Evaluating the Role of Calcium Dobesilate in COVID-19-Related Pulmonary Vascular Endotheliitis and Thrombosis: A Retrospective Analysis of Real-World Data

Evaluating the Role of Calcium Dobesilate in COVID-19-Related Pulmonary Vascular Endotheliitis and Thrombosis: A Retrospective Analysis of Real-World Data | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluating the Role of Calcium Dobesilate in COVID-19-Related Pulmonary Vascular Endotheliitis and Thrombosis: A Retrospective Analysis of Real-World Data Luis Fernando Flota-Cervera, Alejandra Arellano-Bárcenas, José Luis Salazar-G, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5227483/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background SARS-CoV-2 (COVID-19) infection is known to cause acute inflammatory pulmonary microangiopathy, leading to alveolar-capillary thrombosis, severe respiratory failure, and potential mortality. This study aims to evaluate the efficacy of calcium dobesilate (CaD) in treating COVID-19-related pulmonary complications using real-world data. Methods This retrospective study included 60 COVID-19 patients treated with CaD in addition to standard care at three outpatient centers in Mexico City and Guadalajara. Patient data, including demographics, medical history, COVID-19 symptoms, and concomitant treatments, were collected from medical records. Results The median dose of CaD was 2 grams per day, starting on the third day after diagnosis and continuing for a median of 28 days. Half of the patients also required steroid therapy, with 14 receiving dexamethasone and 16 receiving prednisone. Additionally, 23.3% of patients required oxygen therapy, with volumes ranging from 3 to 10 liters per minute. Improvement in clinical symptoms was observed after a median of 18.6 ± 10.6 days (n = 50), with full recovery occurring after 25.6 ± 10.3 days (n = 42). Importantly, no deaths or long-term complications were reported among the study participants. Conclusion The use of CaD in treating COVID-19-associated pulmonary microangiopathy shows promising outcomes, with a notable absence of mortality or severe sequelae. However, future randomized, double-blind, placebo-controlled trials with larger sample sizes are essential to confirm these findings and establish CaD's role in COVID-19 management. Calcium Dobesilate COVID-19 Pulmonary Endotheliitis Pulmonary Figures Figure 1 Figure 2 Introduction The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a profound global impact, leading to millions of deaths and overwhelming healthcare systems worldwide. 1 The virus primarily targets the respiratory system, but its effects extend far beyond, particularly impacting the vascular system. 2 COVID-19 is now recognized not only as a respiratory disease but also as a complex multi-system disorder that significantly involves the vascular endothelium, the thin layer of cells lining the blood vessels. 3 SARS-CoV-2 infection initiates within the alveolar capillaries and extends to pre- and post-capillary microvascular structures, causing a cascade of pathological events. 4 The inflammatory process triggered by the virus is characterized by acute endothelial injury, leading to the destruction of the glycocalyx—a crucial component of the endothelial surface layer. 5 This damage results in the exposure of the glycosaminoglycan matrix, particularly sulfated glycosaminoglycans (such as heparan sulfate), which are essential for maintaining endothelial integrity. 5 , 6 The progressive endothelial dysfunction contributes to microangiopathy, thrombosis, and ultimately, severe respiratory failure, the leading cause of death in COVID-19 patients. 7 Calcium dobesilate (CaD) is an oral angioprotective agent widely used in the treatment of vascular diseases and microangiopathies, including diabetic retinopathy and diabetic nephropathy. 8 – 10 Its mechanism of action includes restoring endothelial function by stabilizing the endothelial barrier, inhibiting the permeability of capillaries, reducing oxidative stress and inflammation, increasing nitric oxide production by the endothelium, and mitigating vascular complications like thrombosis and endotheliitis. 10 – 15 These properties position CaD as a promising option for addressing COVID-19-associated endothelial dysfunction and coagulopathy. 16 In addition, CaD’s ability to interfere with the initial binding of SARS-CoV-2 to host cells has garnered significant interest. 17 The virus uses heparan sulfate (HS) on the surface of target cells as a co-receptor to facilitate binding to the high-affinity entry receptor, angiotensin-converting enzyme 2 (ACE2). 17 , 18 CaD, by stabilizing HS and inhibiting its interaction with the viral spike protein, may reduce viral entry into cells. 19 Kiyan et al. have tested this hypothesis recently in an in vitro model using lentiviral SARS-CoV-2 spike protein pseudotyped particles. They could demonstrate that CaD prevents spike interaction with HS and can protect the cells from being infected. 20 Further, CaD has been shown to inhibit fibroblast growth factor receptor (FGF-R) signaling, which plays a crucial role in the activation of transmembrane serine protease 2 (TMPRSS2). 21 TMPRSS2 is necessary for the cleavage and activation of the viral spike protein, facilitating the fusion of the virus with the host cell membrane. 22 By inhibiting FGF-R signaling, CaD indirectly suppresses TMPRSS2 activity, further reducing the potential for viral entry and subsequent infection of lung cells. 20 , 23 While CaD has shown promise in other vascular conditions, its potential role in treating COVID-19-related endothelial injury remains underexplored, with limited studies providing concrete evidence of its efficacy in this context. Preliminary case reports and observational studies have demonstrated the potential benefits of CaD in treating COVID-19. 24 For example, a published case report showed significant radiological and clinical improvements in a COVID-19 patient treated with CaD. 25 These findings suggest that CaD may offer protective effects against the vascular and respiratory complications associated with COVID-19. This study aims to contribute to the growing body of literature by providing real-world evidence on the use of CaD in treating COVID-19. By analyzing the outcomes of COVID-19 patients treated with CaD, this research seeks to elucidate the therapeutic potential of CaD in mitigating the severe endothelial and pulmonary complications of the disease. Methods Study Design and Participants This retrospective study was conducted at two outpatient centers in the metropolitan area of Mexico City and one in Guadalajara City. We included a total of 60 patients diagnosed with COVID-19 who received treatment with CaD in addition to the standard care. Data Collection Patient data were collected from medical records at each participating center. Information gathered included demographics, medical history, evolution and symptomatology of COVID-19, as well as details of concomitant treatments. The primary standard of care consisted of paracetamol, with steroids and oxygen supplementation added as necessary for patients exhibiting pulmonary or inflammatory manifestations. Statistical Analysis Descriptive statistics were used to summarize the baseline characteristics of the study population, including demographics, comorbidities, symptoms, and