Repositioned Drugs for COVID-19—the Impact on Multiple Organs

This review summarizes published findings of the beneficial and harmful effects on the heart, lungs, immune system, kidney, liver, and central nervous system of 47 drugs that have been proposed to treat COVID-19. Many of the repurposed drugs were chosen for their benefits to the pulmonary system, as well as immunosuppressive and anti-inflammatory effects. However, these drugs have mixed effects on the heart, liver, kidney, and central nervous system. Drug treatments are critical in the fight against COVID-19, along with vaccines and public health protocols. Drug treatments are particularly needed as variants of the SARS-Cov-2 virus emerge with some mutations that could diminish the efficacy of the vaccines. Patients with comorbidities are more likely to require hospitalization and greater interventions. The combination of treating severe COVID-19 symptoms in the presence of comorbidities underscores the importance of understanding the effects of potential COVID-19 treatments on other organs. Supplementary Information The online version contains supplementary material available at 10.1007/s42399-021-00874-8.

Nasal and pulmonary delivery of niclosamide through particles of human lysozyme as a carrier molecule was found to reduce viral load in the lungs of hACE2 transgenic mice infected intranasally with SARS-CoV-2 [270].

Nitazoxanide (NTZ)
Positive: NTZ is a potent TMEM16A antagonist that blocked airway smooth muscle depolarization and contraction and promoted bronchodilation of mouse airways [271]. NTZ reduced the duration of clinical symptoms with acute uncomplicated influenza and reduced influenza viral shedding [272]. It was found to amplify the host innate immune response to viruses and inhibited Ebola virus replication [74]. NTZ was found to inhibit SARS-CoV-2 replication and infection in Vero E6 cells [273,274].
In clinical settings of COVID-19 patients, NTZ showed a positive outcome with some patients weaned from mechanical ventilation [275].

Nitric Oxide (NO)
Positive: The impact of inhalation of NO by patients with severe adult respiratory distress syndrome (ARDS) increases oxygenation [276] and reduces the pulmonary-artery pressure [277]. NO was found to inhibit the replication cycle of SARS CoV in vitro [278]. Inhalation of NO showed improved arterial oxygenation, reduced inspired oxygen therapy and airway pressure support in patients with SARS [279]. In a retrospective cohort study, it was found that both inhaled EPO and inhaled NO were comparable in terms of oxygenation and ventilation parameters for moderate to severe ARDS [207]. The burst of NO increases O 2 saturation and has been suggested that it could be protective against COVID19 [280].
Neutral: In a single-center retrospective case-control study of patients with ARDS treated with iNO, found that half the patients with refractory hypoxaemia (inadequate arterial oxygenation) secondary to COVID-19 ARDS did not show an increase in PaO2/FiO2 ratio in response to iNO and the response was much lower compared with non-COVID-19 ARDS patients [281].

Remdesivir (RDV)
Positive: In nonhuman primates with SARS-CoV-2 infection, RDV administered early had lower viral load in the lungs and less lung damage [282]. In support, a systematic review found RDV inhibits SARS-CoV-2 replication, reduces viral load, and has protective effects in SARS-CoV-2 infected animals [283]. This drug is a nucleotide polymerase inhibitor, known to reduce viral replication [284] and also found to potently block SARS-CoV-2 virus infection in vitro [274]. RDV inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cells, and reduces lung viral load and improved pulmonary function in mice infected with chimeric virus [285]. The efficacy and safety of RDV were analyzed through a literature search of observational and interventional studies of COVID-19 patients. Analyzing the mortality rates, clinical improvement, and adverse events revealed that the 5-day RDV group had a lower severe adverse event rate as compared to 10-day and placebo groups and patients without invasive mechanical ventilation were benefited more [286].
In a compassionate use of RDV for COVID-19 it improved oxygen support but the study lacked a placebo control [287]. In a double-blind, randomized, placebo-controlled trial of intravenous RDV in hospitalized adults with Covid-19 had shortening time to recovery and evidence of lower respiratory tract infection [288].
Neutral: In a randomized, double-blind, placebo-controlled, multicenter clinical trial RDV was not associated with statistically significant reduction in time to clinical improvement, viral clearance, or mortality in adults with severe COVID-19, but requires confirmation in larger study [289].
Neutral: A prospective, multicenter, controlled, randomized, single-blind study of patients with severe COVID19 treated with RUX was not associated with significantly accelerated clinical improvement and RUX recipients had similar median time of virus clearance compared with patients in the control group [292].
Negative: Given that RUX targets IFNα and IFNλ induced by JAK/STAT, a recent study in lung cell line, Calu-3 (IFN-competent cells), found that RUX increased SARS-CoV-2 replication, likely by inhibiting JAK/STAT signaling and IFN types I and III inhibited its replication [293]. A case study found RUX exacerbated pulmonary arterial hypertension in a patient [294], while another study found ARDS developed secondary to RUX use [295].
Neutral: Studies are being conducted to determine the effectiveness of sarilumab in patients with severe cases of COVID-19. Thus far, an open-label cohort study did not find significant difference between sarilumab and standard care, although the drug was associated with faster recovery for a subset of patients with minor lung consolidation [297].
Negative: There have been cases of alveolar hemorrhage associated with sarilumab [298,299].

Sirolimus (Rapamycin)
Positive: Rapamycin may be beneficial for treating various diseases [300]. Improved several parameters of lung function in transgenic mice model of noninflammatory lung disease [301]. Sirolimus stabilized lung function, reduced serum VEGF-D levels in patients with lymphangioleiomyomatosis (LAM) [302]. LAM, a rare cystic lung disease found predominantly in women, is linked to MTOR signaling and tuberous sclerosis complex (TSC) [303]. Has been suggested as a possible therapy for COPD [304], based on studies in a transgenic mouse model [301] and in patients with mild to severe COPD in which rapamycin restored corticosteroid sensitivity [305]. In patients with severe H1N1 pneumonia, corticosteroids plus sirolimus was associated with improvement in multiple organ dysfunction, virus clearance, and shortened need for ventilator [306].
Negative: In a meta-analysis of rapamycin and its analogues for treating TSC, which can occur in multiple organs including the lungs, rapamycin increased the risk of stomatitis but did not improve or increase risk of upper respiratory tract infections [307]. Sirolimus is associated with venous thromboembolism in lung transplant patients [308]. Mixed results when treating bleomycin-induced lung fibrosis in rats and mice [304]. A clinical trial of everolimus (an MTOR inhibitor) found it worsened outcomes in patients with IPF [309].

Sofosbuvir
Positive: Sofosbuvir was found to inhibit SARS-CoV-2 replication in human hepatoma-derived (Huh-2) and Type II pneumocyte-derived (Calu-3) cells [310]. SARS-CoV-2 has an exonuclease-based proofreader to maintain viral genome integrity and sofosbuvir displayed a higher level of resistance to this proofreading activity than remdesivir [311]. In an open-label, multicenter, randomized controlled clinical trial in moderate and severe COVID-19 patients found adding sofosbuvir and daclatasvir to standard care significantly reduced the duration of hospital stay compared with standard care alone [312].
Negative: Case study suggests a possible association with the worsening of pulmonary arterial hypertension (PAH) in HCV patients [313]. Sofosbuvir plus simeprevir could contribute to pulmonary toxicity in HCV infected patients [314].

Statins
Positive: A retrospective study of COVID19 patients found that statins use was associated with a lower prevalence of ARDS and a lower risk of mortality [315].
Neutral: A retrospective multi-center cohort study found that the use of statins was significantly associated with the absence of COVID-19 symptoms in some of the patients. However, the effects of statin intake on serious clinical outcomes (long-stay hospitalization or death) were not statistically significant. In addition, there was no statistically significant association between angiotensinconverting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB) and asymptomatic status [316]. A large cohort study did not find an association between statin use and the incidence of ILD [317].
Negative: Lowers cholesterol levels, however, can cause serious lung injuries. In a case study rosuvastatin caused diffuse ground-glass opacities, several subpleural ground-glass opacity nodules, and a foamy alveolar macrophage appearance [318]. Several cases of statin-induced interstitial lung disease (ILD), which could lead to irreversible fibrosis, have been reported [319].
Stavudine Negative: The time to develop severe drug toxicities were shorter and virological efficacy was lower in the regimens containing stavudine as compared to emtricitabine when used with didanosine and efavirenz [199].
Neutral: An observational prospective study of HIV-infected individuals on tenofovir did not affect their risk of severe SARS-CoV-2 infection [322].
Negative: Human lung cell lines treated with TET reduced cell viability by up to 60%. TET caused acute lung injury in mouse studies with massive bronchiolar and alveolar hemorrhage and edema [326].

Thalidomide (THD)
Positive: A case-report of a patient with severe COVID-19 pneumonia treated with THD in combination with low-dose methylprednisolone suggests that THD had a positive outcome, likely contributing to reducing elevated cytokine levels [327]. THD had anti-inflammatory effect on H1N1-induced acute lung injury in BALB/C mice which contribute to attenuating H1N1-induced pulmonary injury [328]. A single-center study found THD improved cough and respiratory quality of life in patients with IPF [329].
Mixed: Although THD was not found to significantly improve pulmonary function in patients with corticosteroid-dependent sarcoidosis [330], it has been suggested that the drug could be helpful for pulmonary sarcoidosis in patients resistant or with contraindications to corticosteroids [331].
Negative: THD has been found to cause acute pulmonary toxicity in a case study of multiple myeloma patient [332]. THD effectiveness on several pulmonary diseases and lung injuries were performed in animals, nonetheless there are concerns with the use of THD given its undesirable side effects and the associated toxicities [333]. Nonetheless, there is concern in the use of THD with corticosteroids [333].

Tocilizumab (TCZ)
Positive: A case report of COVID-19 patient found TCZ altered the inflammatory response by blocking cellular receptors for IL-6 and resulted in a favorable outcome [334]. In a retrospective study, lung opacities of severe COVID-19 patients were absorbed in over 90% of patients treated with TCZ [335].
In an observational cohort study, TCZ improved lung function in COVID-19 patients with CRS [336]. In a retrospective, observational cohort study of adults with severe COVID-19 pneumonia found TCZ treatment was associated with reduced risk of invasive mechanical ventilation or death [337]. Similarly, another prospective study of COVID-19 pneumonia associated TCZ with significant clinical improvement [338]. In a Rapid Review, a comparison of serum IL-6 concentration in patients with severe or critical COVID-19 with other conditions, found the mean IL-6 levels were ~100 times higher in patients with CRS and 12 times higher in patients with ARS unrelated to COVID-19 [339].
Analysis of a multicenter cohort study of adult COVID-19 patients in intensive care units at 68 hospitals across the US found, after multivariable adjustment, TCZ treatment was associated with a lower risk of invasive mechanical ventilation or death as compared with those not treated with TCZ [340] . An observational study found TCZ administered early during the disease course to patients with severe COVID-19 is associated with decreased intubation and reduced mortality; notably patients requiring ≤45% fraction of inspired oxygen (FiO2) was associated with better clinical outcomes when treated with TCZ than patients requiring >45% FiO2 [341]. An observational study of 239 COVID-19 patients with CRS found TCZ-treated patients with severe COVID-19 disease had higher admission levels of high-sensitivity CRP, received TCZ sooner, and their survival was similar to patients with nonsevere COVID-19 disease [124].
Neutral: In a randomized, double-blind, placebo-controlled trial of hospitalized COVID-19 patients TCZ was not effective in preventing intubation or death in moderately ill patients [342]. See also Negative: ARDS is connected with CRS and IL-6. TCZ is an IL-6 inhibitor and could halt the inflammatory response by blocking cellular receptors for IL-6. However, TCZ was found to induce pulmonary fibrosis in a RA patient [343].

Umifenovir (Arbidol)
Positive: Has an antioxidant effect [344] and efficiently inhibits H1N1 strain and diminishes both viral replication and acute inflammation by modulating inflammatory cytokine expressions [345]. Arbidol (umifenovir) reduced the viral load (RNA level) in the heart and lungs of mice with the Coxsackievirus B5 infection [346]. Arbidol has been suggested as a possible candidate for further investigation as a broad-spectrum respiratory antiviral [347]. This drug was able to inhibit SARS-CoV-2 virus in vitro [160]. In a study of health care professionals, the drug was associated with a lower incidence of SARS-CoV-2 infection but not hospitalization rate [348].

