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No Time to Waste: Real-world Repurposing of Generic Drugs as a Multifaceted Strategy against COVID-19

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  • Drug Rediscovery Group Ltd

Abstract and Figures

UNSTRUCTURED Real-world drug repurposing – the immediate ‘off-label’ prescribing of drugs to address urgent clinical need – is an indispensible strategy gaining rapid traction in the current COVID-19 crisis. Although off-label prescribing (i.e. for a non-approved indication) is legal in most countries, it tends to shift the burden of liability or cost to physicians and patients, respectively. Nevertheless, in urgent public health crises it is often the only realistic source of meaningful potential solutions. To be considered for real-world repurposing, drug candidates should ideally have a track record of safety, affordability, and wide accessibility. Although thousands of such drugs are already available, the absence of a central repository of off-label uses presents a barrier to the immediate identification and selection of the safest potentially useful interventions. Using the current COVID-19 pandemic as an example, we provide a glimpse of the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and pleiotropically target the underlying pathophysiology that makes COVID-19 so dangerous. Having previously fast-tracked this paper to publication in summary form, we now expand on why cimetidine or famotidine, dipyridamole, fenofibrate or bezafibrate, and sildenafil, are worth considering for patients with COVID-19. These examples also reveal the unlimited opportunity to future-proof our health by proactively mining, synthesizing, and cataloging the off-label treatment opportunities of thousands of safe, well established, and affordable generic drugs.
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No Time to Waste:Real-World Repurposing of Generic Drugs as
a Multifaceted Strategy Against COVID-19
Moshe Rogosnitzky1; Esther Berkowitz1, MBChB, MA; Alejandro R Jadad2, MD, DPhil, FRCPC, FCAHS, FRSA,
LLD
1Medinsight Research Institute, Rehovot, Israel
2Program in Impactful Giving, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
Corresponding Author:
Moshe Rogosnitzky
Medinsight Research Institute
Pekeris 4
Weizmann Science Park
Rehovot, 7670204
Israel
Phone: 972 522945520
Email: moshe@medinsight.org
Related Articles:
Peer-Review Report by Ahmed Abdeen Hamed (Reviewer E) https://med.jmirx.org/2020/1/e24453/
Peer-Review Report by Susan Howlett (Reviewer F) https://med.jmirx.org/2020/1/e24481/
Author Responses to Peer-Review Reports https://med.jmirx.org/2020/1/e24485/
Abstract
Real-world drug repurposing—the immediate “off-label” prescribing of drugs to address urgent clinical needs—is an indispensable
strategy gaining rapid traction in the current COVID-19 crisis. Although off-label prescribing (ie, for a nonapproved indication)
is legal in most countries, it tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless,
in urgent public health crises, it is often the only realistic source of a meaningful potential solution. To be considered for real-world
repurposing, drug candidates should ideally have a track record of safety, affordability, and wide accessibility. Although thousands
of such drugs are already available, the absence of a central repository of off-label uses presents a barrier to the immediate
identification and selection of the safest, potentially useful interventions. Using the current COVID-19 pandemic as an example,
we provide a glimpse at the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which
are affordable, supported by decades of safety data, and pleiotropically target the underlying pathophysiology that makes COVID-19
so dangerous. Having previously fast-tracked this paper to publication in summary form, we now expand on why
cimetidine/famotidine (histamine type-2 receptor antagonists), dipyridamole (antiplatelet agent), fenofibrate/bezafibrate
(cholesterol/triglyceride-lowering agents), and sildenafil (phosphodiesterase-5 inhibitor) are worth considering for patients with
COVID-19 based on their antiviral, anti-inflammatory, renoprotective, cardioprotective, and anticoagulation properties. These
examples also reveal the unlimited opportunity to future-proof public health by proactively mining, synthesizing, and cataloging
the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs.
(JMIRx Med 2020;1(1):e19583) doi: 10.2196/19583
KEYWORDS
COVID-19; drug repurposing; fibrates; histamine type-2 receptor antagonists; cimetidine; famotidine; fenofibrate; bezafibrate;
dipyridamole; sildenafil
Introduction
Since the first report of a viral pneumonia of unknown cause
in Wuhan, China, in December 2019, followed by the
identification of the virus SARS-CoV-2 and the designation of
the disease it causes as COVID-19, we have witnessed the rapid
development of a pandemic that has become a global public
health crisis. Although reported mortality rates are between
<1% and 27% depending on factors including age, gender,
health status, and geographic location, this is likely an
underestimation due to underreporting and limited serological
testing [1]. With no approved preventive or therapeutic
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treatments available, the scale and human impact of the
COVID-19 outbreak is daunting.
In this paper, we present candidates for a multifaceted approach
to the management of COVID-19, based on repurposing tried
and tested, affordable, widely available drugs with proven
long-term safety, and mechanisms of action that address the
underlying pathophysiology of the disease. Having recently
published a short summary of our thesis [2], the current paper
expands on why cimetidine or famotidine (histamine type-2
receptor antagonists), dipyridamole (antiplatelet agent),
fenofibrate or bezafibrate (cholesterol/triglycerides-lowering
agents), and sildenafil (phosphodiesterase-5 inhibitor) are worth
considering for patients with COVID-19. The goal is to enable
the rapid introduction of potentially beneficial, low-risk
interventions. We also emphasize the urgency of redoubling
efforts to mine, synthesize, and catalog the considerable existing
body of evidence for promising treatments, in order to
future-proof public health, based on robust science.
Pathophysiology of COVID-19
COVID-19 is characterized by prominent early respiratory signs
and symptoms, including fever, cough, fatigue, and shortness
of breath, that may deteriorate to acute respiratory distress
syndrome (ARDS), coagulopathy, multiorgan failure, and other
life-threatening sequelae (Table 1) [3,4]. On lung imaging,
consolidation, ground glass opacity, and pulmonary infiltration
are evident [3].
Table 1. Common clinical findings, complications, and laboratory abnormalities in patients with laboratory-confirmed COVID-19. CRP: C-reactive
protein.
Prevalence (%)System and clinical finding
Respiratory [3,4]
79-98Fever
58-79Cough
54Respiratory failure
30Acute respiratory distress syndrome
12-28Sputum production
Cardiovascular [3]
23Cardiac failure
20Septic shock
Multisystem [3,4]
59Sepsis
20-44Fatigue
19Coagulopathy
Laboratory abnormalities [3,4]
67-73Lactate dehydrogenase >245 U/L
70Procalcitonin <0.1 ng/mL
65-70D-dimer >1 μg/mL
40-63Lymphopenia
37Aspartate aminotransferase > 40 U/L
22-25Leucopenia
a
Raised CRP
aNot available.
SARS-CoV-2 has also been isolated from feces, urine, blood,
and ophthalmic secretions [5]; COVID-19 affects
extrapulmonary organs and systems in ways that contribute
significantly to overall morbidity and mortality. In a
retrospective cohort study of 191 hospitalized patients with
COVID-19 in Wuhan, sepsis was reported in 112 (59%) patients
admitted to the hospital, while respiratory failure (54%), ARDS
(31%), heart failure (23%), and septic shock (20%) were
reported in 20% of patients, significantly more frequently
among those who died than in survivors (all P<.001) [3].
Similarly, coagulopathy (19%) and acute cardiac (17%) and
renal (15%) injury were widely observed, with a significantly
higher incidence in nonsurvivors [3]. The fact that underlying
cardiovascular, pulmonary, and renal disease have been
associated with significantly increased mortality in COVID-19
patients and that abnormalities of various plasma inflammatory
biomarkers (eg, lymphocyte count, C-reactive protein (CRP),
procalcitonin, D-dimer, and aspartate aminotransferase) appear
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to be widespread [3,4,6,7] highlights the multisystem nature of
the disease and suggests that immune-mediated cytokine
signaling and development of cytokine storm play a key role in
driving disease progression [7].
Laboratory findings support the diverse effects of SARS-CoV-2,
demonstrating, among other derangements, that leukopenia,
lymphopenia, and thrombocytopenia, as well as elevated lactate
dehydrogenase, CRP, and D-dimer, are significantly associated
with a more severe course of disease [3,4,6,8]. Viral load also
correlates strongly with disease severity (lung injury in
particular) [9], while virus-induced endothelial dysfunction
contributes to acute cardiac events that are a recognized
complication of COVID-19 [10]. Although little attention has
focused specifically on disturbed coagulation, evidence suggests
that COVID-19 leads to profoundly altered coagulation function,
with raised D-dimer, fibrinogen, and fibrin/fibrinogen
degradation products [11,12].
Potential Therapies Within the Current
Pharmacopoeia
Widespread attention has been given to repurposing antimalarial
chloroquine/hydroxychloroquine, the antibiotic azithromycin
and, most recently, the antiparasitic agent ivermectin, for
targeting COVID-19. All three drugs possess both anti-infective
and immune-modulating properties [13-19]. While clinical
evidence supporting their use individually or in combination in
patients with COVID-19 have so far been inconclusive [13-19],
partly due to methodological limitations, or are yet unavailable
[20-22], this multitargeted approach of utilizing the safest drugs
with pleiotropic effects is essential to reduce morbidity and
mortality arising from COVID-19 infection. Indeed, a large
number of approved drugs have mechanisms of action that could
be harnessed to address the pathophysiology of COVID-19.
Ideal choices would be safe and widely available generic drugs
that are affordable in any setting, and especially for
under-resourced populations. Below we summarize the safety
profiles and rationale for repurposing several generic drugs that
have demonstrated antiviral, anti-inflammatory, and/or cardio-,
lung- or renal-protective effects. Some also lower elevated
fibrinogen and D-dimer, which are associated with
hypercoagulability and may contribute to the multiorgan failure
seen in patients with COVID-19. Table 2 summarizes the
physiological effects of these agents as they relate to potential
benefits in patients with COVID-19.
Table 2. Approved indications and recognized physiological effects of drugs that could be considered for repurposing in patients with COVID-19.