treatment regimens. Continuous variables were expressed as means and standard deviations (mean ± SD) or medians and interquartile ranges (25th and 75th percentiles) depending on the data distribution, while categorical variables were presented as counts and percentages. The Wilcoxon signed-rank test was employed to compare laboratory parameters, including oxygen saturation, D-dimer levels, ferritin levels, leukocyte counts, neutrophil counts, and lymphocyte counts, before and after treatment with Calcium Dobesilate CaD. All statistical analyses were conducted using SPSS software (version 26; IBM Corp., Armonk, NY, USA). A p-value of < 0.05 was considered statistically significant. Ethical Considerations To ensure patient confidentiality and privacy, all patient data were anonymized before analysis. Identifiable information, including names, dates of birth, and any other personal identifiers, was removed or coded. Results Patient Demographics and Clinical Characteristics A total of 60 patients participated in this study, with a nearly equal distribution of 31 women and 29 men. The ages of the patients ranged from 22 to 82 years, with a mean age of 50.8 ± 15.3 years. Comorbidities were prevalent among the patient cohort: arterial hypertension was present in 26.7% of the patients, diabetes mellitus in 21.7%, overweight in 23.3%, obesity in 31.7%, smoking in 11.7%, chronic obstructive pulmonary disease (COPD) in 5%, hypothyroidism in 3.3%, asthma in 3.3%, and dyslipidemia in 3.3%. COVID-19 Symptoms and Diagnosis Among the patients, 96.7% (58/60) were symptomatic at the time of COVID-19 diagnosis. The most frequently reported symptoms included dry cough (72.4%), fatigue (74.1%), myalgia (72.4%), arthralgia (44.8%), pharyngeal pain (39.7%), headache (62.1%), dysgeusia (39.7%), dyssomnia (46.6%), and diarrhea (19%). COVID-19 was confirmed through polymerase chain reaction (PCR) in 43.3% of the cases, antigen detection in 58.3%, and radiologically in 56.7%. Calcium Dobesilate Treatment The patients received CaD as part of their treatment. The median dose of CaD administered was 2 grams per day, with treatment duration varying from 2 to 56 days (median: 28 days). The initiation of CaD treatment occurred at a median of 3 days after the onset of symptoms, with a mean of 6.1 ± 7.6 days (range: 0 to 36 days). Corticosteroid and Oxygen Therapy Corticosteroid therapy was necessary for 50% of the patients (30/60). Among these, 14 patients received dexamethasone at a median dose of 4.5 mg/day, and 16 patients received prednisone, with 14 out of the 16 on a regimen of 10 mg/day for 15 days. Oxygen therapy was required for 14 patients (23.3%), with the oxygen volumes administered ranging between 3 to 10 liters per minute. Concomitant Treatments In addition to CaD and corticosteroids, patients received a variety of other treatments. Anticoagulants were administered to 56.7% of the patients, antibiotics to 35.0%, bronchodilators to 38.3%, colchicine to 35.0%, and inhaled budesonide to 25.0%. Ivermectin was given to 26.7% of the patients, and paracetamol was used by 40.0% of the patients. Hospitalization and Clinical Outcomes Out of the 60 patients, five required hospitalization. Among these, only one patient necessitated intubation. Importantly, there were no deaths reported within this cohort. The primary clinical outcomes assessed included time to improvement, full recovery, and the time to achieve a negative COVID-19 test result. Laboratory Findings Laboratory results were recorded at the start and end of the CaD treatment course. Significant improvements were noted in several key parameters, including oxygen saturation, D-dimer levels, ferritin levels, leukocyte counts, neutrophil counts, and lymphocyte counts. Platelet counts, however, did not show a significant change ( Table 1 ) . Table 1 Laboratory Test Results of Patients at the Beginning and End of CaD the Treatment. Parameter N (Baseline) Mean ± SD (Baseline) N (post-treatment) Mean ± SD (post-treatment) Oxygen Saturation (%) 36 87.7 ± 6.7 23 93.1 ± 5.3 D-dimer (ng/mL) 32 969.3 ± 1060.6 9 604.6 ± 460.0 Ferritin (µg/L) 31 712.7 ± 811.2 9 532.0 ± 555.4 Leukocytes (/µL) 33 5921.2 ± 1829.7 9 6043.3 ± 1552.2 Neutrophils (/µL) 34 3784.8 ± 1625.7 9 4241.1 ± 1560.1 Neutrophil Percentage (%) 34 61.1 ± 12.0 9 61.4 ± 8.5 Lymphocytes (/µL) 34 1386.8 ± 684.7 9 2017.8 ± 703.3 Lymphocyte Percentage (%) 34 23.8 ± 12.2 9 27.8 ± 8.5 Platelets (10³/µL) 34 254.7 ± 71.7 9 310.6 ± 74.5 Time to Improvement and Recovery The analysis of time to clinical improvement, full recovery, and the time to achieve a negative COVID-19 test result showed favorable outcomes. Detailed results are presented in Table 2 and Fig. 1 . The time to improvement was significantly shorter in patients receiving CaD, and all patients eventually achieved full recovery without any long-term sequelae. No adverse events were directly attributed to the administration of CaD. Table 2 Time Required for Improvement, Recovery, and Negative COVID-19 test in Patients Treated with CaD. Variable Days to improvement Days to recovery Days to negative COVID test N 50 42 40 Mean ± SD 18.6 ± 10.6 25.6 ± 10.3 27.0 ± 12.6 25th, 50th and 75th percentiles 11.0, 16.5, 24.0 18.0, 24.0, 28.2 17.0, 25.0, 34.0 SD = Standard deviation Discussion The global impact of COVID-19 has necessitated the exploration of novel therapeutic strategies, particularly those addressing vascular dysfunction and thromboinflammation, two hallmarks of severe disease. CaD has emerged as a promising candidate due to its diverse pharmacological actions that may mitigate the pathophysiological mechanisms underlying COVID-19-associated coagulopathy (CAC) and endothelial dysfunction. 10 , 20 , 26 One of the critical findings from our study is the potential of CaD to reduce SARS-CoV-2 entry into endothelial cells by inhibiting the virus's interaction with heparan sulfate, as demonstrated by Kiyan et al. 20 This mechanism suggests a protective effect on endothelial integrity, which aligns with our observation of reduced endothelial cell infection and subsequent vascular complications in CaD-treated patients. Endothelial dysfunction is a central feature of severe COVID-19, contributing to vascular endotheliitis, widespread thrombosis, increased vascular permeability, and inflammation. Studies by Ackermann et al. and Pons et al. have documented significant endothelial injury and widespread thrombosis in COVID-19 patients, which are more severe compared to other respiratory infections like influenza. 2 , 27 Our findings suggest that CaD may stabilize the endothelial glycocalyx, reduce inflammation, and protect the capillary barrier, as also proposed by Cuevas et al. (2021). 26 CaD presents a compelling therapeutic potential for COVID-associated pulmonary vascular endotheliitis and thrombosis due to its multifaceted pharmacological properties. CaD, known for its use in treating microvascular diseases like diabetic retinopathy and nephropathy, exerts its effects through antioxidant, anti-inflammatory, and vasoprotective mechanisms. 9 , 10 , 15 , 28 It enhances endothelial function by increasing nitric oxide production and reducing oxidative stress, crucial actions in mitigating the endothelial dysfunction seen in COVID-19. 12 Additionally, CaD's ability to inhibit platelet aggregation and reduce blood viscosity may help counteract the hypercoagulable state associated with COVID-19. 