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DOI: 10.1055/s-0043-1764161
Ultramicronized Palmitoylethanolamide and Luteolin: Drug Candidates in Post-COVID-19 Critical Illness Neuropathy and Positioning-Related Peripheral Nerve Injury of the Upper Extremity
Abstract
Coronavirus disease 2019 (COVID-19) is the most dramatic pandemic of the new millennium and patients with serious infection can stay in intensive care unit (ICU) for weeks in a clinical scenario of systemic inflammatory response syndrome, likely related to the subsequent development of critical illness polyneuropathy (CIP). It is in fact now accepted that COVID-19 ICU surviving patients can develop CIP; moreover, prone positioning-related stretch may favor the onset of positioning-related peripheral nerve injuries (PNI). Therefore, the urgent need to test drug candidates for the treatment of these debilitating sequelae is emerged even more. For the first time in medical literature, we have successfully treated after informed consent a 71-year-old Italian man suffering from post-COVID-19 CIP burdened with positioning-related PNI of the left upper extremity by means of ultramicronized palmitoylethanolamide 400 mg plus ultramicronized luteolin 40 mg (Glìalia), two tablets a day 12 hours apart for 6 months. In the wake of our pilot study, a larger clinical trial to definitively ascertain the advantages of this neuroprotective, neurotrophic, and anti-inflammatory therapy is advocated.
Keywords
coronavirus disease 2019 - critical illness polyneuropathy - positioning-related peripheral nerve injury - palmitoylethanolamide - luteolinAuthors' Contributions
LA and RA were involved in conceptualization and investigation. DG and GDM helped in bibliographic resources. LR and CM contributed to data curation and writing—original draft preparation. NDR and RA supervised the study. All authors have read and agreed to the published version of the manuscript.
Ethical Approval
The study was conducted in accordance with the ethical standards and the Declaration of Helsinki of 1975, as revised in 2008.
Informed Consent
Informed consent was obtained from the subject involved in the study; sensitive data and images have been entirely anonymized.
Data Availability
The data presented in this study are available on request from the corresponding author.
Publication History
Article published online:
13 March 2023
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References
- 1 Bolton CF, Gilbert JJ, Hahn AF, Sibbald WJ. Polyneuropathy in critically ill patients. J Neurol Neurosurg Psychiatry 1984; 47 (11) 1223-1231
- 2 Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol 2011; 10 (10) 931-941
- 3 Maramattom BV, Wijdicks EF. Acute neuromuscular weakness in the intensive care unit. Crit Care Med 2006; 34 (11) 2835-2841
- 4 Hermans G, De Jonghe B, Bruyninckx F, Van den Berghe G. Clinical review: critical illness polyneuropathy and myopathy. Crit Care 2008; 12 (06) 238
- 5 Kress JP, Hall JB. ICU-acquired weakness and recovery from critical illness. N Engl J Med 2014; 370 (17) 1626-1635
- 6 Visser LH. Critical illness polyneuropathy and myopathy: clinical features, risk factors and prognosis. Eur J Neurol 2006; 13 (11) 1203-1212
- 7 Schweickert WD, Hall J. ICU-acquired weakness. Chest 2007; 131 (05) 1541-1549
- 8 Hermans G, Wilmer A, Meersseman W. et al. Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit. Am J Respir Crit Care Med 2007; 175 (05) 480-489
- 9 Johnson KL. Neuromuscular complications in the intensive care unit: critical illness polyneuromyopathy. AACN Adv Crit Care 2007; 18 (02) 167-180 , quiz 181–182
- 10 Roncati L, Corsi L. Nucleoside-modified messenger RNA COVID-19 vaccine platform. J Med Virol 2021; 93 (07) 4054-4057
