Retrospective Analysis of Clinical Repurposing of Dipyridamole and L-Arginine for Treatment of Long COVID Endothelitis

Introduction: The effect of treatment with L-arginine and dipyridamole for the reduction of symptoms of fatigue, difficulty performing activities of daily living (ADLs), dyspnea, and mental health decline in patients with Long COVID endothelitis was studied in this research, leading to conclusions that are presented. Methods: Forty-four patients with documented Long COVID endothelitis were enrolled in this retrospective, IRB-approved analysis evaluating clinician-directed treatment strategies initiated during the COVID-19 pandemic. Patients received either dipyridamole alone, L-arginine alone, or combination therapy. Clinical responses were assessed at 6 weeks and 6 months postinitiation, and a subset of nine patients also completed a structured, patient-reported outcomes survey approximately two years after starting treatment. Results: Of the 44 subjects identified, clinical follow-up at 6 weeks demonstrated a significant overall symptom improvement (p=0.0115). At 6 months, symptom improvement remained substantial but lost statistical significance (p=0.09). Combination therapy (dipyridamole and Larginine) showed sustained improvement at both 6 weeks (68.8%) and 6 months (62.5%). Dipyridamole alone demonstrated high early response (80%) but markedly reduced efficacy at 6 months (20%). Statistical comparisons between combination therapy and monotherapy groups did not yield significant results, likely due to limited sample sizes. Patient-reported outcomes supported clinical findings, with combination therapy yielding the lowest symptom burden in fatigue, dyspnea, and depression, and the highest functional capacity. Discussion: This study addressed a critical unmet need in Long COVID management, a condition affecting middle-aged and older adults with substantial symptom burden, including fatigue (reported in up to 45% of patients), dyspnea, and cognitive dysfunction. The therapeutic benefit observed with dipyridamole and L-arginine likely stems from their complementary mechanisms: dipyridamole's antiplatelet and anti-inflammatory effects may reduce microvascular dysfunction and microthrombosis, while L-arginine enhances nitric oxide production, supporting endothelial function and vascular homeostasis. Both agents possess favorable safety profiles, making them reasonable options in the absence of validated alternatives for Long COVID endothelitis. Conclusion: Treatment with dipyridamole and L-arginine, particularly in combination, was associated with meaningful improvements in fatigue, dyspnea, ability to perform ADLs, and mental health symptoms in patients with Long COVID. These preliminary findings underscore the potential benefit of these therapeutic agents, though larger, randomized controlled studies are necessary to confirm efficacy and enhance statistical power.