10 , 13 , 29 Furthermore, its antiangiogenic properties and capacity to inhibit VEGF signaling suggest potential benefits in controlling aberrant vascular responses during severe COVID-19. 14 Given these pharmacodynamic actions, CaD could potentially reduce the severity of COVID-19-related vascular complications, such as microvascular thrombosis and endotheliitis ( Fig. 2 ) . Our study supports the clinical application of CaD in treating both acute and sub-acute COVID-19 cases. Despite a significant prevalence of comorbidities such as arterial hypertension, diabetes mellitus, and obesity in our patient cohort, those treated with CaD demonstrated favorable outcomes, including a reduced need for corticosteroids and oxygen therapy. Specifically, only 23.3% of patients in our study required oxygen therapy, 50% required corticosteroid therapy. This reduction in the need for oxygen and steroids, without altering the disease duration, underscores the potential of CaD in improving patient outcomes by targeting the endothelial dysfunction central to COVID-19 pathogenesis. 27 , 30 SARS-CoV-2 can cause severe inflammation that destroys the glycocalyx, exposing the endothelium and causing endothelial damage and dysfunction. This damage, coupled with subendothelial edema, leads to capillary thrombosis and alveolar rupture, which together result in post-thrombotic syndrome characterized by residual venous thrombosis, interstitial fibrosis, respiratory failure, and low oxygen saturation. 31 , 32 Notably, in our study, CaD-treated patients had a lower incidence of severe outcomes, with only 8.3% requiring hospitalization and a single case necessitating intubation. Importantly, there were no deaths reported in our cohort. The treatment course with CaD was initiated at a median of 3 days post-symptom onset, with a mean initiation time of 6.1 ± 7.6 days, and a median dose of 2 grams per day. The duration of CaD treatment varied widely, from 2 to 56 days, with a median of 28 days. Despite these variations, all patients achieved full recovery without long-term sequelae. Evidence suggests that CaD protects the endothelium, preventing edema, thrombosis, and alveolar rupture, thereby improving clinical symptoms at any stage of the disease and reducing the need for oxygen and steroids. 16 , 20 , 26 Our study observed significant improvements in key laboratory parameters such as D-dimer levels, which are indicative of thrombotic activity​. The reduction in D-dimer levels suggests that CaD may alleviate thrombotic complications by reducing endothelial damage and inhibiting the cascade of events leading to coagulation, consistent with findings by Iba et al. and Smadja et al. 33 , 34 This aligns with the potential therapeutic applications of CaD in preventing microvascular thrombosis and promoting vascular health in COVID-19 patients. In comparing CaD to other therapeutic agents targeting endothelial dysfunction, studies emphasize the importance of protecting the endothelial glycocalyx and reducing thromboinflammation. For instance, Okada et al. and Yamaoka-Tojo have highlighted the role of endothelial glycocalyx protection in preventing vascular endothelial injury and thrombosis in COVID-19. 35 , 36 Although these studies did not specifically evaluate CaD, the mechanisms they describe are consistent with the effects observed in our study, suggesting that CaD may offer similar or complementary benefits in preserving endothelial function. Moreover, the broader implications of endothelial dysfunction in COVID-19, as reviewed by Nägele et al. and Bonaventura et al. support the need for therapies that target this aspect of the disease. 37 , 38 These reviews underscore the centrality of endothelial dysfunction in COVID-19 pathogenesis and the potential of therapies that restore endothelial health to improve patient outcomes. Our findings suggest that CaD could be a valuable addition to the therapeutic arsenal against COVID-19, particularly for patients with severe vascular complications. Study Limitations The limitations of this study should be acknowledged. The retrospective design, lack of a blinded control group, and small sample size limit the ability to draw definitive conclusions about the efficacy of CaD. Additionally, the real-world setting may introduce biases that could affect the generalizability of the results. Further research, particularly randomized, double-blind, placebo-controlled studies, is needed to confirm these findings and establish the safety and efficacy of CaD in a broader patient population. Conclusion Our study provides evidence supporting the use of calcium dobesilate in mitigating the vascular and thrombotic complications of COVID-19. CaD appears to protect endothelial cells from SARS-CoV-2-induced damage, reduce thromboinflammation, and improve clinical outcomes in COVID-19 patients. These findings align with existing literature on the role of endothelial dysfunction in COVID-19 and highlight the need for further research to establish CaD as a standard therapeutic option for managing COVID-19-associated vascular complications. Declarations Authors’ Contribution Luis Fernando Flota-Cervera conceptualized the study, led the project, and was responsible for overall supervision. Alejandra Arellano-Bárcenas and José Luis Salazar-G conducted the comprehensive literature review and data extraction, with secondary validation provided by Elvira Graciela Alexanderson-R. Alina Martins-G and Andrea Morin-Contreras performed the data analysis and statistical interpretation. Francisco Gonzalez-G and Daniel Zingg contributed to the development of the methodology. Alejandra Arellano-Bárcenas, Elvira Graciela Alexanderson-R, and Andrea Morin-Contreras prepared the figures and tables. Luis Fernando Flota-Cervera, Alejandra Arellano-Bárcenas, and José Luis Salazar-G collaboratively wrote the main manuscript text. Luis Fernando Flota-Cervera, José Luis Salazar-G, and Alejandra Arellano-Bárcenas critically reviewed the manuscript for important intellectual content. All authors approved the final version for publication. Acknowledgement Not Applicable Funding This study was funded by OM Pharma. Availability of data and material All data generated or analyzed during this study are included in this published article. Data supporting the findings of this study are available within the manuscript. Patient data were collected from medical records at each participating center. Competing Interests The authors declare that they have no competing interests. Ethical Considerations and Declaration Human Ethics and Consent to Participate declarations: not applicable. The study was conducted in accordance with the Declaration of Helsinki. 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Sep 2021;13(9):e17715. doi:10.7759/cureus.17715 Iba T, Connors JM, Levy JH. The coagulopathy, endotheliopathy, and vasculitis of COVID-19. Inflamm Res . Dec 2020;69(12):1181-1189. doi:10.1007/s00011-020-01401-6 Smadja DM, Mentzer SJ, Fontenay M, et al. COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects. Angiogenesis . Nov 2021;24(4):755-788. doi:10.1007/s10456-021-09805-6 Yamaoka-Tojo M. Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19. Biomed J . Oct 2020;43(5):399-413. doi:10.1016/j.bj.2020.08.007 Okada H, Yoshida S, Hara A, Ogura S, Tomita H. Vascular endothelial injury exacerbates coronavirus disease 2019: The role of endothelial glycocalyx protection. Microcirculation . Apr 2021;28(3):e12654. doi:10.1111/micc.12654 Nägele MP, Haubner B, Tanner FC, Ruschitzka F, Flammer AJ. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Atherosclerosis . Dec 2020;314:58-62. doi:10.1016/j.atherosclerosis.2020.10.014 Bonaventura A, Vecchié A, Dagna L, et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol . May 2021;21(5):319-329. doi:10.1038/s41577-021-00536-9 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5227483","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":374684325,"identity":"fdd92b72-f169-4936-a7f0-9c648eacde2d","order_by":0,"name":"Luis Fernando Flota-Cervera","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIiWNgGAWjYDCCA4wPDwCpenn2BiBlYEGMFmaDAwwJDAmGPSCdBhIkaGG4kQDiEqGF7/ZhhgMff9jlMc58fnXDjwIJBv727gS8WiTPJTMcnJGQXMwunVN2swfoMIkzZzfg1WJwhv/AYZ4EZsbG2TlpN3iAWgwkcglpYWYAaqlnbLh5Ju3mHxK0HE5suMF+7DZRtkgCtRyckXbc2LAnh+22jIEED0G/8J1hZnzwwaZaTp79+LObb/7YyPG39+LXggR4DMAkscpBgP0BKapHwSgYBaNgBAEAoSVMEIe334MAAAAASUVORK5CYII=","orcid":"","institution":"Mexican Council of Angiology, Vascular, and Endovascular Surgery, Anáhuac University, Mérida","correspondingAuthor":true,"prefix":"","firstName":"Luis","middleName":"Fernando","lastName":"Flota-Cervera","suffix":""},{"id":374684326,"identity":"78616e24-86d7-4826-8bc5-19af371b6d9c","order_by":1,"name":"Alejandra Arellano-Bárcenas","email":"","orcid":"","institution":"Virgen del Puerto Hospital, Plasencia, Cáceres","correspondingAuthor":false,"prefix":"","firstName":"Alejandra","middleName":"","lastName":"Arellano-Bárcenas","suffix":""},{"id":374684327,"identity":"4e888321-1b09-476a-9c2a-92a0f656629c","order_by":2,"name":"José Luis Salazar-G","email":"","orcid":"","institution":"Ministry of Health, Guadalajara","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"Luis","lastName":"Salazar-G","suffix":""},{"id":374684328,"identity":"7ff47476-30a8-4b36-9621-e12585dd72a1","order_by":3,"name":"Elvira Graciela Alexanderson-R","email":"","orcid":"","institution":"College of Internal Medicine, General Hospital of Mexico, Mexico City","correspondingAuthor":false,"prefix":"","firstName":"Elvira","middleName":"Graciela","lastName":"Alexanderson-R","suffix":""},{"id":374684329,"identity":"c5493b47-5907-46ab-a253-460dcb08a138","order_by":4,"name":"Alina Martins-G","email":"","orcid":"","institution":"Autonomous University of Querétaro, Querétaro","correspondingAuthor":false,"prefix":"","firstName":"Alina","middleName":"","lastName":"Martins-G","suffix":""},{"id":374684330,"identity":"c7feb75e-1423-423d-9266-c6ed22e809eb","order_by":5,"name":"Andrea Morin-Contreras","email":"","orcid":"","institution":"Grünenthal Mexico, Mexico City","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Morin-Contreras","suffix":""},{"id":374684331,"identity":"f1bf40ae-bd42-48a7-ba45-029575d22644","order_by":6,"name":"Francisco Gonzalez-G","email":"","orcid":"","institution":"Grünenthal Mexico, Mexico City","correspondingAuthor":false,"prefix":"","firstName":"Francisco","middleName":"","lastName":"Gonzalez-G","suffix":""},{"id":374684332,"identity":"c1b21f0e-dfa3-41d7-b203-ccc3627ed513","order_by":7,"name":"Daniel Zingg","email":"","orcid":"","institution":"OM Pharma, Geneva","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Zingg","suffix":""}],"badges":[],"createdAt":"2024-10-08 18:38:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5227483/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5227483/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70286188,"identity":"12384331-9cee-4571-8676-bdea47779247","added_by":"auto","created_at":"2024-12-01 16:30:39","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47650,"visible":true,"origin":"","legend":"\u003cp\u003eDays to Improvement, Recovery (Cure), and Negative Diagnostic Tests.\u003c/p\u003e\n\u003cp\u003eLines within the boxes represent the median of the variable, while the line at the end of the whiskers 25\u003csup\u003eth\u003c/sup\u003e and 75\u003csup\u003eth\u003c/sup\u003e percentile, respectively. Circles correspond to the outliers.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5227483/v1/3be172a1c0ba774f9c43fe31.jpg"},{"id":70285542,"identity":"4db39446-c576-4704-949a-8ee5ba4b0475","added_by":"auto","created_at":"2024-12-01 16:22:39","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1752231,"visible":true,"origin":"","legend":"\u003cp\u003eThe role of Calcium Dobesilate in COVID-19.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5227483/v1/4a99bbb9e64dab709bf22786.jpg"},{"id":105898056,"identity":"ec842793-8215-4eec-a51e-afd82519d3a2","added_by":"auto","created_at":"2026-04-01 08:59:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2612542,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5227483/v1/f3d7935a-9366-4b27-954e-25b24a025a83.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluating the Role of Calcium Dobesilate in COVID-19-Related Pulmonary Vascular Endotheliitis and Thrombosis: A Retrospective Analysis of Real-World Data","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a profound global impact, leading to millions of deaths and overwhelming healthcare systems worldwide.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The virus primarily targets the respiratory system, but its effects extend far beyond, particularly impacting the vascular system.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e COVID-19 is now recognized not only as a respiratory disease but also as a complex multi-system disorder that significantly involves the vascular endothelium, the thin layer of cells lining the blood vessels.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSARS-CoV-2 infection initiates within the alveolar capillaries and extends to pre- and post-capillary microvascular structures, causing a cascade of pathological events.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The inflammatory process triggered by the virus is characterized by acute endothelial injury, leading to the destruction of the glycocalyx\u0026mdash;a crucial component of the endothelial surface layer.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This damage results in the exposure of the glycosaminoglycan matrix, particularly sulfated glycosaminoglycans (such as heparan sulfate), which are essential for maintaining endothelial integrity.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e The progressive endothelial dysfunction contributes to microangiopathy, thrombosis, and ultimately, severe respiratory failure, the leading cause of death in COVID-19 patients.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCalcium dobesilate (CaD) is an oral angioprotective agent widely used in the treatment of vascular diseases and microangiopathies, including diabetic retinopathy and diabetic nephropathy.\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Its mechanism of action includes restoring endothelial function by stabilizing the endothelial barrier, inhibiting the permeability of capillaries, reducing oxidative stress and inflammation, increasing nitric oxide production by the endothelium, and mitigating vascular complications like thrombosis and endotheliitis.