NotesDemonstrated ef-
fectsa
Proposed doseCurrent indicationsDrug
GFEDCBA
Symptomatic man-
agement of GERDb
Cimetidine
or famoti-
dine [23-46]
Establish baseline prolactin levels and monitor peri-
odically
Cimetidine 200 mg four
times daily
• •
Famotidine 20-40 mg
twice daily May increase serum concentrations of other drugs
Reduces dipyridamole absorption
Relevant trials: NCT04504240 and NCT04370262
Antithrombotic fol-
lowing cardiac valve
replacement
Dipyri-
damole
[47-79]
May cause headaches during the first week of use75 mg thrice daily OR 50-
100 mg once weekly Taking with foods or antacids halves absorption
Relevant trials: NCT04391179, NCT04424901, and
NCT04410328
DyslipidemiaFenofibrate
or bezafi-
brate [80-97]
Significant reduction in D-dimer and fibrinogen
usually seen in days
Fenofibrate 200 mg/day
Bezafibrate 400 mg daily Relevant trial: NCT04517396
Erectile dysfunctionSildenafil
citrate
[98-112]
Avoid grapefruit juice (increases sildenafil levels)25 mg twice daily, on an
empty stomach Cimetidine/famotidine increases sildenafil concen-
tration. If combined, consider lower sildenafil dose
—even 12.5 mg twice daily
Relevant trials: NCT04304313 and NCT04489446
aDemonstrated effects are: A - preliminary efficacy in COVID-19 patients; B - anti-inflammatory effect; C - antiviral effect; D - anticoagulant effect;
E - cardioprotective effect; F - renoprotective effect; G - lung protective effect.
bGERD: gastroesophageal reflux disease.
Cimetidine and Famotidine
The histamine type-2 receptor antagonists (H2RAs) cimetidine
and famotidine were approved by the US Food and Drug
Administration (FDA) in 1977 and 1986, respectively, and both
have been widely used, for decades, for prevention and
symptomatic management of gastroesophageal reflux disease
(GERD) [23]. Ranitidine, another commonly used H2RA, will
soon be largely unavailable in the United States following an
FDA recall based on high levels of a contaminant. Cimetidine
is approved at daily doses of 200-400 mg for heartburn relief,
and up to 1600 mg for the short-term treatment of erosive
GERD, while famotidine is approved at a dose of 10-20 mg
twice daily (bid) for GERD, and 20-40 mg bid for erosive
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esophagitis [23]. Both drugs are available over the counter in
the United States and much of the world, and are generally well
tolerated, with most adverse events reported in <1% of patients.
Drug-drug interactions that may delay metabolism of other
agents due to interaction with the cytochrome P450 system,
limited antiandrogen effects, and stimulation of prolactin are
recognized in particular with cimetidine. Prolactin levels should
therefore be established at baseline and monitored periodically.
Antiviral and Immunomodulatory Activity
Beyond their role as gastric acid reducers, H2RAs have powerful
modulatory effects on innate and adaptive immunity by
interfering with the effects of histamine on a range of leukocytes.
As such, they reverse histamine-mediated immunosuppression
by stimulating the effector functions of a wide range of T and
B cells [24]. The resulting antiviral effects have been
demonstrated in small studies in patients with herpes simplex
virus (HSV) [25] and herpes zoster infection [26], and with
human papillomavirus–related disorders [27]. In preclinical
studies, cimetidine boosted immune cellular response when
used as an adjuvant to viral vaccines for hepatitis B virus [28-31]
and suppressed HIV replication in vitro [32]. Furthermore,
intravenous ranitidine significantly increased the antibody
response to vaccination in patients receiving tetanus toxoid
before major abdominal surgery [33] and in patients with B-cell
chronic lymphocytic leukemia receiving tetanus
toxoid–conjugated Haemophilus influenzae type b vaccine
[34,35]. Beyond antiviral effects, H2RAs have shown
immunomodulatory effects in a range of cancers and allergic
diseases, bone resorption, and during recovery from burn injury
[24].
Cardiovascular Protective Effects
H2RAs also demonstrate a number of cardioprotective effects.
A meta-analysis of 10 randomized controlled trials in patients
with congestive heart failure, most of whom used famotidine,
showed that orally administered H2RAs were associated with
significant negative inotropic and chronotropic effects (reduction
in heart rate vs placebo; P=.02), and also significantly decreased
blood pressure and increased cardiac efficiency, presumably
reducing myocardial oxygen requirement [36]. In another study,
in critically ill patients, a single intravenous infusion of
cimetidine, 200 mg, reduced systolic, diastolic, and mean arterial
blood pressure, and raised heart rate [37]. High-dose intravenous
cimetidine (200 mg four times daily [qid]) administered after
elective cardiac bypass surgery was also shown to reduce levels
of proinflammatory mediators (neutrophil elastase, interleukin-8,
CRP) with no adverse effects, suggesting the potential to
improve cardiac outcomes under certain physiological conditions
[38].
Furthermore, H2RAs also strongly inhibit platelet aggregation
in vitro [39,40] and ranitidine, in combination with
hydrocortisone, has been shown to reduce complications after
arterial thrombolysis in pediatric patients who developed arterial
obstruction after cardiac catheterization [41]. These agents may
therefore exert stabilizing effects on coagulation in patients with
disturbed clotting function, the caveat being the potential for
thrombocytopenia and/or hemolytic anemia [42-46].
Dipyridamole
The antiplatelet agent and phosphodiesterase inhibitor
dipyridamole was first approved in 1961 and is indicated in the
United States at doses of 75-100 mg qid with warfarin to
decrease thrombotic risk following cardiac valve replacement
[47]. It is also sold in the United States as a combined product,
Aggrenox (aspirin 25 mg/extended-release dipyridamole 200
mg), which was approved in 1999 and is taken twice daily to
reduce stroke risk [48]. Outside the United States, including in
Europe, dipyridamole is available as a single agent; in Russia
it is also approved as an antiviral agent [49]. Within the 200-400
mg daily dose range, dipyridamole is considered safe based on
decades of clinical experience: adverse events are usually limited
and transient, the most common being dizziness, gastrointestinal
disturbance, headache, and skin rash [50]. The pleiotropic effects
of dipyridamole derive from increased intracellular levels of
cyclic adenosine monophosphate (cAMP) and cyclic guanine
monophosphate (cGMP), which lead to anti-inflammatory,
antioxidant, anticoagulation, and vasodilatory effects [51].
Antiviral Effects
Dipyridamole possesses very broad spectrum antiviral activity
as shown in numerous preclinical studies that demonstrated
efficacy, alone or as a potentiator of other agents, against HSV,
HIV, varicella zoster, cytomegalovirus, and mengovirus, as well
as a range of viruses from the picornavirus, togavirus,
orthomyxovirus, paramyxovirus, and pox virus families [52-56].
Induction of interferon responses have been identified as an
important contributory factor to its antiviral effects [57]. A
number of clinical studies have confirmed the antiviral effects
of dipyridamole which, at a dose of 8-100 mg weekly,
significantly reduced the risk of acute respiratory diseases,
including influenza, when administered prophylactically to
at-risk individuals [57-59].
Effects in Patients With COVID-19
A recent study in patients with COVID-19 in China illustrates
that dipyridamole suppressed SARS-CoV-2 replication in vitro,
induced potent antiviral immunity, and improved survival in a
mouse model of pneumonia [60]. In a clinical study of 12
COVID-19 patients that was conducted alongside these
preclinical investigations and reported within the same
publication, dipyridamole increased lymphocyte and platelet
counts, decreased D-dimer levels, and markedly improved
clinical outcomes when dosed at 50 mg three times daily for 1
week. In this small but very promising study, three of the six
patients with severe disease were discharged, and four (33%)
mild cases achieved clinical remission. Data from an ongoing
multicenter study examining dipyridamole in 460 patients with
COVID-19 in China (ChiCTR2000030055) will add to our
understanding [61].
Anti-Inflammatory, Antioxidant, and Endothelial
Protective Effects
A large number of preclinical studies have demonstrated that
dipyridamole limits oxidative stress in platelets and endothelial
cells, inhibits release of proinflammatory cytokines, and reduces
inflammatory responses, independent of its antiplatelet activity
[51,62]. This has implications for a wide range of pathologies
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beyond thrombosis prevention, including reduced brain
endothelial injury after inflammatory and metabolic insult [63].
The combination of dipyridamole with prednisolone has been
shown to lead to significant reductions in interferon-γ,
interleukin-6, and CRP in subjects with periodontitis [64], and
widening of the therapeutic window of glucocorticoid activity
[65]. This is due to the ability of dipyridamole to selectively
potentiate the effects of prednisolone and other glucocorticoids.
Dipyridamole was also shown to increase extracellular levels
of the immune-dampening nucleoside, adenosine, and decrease
CD4+ T cell activation by 11.1% (P=.006) in patients with
chronic HIV infection receiving antiviral therapy [66].
Antihypercoagulation Effects
Hypercoagulability is a potentially life-threatening complication
of certain clinical conditions and a serious risk during
mechanical circulatory support. Besides its well-established
antiplatelet effects, dipyridamole has shown efficacy as one
component of a near-universal anticoagulant when administered
in combination with citrate, theophylline, and adenosine (as
CTAD [citrate-theophylline-adenosine-dipyridamole]) in
veterinary practice [67,68] and in human subjects [69]. When
combined with heparin or aspirin in small numbers of pediatric
patients on circulatory support [70] or with disseminated
intravascular coagulation [71], dipyridamole has led to clinical
recovery in the majority of subjects.
Cardioprotective Effects
Adenosine serves as an endogenous cardioprotective agent.