Neutral:
In an exploratory randomized controlled clinical trial arbidol monotherapy was used to treat mild to moderate COVID-19 cases and did not provide significant advantage over supportive care. Arbidol did not significantly improve recovery time or alleviate symptoms, and no difference was observed in the rates of antipyresis, cough alleviation, or improvement of chest computed tomography [253]. In a single-center retrospective study, patients with SARS-CoV-2 infection (not in ICU) treated with umifenovir did not appear to improve CT score, recovery time, or length of stay in the hospital [349].

Valganciclovir/ Ganciclovir
Positive: A lower incidence of CMV infection/disease and acute rejections in lung transplant patients treated with valganciclovir as compared to ganciclovir [350,351].

Zidovudine (AZT)
Negative: AZT affects the structural development of human fetal lung tissue in vitro [352]. AZT was found to exert cytotoxic effects on human myogenic cells [353] and contribute to myopathy associated with this drug [354].

Drugs Heart
Abacavir Positive: In healthy, virologically suppressed HIV-infected patients, abacavir did not cause inflammation, endothelial dysfunction, insulin resistance as compared with TAF/emtricitabine [355].
Negative: An increased risk of myocardial infarction has been seen with abacavir [356,357]. Abacavir/lamivudine increased total and LDL cholesterol [355]. Abacavir was independently associated with impaired endothelial function, a marker for CVD risk [358].

Anakinra
Positive: Improved coronary flow, left ventricle function, endothelial function and reduced inflammation in RA patients [359]. Anakinra reduced systolic BP in mice with one kidney, deoxycorticosterone acetate implantation, and salt induced hypertension [360]. IL-1 plays a central role in the pathogenesis of cardiac inflammation (myocarditis) and anakinra is effective in treating this condition [361][362][363].
A COVID-19 patient with myocarditis developed acute respiratory failure and cardiogenic shock due to cytokine storm-like syndrome and treated with anakinra and DEX had rapid clinical improvement, reduced serum inflammatory markers and marked recovery in cardiac magnetic resonance-based markers of inflammation and contractile dysfunction [364].

APN01 (rhACE2)
Positive: Attenuates negative effects of ANG II and improves remodeling of post-myocardial infarction [365]. rhACE2 prevented development of hypertension and heart fibrosis in renin transgenic mice and attenuated ANG II-induced cardiac hypertrophy and fibrosis [366]. S Studies of severe COVID-19 patients treated with human rhACE2 markedly reduced angiotensin II [367] and increased ACE2 levels [9].
Ascorbic Acid (AA) Positive: AA significantly improves endothelial dysfunction of epicardial coronary arteries of patients with hypertension [368]. AA in vascular smooth cells may prevent apoptosis, which can help stabilize plaque if atherosclerosis develops [369]. A review of epidemiologic studies suggests vitamin C deficiency is associated with a higher risk of mortality from cardiovascular disease but vitamin C's improvements on endothelial function and lipid profiles are slight, and are more likely to improve for groups with low plasma vitamin C levels [370]. In a mice study, vitamin C was shown to decrease TNFα expression and decrease pathological damage to the myocardium. It also shows some therapeutic and protective effects against the progression of experimental autoimmune myocarditis [371].

Azithromycin (AZM)
Neutral: In a clinical trial no significant increase in arrhythmia, cardiac arrest, acute kidney failure, or QT interval prolongation between the control and AZM group in severe COVID-19 patients in Brazil [372]. A retrospective pharmacoepidemiological study indicate a combination of CQ and AZM did not show pronounced increases in arrhythmias, although the sample size was small [373].
Negative: Five days of AZM therapy was shown to have an increased risk of cardiovascular deaths, more so in patients with higher risk scores for cardiovascular disease, and increased risk of sudden cardiac death [374]. It has been associated with QT-interval prolongation and torsade de pointes [375,376]. In a case study, fulminant myocarditis was associated with AZM exposure [377].
Baloxavir Neutral: No adverse cardiovascular effects observed in preclinical trials for influenza [378].

Baricitinib
Mixed: Meta-analysis of randomized trials of patients with RA treated with baricitinib was associated with a dose response increase in both HDL and LDL cholesterol. This could potentially have adverse cardiovascular effects, however in this study baricitinib did not statistically alter cardiovascular risk [379] Brincidofovir/ Cidofovir Limited Information: Also known as CXM001 and used to prevent CMV in hematopoietic cell transplantation [380].

Camostat Mesylate (CM)
Limited Information: CM's effects on the cardiac system has not been studied. However as a serine protease inhibitor it could affect processes involved in cardiac function (potential to reduce cardiac inflammation and fibrosis) [381].

Chloroquine (CQ)
Neutral: A retrospective cohort study of COVID-19 patients treated with CQ/HCQ and AZM did not find pronounced increases in arrhythmias [373].
Negative: CQ is associated with cardiotoxicity and cardiomyopathy [382]. HCQ/CQ known to produce mild cellular and cardiac toxicities. Other cardiac adverse effects include hypertrophy, HF, valvular dysfunction, and pulmonary arterial hypertension. These adverse outcomes improved in some patients upon HCQ/CQ withdrawal, while the effects were irreversible in some patients or even led to mortality in others [383]. CQ induced QTc prolongation in COVID-19 patients [384,385].

Colchicine
Positive: Colchicine is an anti-inflammatory used to treat gout and has been shown to reduce prevalence of myocardial infarction and cardiovascular events [375,386]. In a randomized, double-blind trial of patients recruited within 30 days after myocardial infarction colchicine treatment led to a significantly lower risk of ischemic cardiovascular events than placebo [387]. A randomized, controlled, double-blind trial of patients with chronic coronary disease the risk of cardiovascular events was significantly in patients taking colchicine [388].
A study of 105 patients in Greece noted significant clinical benefit of colchicine in COVID-19 hospitalized patients, however there were no significant differences in cardiac troponin or CRP levels in the treated vs. control group [26]. In contrast, a single-center randomized, double-blinded, placebo controlled clinical trial of colchicine for moderate to severe COVID-19 found the colchicine group showed significant reduction of serum CRP [389]. In a prospective, open-label, randomized and double blind clinical trial, 100 patients hospitalized with COVID-19 colchicine was found to reduce systemic symptoms by inhibiting inflammatory biomarkers [390].

Neutral:
In an open-label, randomized clinical trial for COVID-19 there was no significant differences in high-sensitivity cardiac troponin or CRP levels in the treated vs. control group of standard care patients [26].
Negative: In a mouse model of coxsackievirus B3 (CVB3)-induced myocarditis, colchicine had negative effects. It increased the viral load in the heart and the pancreas as well as destroying the exocrine pancreas [391]. In case reports, patients with chronic renal insufficiency colchicine was associated with cardiac insufficiency and death [392]. Similarly, colchicine was found to contribute to cardiotoxicity in a heart transplant patient with chronic renal failure [393].

Corticosteroid
Positive: Corticosteroids can increase atrioventricular conduction and is used to treat symptoms caused by pericarditis or myocarditis [394]. A nested case-control analysis suggests that low doses of inhaled corticosteroids may be associated with reduced risk of acute myocardial infarction in COPD patients [395]. In a hospital in France, adding corticosteroids treatment of children with multi-inflammatory syndrome in children with COVID-19 aid in the recovery of cardiac function [396].
A study of 13 Italian cardiology units found treating COVID-19 patients with corticosteroids and heparin were associated with lower mortality, although patients with HF were less likely to be treated with corticosteroid [397].

Mixed:
The use of corticosteroid as an immunomodulatory therapy for influenza is inconclusive and controversial [398].
Negative: Two major adverse effects of glucocorticoids are dyslipidemia and hypertension [399].
In patients without diabetes, corticosteroid treatment increases the risk of glucose intolerance. In patients with diabetes, it is associated with decreasing glycemic control [400]. High dose corticosteroid therapy increases risk of developing atrial fibrillation [401].

Dexamethasone (DEX)
Positive: A case report of a child with multi-viral infection including SARS-CoV-2 with respiratory distress, myocarditis, and coronary aneurysms was treated with intravenous immunoglobulins, aspirin, diuretics, DEX, and HCQ recovered with normalization of left ventricular function [402]. A COVID-19 patients with myocarditis was treated with anakinra and DEX showed clinical improvement, reducing serum inflammatory markers and reduced cardiac magnetic resonance-based markers of inflammation and contractile dysfunction [364].
Negative: Myocardial hypertrophy is associated with Dex therapy in infants with bronchopulmonary dysplasia [403]. Chronic DEX treatment induces insulin resistance, hyperinsulinemia, and hyperglycemia [404,405]. Fetal sheep treated with DEX saw a drop in the partial pressure of oxygen [406] and an increase in their arterial blood pressure [407].

Disulfiram (DS)
Negative: DS could contribute to myocardial infarction, arrhythmia, chronic heart failure (HF), or death [408]. DS was observed to have significant cardiovascular effects such as chest pain, palpitation, tachycardia, and hypotension in patient undergoing alchohol detoxification [409].

Mixed:
The role of CXCL12/CXCR4 on the cardiovascular system (and thereby inhibiting it) could be beneficial (e.g. increase cardiac function) or harmful (e.g. increase TNFα expression and cardiomyocyte apoptosis or reduce infarction size when deficient in CXCR4 ) depending on the condition [411][412][413].

Emtricitabine
Positive: Used to treat HIV and hepatitis B infection [414]. Emtricitabine/TAF elicited decreases in serum total, HDL and LDL cholesterol [415].
Negative: An episode of syncope was reported while treating an HIV patient with tenofovir, emtricitabine and nevirapine [416]. See also TAF.
Entecavir (EVT) Limited Information: Used to treat chronic hepatitis B. Myopathy cases have been reported with NRTIs including EVT [417], however entecavir's effect on the heart is not known.

Epoprostenol (EPO, synthetic equivalent of prostacyclin)
Positive: EPO is a vasodilator and inhibits platelet aggregation. Studies support its use in pulmonary arterial hypertension. PG12 improves cardiac output [418].
Negative: However, it can exacerbate underlying myocardial dysfunction and is contraindicated in HF [419].
Similarly, infusion of EPO in patients with severe left ventricular dysfunction was associated with increased mortality rates, without improvement in quality of life [420]. It can also increase plasma level of atrial natriuretic peptide, which impacts blood pressure [421].

Famotidine
Negative: Based on hemodynamic parameters famotidine treatment exerted a negative effect on cardiac performance and led to reduced stroke volume and cardiac output in healthy patients and patients with CHF [422].
Favipiravir Negative: Treatment increased QTc interval prolongation in an Ebola infected patient [423]. A risk assessment study of several drugs being used for COVID-19 found that there is some risk of long QT with favipiravir [424].

Chloroquine (HCQ)
Positive: HCQ is independently associated with a decreased risk of cardiovascular morbidities in RA patients [425].
Negative: HCQ is known to have a safer profile than CQ. It nonetheless has led to QT prolongation, arrhythmia [425] and cardiomyopathy [426]. QTc interval prolongation risk increased with HCQ and torsades de pointes was also observed in certain COVID-19 patients [427].
In COVID-19 patients combinatory treatment of HCQ and AZM for SARS-CoV-2 significantly prolong the QTc interval [428], but did not appear to promote torsade de pointes or arrhythmiarelated death [429,430]. A systematic review of the arrhythmogenic effect of short courses of CQ or HCQ found significant QT-interval prolongation in patients treated with these drugs [431].

IC14
Limited Information: IC14's effect on the heart has not been thoroughly investigated. However, soluble CD14 plays a role in inflammation, coronary heart disease, and chronic HF [432,433], and IC14 suppressed LPS-stimulated TNF production in patients which could be beneficial in chronic HF patients with systemic immune activation. In patients with chronic HF, IC14 suppressed TNFα expression. The suppression of TNFα was found in both chronic HF and healthy patients [434].