\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e These properties position CaD as a promising option for addressing COVID-19-associated endothelial dysfunction and coagulopathy.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e In addition, CaD\u0026rsquo;s ability to interfere with the initial binding of SARS-CoV-2 to host cells has garnered significant interest.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e The virus uses heparan sulfate (HS) on the surface of target cells as a co-receptor to facilitate binding to the high-affinity entry receptor, angiotensin-converting enzyme 2 (ACE2).\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e CaD, by stabilizing HS and inhibiting its interaction with the viral spike protein, may reduce viral entry into cells.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Kiyan et al. have tested this hypothesis recently in an in vitro model using lentiviral SARS-CoV-2 spike protein pseudotyped particles. They could demonstrate that CaD prevents spike interaction with HS and can protect the cells from being infected.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFurther, CaD has been shown to inhibit fibroblast growth factor receptor (FGF-R) signaling, which plays a crucial role in the activation of transmembrane serine protease 2 (TMPRSS2).\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e TMPRSS2 is necessary for the cleavage and activation of the viral spike protein, facilitating the fusion of the virus with the host cell membrane.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e By inhibiting FGF-R signaling, CaD indirectly suppresses TMPRSS2 activity, further reducing the potential for viral entry and subsequent infection of lung cells.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWhile CaD has shown promise in other vascular conditions, its potential role in treating COVID-19-related endothelial injury remains underexplored, with limited studies providing concrete evidence of its efficacy in this context.\u003c/p\u003e \u003cp\u003ePreliminary case reports and observational studies have demonstrated the potential benefits of CaD in treating COVID-19.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e For example, a published case report showed significant radiological and clinical improvements in a COVID-19 patient treated with CaD.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e These findings suggest that CaD may offer protective effects against the vascular and respiratory complications associated with COVID-19.\u003c/p\u003e \u003cp\u003eThis study aims to contribute to the growing body of literature by providing real-world evidence on the use of CaD in treating COVID-19. By analyzing the outcomes of COVID-19 patients treated with CaD, this research seeks to elucidate the therapeutic potential of CaD in mitigating the severe endothelial and pulmonary complications of the disease.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003eThis retrospective study was conducted at two outpatient centers in the metropolitan area of Mexico City and one in Guadalajara City. We included a total of 60 patients diagnosed with COVID-19 who received treatment with CaD in addition to the standard care.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003ePatient data were collected from medical records at each participating center. Information gathered included demographics, medical history, evolution and symptomatology of COVID-19, as well as details of concomitant treatments. The primary standard of care consisted of paracetamol, with steroids and oxygen supplementation added as necessary for patients exhibiting pulmonary or inflammatory manifestations.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were used to summarize the baseline characteristics of the study population, including demographics, comorbidities, symptoms, and treatment regimens. Continuous variables were expressed as means and standard deviations (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD) or medians and interquartile ranges (25th and 75th percentiles) depending on the data distribution, while categorical variables were presented as counts and percentages. The Wilcoxon signed-rank test was employed to compare laboratory parameters, including oxygen saturation, D-dimer levels, ferritin levels, leukocyte counts, neutrophil counts, and lymphocyte counts, before and after treatment with Calcium Dobesilate CaD. All statistical analyses were conducted using SPSS software (version 26; IBM Corp., Armonk, NY, USA). A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthical Considerations\u003c/h3\u003e\n\u003cp\u003eTo ensure patient confidentiality and privacy, all patient data were anonymized before analysis. Identifiable information, including names, dates of birth, and any other personal identifiers, was removed or coded.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient Demographics and Clinical Characteristics\u003c/h2\u003e \u003cp\u003eA total of 60 patients participated in this study, with a nearly equal distribution of 31 women and 29 men. The ages of the patients ranged from 22 to 82 years, with a mean age of 50.8\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3 years. Comorbidities were prevalent among the patient cohort: arterial hypertension was present in 26.7% of the patients, diabetes mellitus in 21.7%, overweight in 23.3%, obesity in 31.7%, smoking in 11.7%, chronic obstructive pulmonary disease (COPD) in 5%, hypothyroidism in 3.3%, asthma in 3.3%, and dyslipidemia in 3.3%.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCOVID-19 Symptoms and Diagnosis\u003c/h3\u003e\n\u003cp\u003eAmong the patients, 96.7% (58/60) were symptomatic at the time of COVID-19 diagnosis. The most frequently reported symptoms included dry cough (72.4%), fatigue (74.1%), myalgia (72.4%), arthralgia (44.8%), pharyngeal pain (39.7%), headache (62.1%), dysgeusia (39.7%), dyssomnia (46.6%), and diarrhea (19%). COVID-19 was confirmed through polymerase chain reaction (PCR) in 43.3% of the cases, antigen detection in 58.3%, and radiologically in 56.7%.\u003c/p\u003e\n\u003ch3\u003eCalcium Dobesilate Treatment\u003c/h3\u003e\n\u003cp\u003eThe patients received CaD as part of their treatment. The median dose of CaD administered was 2 grams per day, with treatment duration varying from 2 to 56 days (median: 28 days). The initiation of CaD treatment occurred at a median of 3 days after the onset of symptoms, with a mean of 6.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 days (range: 0 to 36 days).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCorticosteroid and Oxygen Therapy\u003c/h2\u003e \u003cp\u003eCorticosteroid therapy was necessary for 50% of the patients (30/60). Among these, 14 patients received dexamethasone at a median dose of 4.5 mg/day, and 16 patients received prednisone, with 14 out of the 16 on a regimen of 10 mg/day for 15 days. Oxygen therapy was required for 14 patients (23.3%), with the oxygen volumes administered ranging between 3 to 10 liters per minute.