\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[english]{babel}



\usepackage{float}








\begin{document}

\title{PARP-inhibitors in a non-oncological indication as COVID-19: are we
aware about its potential role as anti-thrombotic drugs? The discussion
is open.}



\author[1]{Ettore Capoluongo}%
\affil[1]{University of Naples Federico II School of Medicine and Surgery}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{}In the last three months, most research groups have shifted
their focus to the fight against the COVI-2 infection (COVID-19). Many
scientists worked to understand how the virus is transmitted and able to
mutate or how it can be sensitive to new and old drugs. Up to now, the
results obtained in this field were not always promising and, sometimes,
completely inconclusive, as in the case of chloroquine (1). However, the
recent discovery on benefits deriving from use of such anticoagulants
for Covid-19 patients, has increased the success of treatment (2). In
fact, as reported by Tang \emph{et al} (2), since the disseminated
intravascular coagulation and coagulopathy can contribute to patients'
death, anticoagulant administration resulted as being associated with
decreased mortality in severe~COVID-19~pneumonia (2). Tang \emph{et
al}(2) also assessed that low molecular weight heparin (LMWH) regimen
seems to be associated with better prognosis in severe COVID-19 patients
meeting sepsis-induced coagulopathy criteria or with markedly elevated
D-dimer. Along with other experimental treatments, or in combination,
these findings have dramatically reduced the number of patients needing
intensive cares, with a lightening of the workload of the emergency
departments and a definitive improvement in the ratio of deaths to
infected (2,3). However, although with some concerns mainly related to
the schemes of LMWH administration, using of prophylactic-doses of LMWH
was recommended by the International Society on Thrombosis and
Haemostasis (ISTH) for all recovered COVID-19 patients, except for those
with an active haemorrhage or with a platelet count \textless{} 25 x
10\textsuperscript{9}/L. (3).

While many drugs are still under investigation in clinical trials (4),
after a rapid approval by the medical agencies of different countries,
there are no definitive results. In this regard, very recently, a
research group focused on different treatments administered to Chinese
individuals showing as there is no proven regimen from conventional
medicine (4). Nevertheless, most reports managed the patients with
lopinavir/ritonavir, ribavirin, beta-interferon, glucocorticoid and
supportive treatment with remdesivir undergoing clinical trial (4).
After an extensive revision of the latest national and provincial
clinical guidelines, retrospective cohort studies, and case series
regarding the treatment of~COVID-19 by add-on Chinese medicine, Chan et
al. (4) concluded that, due to the paucity of strongly evidence-based
treatments, the current data only suggest that Chinese medicine could be
considered as an adjunctive therapeutic option in the management
of~COVID-19.

In this scenario, where nothing seems to be completely clear, and after
reading the paper published by Berger et al (5), I would like to open
the discussion on the following topic that has not been covered by the
current literature.

I am referring to the fact that no available data are reported about any
possible relationship between Covid-2 effects and patients under
chemotherapy regimen with PARP-1 inhibitors. My empirical consideration,
not still supported by literature data, emerged from my experience
gained in the last ten years research on the oncogenetic features of
PARP-inhibition in women suffering from ovarian cancer (6). Noteworthy,
patients under anti-PARP-1 regimens (5), particularly those with
pancreatic, prostate, ovarian and breast cancers (most of them enrolled
in clinical trials), might be more protected by the Covid-2 severe
effects like the thrombotic events. I underline as for bevacizumab drug
an association with venous thromboembolism has been reported in ovarian
cancer patients, mostly in patients with elevated D-dimer level and high
BMI before chemotherapy (5). These findings were never reported for
Olaparib. Regarding PARP pathway, several studies showed as the
inhibition of poly-ADP ribose polymerase-1 (PARP-1) reduced organ
dysfunction in post-myocardial infarction remodelling,
ischemia-reperfusion injury, diabetic retinopathy, septic shock,
diabetes, and atherosclerosis, attenuating diseases associated with
vascular smooth muscle and endothelial dysfunction. The latter is a
specific feature of Covid-19 (3). Mathews et al. (7) demonstrated that
PARP-1, when activated by oxidative and nitrosative stress, consumes
cellular energy and precipitates endothelial cell death. Therefore,
inhibition of PARP-1 prevented ROS- and RNS-induced HUVEC death, not
only by maintaining cellular energy, but also through a novel mechanism
via VEGFR2, Akt, and Bad phosphorylation. All these findings are very
interesting when translated to the possible mechanisms surrounding the
disseminated intravascular coagulation and coagulopathy processes
leading to either patient's severe symptoms or death related to
Covid-19. Noteworthy, the inflammatory process, cytokine storm, and lung
injury~can result in an increased risk of thrombosis for Covid-2
positive patients (3,4). In this setting, use of anti-PARP drugs in
non-oncological indications, although still under debate, was reported
as being of benefit inflammatory disorders such as arthritis, psoriasis,
colitis, asthma, diabetic complications and cardiovascular diseases (5).
Moreover, although data on total incidence of thrombotic events in
COVID-19 is still uncertain, we can assume that individuals with
increasing age, obesity, comorbidities and cancer are at higher risk of
these events. Based on the scientific evidences regarding a potential
anti-inflammatory and anti-thrombosis effect of PARP-1 inhibitors (5),
the scientific community should be encouraged to investigate the
PARP-1-inhibitors in the treatment of Covid-19, particularly due to the
mitigation effects of all pathways promoting the inflammatory and
thrombotic cascades, respectively (2,3).