Idelalisib
Limited Information: In a study of the efficacy and safety of idelalisib in patients with relapsed, rituximab-and alkylating agent-refractory follicular lymphoma, there were 2 patients with adverse events that were considered possibly (acute cardiac arrest) or probably (drug-induced pneumonitis) related to idelalisib treatment [435]. More studies are needed to assess cardiovascular risk.

IFN-α
Positive: A prospective observational study of patients treated with (LPV/RTV and CQ and IFN-α saw a higher proportion of patients recovered from COVID-19 than those treated with (LPV/RTV and CQ and without IFN-α2b. Patients who did not receive IFN-α2b had higher incidence of comorbidities, such as high blood pressure, ischemic heart disease, and diabetes mellitus, but were also older than those receiving IFN-α2b [436]. Two patients with CHF secondary to enteroviral myocarditis were treated successfully with IFN-a, however this study is small, observational, and was not randomized [437].
Negative: A review of 44 cases of interferon induced toxicity identified some cardiovascular adverse effects including cardiac arrhythmia, dilated cardiomyopathy, and symptoms of ischemic heart disease, including myocardial infarction and sudden death [438].

Leronlimab (PRO 140)
Limited Information: Leronlimab's effect on the heart has not been studied. However inhibiting CCR5 signaling could have beneficial effects on the heart [441].

Lopinavir/ Ritonavir (LPV/RTV)
Neutral: A trial of LPV/RTV in adults hospitalized with severe COVID-19 did not accelerate clinical improvement but it did not show significant QTc prolongation or serious arrhythmic events in either the patients treated with LPV/RTV or the standard care group [442].
A case study of a COVID-19 patient treated with LPV/RTV developed brady arrythmia which resolved when treated was stopped [443].
Negative: HIV protease inhibitor RTV has caused QT and PR interval prolongation [444,445]. It induced endothelial cell injury at concentrations near clinical plasma levels which could have implications on cardiovascular complications. It caused endothelial mitochondrial DNA damage and necrosis [446].

Methyl Prednisolone (MP)
Positive: Has been shown to improve cardiac recovery after ischemic arrest [447]. Used successfully to treat myocarditis [448,449]. A case study of patient with dyspnoea due to COVID-19 develop elevated cardiac enzymes, severe left ventricular dysfunction, and high inflammatory markers was successfully treated with intravenous immunoglobulin (IVIG) and MP [450]. A case study of a patient presented with SARS-CoV-2 related fulminant myocarditis treated with milrinone and MP reduced myocardial inflamation [451].

Nafamostat (NM)
Positive: In an animal study NM treatment prior to ischemia and reperfusion found that it had cardioprotective effect of attenuating myocardial injury [67].
Negative: A case study reported a cardiac arrest caused by treatment of NM as an anticoagulant for hemodialysis [453].

Niclosamide
Limited Information: Used to treat tapeworm infection and potentially useful for treating some cancers [454]. It has not been investigated for its effect on the heart. It targets multiple signaling pathways including WNT signaling [455]. WNT signaling activity is not very active in the cardiovascular system of healthy patients but is activated in many pathologies of heart and blood vessels [456]. The salt version of this drug appears to inhibit artery constriction in rats [457].

Nitazoxanide
No effect: NTZ did not prolong QT interval in healthy male and female volunteers [458]. Little cardiovascular effects observed in a rat study [459].

Nitric Oxide (NO)
Positive: NO is a major signaling molecule in the cardiovascular system [460]. Improved NO production in the endothelium can decrease blood pressure via vasodilation [461]. NO has vasodilatory, anti-thrombotic, and anti-inflammatory effects on vasculature, but when availability of NO is decreased, it can cause endothelial dysfunction [462]. NO protects against ischemia-reperfusion injury [463]. An outpatient with vasoreactive idiopathic pulmonary arterial hypertension and COVID-19 infection recovered upon treatment with inhaled NO [464].
Negative: In autoimmune myocarditis, the presence of excess NO appears to lead to the progression of myocardial damage in rats [465].

Remdesivir (RDV)
Limited information: Originally developed and approved to treat Ebola. Cardiovascular toxicities have not been extensively studied [466,467].
Negative: An Ebola patient developed hypotension followed by cardiac arrest [468]. There has been an instance of torsade de pointes requiring cardiac resuscitation reported with RDV in a COVID-19 patient [469].
In a case study of 4 COVID19 patients, one patient treated with RDV was prematurely discontinued because of a torsade de pointes requiring cardiac resuscitation [470].
In another case study of 2 COVID-19 patients developed sinus bradycardia or QT prolongation when treated with RDV which reversed when discontinued [471].
In a review and analysis of studies and trials of MF patients treated with ruxolitinib indicate that RUX was not associated with the deaths of patients from myocardial infarction or cardiac arrest [473]. A prospective, multicenter, controlled, randomized, single-blind study of patients with severe COVID19 treated with RUX had faster clinical improvement, however one patient developed grade 3 hypertension which was transient and reversible. Serious adverse events, e.g. acute HF, occurred only in the control group [81].

Sarilumab
Limited Information: Sarilumab's effect on the heart has not been studied. IL-6 signaling can have either beneficial or harmful effects on the cardiac system depending on the kinetics of the host response. Increased IL6R protein levels are associated with coronary heart disease (CHD) and targeting IL-6 receptor antagonists could be beneficial [474].

Sirolimus (Rapamycin)
Positive: Sirolimus is an immunosuppressive drug. Although MTOR inhibitors could be beneficial to the heart [475].
Negative: Sirolimus has been associated with significant increases in total cholesterol and triglyceride levels [476]. Sirolimus is associated with venous thromboembolism in cardiac transplant recipients [477,478].

Sofosbuvir
Negative: Sofosbuvir has been associate d with worsening of left ventricular function in a longitudinal study of HCV patients [479]. In a cohort study of 415 HCV patients, 5 patients developed cardiac arrhythmia [480]. Sofosbuvir alone has negligible effect on the cardiomyocyte electrophysiology while amiodarone and sofosbuvir together did affect cardiomyocyte electrophysiology [481,482].
Neutral: Minimal cardiovascular risks observed in treating hepatitis C viral infection in patients with severe renal insufficiency [483]. Nonetheless, there was one cardiac-related event that occurred in a chronic hepatitis C patient with cirrhosis and pre-existing CHF [484].

Statins
Positive: Statins decreased the levels of atherogenic lipoproteins and CRP, and these decreases are associated with slower progression of atherosclerosis [485]. Used to reduce cholesterol levels, it also has anti-inflammatory effects which contributes to their beneficial effects on the cardiovascular system [486]. Although statin appear to reduce severity of experimental myocarditis in animal studies, there are no clinical studies on the use of statins for myocarditis [487]. In-hospital use of statins or statins plus ACE inhibitors or ARBs for COVID-19 patients did not increase the risk of cardiac injury [488].

Stavudine
Mixed: Treatment with stavudine was associated with myocardial infarction in one study that found a significant increase in myocardial infarction and stroke, while several other studies did not find a significant increase in these cardiac events associated with the drug [489].
Tenofovir Positive: TDF is associated with a decreased risk of HF in HIV patients [490] which could be related to its potential lipid-lowering effects.
Negative: Used to treat hepatitis B and HIV infection. TAF is associated with an increased risk of HF in HIV patients [491]. TDF/emtricitabine was associated with a higher likelihood of atherosclerosis in HIV patients [492]. An episode of syncope was reported while treating a HIV patient with tenofovir, emtricitabine and nevirapine [416].

Tetrandrine (TET)
Positive: TET is a calcium channel blocker with antifibrotic effects, preventing human cardiac myofibroblast activation and suppressing collagen synthesis in vitro and limiting myocardial fibrosis in Dahl salt-sensitive hypertensive rats [493]. TET pretreatment had protective effects on isoproterenol-induced myocardial infarction in an animal model. TET lowered the levels of c-troponin I (a cardiac necrosis marker) and malondialdehyde (marker of oxidative stress) in the isoproterenol treated animals [494]. It improved ischemia/reperfusion lesions in rat myocardium by inhibiting neutrophil activation and infiltration, and ROS production [495].

Tocilizumab (TCZ)
Positive: This drug is a humanized IL-6 receptor antibody and used to treat RA [501]. IL-6 receptor signaling adversely affects CHD and inhibiting IL-6R signaling could be beneficial. In a phase 3 clinical trial study of TCZ safety for RA, myocardial infarction was lower in the treated group as compared with the control group [127].
A patient in critical condition with COVID-19 related myocarditis was treated with TCZ, an aldose reductase inhibitor, and corticosteroids. The patient made a full recovery [502]. Improves endothelial function but increases total cholesterol and LDL levels [503].
Negative: Major adverse cardiovascular events in RA patients treated with TCZ were higher than with etanercept (TNF-α inhibitor), but not meaningfully higher [504], it did increase blood pressure and LDL [505].
A study of 43 patients with severe COVID-19 pneumonia treated with TCZ indicated ~7% of the patients developed candidemia, with one developing both endophthalmitis and endocarditis [506].
In a prospective, open-label, randomized clinical trial of hospitalized patients with COVID-19 pneumonia in Italy, TCZ increased CRP levels [507].

Umifenovir (Arbidol)
Positive: Umifenovir has a safe cardiac profile for treatment of influenza [508]. Arbidol reduced the viral load in the heart and lungs of mice with the Coxsackievirus B5 infection [509].

Valganciclovir/ Ganciclovir
Positive: When used as a preventative measure, a protective effect against CMV infection was observed. In addition, the survival of older patients with cardiovascular comorbidities was increased [510].
Valganciclovir was used to resolve myocarditis caused by CMV infection in a patient [511].

Zidovudine (AZT)
Positive: A case study suggests that AZT may be beneficial in treating HIV-associated myocarditis [512].
Negative: Treatment of AZT increased blood pressure and promoted cardiovascular damage. However, these negatives were inhibited by vitamin C [513]. Study was done for 8 months on rats. An association between AZT and the development of cardiomyopathy was reported in patients with HIV, both in children [514] and adults [515]. However, a more recent study suggests immunodeficiency may be influencing the development of cardiomyopathies [516].

Drugs Kidney Effects
Abacavir Negative: Used to treat HIV. Some evidence of patients treated with tenofovir and indinavir, and to a lesser extent abacavir, had a higher risk for chronic kidney disease (CKD). [517] Anakinra Positive: Administering IL-1 receptor antagonist (IL-1ra) has been shown to attenuate tubular necrosis in a rat model [518]. Ischemia/reperfusion injury in organ transplantation or hemorrhagic shock causes renal dysfunction. Anakinra was found to be safe in patients going through renal transplantation [519].
Mixed: Anakinra reduced renal fibrosis but exacerbated renal hypertrophy and had modest effects on renal inflammation and leukocyte infiltration in mice with one kidney, deoxycorticosterone acetate (DOCA) implantation, and salt induced hypertension [520].

APN01 (rhACE2)
Positive: rhACE2 alleviated angiotensin II-mediated renal fibrosis and structural injury in atherosclerosis-prone ApoE-mutant mice. rhACE2 prevented Ang II-mediated increases in superoxide production and mTOR and extracellular receptor kinase (ERK)1/2 phosphorylation signaling, and also reduced TGF-β1, collagen I and fibronectin mRNA levels [521]. rhACE2 ameliorated albuminuria, and reduced kidney fibrosis in mouse models of systemic renin angiotensin system activation. It reduced the AKT (aka protein kinase B) and ERK phosphorylation, which helped protect renal cells from Ang II-induced injuries [522]. Human soluble rhACE2 can inhibit SARS-CoV-2 infection of engineered human blood vessel organoids and human kidney organoids [8].
Ascorbic Acid (AA) Positive: However, L-AA dose-dependently was found to protect renal tubular cells from chromium intoxication-induced oxidative stress and cell death in a cell study. Chromium (K 2 Cr 2 O 7 )-induced ROS production, apoptosis, and autophagy was suppressed with L-AA treatment [523].
Negative: AA breaks down ultimately to oxalate. Supersaturated calcium oxalate in the tubules preferentially deposit as crystals in damaged tubular epithelium, where they are thought to cause both obstruction and apoptosis of tubular epithelial cells [524]. In a case study, excessive vitamin C was believed to contribute to acute tubular injury (ATI) and oxalate nephropathy in two patients with slowly resolving acute kidney injury (AKI) after ARDS due to COVID-19 [525].
There are several case studies that have associated high levels of AA and acute or chronic renal failure [526][527][528][529].