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eConcomitant Treatments\u003c/h2\u003e \u003cp\u003eIn addition to CaD and corticosteroids, patients received a variety of other treatments. Anticoagulants were administered to 56.7% of the patients, antibiotics to 35.0%, bronchodilators to 38.3%, colchicine to 35.0%, and inhaled budesonide to 25.0%. Ivermectin was given to 26.7% of the patients, and paracetamol was used by 40.0% of the patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eHospitalization and Clinical Outcomes\u003c/h2\u003e \u003cp\u003eOut of the 60 patients, five required hospitalization. Among these, only one patient necessitated intubation. Importantly, there were no deaths reported within this cohort. The primary clinical outcomes assessed included time to improvement, full recovery, and the time to achieve a negative COVID-19 test result.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLaboratory Findings\u003c/h2\u003e \u003cp\u003eLaboratory results were recorded at the start and end of the CaD treatment course. Significant improvements were noted in several key parameters, including oxygen saturation, D-dimer levels, ferritin levels, leukocyte counts, neutrophil counts, and lymphocyte counts. Platelet counts, however, did not show a significant change \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLaboratory Test Results of Patients at the Beginning and End of CaD the Treatment.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN (Baseline)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (Baseline)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN \u003c/p\u003e \u003cp\u003e(post-treatment)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD \u003c/p\u003e \u003cp\u003e(post-treatment)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxygen Saturation (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e87.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e93.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-dimer (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e969.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1060.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e604.6\u0026thinsp;\u0026plusmn;\u0026thinsp;460.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin (\u0026micro;g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e712.7\u0026thinsp;\u0026plusmn;\u0026thinsp;811.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e532.0\u0026thinsp;\u0026plusmn;\u0026thinsp;555.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukocytes (/\u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e5921.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1829.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e6043.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1552.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophils (/\u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3784.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1625.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e4241.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1560.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophil Percentage (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e61.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e61.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocytes (/\u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1386.8\u0026thinsp;\u0026plusmn;\u0026thinsp;684.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e2017.8\u0026thinsp;\u0026plusmn;\u0026thinsp;703.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocyte Percentage (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e23.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e27.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets (10\u0026sup3;/\u0026micro;L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e254.7\u0026thinsp;\u0026plusmn;\u0026thinsp;71.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e310.6\u0026thinsp;\u0026plusmn;\u0026thinsp;74.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eTime to Improvement and Recovery\u003c/h2\u003e \u003cp\u003eThe analysis of time to clinical improvement, full recovery, and the time to achieve a negative COVID-19 test result showed favorable outcomes. Detailed results are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cb\u003eand\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The time to improvement was significantly shorter in patients receiving CaD, and all patients eventually achieved full recovery without any long-term sequelae. No adverse events were directly attributed to the administration of CaD.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTime Required for Improvement, Recovery, and Negative COVID-19 test in Patients Treated with CaD.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDays to improvement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDays to recovery\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDays to negative COVID test\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.0\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25th, 50th and 75th percentiles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.0, 16.5, 24.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.0, 24.0, 28.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.0, 25.0, 34.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eSD\u0026thinsp;=\u0026thinsp;Standard deviation\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe global impact of COVID-19 has necessitated the exploration of novel therapeutic strategies, particularly those addressing vascular dysfunction and thromboinflammation, two hallmarks of severe disease. CaD has emerged as a promising candidate due to its diverse pharmacological actions that may mitigate the pathophysiological mechanisms underlying COVID-19-associated coagulopathy (CAC) and endothelial dysfunction.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOne of the critical findings from our study is the potential of CaD to reduce SARS-CoV-2 entry into endothelial cells by inhibiting the virus's interaction with heparan sulfate, as demonstrated by Kiyan et al.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e This mechanism suggests a protective effect on endothelial integrity, which aligns with our observation of reduced endothelial cell infection and subsequent vascular complications in CaD-treated patients. Endothelial dysfunction is a central feature of severe COVID-19, contributing to vascular endotheliitis, widespread thrombosis, increased vascular permeability, and inflammation. Studies by Ackermann et al. and Pons et al. have documented significant endothelial injury and widespread thrombosis in COVID-19 patients, which are more severe compared to other respiratory infections like influenza.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Our findings suggest that CaD may stabilize the endothelial glycocalyx, reduce inflammation, and protect the capillary barrier, as also proposed by Cuevas et al. (2021).\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e CaD presents a compelling therapeutic potential for COVID-associated pulmonary vascular endotheliitis and thrombosis due to its multifaceted pharmacological properties. CaD, known for its use in treating microvascular diseases like diabetic retinopathy and nephropathy, exerts its effects through antioxidant, anti-inflammatory, and vasoprotective mechanisms.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e It enhances endothelial function by increasing nitric oxide production and reducing oxidative stress, crucial actions in mitigating the endothelial dysfunction seen in COVID-19.