PARP enzymes (PARP-1 and PARP-2) play a pivotal role in sustaining the
genome stability. PARP inhibitors are small molecule mimetics of
nicotinamide which bind to PARP's catalytic domain to inhibit
poly-ADP-ribosylation (PARylation) of target proteins (5). Considering
that different forms of PARP inhibitors are present now on the market
(olaparib, veliparib, talazoparib, niraparib and rucaparib), there will
be an easy access to these medications for using in either new clinical
trials and/or in translational studies.

Finally, although a risk of genotoxicity can be also associated to
PARP-1 inhibitors long term administration (5), this issues alone should
not be a reason to exclude a study drug for testing in a non-oncological
indication, like Covid-19 condition. As for LMWH, also in this case
different schemes of administration should be evaluated in order to
achieve the best benefit for patients. Therefore, I agree with
Berger\emph{et al} (5) who stated that there are no~sufficient reasons
to exclude studies based on PARP inhibitor in other non-oncological
settings. For these reasons, why do not encourage both basic and
translational research on PARP-1 inhibitor effects and severe forms of
Covid-19?

The above considerations are far from being provocative, but they are
only aimed to stimulate a thought on this specific topic. I would be
grateful to the Editor if, through the publication of this paper, it
would allow us to open up the debate on the subject.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Capoluongo, E.D., Amato, F., Castaldo, G. (2020). The friendly use of
  chloroquine in the COVID-19 disease: a warning for the G6PD-deficient
  males and for the unaware carriers of pathogenic alterations of the
  G6PD gene. \emph{Clin Chem Lab Med} . 2020 Clin Chem Lab Med, 2020 Apr
  24:/j/cclm.ahead-of-print/cclm-2020-0442/cclm-2020-0442.xml
\item
  Tang, N., Bai, H., Chen, X., Gong, J., Li, D., Sun, Z. (2020).
  Anticoagulant treatment is associated with decreased mortality in
  severe coronavirus disease 2019 patients with coagulopathy. \emph{J
  Thromb Haemost} , 2020;18(5):1094-1099.
\item
  Thachil, J., Tang, N., Gando, S., Falanga, A., Cattaneo, M., Levi, M.,
  Clark, C., Iba, T. (2020). ISTH interim guidance on recognition and
  management of coagulopathy in COVID-19. \emph{J Thromb Hemost} ,
  18(5):1023-1026
\item
  Chan, K.W., Wong, V.T., Tang, S.C.W. (2020). COVID-19: An Update on
  the Epidemiological, Clinical, Preventive and Therapeutic Evidence and
  Guidelines of Integrative Chinese-Western Medicine for the Management
  of 2019 Novel Coronavirus Disease. \emph{Am J Chin Med} ,
  48(3):737-762.
\item
  Berger, N.A., Besson, V.C., Boulares, A.H., \emph{et al} .(2018).
  Opportunities for the repurposing of PARP inhibitors for the therapy
  of non-oncological diseases. Br J Pharmacol;175:192-222.
\item
  Capoluongo, E. (2016). BRCA to the future: towards best testing
  practice in the era of personalised healthcare. \emph{Eur J Hum Genet}
  , 1:S1-2;
\item
  Mathews, M.T., Berk, B.C.(2008). PARP-1 inhibition prevents oxidative
  and nitrosative stress-induced endothelial cell death via
  transactivation of the VEGF receptor 2. \emph{Arterioscler Thromb Vasc
  Biol} ,28:711-717
\end{enumerate}

\selectlanguage{english}
\FloatBarrier
\end{document}