Azithromycin (AZM)
Neutral: In a clinical trial no significant increase in acute kidney failure between the control and AZM group in severe COVID-19 patients in Brazil [155].
A population-based cohort study found a small but statistically significant greater 30-day risk of hospitalization with AKI for patients co-prescribed calcium-channel blockers and clarithromycin as compared with AZM [530].

Baricitinib
Positive: In treating diabetic kidney disease (DKD), baricitinib significantly reduced albuminuria, the most widely accepted clinical biomarker for DKD, in study participants at high risk for disease progression. This JAK1/JAK2 inhibitor shows potential for treating DKD [533].

Brincidofovir/ Cidofovir
Positive: A case study found brincidofovir successfully treated adenoviral infection in a kidney transplant patient that developed renal insufficiency with cidofovir [166].
Negative: Brincidofovir induced severe AKI in a heart and a kidney organ transplant patient with CMV infection, which was reversible [534].
In a retrospective study of pediatric patients with adenovirus infection, cidofovir was associated with greater increases in creatinine levels and AKI [535]. Prolonged use is known to cause severe nephrotoxicity in a monkey study [536].

Camostat Mesilate (CM)
Positive: CM appears to be beneficial for treating diabetic nephropathy [537]. CM attenuates the progression of CKD in an adenine-induced CKD rat model by decreasing the expression and protein levels of fibrotic markers, and the accumulation of oxidative stress [538]. CM appears to have an antihypertensive effect on Dahl salt-sensitive rats fed a high salt diet, which contributed to renoprotective effects [539]. CM exerted renoprotective effects on kidney injury induced by aldosterone and salt in Sprague-Dawley rats by suppressing inflammatory and pro-fibrotic cytokine expression, ROS production and TGF-β signaling. CM inhibited renal plasmin and suppressed plasmin induced pro-fibrotic (collagen I/III) and inflammatory genes (e.g. TGF-β1, TNF-α) in cultured renal fibroblasts. CM attenuated urinary protein excretion, glomerulosclerosis and tubulointerstitial fibrosis [540].

Chloroquine (CQ)
Negative: Renal toxicity has been observed with long-term use of CQ in rats [541]. In a case study, a patient with RA developed muscle weakness and renal insufficiency with CQ, which improved eventually upon cessation of the drug [542]. Furthermore, serious complications occurred in a patient with underlying end-stage kidney failure who got CQ [543].

Colchicine
Positive: There is some evidence that colchicine could be beneficial in renal fibrosis, although more clinical trials are needed [544]. Similarly in animal studies, colchicine was found to mitigate renal fibrosis in a murine unilateral ureteral obstruction model [545].
Negative: Colchicine was associated with kidney injury in a diabetic with stage 4 chronic kidney disease and a renal transplant recipient [546].
Corticosteroids Negative: In a retrospective study, corticosteroids were associated with severe adverse effects (e.g., all-cause mortality, severe or fatal infection, gastrointestinal hemorrhage or gastrointestinal perforation, new-onset diabetes mellitus or cataract, fatal/nonfatal myocardial infarction, fatal/nonfatal stroke, and heart failure) in patients with IgA nephropathy [547].

Dexamethasone (DEX)
Positive: DEX appears to reduce the incidence of severe AKI after cardiac surgery, notably in patients with advanced CKD [548]. Aged human kidneys form tertiary lymphoid tissue (TLT). In a kidney injury mouse model administering DEX halted TLT formation and attenuated renal inflammation and fibrosis [549].
Disulfiram (DS) Positive: Elevated transglutaminase 2 (TG2) activity in the extracellular matrix is associated with renal fibrosis [550,551]. DS was shown to be an irreversible inhibitor of human TG2, but further investigation is needed [552].

Limited information:
The effect of ODSH on the kidneys has not been studied. However, CXCL12/CXCR4 levels are upregulated in kidneys of lupus mouse model and contribute to leukocyte trafficking into the kidneys which may mediate nephritis [553]. As a CXCL12/CXCR4 inhibitor, DSTAT could mitigate renal pathology in lupus nephritis.
Emtricitabine Positive: In a study of 2499 HIV patients, emtricitabine with TDF was associated with a very mild nonprogressive reduction in creatinine clearance [554].
Entecavir (EVT) No effect: As compared to tenofovir, which decreased the estimated glomerular filtration rate (eGFR), EVT did not cause a significant change in eGFR in chronic hepatitis B patients [556].
No negative effects on the kidney were reported in a rat study [557].

Epoprostenol (EPO, synthetic equivalent of prostacyclin)
Mixed: EPO's effect on the kidneys has not been studied, however, prostacyclin infusion was found to increase renal plasma flow, and plasma levels of atrial natriuretic peptide (ANP) [558]. ANP may lead to CKD [559]. It also increased renal levels of angiotensin (ANG) II in healthy controls [558]. Increases in ANG II have been reported in different types of renal diseases [560].

Famotidine
No effect: Famotidine does not appear to interfere with clearance of other basic drugs in patients with chronic renal insufficiency [561].

Favipiravir
No effect: Patients with COVID-19 treated with favipiravir as compared to arbidol did not significantly improve clinical recovery rate but favipiravir did significantly shorten the latency to relief for fever and cough [218].
The results for favipiravir on the kidney is limited. Favipiravir, an RNA-dependent RNA polymerase (RDRP) inhibitor, is predominantly excreted through the urine; thus, patients with eGFR<20 ml/min per 1.73 m 2 are excluded from clinical trials. Favipiravir used in Ebola infection was not associated with a significant decrease in creatine kinase level [562].

Limited information:
A case report of SARS-CoV-2 infection in a kidney transplant recipient treated with HCQ and AZM and favipiravir, followed by TCZ had fatal outcomes [563]. In contrast, another kidney transplant patient with COVID-19 pneumonia was treated with several drugs including favipiravir and TCZ had a favorable outcome [564].

IC14
Limited information: The effect of IC14 on the kidneys has not been studied. However, CD14 levels correlated with polycystic kidney disease (PKD) severity in cpk mice, suggesting a potential for anti-CD14 therapy in PKD [575].

Idelalisib
Positive: A case study of a patient with Waldenström's macroglobulinemia (a rare B-cell lymphoma) and refractory to first-line treatment with rituximab, cyclophosphamide, and DEX, presented with acute renal failure had improvement in his clinical status when treated with idelalisib [576].
Negative: Adverse renal effects of idelalisib on a chronic lymphocytic leukemia patient included hypokalemia, AKI, and hyponatremia but nonetheless had fewer adverse effects than ofatumumab, alemtuzumab and ibrutinib [577].

IFN-
Positive: IFN-therapy for metastatic renal cell carcinoma (RCC) showed a modest survival as compared with placebo [578].
Negative: IFN-treatment has been associated with focal segmental glomerulosclerosis [579]. Systemic IFN-treatment of a lupus prone mice model led to the development of glomerulonephritis and accelerated kidney disease [580].

Ivermectin
Positive: Ivermectin inhibits proliferation and promotes apoptosis in RCC cells and inhibits RCC tumor growth in vivo by inducing mitochondrial dysfunction (i.e.decreasing mitochondrial membrane potential, mitochondrial respiration and ATP production) and oxidative stress. Ivermectin is preferentially cytotoxic to RCC cells compared to normal kidney cells [581].

Leronlimab (PRO 140)
Limited information: The effect of leronlimab on the kidneys has not been studied. CCR5 is a receptor for the C-C chemokine RANTES and is expressed in inflammatory kidney diseases. A study found an association between CCR5-positive T cells and renal insufficiency in glomerular diseases and progression of renal disease [582]. In a study of 413 patients, those with high-sensitivity C-reactive protein (hsCRP) > 10 mg/L and not carrying a deletion allele for CCR5 had the worst survival. The results suggest deletion of CCR5 protected dialysis patients from inflammation associated mortality. A dual CCR2/CCR5 antagonist was found to have antifibrotic and anti-inflammatory effects on the kidney in a mouse model [583]. Therefore, leronlimab could be beneficial by inhibiting CCR5 for fibrotic diseases.
Interacts with renal transport of organic anions, leading to proximal tubular intracellular accumulation of TDF [585]. RTV has been associated with AKI [586]. LPV/RTV have been associated with an adverse effect on renal function in patients without preexisting renal impairment [587]. RTV, LPV, and other protease inhibitors (lamivudine, tenofovir, and didanosine) can interact with the renal transport of organic anions, leading to proximal tubular intracellular accumulation of tenofovir in HIV patients. The clinical and biological characteristics are consistent with Fanconi syndrometype tubulopathy [585].

Methyl Prednisolone (MP)
Positive: MP reduces LPS induced expression of fractalkine through the NF-κB pathway. Fractalkine is involved in the development of human lupus nephritis [588].
Negative: MP has been associated with transient renal failure [589].

Nafamostat (NM)
Positive: NM, a synthetic serine protease inhibitor, is used as an anticoagulant during continuous renal replacement therapy (RRT). In a prospective study NM did not increase the risk of bleeding during continuous RRT in critically ill patients with AKI patients at high risk of bleeding tendencies [590].
Negative: Hyponatremia and hyperkalemia rates were higher in the NM than the gabexate mesilate treated group [591].
A cell study suggested that NM-induced decrease in prostasin (an important physiologic regulator of sodium reabsorption in the kidney and is involved in the development of salt-sensitive hypertension), which leads to a decrease in amiloride-sensitive sodium channels activity, and could account for the hyponatremia or hyperkalemia [592].

Niclosamide
Positive: Niclosamide inhibits proliferation and migration and induces apoptosis in human RCC cells [593]. It reduced proteinuria, glomerulosclerotic lesions, and fibrosis in a mouse model of adriamycin nephropathy [594] and improved kidney injury in db/db mice [595]. It inhibited breast cancer metastases to the kidney in mice [596]. Delivery of niclosamide via particles of human lysozyme as a carrier molecule reduced viral load in the kidneys of hACE2 transgenic mice infected intranasally with SARS-CoV-2 [270].
Negative: It was found to increase markers for kidney injury in rats [598].

Nitric oxide (NO)
Positive: NO is a vasodilator mainly through the eNOS/NO/cGMP pathway. Renal diseases are often associated with NO deficiency [599].
In ischemia/reperfusion induced acute renal failure, NO was protective against kidney injuries [600].
Negative: In contrast, inhaled NO could increase the risk of renal impairment in adult patients with acute respiratory distress syndrome and acute lung injury [600].

Remdesivir (RDV)
Positive: In a single-center study, RDV was tolerated well in patients with CKD and AKI, and many of the patients were on hemodialysis. More research is needed for conclusive results [601].
Negative: Used to treat COVID-19, however, patients with severe AKI and end stage kidney disease (ESKD) were excluded from all RDV trials on the basis of eGFR cutoffs (either 50 or 30 ml/ min per 1.73 m 2 ). Intravenous preparation of RDV uses SBECD as a carrier. Accumulation of SBECD is associated with renal tubule obstruction in animal studies, but is easily removed by continuous RRT and hemodialysis [602].
In support, an analysis of World Health Organization (WHO) databases found significant pharmacovigilance signals of nephrotoxicity associated with RDV [603].

Ruxolitinib (RUX)
Positive: In a retrospective analysis of 100 patients with previously untreated primary MF, RUX was associated with improved renal function as compared to control [604].
Negative: However, RUX also has been associated with renal insufficiency in some patients with MF [605].

Sarilumab
Limited information: Sarilumab is a human monoclonal antibody against IL-6 receptor-α approved for the treatment of RA [606]. Its effect on the kidney has not been studied. Given the relevance of IL-6 is a prognostic indicator of renal diseases, blocking IL-6 receptor-α could be a possible therapy for renal diseases.
Sirolimus decreased kidney transplant rejection comparable to cyclosporin. Unlike cyclosporin, it did not cause nephrotoxicity [610].
Mixed: mTOR signaling in glomerular disease is heterogeneous and the effect (positive or negative) of rapamycin is context-dependent [611].
Negative: In some patients with chronic glomerulopathies, rapamycin was found to cause nephrotoxicity [612].