Disturbances of adenosine in the diseased myocardium include
raised plasma levels and decreased gene expression of certain
receptors in patients with chronic heart failure [72,73] as well
as impaired vasodilation in patients with hyperhomocysteinemia
[74]. By increasing adenosine levels in vivo using dipyridamole
300 mg daily, it was possible to improve numerous functional
measures of disease severity in cases of chronic heart failure
[72,73] and restore adenosine-induced vasodilation in
hyperhomocysteinemic patients [74], highlighting the potential
to augment endogenous cardioprotective mechanisms. The
clinical effects of dipyridamole in mild-to-moderate chronic
heart failure were also revealed in a trial that randomized 28
patients to their usual treatment with or without the addition of
dipyridamole, 75 or 300 mg/day, for 1 year [75].Cardiac
ejection fraction, left ventricular systolic diameter, maximal
oxygen consumption, and plasma B-type natriuretic peptide
level were all significantly improved versus baseline and control
in dipyridamole-treated patients, in a broadly dose-dependent
manner, indicating a role for supplementary dipyridamole in
improving the pathophysiology of chronic heart failure.
Renoprotective Effects
In patients with kidney disease, dipyridamole reduces proteinuria
and improves renal function by inhibiting platelet activation
and enhancing nitric oxide (NO)–induced vasodilation. A
prospective study of >28,000 patients with advanced chronic
kidney disease (CKD) in Taiwan found that dipyridamole
significantly reduced the risk of progression to long-term
dialysis and predialysis death (hazard ratios 0.96 and 0.91,
respectively; both P<.05 versus nonuse) [76]. In another large
Taiwanese study in patients with advanced CKD, dipyridamole
decreased the risk of progression to end-stage renal disease by
approximately 15% and reduced all-cause mortality by 23.5%
(P=.001) [77]. There is also evidence that the vascular
renoprotective effects may benefit patients with immunoglobulin
A nephropathy (when given with warfarin) [78] and protect
against preeclampsia [79].
Fenofibrate and Bezafibrate
The cholesterol-lowering agents fenofibrate and bezafibrate are
indicated for the treatment of dyslipidemias. Fenofibrate is a
peroxisome proliferator–activated receptor-α agonist that was
approved in the United States in 1993 and is used for the
treatment of primary hypertriglyceridemia, mixed dyslipidemia,
and severe hypertriglyceridemia (up to 160 mg once daily) [80].
Abnormal liver tests, elevated liver enzymes and creatine
phosphokinase, and rhinitis are the most frequent adverse events.
Rare instances of myositis or rhabdomyolysis have been
reported, and potentiation of coumarin anticoagulants can cause
bleeding, so a reduced anticoagulant dose is advised [80].
Bezafibrate is currently not approved for use in the United States
but is commonly used in Europe.
Numerous preclinical studies support a role for fenofibrate in
attenuating vascular endothelial dysfunction, oxidative stress,
and inflammation across a range of organs and tissues, with
clinical evidence of cardioprotection and some antiviral effects
[81].
Antiviral Effects
A meta-analysis of eight observational studies of fibrates, with
or without statins, in patients with hepatitis C virus infection,
revealed a significant reduction in viral load, with bezafibrate
demonstrating the greatest antiviral efficacy among the
medications tested. The antiviral potency of bezafibrate was
confirmed in both Asian and European study populations.
Interestingly, the significant clinical effect was found despite
the failure of in vitro studies to demonstrate a significant effect
[82].
Anti-Inflammatory Effects
The anti-inflammatory properties of fibrates that underpin some
of the macrovascular benefits also translate into improved
clinical outcomes in patients with microvascular disease. In in
vitro studies, fenofibrate demonstrated potentially protective
effects on the renal and retinal microvasculature by suppressing
inflammation and apoptosis in human glomerular microvascular
cells and reducing retinal microvascular inflammation [83,84],
while bezafibrate decreased the number of circulating
proinflammatory monocytes in patients with type 2 diabetes
[85]. A beneficial modulatory role for fenofibrate in renal
fibrosis and inflammation has also been proposed, with further
studies required to elucidate the mechanisms involved [81].
Cardioprotective Effects
Preclinical studies provide evidence that fenofibrate can protect
against cardiac ischemia-reperfusion injury and subsequent
arrhythmias and heart failure, autoimmune myocarditis, and
hypertension [81,86,87]. In the clinical setting, a meta-analysis
of studies in which fibrates were used for primary prevention
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of atherosclerotic cardiovascular disease reported a significant
16% decrease in the combined outcome of cardiovascular death,
nonfatal myocardial infarction, and nonfatal stroke [88] while
a 12% reduction in these outcomes was reported when fibrates
were used in secondary prevention [89].
Anticoagulation Effects
Robust data indicate that fibrates lower plasma fibrinogen levels
to a significant degree, independent of their lipid-lowering
effects [90-95]. In a meta-analysis of 22 trials, representing
>2700 participants, fibrates (fenofibrate and bezafibrate)
demonstrated a significantly greater effect than statins in
lowering plasma fibrinogen concentrations (weighted mean
difference –40.7mg/dL, P<.001) [93]. Data from smaller studies
focusing on the antihyperlipidemic effects of fibrates
(fenofibrate 200 mg daily; bezafibrate 400 mg daily) show
concurrent, significant reductions in plasma fibrinogen levels
[90-92,94]. Of note is a study that reported an increase in
fibrinogen levels among patients taking statins [94], which could
be a concern in elderly patients with COVID-19, many of whom
are likely to be taking statins.
In patients with metabolic syndrome, which represents a
hypercoagulable state accompanied by inflammation and
endothelial dysfunction, fenofibrate reduced concentrations of
thrombin-activatable fibrinolysis inhibitor, improved endothelial
function [96], and significantly reduced fibrinogen and D-dimer
concentrations [97], suggesting potential anticoagulant and
cardiovascular protective effects. This potential was borne out
in a short-term randomized controlled trial of patients with acute
ST-elevation myocardial infarction, in whom bezafibrate
lowered fibrinogen concentration more effectively than
conventional therapy (P<.001), with significantly greater
reductions in the incidence of angina (56% vs 4%, P<.001) and
left ventricular failure (24% vs 4%, P=.049) [95].
Sildenafil Citrate
The phosphodiesterase-5 inhibitor (PDE5 inhibitor) sildenafil
citrate is a vasodilator that was approved by the FDA in 1998
for the treatment of erectile dysfunction, at a dose of 25-100
mg once daily [98]. More recently, an indication for pulmonary
arterial hypertension (PAH) was added in 2005, with an oral
dosing of 5 or 20 mg thrice daily, or 2.5 mg or 10 mg as
intravenous bolus [99]. In erectile dysfunction, orally
administered sildenafil has an onset of action within 30 minutes,
maximum effect at 1 hour, and duration of effect of 4-6 hours;
in PAH, the pharmacodynamics are similar although peak effect
occurs 1-2 hours after dosing, and blood pressure levels return
to baseline levels within 8 hours [98,99]. The most common
dose-dependent adverse reactions (5%) include headache,
flushing, dyspepsia, visual disturbance, and nasal congestion.
CYP3A4 inhibitors are known to potentiate sildenafil, while
sildenafil potentiates the hypotensive effects of nitrates and
alpha-blockers.
Sildenafil inhibits breakdown of cGMP through competitive
binding at the phosphodiesterase binding site. It therefore
influences platelet activation, proliferation of T cells, and
production of proinflammatory cytokines, leading to a broad
range of anti-inflammatory, antioxidant, vasodilatory, and other
actions in many body systems [100]. An ongoing phase 3 trial
of sildenafil, 100 mg daily for 14 days, in patients with
COVID-19 (NCT04304313) will help clarify its potential
benefits in this disease [101].
Immunomodulatory Effects
In vitro human studies indicate that sildenafil potentiates the
ability of regulatory T cells to downregulate T effector cell
proliferation, while clinical findings include reduced lymphocyte
count and induction of malignant cell apoptosis in a patient with
B-cell chronic lymphocytic leukemia and in patients with
Waldenstrom’s macroglobulinemia [100]. It was hypothesized
that these effects were mediated by synthesis and release of
cytokines. Sustained increase in NO production, and decreased
vascular inflammatory markers, have also been reported in
patients with type 2 diabetes receiving sildenafil [102,103].
Cardiovascular Protective Effects
One-time and long-term administration of PDE5 inhibitors in
patients at high cardiovascular risk can improve endothelial
function, reduce inflammatory mediators, and increase
endothelial regenerative capacity, which may be sustained for
several months following treatment discontinuation, with
potential applications in a range of cardiovascular disorders
[104,105]. Cardioprotective effects include improved symptoms
and cardiac contractility in patients with systolic heart failure,
reduced myocardial infarct size, reduced blood pressure, and
limitation of ischemia-driven ventricular arrhythmias, with
reduction in cardiovascular events and mortality in high-risk
patients [106-108]. In a British study that followed nearly 6000
men with type 2 diabetes over 7.5 years, the use of PDE5
inhibitors was associated with lower mortality risk overall
(adjusted hazard ratio 0.54, P=.002) and in those with a history
of acute myocardial infarction (heart rate=0.60, P=.001) [108].
These effects are believed to result from improved pulmonary
circulation, as well as direct action on the myocardium,
independent of the vasculature [106].
Lung-Protective Effects
Studies demonstrating sildenafil’s efficacy and tolerability in
PAH continue to accrue, and a 2019 Cochrane systematic review
and meta-analysis comprising 36 studies of nearly 3000 patients
concluded that those with PAH who received PDE5 inhibitors
were 22% less likely to die in the short-term than those receiving
placebo [109]. Additionally, a network meta-analysis reported
moderate-level evidence that sildenafil may reduce mortality
in idiopathic pulmonary fibrosis, an interstitial lung disease
with high mortality [110]. A single case report of a 55-year-old
physician with an atypical respiratory infection and apparently
normal pulmonary arterial blood pressure who experienced
marked symptomatic and functional improvement within 24
hours of starting tadalafil highlights the potential benefits of
PDE5 inhibitors in this indication [111].
Renoprotective Effects
Preliminary evidence suggests that the clinical efficacy of PDE5
inhibitors in CKD extends beyond antihypertensive effects to
active renoprotection. In preclinical studies, PDE5 inhibitors
suppressed mesangial cell proliferation and extracellular matrix
expansion, reduced renal cell apoptosis, and decreased oxidative
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stress and inflammation [107]. A post hoc examination of this
class of medications in a randomized controlled trial also
revealed improved kidney function and functional capacity, and
a trend toward reduced mortality, in patients with PAH who
received sildenafil treatment [112]. Few, if any, clinical studies
of PDE5 inhibitors in patients with acute kidney disease have
been published. Ongoing clinical trials (eg, NCT04304313) will
shed further light on this and may reveal information that could
be applied in the treatment of patients with COVID-19 [101].