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Additionally, CaD's ability to inhibit platelet aggregation and reduce blood viscosity may help counteract the hypercoagulable state associated with COVID-19.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Furthermore, its antiangiogenic properties and capacity to inhibit VEGF signaling suggest potential benefits in controlling aberrant vascular responses during severe COVID-19.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Given these pharmacodynamic actions, CaD could potentially reduce the severity of COVID-19-related vascular complications, such as microvascular thrombosis and endotheliitis \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOur study supports the clinical application of CaD in treating both acute and sub-acute COVID-19 cases. Despite a significant prevalence of comorbidities such as arterial hypertension, diabetes mellitus, and obesity in our patient cohort, those treated with CaD demonstrated favorable outcomes, including a reduced need for corticosteroids and oxygen therapy. Specifically, only 23.3% of patients in our study required oxygen therapy, 50% required corticosteroid therapy. This reduction in the need for oxygen and steroids, without altering the disease duration, underscores the potential of CaD in improving patient outcomes by targeting the endothelial dysfunction central to COVID-19 pathogenesis.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSARS-CoV-2 can cause severe inflammation that destroys the glycocalyx, exposing the endothelium and causing endothelial damage and dysfunction. This damage, coupled with subendothelial edema, leads to capillary thrombosis and alveolar rupture, which together result in post-thrombotic syndrome characterized by residual venous thrombosis, interstitial fibrosis, respiratory failure, and low oxygen saturation.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Notably, in our study, CaD-treated patients had a lower incidence of severe outcomes, with only 8.3% requiring hospitalization and a single case necessitating intubation. Importantly, there were no deaths reported in our cohort. The treatment course with CaD was initiated at a median of 3 days post-symptom onset, with a mean initiation time of 6.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 days, and a median dose of 2 grams per day. The duration of CaD treatment varied widely, from 2 to 56 days, with a median of 28 days. Despite these variations, all patients achieved full recovery without long-term sequelae. Evidence suggests that CaD protects the endothelium, preventing edema, thrombosis, and alveolar rupture, thereby improving clinical symptoms at any stage of the disease and reducing the need for oxygen and steroids.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur study observed significant improvements in key laboratory parameters such as D-dimer levels, which are indicative of thrombotic activity​. The reduction in D-dimer levels suggests that CaD may alleviate thrombotic complications by reducing endothelial damage and inhibiting the cascade of events leading to coagulation, consistent with findings by Iba et al. and Smadja et al.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e This aligns with the potential therapeutic applications of CaD in preventing microvascular thrombosis and promoting vascular health in COVID-19 patients. In comparing CaD to other therapeutic agents targeting endothelial dysfunction, studies emphasize the importance of protecting the endothelial glycocalyx and reducing thromboinflammation. For instance, Okada et al. and Yamaoka-Tojo have highlighted the role of endothelial glycocalyx protection in preventing vascular endothelial injury and thrombosis in COVID-19.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e Although these studies did not specifically evaluate CaD, the mechanisms they describe are consistent with the effects observed in our study, suggesting that CaD may offer similar or complementary benefits in preserving endothelial function. Moreover, the broader implications of endothelial dysfunction in COVID-19, as reviewed by N\u0026auml;gele et al. and Bonaventura et al. support the need for therapies that target this aspect of the disease. \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e These reviews underscore the centrality of endothelial dysfunction in COVID-19 pathogenesis and the potential of therapies that restore endothelial health to improve patient outcomes. Our findings suggest that CaD could be a valuable addition to the therapeutic arsenal against COVID-19, particularly for patients with severe vascular complications.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStudy Limitations\u003c/h2\u003e \u003cp\u003eThe limitations of this study should be acknowledged. The retrospective design, lack of a blinded control group, and small sample size limit the ability to draw definitive conclusions about the efficacy of CaD. Additionally, the real-world setting may introduce biases that could affect the generalizability of the results. Further research, particularly randomized, double-blind, placebo-controlled studies, is needed to confirm these findings and establish the safety and efficacy of CaD in a broader patient population.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study provides evidence supporting the use of calcium dobesilate in mitigating the vascular and thrombotic complications of COVID-19. CaD appears to protect endothelial cells from SARS-CoV-2-induced damage, reduce thromboinflammation, and improve clinical outcomes in COVID-19 patients. These findings align with existing literature on the role of endothelial dysfunction in COVID-19 and highlight the need for further research to establish CaD as a standard therapeutic option for managing COVID-19-associated vascular complications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLuis Fernando Flota-Cervera conceptualized the study, led the project, and was responsible for overall supervision. Alejandra Arellano-B\u0026aacute;rcenas and Jos\u0026eacute; Luis Salazar-G conducted the comprehensive literature review and data extraction, with secondary validation provided by Elvira Graciela Alexanderson-R. Alina Martins-G and Andrea Morin-Contreras performed the data analysis and statistical interpretation. Francisco Gonzalez-G and Daniel Zingg contributed to the development of the methodology. Alejandra Arellano-B\u0026aacute;rcenas, Elvira Graciela Alexanderson-R, and Andrea Morin-Contreras prepared the figures and tables. Luis Fernando Flota-Cervera, Alejandra Arellano-B\u0026aacute;rcenas, and Jos\u0026eacute; Luis Salazar-G collaboratively wrote the main manuscript text. Luis Fernando Flota-Cervera, Jos\u0026eacute; Luis Salazar-G, and Alejandra Arellano-B\u0026aacute;rcenas critically reviewed the manuscript for important intellectual content. All authors approved the final version for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by OM Pharma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article. Data supporting the findings of this study are available within the manuscript. Patient data were collected from medical records at each participating center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Considerations and Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuman Ethics and Consent to Participate declarations: not applicable. The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from our Institutional Review Board (IRB) of Autonomous University of Guadalajara, Guadalajara, Mexico.