Sofosbuvir
Mixed: Patients with HCV treated with sofosbuvir showed viral clearance but had higher incidences of anemia and worsening renal function [613].

Statins
Positive: Statins effect on the kidney is context dependent. It appears to prevent AKI after cardiac surgery and reduce major cardiovascular events and mortality in CKD [614]. Statins protect against nephrolithiasis (kidney stone formation), and not through its lipid-lowering mechanism [615].
In-hospital use of statins or statins plus ACE inhibitors or ARBs did not increase the risk of kidney injury of COVID-19 patients [315].
Negative: Used to treat hyperlipidemia. There appears to be an association between statin and increased incidence of acute and chronic renal disease as well as tubulo-interstitial nephritis, and statins' effects in patients with CKD remain uncertain [614].

Stavudine
Negative: In a case study, stavudine was associated with renal tubular injury [616]. An AIDS patient on stavudine and lamivudine was associated with lactic acidosis [617]. Another case study, an HIV patient developed lactic acidosis and renal failure secondary to acute hepatic failure [618].
Tenofovir Negative: Tenofovir [619] and TDF used to treat HIV is associated with nephrotoxicity and involves mitochondrial abnormalities [620]. Tenofovir increases CKD [621]. A nonrandomized large cohort was associated with a higher incidence of CKD with increasing exposure to tenofovir [622].

Tetrandrine (TET)
Positive: TET is an urate-lowering drug and hyperuricemia could influence on eGFR. Evidence suggest that hyperuricemia has a damaging effect on kidney function, but its benefits maybe context dependent, with less conclusive benefits in patients with high blood pressure [623] and proteinuria [624]. In RCC, proteinuria predicts decline in kidney function [625]. Overexpression of transient receptor potential cation channel protein 6 (TRPC6) caused proteinuria in healthy mice [626]. TET protected podocytes by inhibiting TRPC6-overexpression-induced intracellular Ca 2+ influx, inhibiting podocyte apoptosis and enhancing podocyte growth via inhibition of the RhoA/ROCK pathway [627]. TET treatment decreased growth and viability of RCC cells. TET induced G1 cell cycle arrest and apoptosis in RCC cells, respectively, by increasing expression of cell cycle regulatory protein p21 WAF1/CIP1 and p27 KIP1 , and activating caspase-8, caspase-9, and caspase-3 in TET-treated RCC cells [628]. TET inhibited RCC migration and invasion by downregulating the expression of NF-κB, MMP-9, p-AKT, p-PI3K and p-PDK1 [629].

Thalidomide (THD)
Positive: Used to treat side effects caused by chemotherapy. Renal failure is a concern with multiple myeloma patients. THD, alone or in combination with DEX improved renal function [630]. Treatment with THD prevented cisplatin-induced increase in blood urea nitrogen (BUN) and creatinine levels. Cisplatin-induced cytokines (TNF-α, IL-1β, IL-6, TGF-β1) were reduced by THD in a dose-dependent manner, while IL-10 was elevated. THD prevents renal dysfunction induced by cisplatin by reducing NO-mediated cytotoxicity [631].
Negative: Nephrotoxicity associated with this drug included kidney stones and decreased GFR in clinical practice [632].

Tocilizumab (TCZ)
Positive: Evidence indicates the relevance of IL-6 as a prognostic indicator and blocking IL-6 receptor-α as a therapy for renal diseases [633]. TCZ reduced proteinuria and stabilized renal function in patients with Multicentric Castleman's disease (MCD) which overproduces IL-6 [634,635]. TCZ reduced proteinuria and stabilized amyloid deposits in a patient with nephrotic syndrome due to rapidly progressing AA amyloidosis [636]. Patients with end-stage renal disease with COVID-19 have been successfully treated with TCZ [637,638].
Neutral: Kidney transplant recipients who received TCZ for severe COVID-19 have shown high mortality (possibly due to the TCZ group was more critically ill), and when compared to matched control cohort group TCZ did not have significant beneficial response (e.g. mortality) [639]. The effect of TCZ on kidney transplant patients with COVID-19 pneumonia requires further controlled studies [640].

Umifenovir (Arbidol)
Limited information: It is a broad-spectrum antiviral [641]. The effect of umifenovir/arbidol on the kidneys has not been investigated.
In an in-hospital study of COVID19 patients, there was no significant difference between patients with and without AKI treated with umifenovir [642], ganciclovir, interferon, lopinavir/ritonavir, oseltamivir, and ribavirin.

Valganciclovir/ Ganciclovir
Negative: Used as anti-CMV therapy in kidney transplant recipients. Patients developed acidosis, which was compounded with active viral infection [643]. In kidney transplant patients preemptive post valganciclovir prophylaxis treatment had limited impact on preventing late-onset CMV disease [644].

Zidovudine (AZT)
Positive: HIV transgenic mice treated with AZT had significant reductions in glomerulosclerosis, interstitial fibrosis, and tubular atrophy, but not cortical inflammation or tubular cast formation. However, it is unclear if AZT had a protective effect independent of darunavir [645].

Negative:
In several case studies, AZT treatment of HIV patients was associated with fatal lactic acidosis [646].

Drugs Liver Effects
Abacavir Negative: Abacavir hypersensitivity is associated with abnormal liver enzyme levels [647]. Abacavir induces multiorgan toxicity in people who carry the HLA-B*57:01 allele [648]. Mice carrying this allele did not increase markers of liver injury unless also treated with CpG oligodeoxynucleotide [649]. In Hep3B and human liver tissue abacavir combined with acetaminophen (even at low doses) negatively impacted mitochondrial function and increased risk for liver injury, and is relevant to HIV patients taking NRTIs, given that HIV increases oxidative stress which can affect mitochondrial function [650].
Negative: In a case study, a patient treated with anakinra for RA displayed elevated liver enzymes and hepatotoxicity [653].

APN01 (rhACE2)
Positive: Adeno-associated viral vector delivery of rhACE2 sustained overexpression and activity of ACE2 which reduced the ratio of Ang II to Ang-(1-7) and reduced hepatic stellate cell activation, oxidative stress, release of proinflammatory, and profibrotic mediators, and thereby inhibited liver fibrosis in three different models of liver disease in mice [654].

Ascorbic Acid (AA)
Positive: AA could protect the liver from arsenic induced lipid peroxidation by improving mitochondrial function and preventing DNA fragmentation likely due to its antioxidative properties [655]. A cross-sectional study suggests that AA could have an inverse relationship to non-alcoholic fatty liver disease (NAFLD) [656].

Azithromycin (AZM)
Positive: In cells, AZM showed anti-tumor effects and suppressed the proliferation of HepG2 cells by inducing apoptosis through both the extrinsic/intrinsic apoptotic pathways [657].
Negative: A patient developed cholestatic hepatitis after four days of therapy with high-dose AZM for the treatment of suspected bronchitis. This case study of AZM being used to treat bronchitis was associated with adverse hepatic reactions [658]. A review of publications in 2015 found that acute drug-induced liver injury was more severe and potentially fatal in patients with underlying liver disease than in patients without liver disease, and AZM increased the risk of hepatotoxicity in these patients [659].

Baloxavir
Limited information: Little evidence that baloxavir caused liver injury, however instances of elevated ALT levels have been observed [660].

Baricitinib
No effect: Used to treat RA. Patients with inadequate response to methotrexate, treated with baricitinib, increased LDL and HDL cholesterol levels compared with placebo. Increases in creatinine and creatine phosphokinase were non-clinically significant [661].

Brincidofovir/ Cidofovir
Positive: Brincidofovir and cidofovir are more effective than ribavirin at inhibiting pathology and replication of adenovirus (Ad)5 in the liver of hamsters with this infection. Both drugs reduce liver damage, morbidity, and mortality when given prophylactically or therapeutically [20,662].
Negative: However, a case report of drug-induced liver injury (DILI) due to CM, benzbromarone, or a combination of the two, was associated with autoimmune hepatitis [665].

Chloroquine (CQ)
Positive: CQ attenuated acute liver injury in carbon tetrachloride (CCl 4 ) treated mice by inhibiting inflammation and inducing apoptosis. Pretreatment with CQ down regulated hepatic tissue and serum levels of HMGB1, IL-6, and TNF-α. HMGB1-mediated the inflammatory responses. CQ pretreatment also inhibited autophagy, and promoted apoptotic cell death of non-recoverable cells [666].
Mixed: Rats pretreated with CQ prevents ischemic liver damage early but aggravates liver damage in late phase of ischemia/reperfusion [667].

Colchicine
Positive: There is evidence suggesting colchicine could reduce some of the clinical manifestation of cirrhosis [668]. Treatment with colchicine prevents and delays the development of hepatocellular carcinoma (HCC) in patients with hepatitis virus-related cirrhosis. The protective mechanisms could be related to antiinflammatory properties and inhibition of mitosis [669]. In a prospective, open-label, randomized and double blind clinical trial, hospitalized COVID-19 patients treated with colchicine + standard care (HCQ) reduced AST and ALT levels as compared to standard care [670].
Negative: Colchicine was found to contribute to liver damage in a heart transplant patient with chronic renal failure, which improved upon ceasing colchicine [671]. In another case report, it was found to contribute to hepatotoxicity and elevated liver enzymes which return to normal after discontinuing colchicine [672].
Corticosteroids Positive: As an immunosuppressive agent, corticosteroids have been used to effectively treat DILI involving the autoimmune response (e.g. drug-induced autoimmune hepatitis) and to a lesser extent drug-induced hypersensitivity [673].
Negative: A case report of idiopathic thrombocytopenic purpura treated with corticosteroid developed non-traumatic osteonecrosis of the femoral head, elevated ALT and AST levels, and NAFLD [674].
Negative: DEX has been shown to inhibit mitochondrial beta-oxidation, decrease hepatic triglyceride secretion leading to microvesicular steatosis [679] and to induce fatty liver in mouse models [680].

Disulfiram (DS) Positive: DS influences L-tryptophan metabolism by increasing hepatic 3-hydroxykynurenine (3-HK)
and 3-hydroxyanthranilic acid (3-HAA) levels, which possess alcohol-aversive and immunosuppressant properties [681]. DS has been investigated for treating HCC. DS combined with copper inhibited tumor progression in SCID mice but not in C57BL/6 mice, suggesting intact immune system compromises the therapeutic efficacy of DS plus copper [682].
Negative: There is evidence that DS could induce hepatotoxicity [683,684].
Dociparstat sodium (DSTAT, aka ODSH) Limited information: The effect of ODSH on the liver has not been studied. However, CXCL12/CXCR4 pathways involved in advanced liver disease are associated with hepatitis B and C [685]. As a CXCL12/CXCR4 inhibitor, DSTAT could mitigate the inflammation and fibrosis activated by these pathways.

Emtricitabine
Negative: Emtricitabine in chronic HBV has been associated with elevated ALT level [686] and exacerbation of chronic hepatitis B posttreatment, with one requiring liver transplantation [687]. A combination of efavirenz, emtricitabine, and tenofovir treatment of an HIV patient was associated with hepatotoxicity exhibiting extremely elevated aminotransferase levels, but resolved without acute liver failure [688].
Entecavir (EVT) Positive: Reversal of cirrhosis has been observed with EVT, including decreased ALT and AST levels and improved liver function of chronic hepatits B and liver cirrhosis patients. CD34⁺ cells increased in peripheral blood and liver tissues, suggested that these progenitor cells may migrate to the liver and help regenerate or repair the liver tissue [689].
Negative: Chronic hepatitis B patients with impaired liver function treated with EVT was associated with severe lactic acidosis [690]. Elevated ALT levels have resulted in chronic hepatitis B patients treated with EVT [691]. EVT is primarily used for hepatitis B treatment, and was found to have a higher risk of HCC as compared to tenofovir [692].

Epoprostenol (EPO, synthetic equivalent of prostacyclin)
Positive: EPO's effect on the liver has not been studied, however, prostacyclin (PGI2) and a prostaglandin analogue when administered early prevented galactosamine-induced hepatic necrosis and mortality in an animal model [693].