Conclusions
Under the extraordinary COVID-19 pandemic conditions that
have brought the world to the brink of an irreversible crisis,
time is of the essence for the success of life-saving efforts. Until
a vaccine is developed to treat this disease, the urgency of
finding safe and effective treatments cannot be overstated. To
ensure that patients with COVID-19 have rapid access to safe
treatments, and to ensure the responsible use of available
resources, it would be wise to mine the existing pharmacopeia
for safe generic drugs that address the pathophysiologies
underlying COVID-19. Moreover, beyond the current
emergency there remains the likelihood of future re-emergence
of another coronavirus or similar virus. The efforts we make
now to facilitate access to information on the off-label
applications of well-understood drugs, regardless of the manner
in which the information has been discovered, are an investment
in our future health that also addresses current needs. While
clinical trials to assess efficacy will be important in due course,
judicious use of one or more of these approved drugs, with
caution toward potential interactions with concomitant
medications, represents a rational and ethical approach that may
prove effective in the short term. There is no time to waste and
little to lose.
Epilogue
Since the initial submission of this article as a preprint in April
2020, new developments and evidence have emerged that further
support the therapeutic potential of the drugs proposed in this
paper for use in the treatment of COVID-19. The new
developments and evidence are summarized below and are
current as of August 31, 2020.
Dipyridamole
Research aimed at assessing the therapeutic potential of
dipyridamole continues. One ongoing phase 3 clinical trial
(ClinicalTrials.gov ID NCT04410328) randomized patients
(n=132) to receive dipyridamole ER 200 mg and aspirin 25 mg
orally/enterally plus standard care or standard care alone [113].
Researchers are also evaluating dipyridamole in two other
ongoing clinical trials with a focus on determining the extent
to which the drug can reduce excessive coagulation [114] and
treat respiratory tract infection and circulatory dysfunction
caused by SARS-CoV-2 [115] in hospitalized COVID-19
patients.
Famotidine
The therapeutic potential of famotidine (combined with
cetirizine) in COVID-19 treatment was recently boosted by an
American cohort study evaluating the efficacy of dual-histamine
blockade in patients with COVID-19. In the study, hospitalized
COVID-19 patients with severe-to-critical symptoms were
treated with cetirizine 10 mg and famotidine 20 mg bid in
addition to standard care. This combination reduced symptom
progression when compared to published reports of COVID-19
patients [116]. The safety and efficacy of famotidine in
COVID-19 is further supported by a case series of 10 US
patients with COVID-19 who self-administered high-dose oral
famotidine (80 mg thrice daily was the most frequent regimen
used) for 11 days. All patients reported marked improvements
in COVID-19–related symptoms, suggesting that high-dose oral
famotidine is well tolerated and associated with improved
patient-reported outcomes in nonhospitalized patients with
COVID-19 [117].
Another case series of 14 COVID-19 hospitalized patients from
Beloit Memorial Hospital, United States, reported improvement
in supplemental oxygen requirements, ground-glass computed
tomography findings, and serum levels of lactate dehydrogenase,
ferritin, CRP, D-dimer, and lymphocytes in patients who
received famotidine 80 mg qid plus celecoxib (as adjuvant
therapy) [118]. This treatment combination was associated with
a 100% survival rate. Similar clinical improvements have been
reported by Freedberg et al [119] among hospitalized COVID-19
patients. Despite clinical evidence suggesting that famotidine
may mitigate COVID-19, its mechanism of action remains a
matter of debate. A recent study by Malone et al [120] suggests
that the drug’s therapeutic action in COVID-19 involves
on-target histamine receptor-H2 activity, which has face validity
since the development of clinical symptoms involves
dysfunctional mast cell activation and histamine release.
Fenofibrate
Researchers from the Hebrew University of Jerusalem, Israel,
and Icahn School of Medicine at Mount Sinai (United States)
studied the metabolic changes induced by SARS-CoV-2
infection in bronchial epithelial cells using lung biopsy samples
from patients with COVID-19. The researchers reported a
significant metabolic response in SARS-CoV-2–infected lungs
in addition to changes in lipid metabolism and the induction of
inositol-requiring enzyme-1 and RNA-activated protein kinase
pathways of endoplasmic stress. The study showed that
fenofibrate reversed the metabolic changes induced by
SARS-CoV-2, blocking viral production and suppressing the
pathogenesis of COVID-19 in lung tissue [121].
Sildenafil
A recent systematic review carried out by researchers from the
University of Rome, Italy, consolidated evidence of the
involvement of the NO-cGMP-PDE5 axis in the
pathophysiology of COVID-19, presenting ongoing clinical
trials aimed at modulating this axis, including the DEDALO
(silDEnafil administration in DiAbetic and dysmetaboLic
patients with COVID-19) trial [122]. Reviewed data indicate
that PDE5 inhibitors could be effective in managing patients
with COVID-19 by counteracting the Ang-II–mediated
downregulation of the AT-1 receptor, exhibit action on
monocyte switching, reducing proinflammatory cytokines and
interstitial infiltration; and inhibit the transition of endothelial
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and smooth muscle cells to mesenchymal cells in the pulmonary
artery, preventing clotting and thrombotic complications. With
sildenafil’s low cost, well-established safety, wide availability,
and efficacy arising from observational studies and clinical trials
(including the new “Sildenafil in COVID-19” trial;
ClinicalTrials.gov ID NCT04489446), it, and other PDE5
inhibitors, could potentially become key COVID-19 treatment
options [122,123].
Conflicts of Interest
None declared.
References
1. Auwaerter PG. Johns Hopkins ABX Guide: Coronavirus COVID-19 (SARS-CoV-2). The Johns Hopkins University. 2020
Aug. URL: http://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540747/all/
Coronavirus_COVID_19__SARS_CoV_2_ [accessed 2020-03-31]
2. Rogosnitzky M, Berkowitz E, Jadad A. Delivering Benefits at Speed Through Real-World Repurposing of Off-Patent
Drugs: The COVID-19 Pandemic as a Case in Point. JMIR Public Health Surveill 2020 May 13;6(2):e19199 [FREE Full
text] [doi: 10.2196/19199] [Medline: 32374264]
3. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with
COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet 2020 Mar;395(10229):1054-1062. [doi:
10.1016/S0140-6736(20)30566-3]
4. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in
Wuhan, China. The Lancet 2020 Feb;395(10223):497-506. [doi: 10.1016/s0140-6736(20)30183-5]
5. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens.
JAMA 2020 May 12;323(18):1843-1844 [FREE Full text] [doi: 10.1001/jama.2020.3786] [Medline: 32159775]
6. Epidemiology Working Group for NCIP Epidemic Response‚ Chinese Center for Disease Control and Prevention. [The
epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China]. Zhonghua Liu
Xing Bing Xue Za Zhi 2020 Feb 10;41(2):145-151. [doi: 10.3760/cma.j.issn.0254-6450.2020.02.003] [Medline: 32064853]
7. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on the Cardiovascular System:
A Review. JAMA Cardiol 2020 Jul 01;5(7):831-840. [doi: 10.1001/jamacardio.2020.1286] [Medline: 32219363]
8. Zhang F, Yang D, Li J, Gao P, Chen T, Cheng Z. Myocardial injury is associated with in-hospital mortality of confirmed
or suspected COVID-19 in Wuhan, China: A single center retrospective cohort study. medRxiv 2020 Mar:e [FREE Full
text] [doi: 10.1101/2020.03.21.20040121]
9. Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, et al. Clinical and biochemical indexes from 2019-nCoV infected
patients linked to viral loads and lung injury. Sci China Life Sci 2020 Mar 11;63(3):364-374 [FREE Full text] [doi:
10.1007/s11427-020-1643-8] [Medline: 32048163]
10. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of
heart injury among patients infected with SARS-CoV-2. Cardiovasc Res 2020 May 01;116(6):1097-1100 [FREE Full text]
[doi: 10.1093/cvr/cvaa078] [Medline: 32227090]
11. Han H, Yang L, Liu R, Liu F, Wu K, Li J, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2
infection. Clin Chem Lab Med 2020 Jun 25;58(7):1116-1120. [doi: 10.1515/cclm-2020-0188] [Medline: 32172226]
12. Gao Y, Li T, Han M, Li X, Wu D, Xu Y, et al. Diagnostic utility of clinical laboratory data determinations for patients with
the severe COVID-19. J Med Virol 2020 Jul 17;92(7):791-796 [FREE Full text] [doi: 10.1002/jmv.25770] [Medline:
32181911]
13. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19
associated pneumonia in clinical studies. Biosci Trends 2020 Mar 16;14(1):72-73 [FREE Full text] [doi:
10.5582/bst.2020.01047] [Medline: 32074550]
14. Gautret P, Lagier J, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment
of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents 2020
Jul;56(1):105949. [doi: 10.1016/j.ijantimicag.2020.105949]
15. Gautret P, Lagier J, Parola P, Hoang VT, Meddeb L, Sevestre J, et al. Clinical and microbiological effect of a combination
of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational
study. Travel Med Infect Dis 2020 Apr;34:101663 [FREE Full text] [doi: 10.1016/j.tmaid.2020.101663] [Medline: 32289548]
16. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D. Efficacy of hydroxychloroquine in patients with COVID-19: results of a
randomized clinical trial. MedRxiv 2020 Apr:e [FREE Full text] [doi: 10.1101/2020.03.22.20040758]
17. Huang M, Tang T, Pang P, Li M, Ma R, Lu J, et al. Treating COVID-19 with Chloroquine. J Mol Cell Biol 2020 May
18;12(4):322-325 [FREE Full text] [doi: 10.1093/jmcb/mjaa014] [Medline: 32236562]
18. Magagnoli J, Narendran S, Pereira F, Cummings TH, Hardin JW, Sutton SS, et al. Outcomes of Hydroxychloroquine Usage
in United States Veterans Hospitalized with COVID-19. Med (N Y) 2020 Jun 05:e [FREE Full text] [doi:
10.1016/j.medj.2020.06.001] [Medline: 32838355]
JMIRx Med 2020 | vol. 1 | iss. 1 | e19583 | p. 8https://med.jmirx.org/2020/1/e19583/ (page number not for citation purposes)
Rogosnitzky et alJMIRx Med
XSL
FO
RenderX
19. Mahevas M, Tran V, Roumier M, Chabrol A, Paule R, Guillaud C. No evidence of clinical efficacy of hydroxychloroquine
in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data
to emulate a target trial. medRxiv 2020 Apr:e [FREE Full text] [doi: 10.1101/2020.04.10.20060699]
20. Chaccour C, Hammann F, Ramón-García S, Rabinovich NR. Ivermectin and COVID-19: Keeping Rigor in Times of
Urgency. Am J Trop Med Hyg 2020 Jun;102(6):1156-1157 [FREE Full text] [doi: 10.4269/ajtmh.20-0271] [Medline:
32314704]
21. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of
SARS-CoV-2 in vitro. Antiviral Res 2020 Jun;178:104787 [FREE Full text] [doi: 10.1016/j.antiviral.2020.104787] [Medline:
32251768]
22. Patrì A, Fabbrocini G. Hydroxychloroquine and ivermectin: A synergistic combination for COVID-19 chemoprophylaxis
and treatment? J Am Acad Dermatol 2020 Jun;82(6):e221 [FREE Full text] [doi: 10.1016/j.jaad.2020.04.017] [Medline:
32283237]
23. Gastric acid reducers. Merck Manual Professional Version. 2020. URL: https://www.merckmanuals.com/professional/
gastrointestinal-disorders/gastritis-and-peptic-ulcer-disease/drug-treatment-of-gastric-acidity#v892554 [accessed 2020-03-31]
24. Jafarzadeh A, Nemati M, Khorramdelazad H, Hassan ZM. Immunomodulatory properties of cimetidine: Its therapeutic
potentials for treatment of immune-related diseases. Int Immunopharmacol 2019 May;70:156-166. [doi:
10.1016/j.intimp.2019.02.026] [Medline: 30802678]
25. Kurzrock R, Auber M, Mavligit GM. Cimetidine therapy of herpes simplex virus infections in immunocompromised patients.
