Chapter 5

Treatment

5.1. Current treatment options for PD patients

There are presently no disease-modifying treatments for PD, so management mainly composed
of dopaminergic drugs. The most widely used of these are preparations of levodopa, the
dopamine precursor, which are given in conjunction with a dopa-decarboxylase inhibitor to
reduce some of the side effects such as nausea (Stoker, Torsney and Barker, 2018). Ropinirole
and rotigotine, both dopamine agonists, are also used. To minimize the metabolism of
endogenous dopamine, monoamine oxidase B inhibitor like rasagiline and selegiline, as well as
catechol-O-methyltransferase (COMT) inhibitors such as entacapone, can be used. These
medicines have the potential to restore dopaminergic activity in the striatum, heralding
enhancement in the motor characteristics of PD. However, they do not, cure many of the non-
motor aspects that are particularly debilitating for many individuals. Indeed, in certain situations,
therapies may aggravate non-motor symptoms such as postural hypotension along with
neuropsychiatric issues (Young et al., 1997; Kujawa et al., 2000).

Although these therapies can result in remarkable enhancement in the motor characteristics of
PD, particularly in the early stages, long-term use of levodopa has considerable side
consequences that are an essential component of the clinical image in advanced PD. The
troublesome dyskinesias are assumed to be caused by the non-physiological continuous flow of
dopamine to the striatum (abnormal involuntary jerky movements) (Jenner, 2003; Huot et al.,
2013), and serious fluctuations in motor function can happen because erratic absorption of the
drug as well as irregular transit of levodopa into the brain, resulting in the so-called on-off
phenomena (Nutt et al., 1984). These drugs also have off-target effects since they are sent to
parts of the brain other than the striatum, which is considered to be the reason for the
neuropsychiatric side effects that might develop, such as hallucinations and impulse control
problem (Ernst, 1969; Voon et al., 2009).
Deep brain stimulation (DBS) is another therapeutic option that can be quite helpful in treating
the movement disorder of Parkinson's disease (PD), but, like dopaminergic drugs, it does not
assist with most of the non-motor indications (Kalia et al., 2013). Though DBS is a secure
treatment method, there are additional potentially significant adverse effects such as speech
difficulty and psychological disruption, as well as the general hazards involved with a
neurosurgical surgery, and this treatment is only appropriate in a minority of PD cases. (Benabid,
2003).

The use of levodopa-intestinal gel, which leads in a more predictable release of dopamine than
oral formulations, is one strategy of administering dopamine in a more physiological manner.
This may be effective in lowering the motor side effects of dopaminergic medication, but it is
presently prohibitively costly for general usage, and it is fraught with difficulties due to the
surgery required for its installation (Olanow et al., 2014). Furthermore, like with DBS and
apomorphine pumps, patients are tethered to a device that must be worn at all times, which is
unsuitable for many people (Jiang et al., 2016; Siddiqui et al., 2018; Borovac et al., 2016).

So, while there are successful therapy choices for the motor elements of PD, they come with
major drawbacks, and none of them can reduce disease progression or ameliorate the debilitating
non-motor symptoms. (Nikolaus et al., 2019). 
5.2. Repurposed drugs for COVID-19
There is currently no clinical trial reference for any medicine that can support therapeutic or

preventive results in patients infected with or suspected of having COVID-19. 100 clinical trials

using existing repurposed pharmaceuticals are now underway (Anwar et al., 2020). In the current

context, medication repositioning might be viewed as a potential therapy option for COVID-19.

(Singh et al., 2020). 

Remdesivir is now licensed for the treatment of COVID-19. It is a prodrug that is activated to
Cadenosine triphosphate and has selective action against host polymerase against RNA viruses
such as Coronaviridae and Flaviviridae, including the Ebola virus (Barkoff and Mousa, 2021).
Still, there is no treatment available for COVID-19 as a result esearchers are testing a variety of
possible treatments which include (Singh et al., 2020):

Favipiravir 

According to information collected by Dong and colleagues from a Chinese news station,

favirpiravi was approved for use against SARS-CoV2 infected patients in China on February 15,

2020, because it significantly reduced the disease of SARS-CoV2 infected patients. (Dong, Hu

and Gao, 2020). It operates by blocking the enzyme RNA polymerase. (Zhao et al., 2015).

Monoclonal antibodies 

SARS-CoV-2 possesses a spike protein on its surface that aids viral attachment and entry into

human cells. Several monoclonal antibodies have been designed that bind to the SARS-CoV-2

spike protein and prevent the virus from infecting human cells. COVID-19 patients may be given

an intravenous (IV) infusion of a monoclonal antibody. Two combination products,

bamlanivimab plus etesevimab and casirivimab plus imdevimab, are approved by the FDA for

the treatment of mild to moderate COVID-19 in non-hospitalized patients with laboratory

confirmed SARS-CoV-2 infection who are at high risk of progressing to severe disease and/or

hospitalization (Lloyd, Gandhi and Petty, 2021).

Chloroquine and Hydroxychloroquine

The United States Food and Drug Administration has discontinued its emergency use
authorisation for chloroquine and hydroxychloroquine for COVID-19 patients (Singh et al.,
2020). CQ and HCQ both are weak bases that raise the pH of acidic intracellular organelles such
as lysosomes/endosomes, which require a low pH for maturation as well as function.
Furthermore, CQ was discovered to generate alterations in the glycosylation of the ACE2 spike
protein and receptor, which eventually inhibits the entry step and the post-entry phase of SARS-
CoV-2.12 HCQ demonstrated the capacity to exert the same mechanism in the time-of-addition
experiment. (Saghir et al., 2021).