Famotidine
Positive: Overall has a good safety profile, it increases glycogen stores by inhibiting glycogen synthase kinase-3β and improves oral glucose tolerance (decreases serum glucose levels) in healthy volunteers [694]. A retrospective cohort study of hospitalized COVID-19 patients found that patients receiving famotidine had a statistically significant reduced risk of clinical deterioration leading to death or intubation [213].
Negative: There has been a case study in which a hepatitis C patient developed acute hepatitis associated with famotidine [695].

Favipiravir
Positive: Favipiravir and ribavirin exert a synergistic activity against HCV in human hepatoma cells [696]. Favipiravir may act as a mutagenic agent in influenza viruses in vitro [697] and viral RNA chain terminator [696]. Favipiravir used in Ebola infection was associated with a significant decrease in ALT and AST levels [562].

Hydroxy
Positive: When used to treat patients with SLE or RA, it reduced serum cholesterol and LDL levels Chloroquine (HCQ) compared to those treated with corticosteroids [698]. HCQ helped to improve obesity-associated insulin resistance and hepatic steatosis. In high fat diet (HFD)-induced obese C57BL/6J mice, HCQ reduced blood glucose levels, serum lipids, and hepatic steatosis. It also downregulated de novo lipogenesis genes and lipogenic enzyme levels in liver tissues, which had a hepatoprotective effect [699]. Antimalarials inhibit platelet aggregation and adhesion and reduce blood viscosity and thrombus size. They positively affect serum lipid profile and glucose concentration by preventing the formation of autoantibodies and immune-complexes, diminishing inflammation, and favorably acting at the vascular endothelial level [565] Negative: HCQ caused a ten-fold increase in transaminase levels in a patient with ARDS caused by COVID-19 infection. Discontinuation of HCQ improved levels within 5 days [700]. HCQ-induced acute toxic hepatitis in a SLE patient, which resolved after ceasing HCQ and administering mycophenolate mofetil [701].

IC14
Limited information: The effect on IC14 on the liver has not been studied. However, CD14 levels in nonalcoholic steatohepatitis (NASH) patients correlate with liver inflammation, suggesting a potential for anti-CD14 therapy in NASH [702].

Idelalisib
Negative: Idelalisib, a PI3Kδ inhibitor, is associated with elevated transaminase levels in CLL patients [703]. In patients treated for CLL, idelalisib can cause immune-mediated severe hepatotoxicity (recorded in 54% of patients) [53]. The toxicity was immune-mediated, as evidenced by increased levels of chemokine ligand (CCL)-3 and CCL-4. Discontinuing the drug and/or beginning immunosuppressants remedied the complications [53].

IFN-
Positive: IFN-induced apoptosis independent of p53 in HCC cell lines. IFN-induces the tumor suppressor promyelocytic leukemia protein (PML) and the tumor necrosis factor-related apoptosisinducing ligand (TRAIL), which is mediated by PML [704].

Ivermectin
Negative: A case of ivermectin induced severe hepatitis has been reported [712]. Ivermectin is metabolized via P4503A4 and if taken along with drugs like LPV/RTV or darunavir/cobicistat which inhibit P4503A4 will increase systemic exposure of ivermectin [713].

Leronlimab (PRO 140)
Limited information: The effect on leronlimab on the liver has not been studied. However, a study found inflammation in the early stages of HCV disease in patients carrying the CCR5Δ32 allele was significantly reduced as compared to control. CCR5Δ32 is a deletion mutation in the chemokine receptor CCR5 which results in significant reduction of CCR5 expression. The study suggests that CCR5 may be involved in the recruitment of immune cells in the liver and viral clearance during chronic HCV infection [714].

Lopinavir/ Ritonavir (LPV/RTV)
Mixed: LPV/RTV has been reported to elevate liver enzymes [715] and contribute to hepatotoxicity and full dose of RTV was associated with an increased risk of liver injury, while low dose RTV to LPV is not associated with greater risk of liver injury as compare with other HIV protease inhibitors [716]. See also umifenovir/arbidol. Overdose can activate the ER stress signaling, inhibit proliferation of hepatocytes, induce apoptosis of hepatocytes through caspase activation, induce inflammatory reactions, and accelerate liver injury by aggravating oxidative stress [717]. RTV is associated with elevated liver transaminase levels in HIV-infected patients [718]. Using a PXR-humanized mouse model it was found that pregnane X receptor (PXR) modulates RTV hepatotoxicity through CYP3A4-dependent pathways [719].

Methyl Prednisolone (MP)
Positive: A study with rats found MP protected against hypoxia-induced liver injury by preventing mitochondrial membrane depolarization [720].

Nafamostat (NM)
Positive: Studies have found that NM has the potential to inhibit cancer progression, including HCC [725]. NM attenuates the acute decrease in blood pressure after reperfusion that frequently occurs during liver transplantation [726]. NM did not have an effect in reducing blood loss/bleeding but did suppress coagulation activity, as indicated by a reduced plasma levels of thrombin-antithrombin III complex and fibrinopeptide in liver surgery [727]. The is relevant since the level of thrombin-antithrombin comples and fibrinogen are higher in COVID19 patients than healthy controls and also higher in patients with thrombotic disease (who had higher case-fatality) than without thrombotic disease [728].

Nitazoxanide (NTZ)
Positive: Chronic HCV treated with NTZ and peginterferon, with or without NTZ, showed normalization of their ALT level as did the patients treated with standard care (peginterferon alfa-2a and ribavirin). NTZ was associated with fewer relapses as opposed to standard care [731]. A case study suggests a potential role of this drug for treating HBV [732].
Negative: NTZ was found to increase ALT, AST, and alkaline phosphatase (ALP) levels in rats but these elevation decreased gradually with time [598].
Mixed: Exogenous NO plays a dual role in glycochenodeoxycholate-induced hepatocellular apoptosis. It can be anti-apoptotic at specific/limited concentration range and inhibited proliferative at high concentration, which may reflect the pathological role of iNOS/NO [735,736].

Remdesivir (RDV)
Positive: RDV attenuated metabolic syndrome in HFD-induced NAFLD in mice. Liver weight, hepatic dysfunction and lipid accumulation was significantly reduced with RDV treatment. RDV supplementation suppressed the systemic and hepatic inflammation, reducing inflammatory cytokines and NF-κB activation. RDV reduced HFD-induced stimulator of interferon genes (STING) and its downstream factor IRF3 in livers of mice [737]. A liver transplant patient treated with RDV did not require ICU admission and was discharged after 5 days [738].
Negative: There is evidence that RDV increases ALT/AST levels indicating liver injury. There have been reports of elevated liver enzymes in COVID-19 patients treated with RDV. However the adverse effect did not progress to severe liver damage or liver failure in these patients whom did not have prior chronic liver disease [739]. RDV is not water soluble, so SBECD is used as a carrier. SBECD is associated with elevated transaminases, and accumulation of SBECD is associated with liver necrosis in animal studies [602]. In a study where RDV was used to treat COVID-19, one of the most common adverse events was increased hepatic enzymes [287].

Ruxolitinib (RUX)
Positive: A case study found RUX improved bilirubin levels in a patient with diagnosed primary MF and suspected of liver failure [740].

Mixed:
In some RA patients, sarilumab is associated with elevated levels of liver enzymes (ALT and AST) as well as total cholesterol, LDL, and HDL [741]. Despite the frequent elevations in liver tests, sarilumab has not been linked to instances of clinically apparent liver injury and most aminotransferase elevations were self-limited and without symptoms [742].

Sirolimus (Rapamycin)
Positive: Sirolimus reduced polycystic liver volume compared to treatment with tacrolimus in patients with autosomal dominant polycystic kidney disease by inhibiting mTOR in epithelial cells lining the liver cysts [743].
Mixed: Sirolimus has been associated with hepatotoxicity. It could have negative effects in liver transplant patients but in a prospective analysis it could be helpful in HCC [744].

Sofosbuvir
Negative: Case study of patients with hepatitis C cirrhosis developed severe DILI with administration of sofosbuvir and ribavirin [745].

Statins
Positive: In-hospital use of statins or statins plus ACE inhibitors or ARBs did not increase the risk of liver injury of COVID-19 patients [315].
Negative: Has well-researched lipid-lowering properties. Statins are associated with a very low risk of serious liver injury, although asymptomatic and transient elevation of aminotransferases have been observed [746]. It has been associated with cases of drug-induced liver injury [747].

Stavudine
Negative: According to the WHO database, stavudine is one of the five most common drugs associated with fatalities [748]. Stavudine was associated with hyperlactatemia [749], lactic acidosis [750], hepatic steatosis [751,752], hepatotoxicity [618] and acute liver failure [753] in HIV patients. In primary rat hepatocytes, stavudine impaired fatty acid (palmitate) oxidation and at very high doses led to cell death [754], and could lead to steatosis, and in the worst case liver failure [755].

Tenofovir
Positive: In a mouse study of CCl 4 -induced liver fibrosis tenofovir treatment reduced liver fibrosis in this model [756]. TAF and TDF attenuated liver fibrosis and inflammation by downregulating the TGFβ1/Smad3 and NF-κB/NLRP3 signaling in the CCl 4 -induced liver fibrosis mouse model [757].
Negative: In a patient with HBV infection, TAF [758] and TDF were found to induce liver failure or severe liver injury.

Tetrandrine (TET)
Positive: TET inhibited human HCC metastasis in vitro by inhibiting EMT; it also inhibited metastasis to the lung in mice [759]. TET has anti-cancer potential towards several cancers, including liver [760]. TET attenuates LPS-D-galactosamine-induced liver injury in mice [761].
Negative: TET is a Chinese plant-derived alkaloid, and is an urate-lowering drug used to treat hyperuricemia. It could lead to decline in survival rate of L-02 (hepatic) cell line, increase the activities of AST, ALT, lactate dehydrogenase (LDH) and ALP [762]. Maximum dose exposure to TET caused elevations in ALT, AST, GGT, and LDH in mice [763].

Thalidomide (THD)
Positive: A patient with liver cirrhosis and advanced HCC went into remission with low dose THD therapy [764]. Used to treat endotoxin-induced liver injury and mortality in rats. By preventing the increase in [Ca 2+ ] i due to LPS, THD reduces the production of TNF-α by Kupffer cells. THD prevented LPSinduced mortality and liver injury [765].
Negative: There have been case reports indicating that THD could cause hepatotoxicity [766]. THD treatment of a patient with end-stage plasma cell leukemia developed hepatotoxicity [767].
In a study of a multiple myeloma patient treated with DEX and THD developed acute liver injury [768]. Other studies of multiple myeloma patients found that treatment of one patient with THD developed fatal fulminant hepatic failure (FHF) [769], while THD treatment induced hepatitis in another [770].

Tocilizumab (TCZ)
Positive: Although, mean value elevations of liver functional tests (AST, ALT and total bilirubin) in RA patients with inadequate response to methotrexate were observed in the TCZ group as well as in the control group, they were within normal range. These abnormalities were clinically not significant and no hepatitis was observed. Therefore, TCZ monotherapy appears to be tolerable in terms of liver function [771]. COVID-19 patients with elevated liver enzymes, IL-6 levels, and impaired lung function did not improve after HCQ, AZM and LPV/RTV treatment, were treated with TCZ, which improved their clinical condition and normalized their liver function within 3 weeks of treatment [772]. In a case report, TCZ had a positive outcome in a liver transplant recipient on hemodialysis with COVID-19 [773].
Negative: TCZ is associated with elevated ALT levels in RA patients [127,774,775]. There has been an instance of acute liver injury associated with TCZ [776]. A case report of a RA patient who was refractory to standard therapies was treated with TCZ and had normal liver enzyme levels but developed hepatosplenomegaly as a symptom [653]. A patient with COVID-19 treated with TCZ developed acute hypertriglyceridaemia [777].

Umifenovir (Arbidol)
Negative: A retrospective observational study of COVID-19 patients indicates that combined treatment of LPV/RTV and arbidol were risk factors for liver injury in non-critically ill patients. It is thought that the inhibiting metabolism of arbidol by LPV/RTV could contribute to drug-related liver injury [778].