Clin Exp Dermatol 1987 Sep;12(5):326-331. [doi: 10.1111/j.1365-2230.1987.tb02501.x] [Medline: 3446417]
26. Kapińska-Mrowiecka M, Turowski G. [Efficacy of cimetidine in treatment of Herpes zoster in the first 5 days from the
moment of disease manifestation]. Pol Tyg Lek 1996 Jun;51(23-26):338-339. [Medline: 9273526]
27. Harcourt J, Worley G, Leighton S. Cimetidine treatment for recurrent respiratory papillomatosis. International Journal of
Pediatric Otorhinolaryngology 1999 Dec;51(2):109-113. [doi: 10.1016/s0165-5876(99)00279-7]
28. Niu X, Yang Y, Wang J. Synergistic and additive effects of cimetidine and levamisole on cellular immune responses to
hepatitis B virus DNA vaccine in mice. Scand J Immunol 2013 Feb 24;77(2):84-91 [FREE Full text] [doi: 10.1111/sji.12018]
[Medline: 23298196]
29. Xie X, Geng S, Liu H, Li C, Yang Y, Wang B. Cimetidine synergizes with Praziquantel to enhance the immune response
of HBV DNA vaccine via activating cytotoxic CD8(+) T cell. Hum Vaccin Immunother 2014 Mar 18;10(6):1688-1699
[FREE Full text] [doi: 10.4161/hv.28517] [Medline: 24643207]
30. Zhang W, Wang J, Su B, Li R, Ding Z, Kang Y, et al. Cimetidine augments Th1/Th2 dual polarized immune responses to
recombinant HBV antigens. Vaccine 2011 Jun 24;29(29-30):4862-4868. [doi: 10.1016/j.vaccine.2011.03.091] [Medline:
21481324]
31. Wang J, Su B, Ding Z, Du X, Wang B. Cimetidine enhances immune response of HBV DNA vaccination via impairment
of the regulatory function of regulatory T cells. Biochem Biophys Res Commun 2008 Aug 01;372(3):491-496. [doi:
10.1016/j.bbrc.2008.04.191] [Medline: 18502198]
32. Bourinbaiar AS, Fruhstorfer EC. The effect of histamine type 2 receptor antagonists on human immunodeficiency virus
(HIV) replication: Identification of a new class of antiviral agents. Life Sciences 1996 Nov;59(23):PL365-PL370. [doi:
10.1016/s0024-3205(96)00553-x]
33. Nielsen HJ, Hammer JH, Moesgaard F, Heron I, Kehlet H. Ranitidine improves postoperative suppression of antibody
response to preoperative vaccination. Surgery 1992 Jan;111(1):69-73. [Medline: 1728077]
34. Van der Velden AMT, Van Velzen-Blad H, Claessen AME, Van der Griend R, Oltmans R, Rijkers GT, et al. The effect
of ranitidine on antibody responses to polysaccharide vaccines in patients with B-cell chronic lymphocytic leukaemia. Eur
J Haematol 2007 Jul;79(1):47-52. [doi: 10.1111/j.1600-0609.2007.00862.x] [Medline: 17532765]
35. Jurlander J, de Nully Brown P, Skov PS, Henrichsen J, Heron I, Obel N, et al. Improved vaccination response during
ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukemia.
Leukemia 1995 Nov;9(11):1902-1909. [Medline: 7475282]
36. Zhang J, Cai W, Zhang Z, Wang P, Lin X, Feng J, et al. Cardioprotective effect of histamine H2 antagonists in congestive
heart failure: A systematic review and meta-analysis. Medicine (Baltimore) 2018 Apr;97(15):e0409 [FREE Full text] [doi:
10.1097/MD.0000000000010409] [Medline: 29642208]
37. Breuer HM, Hartung H, Goeckenjan G, Abendroth R, Curtius JM, Trampisch HJ, et al. [Cimetidine and ranitidine in
intensive care patients. Double-blind randomized cross-over study on intravenous administration: hemodynamics, plasma
coagulation, blood gases and acid-base status]. Dtsch Med Wochenschr 1985 Jul 26;110(30):1151-1156. [doi:
10.1055/s-2008-1068976] [Medline: 3893961]
38. Tayama E, Hayashida N, Fukunaga S, Tayama K, Takaseya T, Hiratsuka R, et al. High-dose cimetidine reduces
proinflammatory reaction after cardiac surgery with cardiopulmonary bypass. The Annals of Thoracic Surgery 2001
Dec;72(6):1945-1949. [doi: 10.1016/s0003-4975(01)03225-8]
39. Nakamura K, Kariyazono H, Shinkawa T, Yamaguchi T, Yamashita T, Ayukawa O, et al. Inhibitory effects of H2-receptor
antagonists on platelet function in vitro. Hum Exp Toxicol 1999 Aug 02;18(8):487-492. [doi: 10.1191/096032799678847069]
[Medline: 10462360]
JMIRx Med 2020 | vol. 1 | iss. 1 | e19583 | p. 9https://med.jmirx.org/2020/1/e19583/ (page number not for citation purposes)
Rogosnitzky et alJMIRx Med
XSL
FO
RenderX
40. Mikhailidis DP, Christofides J, Barradas MA, Jeremy JY, Dilawari J, Dandona P. The effect of cimetidine on platelet
function: a study involving gastric fluid measurements. Agents and Actions 1986 Oct;19(1-2):34-41. [doi:
10.1007/bf01977253]
41. Noori N, Miri Aliabad G, Mohammadi M, Mahjoubifard M, Jahangiri Fard A. The effects of ranitidine and hydrocortisone
on the complications of femoral artery obstruction treated by streptokinase following cardiac catheterization in pediatric
patients with congenital heart diseases. Iran Red Crescent Med J 2013 Feb 19;15(2):117-121 [FREE Full text] [doi:
10.5812/ircmj.7248] [Medline: 24693416]
42. Glotzbach RE. Cimetidine-induced thrombocytopenia. South Med J 1982 Feb;75(2):232-234. [doi:
10.1097/00007611-198202000-00030] [Medline: 7058369]
43. Gentilini G, Curtis BR, Aster RH. An antibody from a patient with ranitidine-induced thrombocytopenia recognizes a site
on glycoprotein IX that is a favored target for drug-induced antibodies. Blood 1998 Oct 01;92(7):2359-2365. [Medline:
9746775]
44. Gafter U, Zevin D, Komlos L, Livni E, Levi J. Thrombocytopenia associated with hypersensitivity to ranitidine: possible
cross-reactivity with cimetidine. Am J Gastroenterol 1989 May;84(5):560-562. [Medline: 2719014]
45. Takimoto R, Mogi Y, Kura T, Niitsu Y. [Hemolytic anemia and thrombocytopenia induced by cimetidine: recurrence with
ranitidine administration]. Rinsho Ketsueki 1997 Feb;38(2):124-128. [Medline: 9059066]
46. Hoste L, George I. Ranitidine-induced Thrombocytopenia in a Neonate - A Case Report and Review of Literature. J Pediatr
Pharmacol Ther 2019 Jan;24(1):66-71 [FREE Full text] [doi: 10.5863/1551-6776-24.1.66] [Medline: 30837818]