- 11 Boehme AK, Doyle K, Thakur KT. et al. Disorders of consciousness in hospitalized patients with COVID-19: the role of the systemic inflammatory response syndrome. Neurocrit Care 2022; 36 (01) 89-96
- 12 Roncati L, Nasillo V, Lusenti B, Riva G. Signals of Th2 immune response from COVID-19 patients requiring intensive care. Ann Hematol 2020; 99 (06) 1419-1420
- 13 Roncati L, Ligabue G, Nasillo V. et al. A proof of evidence supporting abnormal immunothrombosis in severe COVID-19: naked megakaryocyte nuclei increase in the bone marrow and lungs of critically ill patients. Platelets 2020; 31 (08) 1085-1089
- 14 Roncati L, Corsi L, Barbolini G. Abnormal immunothrombosis and lupus anticoagulant in a catastrophic COVID-19 recalling Asherson's syndrome. J Thromb Thrombolysis 2021; 52 (04) 1043-1046
- 15 Roncati L, Ligabue G, Fabbiani L. et al. Type 3 hypersensitivity in COVID-19 vasculitis. Clin Immunol 2020; 217: 108487
- 16 Bawiskar N, Talwar D, Kumar S, Acharya S. Critical illness polyneuropathy as a sequela of COVID-19. J Glob Infect Dis 2022; 14 (02) 90
- 17 Intiso D, Marco Centra A, Giordano A, Santamato A, Amoruso L, Di Rienzo F. Critical illness polyneuropathy and functional outcome in subjects with Covid-19: report on four patients and a scoping review of the literature. J Rehabil Med 2022; 54: jrm00257
- 18 Stoian A, Bajko Z, Maier S. et al. High-dose intravenous immunoglobulins as a therapeutic option in critical illness polyneuropathy accompanying SARS-CoV-2 infection: a case-based review of the literature (Review). (review) Exp Ther Med 2021; 22 (04) 1182
- 19 Kayim Yildiz O, Yildiz B, Avci O, Hasbek M, Kanat S. Clinical, neurophysiological and neuroimaging findings of critical illness myopathy after COVID-19. Cureus 2021; 13 (03) e13807
- 20 Bax F, Lettieri C, Marini A. et al. Clinical and neurophysiological characterization of muscular weakness in severe COVID-19. Neurol Sci 2021; 42 (06) 2173-2178
- 21 Novak P, Cunder K, Petrovič O. et al. Rehabilitation of COVID-19 patients with respiratory failure and critical illness disease in Slovenia: an observational study. Int J Rehabil Res 2022; 45 (01) 65-71
- 22 Bocci T, Campiglio L, Zardoni M. et al. Critical illness neuropathy in severe COVID-19: a case series. Neurol Sci 2021; 42 (12) 4893-4898
- 23 Hokkoku K, Erra C, Cuccagna C. et al. Intensive care unit-acquired weakness and positioning-related peripheral nerve injuries in COVID-19: a case series of three patients and the latest literature review. Brain Sci 2021; 11 (09) 1177
- 24 Fernandez CE, Franz CK, Ko JH. et al. Imaging review of peripheral nerve injuries in patients with COVID-19. Radiology 2021; 298 (03) E117-E130
- 25 Malik GR, Wolfe AR, Soriano R. et al. Injury-prone: peripheral nerve injuries associated with prone positioning for COVID-19-related acute respiratory distress syndrome. Br J Anaesth 2020; 125 (06) e478-e480
- 26 Miller C, O'Sullivan J, Jeffrey J, Power D. Brachial plexus neuropathies during the COVID-19 pandemic: a retrospective case series of 15 patients in critical care. Phys Ther 2021; 101 (01) pzaa191
- 27 Gugliandolo E, Peritore AF, Piras C, Cuzzocrea S, Crupi R. Palmitoylethanolamide and related ALIAmides: prohomeostatic lipid compounds for animal health and wellbeing. Vet Sci 2020; 7 (02) 78
- 28 Aloe L, Leon A, Levi-Montalcini R. A proposed autacoid mechanism controlling mastocyte behaviour. Agents Actions 1993; 39 (Spec No): C145-C147
- 29 D'Amico R, Impellizzeri D, Cuzzocrea S, Di Paola R. ALIAmides update: palmitoylethanolamide and its formulations on management of peripheral neuropathic pain. Int J Mol Sci 2020; 21 (15) 5330
- 30 Cordaro M, Scuto M, Siracusa R. et al. Effect of N-palmitoylethanolamine-oxazoline on comorbid neuropsychiatric disturbance associated with inflammatory bowel disease. FASEB J 2020; 34 (03) 4085-4106
- 31 López-Lázaro M. Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem 2009; 9 (01) 31-59
