Soon after the start of the coronavirus disease 2019 (COVID-19) pandemic, it was recognized that its causative severe acute respiratory syndrome virus (SARS-CoV2) virus was somehow less deadly than its pervious fellow, SARS-COV. Yet some features of the new virus qualified it to be a tremendously greater threat to humanity than its older version and those included very high infectivity, transmission from asymptomatic people and great variability of its clinical features. COVID-19 manifestations range from mild to rapidly progressive severe acute respiratory distress syndrome (ARDS), respiratory and circulatory failure, sepsis, and death. 1 Older age and various forms of comorbidities were found to be associated with poorer outcomes, including fatalities. Reported risk factors included: cardiovascular, chronic kidney disease, and diabetes mellitus. As until 14 of July, 13 266 181 cases have been reported worldwide in about 4.34% mortality rate. 2 The angiotensin-converting enzyme 2 (ACE2), is a cell surface enzyme present in almost all organs. ACE2 is widely expressed in the lower respiratory tract cells besides its cardiac, renal, and intestinal expression. 3 ACE2 is believed to be the SARS-CoV2 receptor. It facilitates cellular invasion, replication, and viral pathogenicity. 4 This could explain its ability to affect various organs, especially the gastrointestinal tract, the heart and the kidneys. A precise antiviral or a specific immunization has not been identified yet, raising a need for adjuvant pharmacologic therapy. We believe that targeted therapies based on the known COVID-19 pathogenesis should be considered. Nicorandil (N-[2-hydroxyethyl]-nicotinamide nitrate) is a therapeutic agent used clinically for the treatment of angina. Nicorandil is believed to act by increasing nitric oxide availability and by opening ATP-sensitive K channels (K + ATP). 5 Several studies have also shown the involvement of nicorandil in inflammatory process and oxidative stress regulation.

Despite cyclosporine-A (CsA) is a widely used immunosuppressive drug; its nephrotoxic effect puts a limitation for chronic administration. Herein we tried to investigate its renal effect on endothelial dysfunction targeting the hypoxia-inducible factor (HIF-1α)/vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) pathway and the possible modulation by nicorandil. Eight groups of adult male Wistar rats were included; 1: control, 2: vehicle group (received oil), 3: glibebclamide 5mg/kg/day/orally was administered. 4: group received nicorandil 10mg/kg/day/orally. 5: group received cyclosporine 25mg/kg/day/orally. 6: combined cyclosporine and nicorandil, 7: glibenclamide was added to cyclosporine, and 8: group received both cyclosporine and nicorandil combined with glibenclamid. The treatment continued for 6 weeks. Combined nicorandil with cyclosporine improved renal function deterioration initiated by cyclosporine. Cyclosporine decreased the renal expression levels (P<0.001) of HIF-1α, eNOS, and VEGF inducing endothelial dysfunction and the triggered inflammation, and upregulated the pro-fibrotic marker transforming growth factor (TGF-β). Nicorandil fixed the disturbed HIF-1α/VEGF/eNOS signaling. Nicorandil corrected the renal functions confirmed by improved the histological glomerular tuft retraction that was obvious in the cyclosporine group, without significant influence by glibenclamid. Proper protection from CsA-induced nephrotoxicity was achieved by nicorandil. Nicorandil reversed the disturbed HIF-1α/VEGF/eNOS pathway created by cyclosporine.

Cardiac dysfunction is one of the leading causes of death in epilepsy. The anti‐arrhythmic drug, amiodarone, is under investigation for its therapeutic effects in epilepsy. We aimed to evaluate the possible effects of amiodarone on cardiac injury during status epilepticus, as it can cause prolongation of the QT interval. Five rat groups were enrolled in the study; three control groups (1) Control, (2) Control‐lithium and (3) Control‐Amio, treated with 150 mg/kg/intraperitoneal amiodarone, (4) Epilepsy model, induced by sequential lithium/pilocarpine administration, and (5) the epilepsy‐Amio group. The model group expressed a typical clinical picture of epileptiform activity confirmed by the augmented electroencephalogram alpha and beta spikes. The anticonvulsive effect of amiodarone was prominent, it diminished (p < 0.001) the severity of seizures and hence, deaths and reduced serum noradrenaline levels. In the model group, the electrocardiogram findings revealed tachycardia, prolongation of the corrected QT (QTc) interval, depressed ST segments and increased myocardial oxidative stress. The in‐vitro myocardial performance (contraction force and – (df/dt)max) was also reduced. Amiodarone decreased (p < 0.001) the heart rate, improved ST segment depression, and myocardial contractility with no significant change in the duration of the QTc interval. Amiodarone preserved the cardiac histological structure and reduced the myocardial injury markers represented by serum Troponin‐I, oxidative stress and IL‐1. Amiodarone pretreatment prevented the anticipated cardiac injury induced during epilepsy. Amiodarone possessed an anticonvulsive potential, protected the cardiac muscle and preserved its histological architecture. Therefore, amiodarone could be recommended as a protective therapy against cardiac dysfunction during epileptic seizures with favourable effect on seizure activity.

The long‐term side effect of the antiarrhythmic drug, amiodarone (AMIO), such as lung toxicity, remains a critical clinical issue. The previous knowledge denotes diverse antioxidant, anti‐inflammatory, and antifibrotic properties of the anti‐anginal drug, nicorandil (NI). Therefore, we aimed to investigate the possible protective effect of NI on pulmonary tissue remodelling following AMIO‐induced lung toxicity. The included rats were assigned into four equal groups (n = 8): (1) control, (2) control group that received NI 10 mg kg−1 day−1, (3) model group that received AMIO in a dose of 60 mg kg−1 day−1, and (4) treated group (AMIO‐NI) that were treated with AMIO plus NI as shown above. Drug administration continued for 10 weeks. AMIO resulted in deteriorated (p < 0.001) pulmonary functions accompanied by respiratory acidosis. AMIO showed an obvious histological injury score with intense collagen deposition, disturbed nitric oxide synthase enzymes (NOS/iNOS), and increased alpha smooth muscle actin expression. Furthermore, AMIO upregulated the transforming growth factor (TGF‐β1)/phosphoinositide‐3 kinase (PI3K)‐Akt1‐p/mammalian target of rapamycin (mTOR) axis, which determined the possible mechanism of AMIO on pulmonary remodelling. NI treatment significantly (p < 0.001) prevented the AMIO‐induced lung toxicity, as well as inhibited the TGF‐β1/PI3K/Akt1‐p/mTOR axis in the lung tissue of rats. The results were confirmed by an in‐vitro study. Conclusion The current results revealed that NI was effective in preserving the lung structure and functions. Amelioration of the oxidative stress and modulation of TGF‐β1/PI3K/Akt1‐p/mTOR have been achieved. This study suggests NI administration as a preventive therapy from the serious pulmonary fibrosis side effect of AMIO.

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