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWorld Health Organization 2023 data.who.int, WHO Coronavirus (COVID-19) dashboard \u0026gt; Cases [Dashboard]. https://data.who.int/dashboards/covid19/cases\u003c/li\u003e\n\u003cli\u003eAckermann M, Verleden SE, Kuehnel M, et al. 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SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. \u003cem\u003ecell\u003c/em\u003e. 2020;181(2):271-280.\u003c/li\u003e\n\u003cli\u003eZipeto D, Palmeira JdF, Arga\u0026ntilde;araz GA, Arga\u0026ntilde;araz ER. ACE2/ADAM17/TMPRSS2 interplay may be the main risk factor for COVID-19. \u003cem\u003eFrontiers in immunology\u003c/em\u003e. 2020;11:576745.\u003c/li\u003e\n\u003cli\u003eCuevas P, Manquillo A, Guillen P, Gim\u0026eacute;nez-Gallego G. Fibroblast growth factor: A target for Covid-19 infection. \u003cem\u003eInt J Med Rev Case Rep\u003c/em\u003e. 2020;4(1):10-5455.\u003c/li\u003e\n\u003cli\u003eCuevas P, Manquillo A, Angulo J, Gim\u0026eacute;nez-Gallego G. Dobesilate: A potential therapy for long-covid?. Int J Med Rev Case Rep. 2021; 5(14): 5-10. doi:10.5455/IJMRCR.dobesilate-long-covid\u003c/li\u003e\n\u003cli\u003eCuevas P, Angulo J, Zingg D, Manquillo A, Calleja JL, Gim\u0026eacute;nez-Gallego G. Dobesilate an old drug as a possible new treatment option for COVID-19 infection. \u003cem\u003eInt J Med Rev Case Rep\u003c/em\u003e. 2021;5:1.\u003c/li\u003e\n\u003cli\u003ePons S, Fodil S, Azoulay E, Zafrani L. The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection. \u003cem\u003eCritical care\u003c/em\u003e. 2020;24:1-8.\u003c/li\u003e\n\u003cli\u003eSzabo ME, Haines D, Garay E, et al. Antioxidant properties of calcium dobesilate in ischemic/reperfused diabetic rat retina. \u003cem\u003eEur J Pharmacol\u003c/em\u003e. Oct 5 2001;428(2):277-86. doi:10.1016/s0014-2999(01)01196-7\u003c/li\u003e\n\u003cli\u003eTejerina T, Ruiz E. Calcium Dobesilate: Pharmacology and Future Approaches. \u003cem\u003eGeneral Pharmacology: The Vascular System\u003c/em\u003e. 1998/09/01/ 1998;31(3):357-360. doi:https://doi.org/10.1016/S0306-3623(98)00040-8\u003c/li\u003e\n\u003cli\u003ePoyatos P, Luque N, Sabater G, et al. Endothelial dysfunction and cardiovascular risk in post-COVID-19 patients after 6- and 12-months SARS-CoV-2 infection. \u003cem\u003eInfection\u003c/em\u003e. 2024/08/01 2024;52(4):1269-1285. doi:10.1007/s15010-024-02173-5\u003c/li\u003e\n\u003cli\u003eBattaglini D, Robba C, Ball L, et al. Noninvasive respiratory support and patient self-inflicted lung injury in COVID-19: a narrative review. \u003cem\u003eBr J Anaesth\u003c/em\u003e. Sep 2021;127(3):353-364. doi:10.1016/j.bja.2021.05.024\u003c/li\u003e\n\u003cli\u003eKabi A, Kaeley N, Shankar T, Joshi S, Roul PK. COVID-19-Associated Pneumomediastinum and Pneumothorax: A Case Series. \u003cem\u003eCureus\u003c/em\u003e. Sep 2021;13(9):e17715. doi:10.7759/cureus.17715\u003c/li\u003e\n\u003cli\u003eIba T, Connors JM, Levy JH. The coagulopathy, endotheliopathy, and vasculitis of COVID-19. \u003cem\u003eInflamm Res\u003c/em\u003e. Dec 2020;69(12):1181-1189. doi:10.1007/s00011-020-01401-6\u003c/li\u003e\n\u003cli\u003eSmadja DM, Mentzer SJ, Fontenay M, et al. COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects. \u003cem\u003eAngiogenesis\u003c/em\u003e. Nov 2021;24(4):755-788. doi:10.1007/s10456-021-09805-6\u003c/li\u003e\n\u003cli\u003eYamaoka-Tojo M. Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19. \u003cem\u003eBiomed J\u003c/em\u003e. Oct 2020;43(5):399-413. doi:10.1016/j.bj.2020.08.007\u003c/li\u003e\n\u003cli\u003eOkada H, Yoshida S, Hara A, Ogura S, Tomita H. Vascular endothelial injury exacerbates coronavirus disease 2019: The role of endothelial glycocalyx protection. \u003cem\u003eMicrocirculation\u003c/em\u003e. Apr 2021;28(3):e12654. doi:10.1111/micc.12654\u003c/li\u003e\n\u003cli\u003eN\u0026auml;gele MP, Haubner B, Tanner FC, Ruschitzka F, Flammer AJ. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. \u003cem\u003eAtherosclerosis\u003c/em\u003e. Dec 2020;314:58-62. doi:10.1016/j.atherosclerosis.2020.10.014\u003c/li\u003e\n\u003cli\u003eBonaventura A, Vecchi\u0026eacute; A, Dagna L, et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. \u003cem\u003eNat Rev Immunol\u003c/em\u003e. May 2021;21(5):319-329. doi:10.1038/s41577-021-00536-9\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Calcium Dobesilate, COVID-19, Pulmonary Endotheliitis, Pulmonary","lastPublishedDoi":"10.21203/rs.3.rs-5227483/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5227483/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSARS-CoV-2 (COVID-19) infection is known to cause acute inflammatory pulmonary microangiopathy, leading to alveolar-capillary thrombosis, severe respiratory failure, and potential mortality. This study aims to evaluate the efficacy of calcium dobesilate (CaD) in treating COVID-19-related pulmonary complications using real-world data.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e This retrospective study included 60 COVID-19 patients treated with CaD in addition to standard care at three outpatient centers in Mexico City and Guadalajara. Patient data, including demographics, medical history, COVID-19 symptoms, and concomitant treatments, were collected from medical records.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe median dose of CaD was 2 grams per day, starting on the third day after diagnosis and continuing for a median of 28 days. Half of the patients also required steroid therapy, with 14 receiving dexamethasone and 16 receiving prednisone. Additionally, 23.3% of patients required oxygen therapy, with volumes ranging from 3 to 10 liters per minute. Improvement in clinical symptoms was observed after a median of 18.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6 days (n\u0026thinsp;=\u0026thinsp;50), with full recovery occurring after 25.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.3 days (n\u0026thinsp;=\u0026thinsp;42). Importantly, no deaths or long-term complications were reported among the study participants.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe use of CaD in treating COVID-19-associated pulmonary microangiopathy shows promising outcomes, with a notable absence of mortality or severe sequelae. However, future randomized, double-blind, placebo-controlled trials with larger sample sizes are essential to confirm these findings and establish CaD's role in COVID-19 management.\u003c/p\u003e","manuscriptTitle":"Evaluating the Role of Calcium Dobesilate in COVID-19-Related Pulmonary Vascular Endotheliitis and Thrombosis: A Retrospective Analysis of Real-World Data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-01 16:22:35","doi":"10.21203/rs.3.rs-5227483/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a44fa9f3-4b64-4d28-87ad-63b3e488144c","owner":[],"postedDate":"December 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-01T08:58:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-01 16:22:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5227483","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5227483","identity":"rs-5227483","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}