47. Dipyridamole [Persantine]: Prescribing Information. Boehringer Ingelheim International GmbH. 2019. URL: https://www.
accessdata.fda.gov/drugsatfda_docs/label/2019/012836s061lbl.pdf [accessed 2020-03-31]
48. Aspirin/Extended-Release Dipyridamole [Aggrenox]: Highlights of prescribing information Internet. Boehringer Ingelheim
International GmbH. 2019 Dec. URL: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/
Aggrenox%20Caps/Aggrenox.pdf [accessed 2020-03-31]
49. Curantyl 25 (dipyridamole) prescribing information. Russian Drug Register. 2005. URL: https://pda.rlsnet.ru/
tn_index_id_3874.htm#pokazaniya-preparata-kurantil- [accessed 2020-04-02]
50. Lette J, Tatus J, Fraser S, Miller D, Waters D, Heller G, et al. Safety of dipyridamole testing in 73,806 patients: The
Multicenter Dipyridamole Safety Study. Journal of Nuclear Cardiology 1995 Jan;2(1):3-17. [doi:
10.1016/s1071-3581(05)80003-0]
51. Balakumar P, Nyo YH, Renushia R, Raaginey D, Oh AN, Varatharajan R, et al. Classical and pleiotropic actions of
dipyridamole: Not enough light to illuminate the dark tunnel? Pharmacol Res 2014 Sep;87:144-150. [doi:
10.1016/j.phrs.2014.05.008] [Medline: 24861566]
52. Tonew M, Tonew E, Mentel R. The antiviral activity of dipyridamole. Acta Virol 1977 Mar;21(2):146-150. [Medline:
17283]
53. Tonew M, Dzeguze D. Dipyridamole, an inhibitor of mengovirus replication in FL and L cells. Chemotherapy 1977 Aug
5;23(3):149-158. [doi: 10.1159/000221983] [Medline: 189976]
54. Tenser RB, Gaydos A, Hay KA. Inhibition of Herpes Simplex Virus Reactivation by Dipyridamole. Antimicrob Agents
Chemother 2001 Dec 01;45(12):3657-3659. [doi: 10.1128/aac.45.12.3657-3659.2001]
55. Patel SS, Szebeni J, Wahl LM, Weinstein JN. Differential inhibition of 2'-deoxycytidine salvage as a possible mechanism
for potentiation of the anti-human immunodeficiency virus activity of 2',3'-dideoxycytidine by dipyridamole. Antimicrob
Agents Chemother 1991 Jun 01;35(6):1250-1253 [FREE Full text] [doi: 10.1128/aac.35.6.1250] [Medline: 1656858]
56. Snoeck R, Andrei G, Balzarini J, Reymen D, De Clercq E. Dipyridamole Potentiates the Activity of Various Acyclic
Nucleoside Phosphonates against Varicella-Zoster Virus, Herpes Simplex Virus and Human Cytomegalovirus. Antivir
Chem Chemother 2016 Jun 23;5(5):312-321. [doi: 10.1177/095632029400500505]
57. Kuzmov K, Galabov AS, Radeva K, Kozhukharova M, Milanov K. [Epidemiological trial of the prophylactic effectiveness
of the interferon inducer dipyridamole with respect to influenza and acute respiratory diseases]. Zh Mikrobiol Epidemiol
Immunobiol 1985 Jun(6):26-30. [Medline: 3898670]
58. Fedorova GI, Slepushkin AN. [Epidemiologic and economic efficacy of massive prophylaxis of influenza and other acute
respiratory viral infections using curantil in Moscow enterprises]. Ter Arkh 2002;74(11):18-21. [Medline: 12498118]
59. Guchev IA, Klochkov OI. [Dipyridamole prevention of outbreaks of respiratory infections in the homogeneous population].
Klin Med (Mosk) 2004;82(11):45-49. [Medline: 15656399]
60. Liu X, Li Z, Liu S, Sun J, Chen Z, Jiang M, et al. Potential therapeutic effects of dipyridamole in the severely ill patients
with COVID-19. Acta Pharm Sin B 2020 Jul;10(7):1205-1215 [FREE Full text] [doi: 10.1016/j.apsb.2020.04.008] [Medline:
32318327]
61. Multicenter study for the treatment of Dipyridamole with novel coronavirus pneumonia (COVID-19) (ChiCTR2000030055
). Chinese Clinical Trial Registry. 2020. URL: http://www.chictr.org.cn/showprojen.aspx?proj=49864 [accessed 2020-08-28]
62. Kim H, Liao JK. Translational therapeutics of dipyridamole. Arterioscler Thromb Vasc Biol 2008 Mar;28(3):s39-s42 [FREE
Full text] [doi: 10.1161/ATVBAHA.107.160226] [Medline: 18174451]
63. Guo S, Stins M, Ning M, Lo EH. Amelioration of inflammation and cytotoxicity by dipyridamole in brain endothelial cells.
Cerebrovasc Dis 2010 Aug;30(3):290-296 [FREE Full text] [doi: 10.1159/000319072] [Medline: 20664263]
JMIRx Med 2020 | vol. 1 | iss. 1 | e19583 | p. 10https://med.jmirx.org/2020/1/e19583/ (page number not for citation purposes)
Rogosnitzky et alJMIRx Med
XSL
FO
RenderX
64. Renvert S, Lindahl C, Roos-Jansåker AM, Lessem J. Short-term effects of an anti-inflammatory treatment on clinical
parameters and serum levels of C-reactive protein and proinflammatory cytokines in subjects with periodontitis. J Periodontol
2009 Jun;80(6):892-900 [FREE Full text] [doi: 10.1902/jop.2009.080552] [Medline: 19485818]
65. Zimmermann GR, Avery W, Finelli AL, Farwell M, Fraser CC, Borisy AA. Selective amplification of glucocorticoid
anti-inflammatory activity through synergistic multi-target action of a combination drug. Arthritis Res Ther 2009;11(1):R12
[FREE Full text] [doi: 10.1186/ar2602] [Medline: 19171052]
66. Macatangay B, Jackson E, Abebe K, Comer D, Cyktor J, Klamar-Blain C, et al. A Randomized, Placebo-Controlled, Pilot
Clinical Trial of Dipyridamole to Decrease Human Immunodeficiency Virus-Associated Chronic Inflammation. J Infect
Dis 2020 Apr 27;221(10):1598-1606. [doi: 10.1093/infdis/jiz344] [Medline: 31282542]
67. Granat F, Monzali C, Jeunesse E, Guerlin M, Trumel C, Geffré A, et al. Comparison of different anticoagulant associations
on haemostasis and biochemical analyses in feline blood specimens. Journal of Feline Medicine and Surgery 2016 Jul
09;19(4):394-402. [doi: 10.1177/1098612x16628579]
68. Granat FA, Geffré A, Lucarelli LA, Braun JD, Trumel C, Bourgès-Abella NH. Evaluation of CTAD
(citrate-theophylline-adenosine-dipyridamole) as a universal anticoagulant in dogs. J Vet Diagn Invest 2017 Sep
03;29(5):676-682. [doi: 10.1177/1040638717713793] [Medline: 28673194]
69. Yokota M, Tatsumi N, Tsuda I, Nishioka T, Takubo T. CTAD as a universal anticoagulant. J Autom Methods Manag Chem
2003;25(1):17-20 [FREE Full text] [doi: 10.1155/S1463924603000038] [Medline: 18924886]
70. Copeland H, Nolan P, Covington D, Gustafson M, Smith R, Copeland J. A method for anticoagulation of children on
mechanical circulatory support. Artif Organs 2011 Nov;35(11):1018-1023. [doi: 10.1111/j.1525-1594.2011.01391.x]
[Medline: 22097979]
71. Gomes OM, Gomes ES. Dipyridamole and low doses of heparin as a new successful physiopathologic and therapeutic
approach in 2 cases of disseminated intravascular coagulation. Heart Surg Forum 2010 Feb 11;13(1):E49-E51. [doi:
10.1532/HSF98.20091134] [Medline: 20150041]
72. Asakura M, Asanuma H, Kim J, Liao Y, Nakamaru K, Fujita M, et al. Impact of adenosine receptor signaling and metabolism
on pathophysiology in patients with chronic heart failure. Hypertens Res 2007 Sep;30(9):781-787. [doi:
10.1291/hypres.30.781] [Medline: 18037770]
73. Kitakaze M, Minamino T, Node K, Takashima S, Funaya H, Kuzuya T, et al. Adenosine and cardioprotection in the diseased
heart. Jpn Circ J 1999 Apr;63(4):231-243 [FREE Full text] [doi: 10.1253/jcj.63.231] [Medline: 10475769]
74. Riksen N, Rongen G, Blom H, Boers G, Smits P. Reduced adenosine receptor stimulation as a pathogenic factor in
hyperhomocysteinemia. Clin Chem Lab Med 2005;43(10):1001-1006. [doi: 10.1515/CCLM.2005.175] [Medline: 16197288]
75. Sanada S, Asanuma H, Koretsune Y, Watanabe K, Nanto S, Awata N, et al. Long-term oral administration of dipyridamole
improves both cardiac and physical status in patients with mild to moderate chronic heart failure: a prospective
open-randomized study. Hypertens Res 2007 Oct;30(10):913-919. [doi: 10.1291/hypres.30.913] [Medline: 18049022]
76. Kuo K, Hung S, Tseng W, Liu J, Lin M, Hsu C, et al. Dipyridamole decreases dialysis risk and improves survival in patients
with pre-dialysis advanced chronic kidney disease. Oncotarget 2018 Jan 12;9(4):5368-5377 [FREE Full text] [doi:
10.18632/oncotarget.19850] [Medline: 29435184]
77. Hung C, Yang M, Lin M, Lin HY, Lim L, Kuo H, et al. Dipyridamole treatment is associated with improved renal outcome
and patient survival in advanced chronic kidney disease. Kaohsiung J Med Sci 2014 Dec;30(12):599-607 [FREE Full text]
[doi: 10.1016/j.kjms.2014.10.002] [Medline: 25476097]
78. Lee G, Choong H, Chiang G, Woo K. Three-year randomized controlled trial of dipyridamole and low-dose warfarin in
patients with IgA nephropathy and renal impairment Internet. Nephrology 1997;3(1):117-121. [doi:
10.1111/j.1440-1797.1997.tb00201.x]
79. Beaufils M, Uzan S, Donsimoni R, Colau JC. Prospective controlled study of early antiplatelet therapy in prevention of
preeclampsia. Adv Nephrol Necker Hosp 1986;15:87-94. [Medline: 3082120]
80. Fenofibrate [Triglide]: Highlights of Prescribing Information. Shionogi, Inc. 2012. URL: https://www.accessdata.fda.gov/
drugsatfda_docs/label/2013/021350s013lbl.pdf [accessed 2020-03-31]
81. Balakumar P, Sambathkumar R, Mahadevan N, Muhsinah AB, Alsayari A, Venkateswaramurthy N, et al. Molecular targets