- 32 Ashaari Z, Hadjzadeh MA, Hassanzadeh G. et al. The flavone luteolin improves central nervous system disorders by different mechanisms: a review. J Mol Neurosci 2018; 65 (04) 491-506
- 33 Fan X, Du K, Li N. et al. Evaluation of anti-nociceptive and anti-inflammatory effect of luteolin in mice. J Environ Pathol Toxicol Oncol 2018; 37 (04) 351-364
- 34 Cordaro M, Cuzzocrea S, Crupi R. An update of palmitoylethanolamide and luteolin effects in preclinical and clinical studies of neuroinflammatory events. Antioxidants 2020; 9 (03) 216
- 35 Bertolino B, Crupi R, Impellizzeri D. et al. Beneficial effects of co-ultramicronized palmitoylethanolamide/luteolin in a mouse model of autism and in a case report of autism. CNS Neurosci Ther 2017; 23 (01) 87-98
- 36 Peritore AF, D'Amico R, Siracusa R. et al. Management of acute lung injury: palmitoylethanolamide as a new approach. Int J Mol Sci 2021; 22 (11) 5533
- 37 Roncati L, Lusenti B, Pellati F, Corsi L. Micronized / ultramicronized palmitoylethanolamide (PEA) as natural neuroprotector against COVID-19 inflammation. Prostaglandins Other Lipid Mediat 2021; 154: 106540
- 38 Fessler SN, Liu L, Chang Y, Yip T, Johnston CS. Palmitoylethanolamide reduces proinflammatory markers in unvaccinated adults recently diagnosed with COVID-19: a randomized controlled trial. J Nutr 2022; 152 (10) 2218-2226
- 39 Raciti L, De Luca R, Raciti G, Arcadi FA, Calabrò RS. The use of palmitoylethanolamide in the treatment of long COVID: a real-life retrospective cohort study. Med Sci (Basel) 2022; 10 (03) 37
- 40 Albanese M, Marrone G, Paolino A. et al. Effects of ultramicronized palmitoylethanolamide (um-PEA) in COVID-19 early stages: a case-control study. Pharmaceuticals (Basel) 2022; 15 (02) 253
- 41 Del Re A, Corpetti C, Pesce M. et al. Ultramicronized palmitoylethanolamide inhibits NLRP3 inflammasome expression and pro-inflammatory response activated by SARS-CoV-2 spike protein in cultured murine alveolar macrophages. Metabolites 2021; 11 (09) 592
- 42 Fonnesu R, Thunuguntla VBSC, Veeramachaneni GK. et al. Palmitoylethanolamide (PEA) inhibits SARS-CoV-2 entry by interacting with S protein and ACE-2 receptor. Viruses 2022; 14 (05) 1080
- 43 De Luca P, Camaioni A, Marra P. et al. Effect of ultra-micronized palmitoylethanolamide and luteolin on olfaction and memory in patients with long COVID: results of a longitudinal study. Cells 2022; 11 (16) 2552
- 44 Versace V, Ortelli P, Dezi S. et al. Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome. Clin Neurophysiol 2023; 145: 81-88
- 45 Roncati L, Gianotti G, Gravina D. et al. Carpal, cubital or tarsal tunnel syndrome after SARS-CoV-2 infection: a causal link?. Med Hypotheses 2021; 153: 110638
- 46 Roncati L, Gravina D, Marra C, Della Rosa N, Adani R. Cubital tunnel syndrome temporally after COVID-19 vaccination. Trop Med Infect Dis 2022; 7 (04) 62
- 47 Impellizzeri D, Bruschetta G, Cordaro M. et al. Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain. J Neuroinflammation 2014; 11: 136
- 48 Bauer L, Laksono BM, de Vrij FMS, Kushner SA, Harschnitz O, van Riel D. The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2. Trends Neurosci 2022; 45 (05) 358-368
- 49 Paternostro-Sluga T, Grim-Stieger M, Posch M. et al. Reliability and validity of the Medical Research Council (MRC) scale and a modified scale for testing muscle strength in patients with radial palsy. J Rehabil Med 2008; 40 (08) 665-671
- 50 Shooter D. Use of two-point discrimination as a nerve repair assessment tool: preliminary report. ANZ J Surg 2005; 75 (10) 866-868
- 51 Arnaout A, Fontaine C, Chantelot C. Sensory recovery after primary repair of palmar digital nerves using a Revolnerv(®) collagen conduit: a prospective series of 27 cases. Chir Main 2014; 33 (04) 279-285