Valganciclovir/ Ganciclovir
Positive: Used to treat adenovirus infection. Ganciclovir and valganciclovir inhibit Ad5 replication in hamster livers. It has efficacy both prophylactically and therapeutically. It inhibits Ad5 DNA synthesis possibly through inhibition of the adenoviral DNA polymerase [779,780].
Negative: In a case study, ganciclovir was associated with acute liver injury in a lupus patient [781].

Zidovudine (AZT)
Negative: AZT treatment of HIV patients was associated with hepatic failure [646]. Long-term monotherapy with AZT is known to cause hepatotoxicity [782]leading to death [783]. AZT causes mitochondrial DNA depletion through inhibition of thymidine salvage [784].

Drugs Neurological Effects
Abacavir Positive: In children with HIV, abacavir was able to reduce viral and pro-inflammatory marker concentrations in CSF, as well as improving the neuropsychological outcome of children under 6. [785] Negative: In 6 separate case studies, abacavir caused psychiatric effects severe enough to discontinue treatment. These effects appeared within one month of beginning treatment and resolved after treatment was stopped. [786] Abacavir may be linked to increased stroke risk, although this is somewhat controversial as studies both indicate it does [787] and does not [788] increase stroke risk.

Anakinra
Positive: Anakinra acts as an anti-inflammatory drug to reduce cytokine concentration in the brain in patients with various conditions (traumatic brain injury (TBI), stroke, and subarachnoid hemorrhage). [789] In addition to the primary anti-inflammatory function, anakinra has been shown to reduce the frequency of seizures in several patients with intractable seizures. [790] In patients with epileptic encephalopathy, anakinra reduced seizure recurrence in both the acute and chronic phases of the disease. This effect was due primarily to reduction of inflammatory factors within the brain. [791] APN01 (rhACE2) Positive: rhACE2's impact on the cardiovascular system may also extend to the nervous system, helping to prevent stroke in patients with COVID-19. [792] Neutral: In a clinical study of healthy patients, no severe adverse effects, neurological or otherwise, were seen after administering rhACE2 daily for one week. 6 patients reported headaches, but not severe enough to discontinue treatment. [793] Note: these sources referenced rhACE2, not APN01 specifically.
Ascorbic Acid (AA) Positive: In diabetic rats, AA showed neuroprotective effects after ischemic injury. Since AA is lower in diabetic tissues, this may be more helpful for diabetic patients, since a normal level of AA may be sufficient to give this same effect. The improvement following AA administration was attributed to reduction of oxidative stress, which is made worse by diabetes. [794] In rats with epilepsy induced by penicillin, AA reduced frequency and amplitude of epileptic activity. An experiment in rats suggests that AA required the endothelial-NOS/nitric oxide pathway to achieve this anti-seizure effect. [795] Azithromycin (AZM) Positive: In humans with cystic fibrosis, AZM activates anti-inflammatory macrophages following spinal cord injury. AZM also lowered neurotoxic potential of M1 macrophages. [796] Negative: Negative neurological side effects of AZM seem to be relatively uncommon, most reports are case studies rather than large cohort studies. However, the side effects can be severe. One patient showed agitation and choreoathetoid upper body movements after two separate administrations of AZM. Other case studies discussed toxic catatonia, myasthenic crisis, hearing loss, and loss of taste. [797] Baloxavir Neutral: No effects on the CNS were detected in animal models, even at levels higher than the recommended dose in humans. [798] Positive: In patients with various interferonopathies (CANDLE, SAVI, and others), baricitinib improved clinical symptoms and reduced serum levels of inflammatory markers, including chemokines. This effect is achieved by inhibition of JAK1/2 signaling pathways. [799] In a mouse model of HIV, the drug reversed cognitive deficits and decreased levels of proinflammatory markers and macrophages in the brain. [800] Brincidofovir/ Cidofovir Positive: For short-term (3 week) use in treating smallpox, brincidofovir was well tolerated, with no severe neurologic adverse effects reported -the most common were GI complaints, and the majority of all adverse effects were classified as mild. [801] In HIV+ progressive multifocal leukoencephalopathy patients, cidofovir did not have an effect on mortality or residual disability. In vitro, brincidofovir is able to inhibit viral replication in human brain derived cell lines, but this benefit has not been observed in a clinical trial. [802] Has led to neurological stabilization in idiopathic CD4 lymphocytopenia. [803] Camostat Mesylate (CM) Positive: In rats, CM prevented pancreatic pain induced by increased spinal Fos protein expression. A potential role in anti-inflammatory action in the spinal cord was also identified, also through inhibition of Fos expression. [804] Since CM is able to penetrate into the CNS, it is possible that its activity of preventing viral entry into target cells may extend into the CNS as well as being demonstrated in other cell lines. [264] Chloroquine (CQ) Positive: In rats, CQ was found to be neuroprotective following TBI, reducing neuronal autophagy and cytokine expression. [805] CQ and HCQ are effective for controlling neurological sarcoidosis. [806] Negative: A 2020 review of the FDA's Adverse Event reporting system found that 12% of 4336 cases with exposure to CQ reported psychiatric adverse effects including amnesia, delirium, hallucinations, depression, and loss of consciousness. The diseases present in these cases were not specified. [807] Colchicine Positive: Colchicine can reduce stroke risk in patients with a history of coronary artery disease at low doses. [808] In a TBI model with rats, colchicine increased neuronal survival over a 2-week period. This, in addition to the early neuroprotective effect, is suspected to be related to interaction with the iNOS pathway. [809] Negative: When plasma levels are elevated above the given dose (due to altered renal function or other causes), colchicine can lead to myopathies, usually weakness, and axonal polyneuropathy. The myopathy usually resolved 3-4 weeks after the drug was stopped, while the neuropathy resolved more slowly. [810] A patient on colchicine for 6 years developed colchicine myoneuropathy which improved upon discontinuation of the drug. [811] Since colchicine can affect the absorption of vitamin B12, colchicine neuropathy may be due to vitamin B12 deficiency. [812] Corticosteroids Positive: Corticosteroids act as an anti-inflammatory and immunosuppressant agent, which can help to combat the inflammation in the brain caused by COVID-19. Glucocorticoids have been successfully used to treat encephalopathy caused by SARS in 5 patients in a hospital in Geneva. [813] Negative: Continued high-dose use can lead to psychiatric side effects, including depression, mania, and psychosis (approximately 20% of patients). Usually these symptoms resolve after treatment is discontinued. [814] Dexamethasone (DEX) Positive: In rats, DEX prevents osmotic demyelination induced after rapid correction of hyponatremia. This effect could be due to DEX preventing BBB disruption. [815] Treatment of tuberculosis infected human microglial cell culture with DEX reduced proinflammatory cytokine and chemokine concentration. [816] Negative: In a clinical study of cerebral malaria, DEX was found to prolong recovery times and increase secondary adverse effects. Complications in DEX-treated patients included a longer comatose state, as well as non-neurological effects like pneumonia. [817] Male infants treated with DEX for prevention of chronic lung disease had a higher incidence of neuromotor dysfunction than the control group. [818] Disulfiram (DS) Negative: Several sources indicate that DS can cause neuropathies in patients if used in high doses or for long periods of time. While the long period of time may not be an issue for COVID treatment, this is still something to consider. The symptoms do resolve after treatment is discontinued. [819] The rate of occurrence of negative neurological effects increases with the duration of DS treatment. DS can decrease clearance of oxidatively metabolized drugs and increases the effect of both caffeine and alcohol. [820] Dociparstat Sodium (DSTAT, aka ODSH)

Positive:
In rats, ODSH acted as an anti-inflammatory without increasing the risk of hemorrhage following ischemic brain injury. This reduced damage from reperfusion injury common after ischemic stroke. [821] After TBI in mice, ODSH reduced leukocyte accumulation in the brain, decreasing inflammatory effects. It also improved acute neurologic recovery as indicated by performance on water maze tests. [822] CXCL12 affects communication between the immune system and the brain, allowing for coordination of activity, but resulting in an increased inflammatory response to mechanisms that target CXCR4. DSTAT inhibition of CXCL12 can help to reduce inflammation by this mechanism. [32] Emtricitabine Negative: When combined with tenofovir and raltegravir (a somewhat common combination for HIV treatment), emtricitabine inhibits neural progenitor cell proliferation in the mouse dentate gyrus. This leads to difficulty repairing damage caused either by treatments or by a disease. [823] Emtricitabine has little mitochondrial toxicity or neurological effect but did have a higher rate of headache occurrence than lamivudine. [824] Note: hard to find much clinically on emtricitabine alone, as it is so often used as one part of combination therapy for HIV/AIDS.