of fenofibrate in the cardiovascular-renal axis: A unifying perspective of its pleiotropic benefits. Pharmacol Res 2019
Jun;144:132-141. [doi: 10.1016/j.phrs.2019.03.025] [Medline: 30970278]
82. Grammatikos G, Farnik H, Bon D, Böhlig A, Bader T, Berg T, et al. The impact of antihyperlipidemic drugs on the viral
load of patients with chronic hepatitis C infection: a meta-analysis. J Viral Hepat 2014 Aug 18;21(8):533-541. [doi:
10.1111/jvh.12274] [Medline: 24943517]
83. Tomizawa A, Hattori Y, Inoue T, Hattori S, Kasai K. Fenofibrate suppresses microvascular inflammation and apoptosis
through adenosine monophosphate-activated protein kinase activation. Metabolism 2011 Apr;60(4):513-522. [doi:
10.1016/j.metabol.2010.04.020] [Medline: 20580385]
84. Usui-Ouchi A, Ouchi Y, Ebihara N. The peroxisome proliferator-activated receptor pan-agonist bezafibrate suppresses
microvascular inflammatory responses of retinal endothelial cells and vascular endothelial growth factor production in
retinal pigmented epithelial cells. Int Immunopharmacol 2017 Nov;52:70-76. [doi: 10.1016/j.intimp.2017.08.027] [Medline:
28866026]
JMIRx Med 2020 | vol. 1 | iss. 1 | e19583 | p. 11https://med.jmirx.org/2020/1/e19583/ (page number not for citation purposes)
Rogosnitzky et alJMIRx Med
XSL
FO
RenderX
85. Terasawa T, Aso Y, Omori K, Fukushima M, Momobayashi A, Inukai T. Bezafibrate, a peroxisome proliferator-activated
receptor α agonist, decreases circulating CD14(+)CD16(+) monocytes in patients with type 2 diabetes. Transl Res 2015
Feb;165(2):336-345. [doi: 10.1016/j.trsl.2014.07.008] [Medline: 25134759]
86. Huang W, Yin W, Chen J, Huang P, Chen J, Lin S. Fenofibrate Reverses Dysfunction of EPCs Caused by Chronic Heart
Failure. J Cardiovasc Transl Res 2020 Apr 7;13(2):158-170. [doi: 10.1007/s12265-019-09889-y] [Medline: 31701352]
87. Oidor-Chan VH, Hong E, Pérez-Severiano F, Montes S, Torres-Narváez JC, Del Valle-Mondragón L, et al. Fenofibrate
plus Metformin Produces Cardioprotection in a Type 2 Diabetes and Acute Myocardial Infarction Model. PPAR Res
2016;2016:8237264-8237214 [FREE Full text] [doi: 10.1155/2016/8237264] [Medline: 27069466]
88. Jakob T, Nordmann A, Schandelmaier S, Ferreira-González I, Briel M. Fibrates for primary prevention of cardiovascular
disease events. Cochrane Database Syst Rev 2016 Nov 16;11:CD009753 [FREE Full text] [doi:
10.1002/14651858.CD009753.pub2] [Medline: 27849333]
89. Wang D, Liu B, Tao W, Hao Z, Liu M. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane
Database Syst Rev 2015 Oct 25;10(10):CD009580 [FREE Full text] [doi: 10.1002/14651858.CD009580.pub2] [Medline:
26497361]
90. Jonkers IJAM, de Man FHAF, van Tilburg NH, van der Laarse A, Sandset PM, Smelt AHM, et al. Alterations in the extrinsic
pathway in hypertriglyceridemia do not cause a 'procoagulant state': effects of bezafibrate therapy. Blood Coagul Fibrinolysis
2001 Dec;12(8):705-712. [doi: 10.1097/00001721-200112000-00013] [Medline: 11734672]
91. Ceska R, Sobra J, Kvasnicka J, Procházková R, Kvasilová M, Haas T. [The effect of micronized fenofibrate on lipid
parameters and fibrinogen in heterozygous familial hypercholesterolemia and familial combined hyperlipidemia]. Cas Lek
Cesk 1996 Jul 26;135(13):413-416. [Medline: 8925538]
92. Durrington P, Mackness M, Bhatnagar D, Julier K, Prais H, Arrol S, et al. Effects of two different fibric acid derivatives
on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb
hyperlipoproteinaemia. Atherosclerosis 1998 May;138(1):217-225. [doi: 10.1016/s0021-9150(98)00003-3]
93. Sahebkar A, Serban M, Mikhailidis DP, Toth PP, Muntner P, Ursoniu S, LipidBlood Pressure Meta-analysis Collaboration
(LBPMC) Group. Head-to-head comparison of statins versus fibrates in reducing plasma fibrinogen concentrations: A
systematic review and meta-analysis. Pharmacol Res 2016 Jan;103:236-252. [doi: 10.1016/j.phrs.2015.12.001] [Medline:
26657419]
94. Maison P, Mennen L, Sapinho D, Balkau B, Sigalas J, Chesnier M, et al. A pharmacoepidemiological assessment of the
effect of statins and fibrates on fibrinogen concentration. Atherosclerosis 2002 Jan;160(1):155-160. [doi:
10.1016/s0021-9150(01)00552-4]
95. Madrid-Miller A, Moreno-Ruiz LA, Borrayo-Sánchez G, Almeida-Gutiérrez E, Martínez-Gómez DF, Jáuregui-Aguilar R.
Ipact of bezafibrate treatment in patients with hyperfibrinogenemia and ST-elevation acute myocardial infarction: a
randomized clinical trial. Cir Cir 2010;78(3):229-237. [Medline: 20642906]
96. Kilicarslan A, Yavuz B, Guven GS, Atalar E, Sahiner L, Beyazit Y, et al. Fenofibrate improves endothelial function and
decreases thrombin-activatable fibrinolysis inhibitor concentration in metabolic syndrome. Blood Coagulation & Fibrinolysis
2008;19(4):310-314. [doi: 10.1097/mbc.0b013e3283009c69]
97. Ueno H, Saitoh Y, Mizuta M, Shiiya T, Noma K, Mashiba S, et al. Fenofibrate ameliorates insulin resistance, hypertension
and novel oxidative stress markers in patients with metabolic syndrome. Obes Res Clin Pract 2011 Oct;5(4):e267-e360.
[doi: 10.1016/j.orcp.2011.03.012] [Medline: 24331137]
98. Sildenafil citrate [Viagra]: Highlights of Prescribing Information. Pfizer, Inc. 2017. URL: https://www.accessdata.fda.gov/
drugsatfda_docs/label/2014/20895s039s042lbl.pdf [accessed 2020-04-10]
99. Sildenafil citrate [Revatio]: Highlights of Prescribing Information. Pfizer, Inc. 2014 Jan. URL: https://www.
accessdata.fda.gov/drugsatfda_docs/label/2014/021845s011,022473s004,0203109s002lbl.pdf [accessed 2020-03-31]
100. Kniotek M, Boguska A. Sildenafil Can Affect Innate and Adaptive Immune System in Both Experimental Animals and
Patients. J Immunol Res 2017;2017:4541958-4541958 [FREE Full text] [doi: 10.1155/2017/4541958] [Medline: 28316997]
101. A Pilot Study of Sildenafil in COVID-19 (NCT04304313). ClinicalTrials.gov. 2020. URL: https://clinicaltrials.gov/ct2/
show/NCT04304313 [accessed 2020-08-28]
102. Santi D, Giannetta E, Isidori A, Vitale C, Aversa A, Simoni M. Therapy of endocrine disease. Effects of chronic use of
phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: a meta-analysis. Eur J Endocrinol 2015
Mar;172(3):R103-R114. [doi: 10.1530/eje-14-0700]
103. Aversa A, Vitale C, Volterrani M, Fabbri A, Spera G, Fini M, et al. Chronic administration of Sildenafil improves markers
of endothelial function in men with Type 2 diabetes. Diabet Med 2008 Jan;25(1):37-44. [doi:
10.1111/j.1464-5491.2007.02298.x] [Medline: 18199130]
104. Tzoumas N, Farrah TE, Dhaun N, Webb DJ. Established and emerging therapeutic uses of PDE type 5 inhibitors in
cardiovascular disease. Br J Pharmacol 2019 Nov 12:e. [doi: 10.1111/bph.14920] [Medline: 31721165]
105. Mostafa T. Non-Sexual Implications of Phosphodiesterase Type 5 Inhibitors. Sexual Medicine Reviews 2017
Apr;5(2):170-199. [doi: 10.1016/j.sxmr.2016.02.004]
JMIRx Med 2020 | vol. 1 | iss. 1 | e19583 | p. 12https://med.jmirx.org/2020/1/e19583/ (page number not for citation purposes)
Rogosnitzky et alJMIRx Med
XSL
FO
RenderX
106. Hutchings DC, Anderson SG, Caldwell JL, Trafford AW. Phosphodiesterase-5 inhibitors and the heart: compound
cardioprotection? Heart 2018 Aug 08;104(15):1244-1250 [FREE Full text] [doi: 10.1136/heartjnl-2017-312865] [Medline:
29519873]
107. Brown KE, Dhaun N, Goddard J, Webb DJ. Potential therapeutic role of phosphodiesterase type 5 inhibition in hypertension
and chronic kidney disease. Hypertension 2014 Jan;63(1):5-11. [doi: 10.1161/HYPERTENSIONAHA.113.01774] [Medline:
24101666]
108. Anderson SG, Hutchings DC, Woodward M, Rahimi K, Rutter MK, Kirby M, et al. Phosphodiesterase type-5 inhibitor use
in type 2 diabetes is associated with a reduction in all-cause mortality. Heart 2016 Nov 01;102(21):1750-1756 [FREE Full
text] [doi: 10.1136/heartjnl-2015-309223] [Medline: 27465053]
109. Barnes H, Brown Z, Burns A, Williams T. Phosphodiesterase 5 inhibitors for pulmonary hypertension. Cochrane Database
Syst Rev 2019 Jan 31;1:CD012621 [FREE Full text] [doi: 10.1002/14651858.CD012621.pub2] [Medline: 30701543]
110. Rochwerg B, Neupane B, Zhang Y, Garcia CC, Raghu G, Richeldi L, et al. Treatment of idiopathic pulmonary fibrosis: a
network meta-analysis. BMC Med 2016 Feb 03;14(1):18 [FREE Full text] [doi: 10.1186/s12916-016-0558-x] [Medline:
26843176]
111. Ashworth AJ. Enhanced recovery from respiratory infection following treatment with a PDE-5 inhibitor: a single case
study. Prim Care Respir J 2012 Mar 27;21(1):17-17 [FREE Full text] [doi: 10.4104/pcrj.2012.00016] [Medline: 22382866]
112. Webb DJ, Vachiery J, Hwang L, Maurey JO. Sildenafil improves renal function in patients with pulmonary arterial
hypertension. Br J Clin Pharmacol 2015 Aug 19;80(2):235-241 [FREE Full text] [doi: 10.1111/bcp.12616] [Medline:
25727860]
113. Aggrenox To Treat Acute Covid-19 (NCT04410328). ClinicalTrials.gov. 2020. URL: https://clinicaltrials.gov/show/
NCT04410328 [accessed 2020-08-28]
