol, (2017); 8:82.

Alwazzan A, Mehboob R, Hassan A, Perveen S, Sadaf, et al. Elevated neurokinin-1 receptor expression in uterine products of conception is associated with first trimester miscarriages. Frontiers in Physiology, (2020); 11554766.

Pakai E, Tekus V, Zsiboras C, Rumbus Z, Olah E, Keringer P, Khidhir N, Matics R, Deres L, Ordog K, Szentes N, Pohoczky K, Kemeny A, Hegyi P, Pinter E, Garami A. The Neurokinin-1 Receptor Contributes to the Early Phase of Lipopolysaccharide-Induced Fever via Stimulation of Peripheral Cyclooxygenase-2 Protein Expression in Mice. Front Immunol, (2018);9:166.

Szereda-Przestaszewska M, Kaczyńska K. Serotonin and substance P: Synergy or competition in the control of breathing. Auton Neurosci, (2020);225:102658.

Yeh S-Y, Huang W-H, Wang W, Ward CS, Chao ES, et al. Respiratory network stability and modulatory response to substance P require Nalcn. Neuron, (2017); 94(2): 294-303. e294.

Dehlin HM, Levick SP. Substance P in heart failure: the good and the bad. International journal of cardiology, (2014); 170(3): 270-277.

Iftikhar K, Siddiq A, Baig SG, Zehra S. Substance P: A neuropeptide involved in the psychopathology of anxiety disorders. Neuropeptides, (2020); 79101993.

Douglas SD, Ho W-Z, Gettes DR, Cnaan A, Zhao H, et al. Elevated substance P levels in HIV-infected men. Aids, (2001); 15(15): 2043-2045.

Mehboob R, Lavezzi AM. Neuropathological explanation of minimal COVID-19 infection rate in newborns, infants and children - a mystery so far. New insight into the role of Substance P. J Neurol Sci, (2021);420:117276.

Sámano C, Kaur J, Nistri A. A study of methylprednisolone neuroprotection against acute injury to the rat spinal cord in vitro. Neuroscience, (2016); 315136-149.

Hong S, Wang H, Zhang Z, Qiao L. The roles of methylprednisolone treatment in patients with COVID-19: A systematic review and meta-analysis. Steroids, (2022); 183109022.

Kaur J, Flores Gutiérrez J, Nistri A. Neuroprotective effect of propofol against excitotoxic injury to locomotor networks of the rat spinal cord in vitro. European Journal of Neuroscience, (2016); 44(7): 2418-2430.

Mehboob R, Ahmad FJ, Qayyum A, Rana MA, Gilani SA, et al. Aprepitant as a combinant with Dexamethasone reduces the inflammation via Neurokinin 1 Receptor Antagonism in severe to critical Covid-19 patients and potentiates respiratory recovery: A novel therapeutic approach. MedRxiv, (2020); 2020.2008. 2001.20166678. https://www.medrxiv.org/content/10.1101/2020.08.01.20166678v3.article-metrics

Vilisaar J, Kawabe K, Braitch M, Aram J, Furtun Y, et al. Reciprocal regulation of substance P and IL-12/IL-23 and the associated cytokines, IFNγ/IL-17: A perspective on the relevance of this interaction to multiple sclerosis. Journal of Neuroimmune Pharmacology, (2015); 10457-467.

Ziche M, Morbidelli L, Pacini M, Geppetti P, Alessandri G, et al. Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvascular research, (1990); 40(2): 264-278.

Ziche M, Morbidelli L, Masini E, Amerini S, Granger HJ, et al. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. The Journal of clinical investigation, (1994); 94(5): 2036-2044.

Lundberg J, Hökfelt T, Martling C-R, Saria A, Cuello C. Substance P-immunoreactive sensory nerves in the lower respiratory tract of various mammals including man. Cell and tissue research, (1984); 235251-261.

Borson D, Brokaw J, Sekizawa K, McDonald D, Nadel J. Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections. Journal of Applied Physiology, (1989); 66(6): 2653-2658.

Sekizawa K, Tamaoki J, Nadel J, Borson D. Enkephalinase inhibitor potentiates substance P-and electrically induced contraction in ferret trachea. Journal of Applied Physiology, (1987); 63(4): 1401-1405.

Baker AP, Hillegass LM, Holden DA, Smith WJ. Effect of kallidin, substance P, and other basic polypeptides on the production of respiratory macromolecules. American Review of Respiratory Disease, (1977); 115(5): 811-817.

Lundberg J, Saria A, Brodin E, Rosell S, Folkers K. A substance P antagonist inhibits vagally induced increase in vascular permeability and bronchial smooth muscle contraction in the guinea pig. Proceedings of the National Academy of Sciences, (1983); 80(4): 1120-1124.

Sellick H, Widdicombe J. Stimulation of lung irritant receptors by cigarette smoke, carbon dust, and histamine aerosol. Journal of applied physiology, (1971); 31(1): 15-19.

Wang FL, Zhang GT, Zhou YN, Yang XX, Zhou L, et al. The expanded effects of sevoflurane on the nervous system: the harmful effect of residual concentration of sevoflurane on the respiratory system through neurogenic inflammation. Ibrain, (2021); 7(2): 68-79.




DOI: http://dx.doi.org/10.62940/als.v10i3.1842

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