Entecavir (EVT)
Negative: While uncommon, neuropathy is a potential side effect of EVT if given for long periods of time, at high dosages, or to hepatitis B patients with other risk factors for neuropathies. [825] Epoprostenol (EPO, synthetic equivalent of prostacyclin) Positive: PG12 (aka EPO) reduced vasospasm induced by subarachnoid hemorrhage in a clinical study. The study suggests that low doses of PG12 could be a means of reducing cerebral vasospasms which do not respond to other means of treatment. [826] PG12 increased oligodendrocyte precursor cell migration to the site of spinal cord injury, aiding in remyelination and repair of the injury site. [827] Famotidine Positive: Famotidine improved the condition of schizophrenic patients when administered in conjunction with their existing medications. [828] In case studies of non-hospitalized COVID-19 patients, high-dose oral famotidine improved diseaserelated neurologic symptoms, including headaches and anosmia. [829] Negative: Case study: woman treated with famotidine developed mania and seizures after administration. Manic symptoms continued for 3 months after discontinuation, requiring treatment with other psychiatric medications. While this was a singular case, this could potentially be an important adverse effect. [830] In some patients, renal failure caused CSF levels of famotidine to be elevated above what was expected given the dose. These patients were observed to have mental deterioration and convulsions, suggesting that the adverse effects may be linked to unexpectedly high concentrations of famotidine within the CNS. [831] In a mouse model, famotidine reduced the anticonvulsant function of antiepileptic drugs. [832] Favipiravir Positive: In treating rabies in mice, a very high dose (2-3X standard dosage) is required to achieve penetration into the central nervous system (CNS). At these high doses however, Favipiravir was successful in reducing viral replication within the CNS. Unless a high dose is given, Favipiravir will not have significant effects on the CNS due to low penetration. [833] Favipiravir patients recovered more quickly from fever than lopinavir/ritonavir patients, and did not display significantly higher rates of adverse effects. [834] In COVID-19 patients, Favipiravir showed only mild psychiatric effects, and had similar 7-day recovery rates (61% of patients) to umifenovir. Favipiravir had shortened latency to relief from cough and pyrexia compared to umifenovir. [218] Hydroxy Chloroquine (HCQ) Positive: In cell culture of human microglia, HCQ treatment administered before LPS activation reduced production of both pro-and anti-inflammatory cytokines. It also reduced demyelination in the spinal cord of mice. [835] A review of WHO's database showed a very low incidence of psychiatric and neurological side effects (<1%, except headaches which was 2.8%). [836] Negative: HCQ and CQ interact with lysosome activities which may contribute to retinopathy. [837] Increased risk of retinopathy was observed with high dose and long-term (5+ years) use of HCQ. [838] IC14 Positive: In humans, IC14 administration reduced LPS induced TNF and IL-10 levels. It also reduced the occurrence of symptoms including headache, fever, and vomiting. It significantly inhibited proinflammatory cytokine release that was induced by LPS injection. [226] Idelalisib Neutral: This study says that idelalisib and other PI3K inhibitors have low neurologic toxicity because they are unable to cross the BBB in a healthy animal model. [839] Negative: One case study in a patient with Hodgkin's lymphoma found idelalisib to induce polyradiculopathy (demyelination that led to difficulty with movement and neuropathic pain), however this toxicity is unusual. [840] IFN-α Negative: Leukemia patients treated with IFN-α for an average of 26 months exhibited a variety of cognitive deficits, including verbal memory, speed of visual scanning and sequencing, and executive function. These deficits were more severe in the IFN treatment group compared to patients with leukemia who had not received IFN treatment. [841] IFN-α treatment of 31 patients with HCV increased glutamate concentration in the dorsal anterior cingulate cortex and the basal ganglia, consistent with what is observed in bipolar depression. Depressive symptoms were observed in patients treated with IFN-α. [842] IFN treatment in cancer patients is associated with cognitive deficits and mood disorders. Risk factors include treatment duration of more than 2-3 months and high dose, as well as a history of neurologic or psychiatric illness. It is possible to alleviate these effects by using other pharmacologic treatments, including antidepressants, psychostimulants, and opioid agonists, simultaneously. [843] Ivermectin Negative: While negative neurological effects only occur in a small number of people, when they do occur they are severe: coma and death. There is limited data on these cases and most of them occurred in rural Cameroon. These side effects are believed to be associated with elevated levels of Loa loa microfilariae (Mf). Microfilariae death in CNS tissue was also observed. [844] Based on molecular studies, ivermectin use combined with the hyperinflammatory state induced by COVID-19 may cause interaction with GABA gated chlorine channels leading to neurotoxicity. [713] Serious adverse neurological events can occur when Ivermectin is used to treat Onchocerciasis volvulus. While the mechanism of these effects was thought to be due to Loa loa coinfections, a review of VigiBase adverse event reports suggests that while serious adverse effects of Ivermectin are rare, they can occur in the treatment of any disease. [845] Leronlimab (PRO 140) Limited Information: Not many studies focused on the CNS exclusively. The drug reduced plasma levels of IL-6 and decreased the amount of SARS-CoV-2 virus in 10 severely ill COVID patients.
There are studies currently ongoing, with no results published as of yet. These preliminary results however do indicate that leronlimab may have an anti-inflammatory effect that could be useful in combating neurological impacts of COVID. [246] Lopinavir/ Ritonavir (LPV/RTV) Negative: LPV/RTV has been shown to induce serotonin syndrome, which is a potentially lifethreatening condition [846], in some HIV patients [847], and more recently the first two cases of serotonin syndrome in COVID19 patients receiving this treatment was reported. This is mainly due to coadministration of other substances that increase serotonin levels, since RTV only reduces elimination rate, which on its own is usually not enough to induce serotonin syndrome. [848] LPV causes oxidative stress in neurons in vitro, triggering the endogenous antioxidant response. It also caused a 54% loss of MAP2, which is a measure of neuronal health and function. [849] Methyl Prednisolone (MP) Positive: High dose MP reduced the expression of adhesion molecules on cerebral epithelial cells, decreasing the amount of MNC migration into the CNS. [850] MP is effective in treating spinal cord injury by reducing edema and protecting cells against peroxidation. [851] Nafamostat (NM) Positive: NM shows neuroprotective effects in patients with neurovascular ischemia, reducing neuronal cell death (necrosis and apoptosis) and preventing changes to the BBB. Potential effects include reducing cerebral edema, BBB disruption, and inflammatory cytokines (IL-1B, TNF-a); increasing anti-inflammatory cytokines (IL-4,IL-10,TGF-β), p53 and RELB. [725] In a rodent model, NM improved functional recovery following stroke by inhibiting neuroinflammation. NM both decreased expression of proinflammatory molecules and increased expression of anti-inflammatory molecules at different timepoints throughout recovery. [66] NM was found to prevent infection with Middle East coronavirus infection. Potential neurologic side effects may include headaches and easy bleeding in the brain. [852] Niclosamide Positive: It reversed mechanical hyperalgesia (hypersensitivity to pain) in a rat model of neuropathic pain. [853] Nasal and pulmonary delivery of niclosamide (via particles of human lysozyme as a carrier molecule) was found to reduce viral load in the brain of hACE2 transgenic mice infected intranasally with SARS-CoV-2. [854] Nitazoxanide (NTZ) Positive: In patients with hepatic encephalopathy (a neurological disorder caused by liver dysfunction), NTZ induced clinical improvement. [855] In equine protozoal myeloencephalitis, NTZ is considered to be an effective treatment, supporting its ability to combat encephalopathies. [856] Negative: In a clinical trial, 4.8% of patients treated with NTZ for B hominis infection reported headaches. The side effect was not severe enough to discontinue treatment. [857] Nitric Oxide (NO) Negative: In cerebral ischemia, NO can contribute to neuronal death. NO reaction with O forms reactive intermediates which can then react with proteins, DNA, and other compounds within the cell. The endogenous mechanisms for preventing NO toxicity, but at high NO concentrations these mechanisms are overwhelmed and neurotoxic effects are observed. [858] Remdesivir (RDV) Neutral: In COVID-19 patients, no significant negative neurological effects were reported with RDV. [859] Does not appear to have significant effects on the CNS either positive or negative. [860] Ruxolitinib (RUX) Positive: In human cell lines, RUX inhibited HIV replication in macrophages, and reduced HIV activation of monocytes and macrophages. In a mouse model with HIV encephalitis, the drug was detected within the brain and reduced astrogliosis. [861] Sarilumab Positive: When used long-term (5 years) in RA patients, sarilumab exhibited no severe neurological adverse effects. [862] In RA patients who switched from adalimumab to sarilumab, improvement in symptoms, including neurologic pain, was reported with no severe adverse neurological effects. [863] Sirolimus (Rapamycin) Positive: In mice with tuberous sclerosis complex, rapamycin prevented development of epilepsy if administered early enough, and if administered after the onset of epilepsy the drug suppressed seizures and increased survival time. [864] In various CNS tumors, human case studies and early clinical trials have suggested that rapamycin may help to inhibit abnormal growth through mTOR inhibition. Animal models have also suggested a correlation between rapamycin and reduced learning and behavioral deficits but did not conclusively confirm that the deficits are due to rapamycin alone, and the human subjects didn't undergo neuropsychiatric evaluation. In the human subjects, no significant neurological adverse effects were noted. [865] Sofosbuvir Positive: A study suggests that sofosbuvir protects against SARS-CoV-2 infection in human brain organoids. [866] Negative: Case study shows sofosbuvir induced syncope in two HCV patients. The study suggests that this may be indicative of other autonomic nervous system disturbances by Sofosbuvir, which should be investigated further. [867] Headaches and fatigue appear as common adverse effects of sofosbuvir treatments. Headaches can be severe enough to cause poor adherence to treatment plans, causing issues with effectiveness. [868] Statins Positive: Simvastatin and lovastatin reduce migration of MS derived monocytes and lymphocytes across the blood brain barrier (BBB). In vitro, the mechanism involved alteration of the isoprenylation processes of BBB epithelial cells. Specifically, the statins reduced secretion of CCL2 and CXCL10 chemokines by the human BBB cells. [869] Stavudine Positive: In a trial with HIV patients, stavudine used with lamivudine reduced viral RNA count in the cerebrospinal fluid (CSF), indicating that it is effective in combating HIV infection within the CNS. This combination was found to be equally as effective as zidovudine plus lamivudine. [870] Negative: Stavudine was found to reduce N-acetylaspartate (a marker of mitochondrial function) in the frontal lobe of HIV patients. Stavudine has a mitochondrial toxicity in the brain which worsens the longer the drug is administered. [871] Peripheral neuropathies were observed in 20% of HIV patients treated with stavudine. Patients who were on stavudine for longer than two years had a 30% rate of occurrence, suggesting that the likelihood of peripheral neuropathy increases with duration of treatment. [872] Stavudine in combination with didanosine and efavirenz had a higher rate of occurrence of neuropathy and paresthesia than emtricitabine in the same combination. [199] Tenofovir Neutral: Considered to have low penetration of the CNS (compared to other antiretroviral drugs). [873] This study further supports the low penetration of tenofovir into the CNS; tenofovir is thus unlikely to directly cause negative (or positive) effects on the CNS. From the results of three large clinical trials, the most common neuropsychiatric adverse effects were headaches and depression. [874] Negative: In patients with HIV who had never previously received antiviral therapy (ART), tenofovir induced sensory neuropathy (including symptomatic and asymptomatic) in 17% of patients. [875] Headache and fatigue were among the most commonly reported adverse effects associated with tenofovir treatment in chronic hepatitis B. The effects were mild and did not require discontinuation of treatment. [876] Tetrandrine (TET) Positive: In a mouse model of cerebral ischemia, TET inhibited the NLRP3 inflammasome via upregulation of Sirtuin-1. TET reduced neurological deficits and cerebral water volume, providing an overall anti-inflammatory effect. [877] Negative: At high concentrations, TET can become cytotoxic. In mouse neuroblastoma cells, 10uM of TET induced apoptosis through oxidative stress. Pretreatment with antioxidants was effective in preventing TET induced apoptosis. Appropriate levels of TET in the brain must be maintained for successful treatment, as its effects on cellular redox activity can become harmful at high concentrations. [878] Thalidomide (THD) Negative: When used to treat dermatologic disorders (prurigo nodularis and aphthous stomatitis), long-term use led to peripheral neuropathy. Only short-term use is recommended due to neurotoxic effects. [879] In lupus patients, THD induced neuropathies are potentially irreversible, even after discontinuing treatment. [880] Neuropathies caused by THD become an issue in long-term, but short-term use hasn't been linked to these same effects. Neuropathies appeared 10 months after starting treatment in the majority of patients. [881] Doses of THD greater than 150 mg per day increases the likelihood of peripheral neuropathy. 39% of all patients in the study treated with THD experienced peripheral neuropathy. [882] Long-term treatment (>1 year) using THD for patients with multiple myeloma has been shown to cause neurotoxicity. [883] In a case study, a woman being treated with THD for multiple myeloma developed encephalopathy as a result of fatal hepatic failure. [769] Tocilizumab (TCZ) Positive: In a case study of two patients with epilepsy, TCZ was effective in reducing seizures. The most likely mechanism proposed is by blocking binding of IL-6, a pro-inflammatory marker that may be involved in refractory epilepsy. [884] TCZ inhibits the transcription of many different cytokines, including IL-1 and IL-6, and chemokines which are upregulated in amyotrophic lateral sclerosis (ALS). TCZ also decreased secretion of IL-1β, IL-6, and TNFα. Essentially, TCZ has anti-inflammatory action in the CNS. [885] Has been used successfully to treat T-cell mediated CRS. [886] In an observational study of patients with RA, TCZ caused a clinically significant reduction in symptoms of fatigue, pain, and depression. [887] Neutral: In a clinical study of 27 COVID patients, only 3 showed neurological adverse effects, which may not necessarily be due to the drug but rather COVID itself. This was a small study without a control group. [888] Negative: A case report found that TCZ contributed to an acute-onset of cerebral multifocal microangiopathy in a RA patient. [889] Umifenovir (Arbidol) Positive: Clinically severe psychiatric adverse effects were observed only in one patient (0.83%) taking umifenovir in a clinical trial on COVID-19 patients comparing umifenovir with favipiravir. Dizziness occurred in five (4.17%) patients. No other neurological effects were reported. This study did not have a placebo control group. [218] Umifenovir has in vitro activity (in Vero cells) against the virus that causes tick borne encephalitis. In vivo results were not obtained. [890] Valganciclovir/ Ganciclovir Positive: Can be used to treat CNS CMV infections, as the drug can penetrate into the CNS. However, CSF concentrations only reach 15% of plasma levels, so high dosages may be required. Neurologic adverse effects are rare. [891] Negative: Headache, insomnia, and peripheral neuropathy are among the most commonly reported adverse effects during maintenance therapy of CMV with Valganciclovir. These adverse effects generally weren't severe enough to discontinue treatment. [892] Zidovudine (AZT) Positive: AZT is effective in reducing viral RNA concentrations within the CSF of HIV patients. [870] AZT has been shown to help reduce neurological symptoms of HIV/AIDS patients. It has improved outcomes for children with progressive encephalopathy caused by HIV, as well as reducing HIVrelated changes to brain tissue as observed at autopsy. [893] Negative: Adverse neurological effects of AZT are rare but can be serious, including seizures, dosereduction encephalopathy, and myopathy. The likelihood of these adverse effects occurring increases the longer the drug is administered. [354] 23.