114. Dipyridamole to Prevent Coronavirus Exacerbation of Respiratory Status (DICER) in COVID-19 (NCT04391179).
ClinicalTrials.gov. 2020. URL: https://clinicaltrials.gov/show/NCT04391179 [accessed 2020-08-28]
115. Trial of Open Label Dipyridamole - In Hospitalized Patients With COVID-19 (NCT04424901). ClinicalTrials.gov. 2020.
URL: https://clinicaltrials.gov/show/NCT04424901 [accessed 2020-08-28]
116. Hogan II RB, Hogan III RB, Cannon T, Rappai M, Studdard J, Paul D, et al. Dual-histamine receptor blockade with cetirizine
- famotidine reduces pulmonary symptoms in COVID-19 patients. Pulm Pharmacol Ther 2020 Aug 29;63:101942 [FREE
Full text] [doi: 10.1016/j.pupt.2020.101942] [Medline: 32871242]
117. Janowitz T, Gablenz E, Pattinson D, Wang TC, Conigliaro J, Tracey K, et al. Famotidine use and quantitative symptom
tracking for COVID-19 in non-hospitalised patients: a case series. Gut 2020 Sep 04;69(9):1592-1597. [doi:
10.1136/gutjnl-2020-321852] [Medline: 32499303]
118. Tomera K, Kittah J. Famotidine with celecoxib adjuvant therapy on hospitalized COVID-19 patients: A case series. SSRN.
2020. URL: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3646583 [accessed 2020-09-15]
119. Freedberg DE, Conigliaro J, Wang TC, Tracey KJ, Callahan MV, Abrams JA, Famotidine Research Group. Famotidine
Use Is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched
Retrospective Cohort Study. Gastroenterology 2020 May 22:e [FREE Full text] [doi: 10.1053/j.gastro.2020.05.053] [Medline:
32446698]
120. Malone R, Tisdall P, Fremont-Smith P, Liu Y, Huang X, White K, et al. COVID-19: Famotidine, Histamine, Mast Cells,
and Mechanisms. Res Sq 2020 Jun 22:37 [FREE Full text] [doi: 10.21203/rs.3.rs-30934/v2] [Medline: 32702719]
121. Ehrlich A, Uhl S, Ioannidis K, Hofree M, tenOever B, Nahmias Y. The SARS-CoV-2 transcriptional metabolic signature
in lung epithelium. SSRN. 2020. URL: https://papers.ssrn.com/abstract=3650499 [accessed 2020-08-30]
122. Isidori AM, Giannetta E, Pofi R, Venneri MA, Gianfrilli D, Campolo F, et al. Targeting the NO-cGMP-PDE5 pathway in
COVID-19 infection. The DEDALO project. Andrology 2020 Jun 11:e [FREE Full text] [doi: 10.1111/andr.12837] [Medline:
32526061]
123. Sildenafil in COVID-19 (NCT04489446). ClinicalTrials.gov. 2020. URL: https://clinicaltrials.gov/show/NCT04489446
[accessed 2020-08-28]
Abbreviations
ARDS: acute respiratory distress syndrome
bid: twice daily
cAMP: cyclic adenosine monophosphate
cGMP: cyclic guanine monophosphate
CKD: chronic kidney disease
CRP: C-reactive protein
CTAD: citrate-theophylline-adenosine-dipyridamole
DEDALO: silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID-19
FDA: Food and Drug Administration
GERD: gastroesophageal reflux disease
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H2RA: histamine type-2 receptor antagonist
HSV: herpes simplex virus
NO: nitric oxide
PAH: pulmonary arterial hypertension
PDE: phosphodiesterase-5
qid: four times daily
Edited by G Eysenbach; submitted 23.04.20; peer-reviewed by A Hamed, S Howlett, E Sutcliffe; comments to author 20.08.20; revised
version received 01.09.20; accepted 14.09.20; published 30.09.20
Please cite as:
Rogosnitzky M, Berkowitz E, Jadad AR
No Time to Waste: Real-World Repurposing of Generic Drugs as a Multifaceted Strategy Against COVID-19
JMIRx Med 2020;1(1):e19583
URL: https://med.jmirx.org/2020/1/e19583/
doi: 10.2196/19583
PMID:
©Moshe Rogosnitzky, Esther Berkowitz, Alejandro R Jadad. Originally published in JMIRx Med (https://med.jmirx.org),
30.09.2020. This is an open-access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work, first published in the JMIRx Med, is properly cited. The complete bibliographic information, a link
to the original publication on https://med.jmirx.org/, as well as this copyright and license information must be included.
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... Sildenafil is an orally administered phosphodiesterase type 5 (PDE5) inhibitor that permits corpus cavernosum smooth muscle to relax and potentiating erections during sexual stimulation (Langtry and Markham, 1999;Georgiadis et al., 2020;Iordache et al., 2020a). It is also reported that the sildenafil can inhibit the breakdown of cyclic guanosine monophosphate (cGMP) through binding at the phosphodiesterase binding site (Iordache et al., 2020b;Rogosnitzky et al., 2020). A pilot study of sildenafil is designed in phase 3 clinical trial (NCT04304313) to check its citrate form tablet's safety, efficacy, and tolerability at a dose of 0.1g/day for 14 days in 10 COVID-19 patients (Clinicaltrials.Gov, 2020ba). ...
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Real-world drug repurposing - the immediate 'off-label' prescribing of drugs to address urgent clinical need - is a widely overlooked opportunity. Off-label prescribing (i.e. for a non-approved indication) is legal in most countries, and tends to shift the burden of liability or cost to physicians and patients, respectively. Nevertheless, health crises may mean that real-world repurposing is the only realistic source of solutions. Optimal real-world repurposing requires a track record of safety, affordability, and access for drug candidates. Although thousands of such drugs are already available, there is no central repository of off-label uses to facilitate immediate identification and selection of potentially useful interventions during public health crises. Using the current COVID-19 pandemic as an example, we provide a glimpse of the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and target the underlying pathophysiology that makes COVID-19 so deadly. This paper briefly summarizes why cimetidine or famotidine, dipyridamole, fenofibrate or bezafibrate, and sildenafil citrate, are worth considering for patients with COVID-19. Clinical trials to assess efficacy are already underway for famotidine, dipyridamole, and sildenafil, and further trials of all these agents will be important in due course. These examples also reveal the unlimited opportunity to future-proof our healthcare systems by proactively mining, synthesizing, cataloging, and evaluating the off-label treatment opportunities of thousands of safe, well established, and affordable generic drugs.
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BACKGROUND: Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence. METHODS: We performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented. RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group. CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with Corona Virus Disease 2019 (COVID-19), we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. Food and Drug Administration (FDA) approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P<0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.
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Background Despite limited and conflicting evidence, hydroxychloroquine, alone or in combination with azithromycin, is widely used in COVID-19 therapy. Methods We performed a retrospective study of electronic health records of patients hospitalized with confirmed SARS-CoV-2 infection in United States Veterans Health Administration medical centers between March 9, 2020 and April 29, 2020. Patients hospitalized within 24 hours of diagnosis were classified based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) or no HC as treatments. The primary outcomes were mortality and use of mechanical ventilation. Findings A total of 807 patients were evaluated. Compared to the no HC group, after propensity score adjustment for clinical characteristics, the risk of death from any cause was higher in the HC group (adjusted hazard ratio (aHR), 1.83; 95% CI, 1.16 to 2.89; P=0.009) but not in the HC+AZ group (aHR, 1.31; 95% CI, 0.80 to 2.15; P=0.28). Both the propensity score-adjusted risks of mechanical ventilation and death after mechanical ventilation were not significantly different in the HC group (aHR, 1.19; 95% CI, 0.78 to 1.82; P=0.42 and aHR, 2.11; 95% CI, 0.96 to 4.62; P=0.06, respectively) or in the HC+AZ group (aHR, 1.09; 95% CI, 0.72 to 1.66; P=0.69 and aHR, 1.25; 95% CI, 0.59 to 2.68; P=0.56, respectively), compared to the no HC group. Conclusions Among patients hospitalized with COVID-19, this retrospective study did not identify any significant reduction in mortality or in the need for mechanical ventilation with hydroxychloroquine treatment with or without azithromycin. Funding University of Virginia Strategic Investment Fund.