Convalescent plasma transfusion

It is useful in the treatment of severely ill COVID-19 patients (Shen et al., 2020) and already
been utilized in the treatment of SARS infection. In one uncontrolled research of five severely
sick COVID-19 patients, the delivery of plasma containing neutralized antibodies demonstrated
encouraging effects in terms of these patients' clinical state (Chen et al., 2020). A meta-analysis
of plasma treatment for SARS and influenza found that it was related with a lower death rate (95
percent CI), minimal side effects, and a low risk. However, the efficacy of plasma treatment in
Parkinson's disease patients with COVID-19 is yet unknown and is under clinical trial (Parker et
al., 2020).

5.3. Treatment of PD patients with COVID-19

Favipiravir 

It will be difficult to determine the appropriate dose of favipiravir for those above the age of 60,
particularly PD sufferers because most  of  the  PD  patients might  have  one  or  more chronic
disease such as hypertension, diabetes  along with  other complications(Anwar et al.,
2020) . Also, COVID-19 is frequently linked with acute respiratory distress. So, it is very crucial
to understand the drug interaction for such patients. Favipiravir  interacts  with  acetaminophen
because of the inhibition  of  sulphate  transferase  in  the  liver, which makes  it very important
to understand the drug interaction for the PD patients before recommending this drug. Aldehyde
oxidase (AO) metabolizes FPV in the cytosol; many drugs are metabolized by this enzyme.  PD 
patients  on  any  of  AO  inhibitors  like cimetidine, calcium channel blocker, antiarrhythmic
drug propafenone  or  any  other  tricyclic  antidepressant need to adjust the dose before going
for FPV (Zhao et al., 2015).

Azithromycin
In the treatment of lung infection, AZM is also found to have anti-inflammatory action via
suppressing IL-6. This impact has the potential to alleviate the inflammatory process produced
by SARS-CoV-2 (Gérard et al., 2020). Therefore, it functions as a medication with the ability to
eliminate senescent cells up to 97 percent of the time. It works as an anti-fibrotic agent in cystic
fibrosis patients by targeting myofibroblast cells. Fibrosis is an age-related condition
characterized by an increase in the number of myofibroblast cells (Song et al., 2020). PD is also
an age-related condition, and an increase in myofibroblast cells cannot be ruled out in such
individuals. It has been demonstrated that AZM, a regularly used antibiotic that suppresses viral
replication and IL-6 production, can be utilized as an option in the treatment of COVID-19
illness in PD patients (Anwar et al., 2020).

Amantadine

Amantadine was the first FDA-approved medicine in the United States, and it is the only
medicine that indicates its dual function in the treatment of Parkinson's disease and COVID-19
(Araújo, Aranda-Martínez and Aranda-Abreu, 2020). It affects various neurotransmitters
implicated in Parkinson's disease, including an increase in dopamine release (Nikolaus et al.,
2019), blocks cholinergic receptors (Fryml et al., 2017), and inhibits N-methyl D-aspartate
(NMDA) receptors (Oertel et al., 2017).Thus, it was employed to counteract the effects of
COVID-19 through two separate processes (Butterworth, 2020), namely:

Down-regulation of host cell proteases, including but not necessarily limited to cathepsin L,
resulting in defective fusion of viral and host cell membranes, resulting in defective release of
the viral genome into the host cell's cytoplasm. Reduced viral entry has the potential to reduce
viral load in SARS-CoV-2 infected individuals, leading to improved clinical outcomes. To
determine the therapeutic effectiveness of amantadine for the treatment of COVID-19 infection,
appropriately planned, properly powered controlled clinical studies are presently required.
(Butterworth, 2020).

Amantadine is a highly effective noncompetitive NMDA receptor antagonist. Experiments with

coronaviruses show that such medicines can restrict viral proliferation while also improving
neurological results. NMDA receptors are found in various locations in mammalian lungs and
airways, and a function for these receptors in the activation of NMDA receptors in various kinds
of acute lung damage as well as the pathogenesis of the acute respiratory distress syndrome has
been hypothesized (Li, Bai and Hashikawa, 2020).

However, this medication has been linked to side effects such as hallucination, disorientation,
anxiety, and restlessness. (Grieb et al., 2021).

5.3.1. Link among Amantadine, COVID-19 and PD

Amantadine is advantageous due to its activities in promoting dopaminergic synaptic activation.
Several processes, including increased dopamine synthesis, turnover, and release, have been
hypothesized. Positron Emission Tomography (PET) studies in Parkinson's disease patients give
data consistent with the idea that amantadine increases dopamine production as a result of
antagonism of the NMDA subtype of glutamate receptors in the brain. (Deep et al., 1999, Kong
et al., 2017).

Although it has not been determined whether amantadine's NMDA receptor antagonist property
is involved in the agent's protective effects against COVID-19 or its neurological complications,
there is evidence to suggest that NMDA receptor antagonists may be useful in the treatment of
other coronaviruses. For example, the human coronavirus strain HCoV-OC43 is known to infect
as well as persist in human neural cells where it activates neuroinflammatory and
neurodegenerative mechanisms along with treatment with HCoV-OC43-infected mice with the
non-competitive NMDA receptor antagonist memantine, an agent that is structurally-related to
amantadine, has been found to limit viral replication and to improve neurological symptoms.
Moreover, the expression of NMDA receptors in the lungs as well as airways may underpin the
signaling mechanisms implicated in the pathogenesis of acute lung injury and the acute
respiratory distress syndrome that is characteristic of COVID-19 (Desforges et al., 2019;
Butterworth, 2020).