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1
FACULTY OF SCIENCE, ENGINEERING
AND COMPUTING
School of Life Sciences, Pharmacy and Chemistry
BSc (Hons) DEGREE IN
Pharmaceutical Science
Abderazak Bouziane
K1124469
Parkinson’s disease: A study of levodopa treatment in both more and less economically developed countries and its effect on patients’ quality of life.
29/03/2016
Supervisor: Dr Caroline Kim
WARRANTY STATEMENT This is a student project. Therefore, neither the student nor Kingston University makes any
warranty, express or implied, as to the accuracy of the data or conclusion of the work
performed in the project and will not be held responsible for any consequences arising out of
any inaccuracies or omissions therein.
2
ACKNOWLEDGEMENTS
As this dissertation has proven to be one of the biggest challenges I have encountered in my
academic years, my praise and gratefulness go firstly to Allāh, The All Powerful, for giving
me the ability to overcome this hardship.
I would also like to extend great gratitude towards my supervisor and mentor, Dr Caroline
Kim, who has showed nothing but support throughout the academic year. I appreciate her
being understanding towards the few tough times I experienced, and for that I will forever
be grateful.
It is befitting that I acknowledge other university members who have been a great help
towards me attaining my degree; the thoughtful advice I have received from the likes of Dr
Freestone and Dr Kishi, alongside their down-‐to-‐earth nature has been both inspiring and
reassuring.
Finally, I would like to thank the two important women in my life, my mother and my wife,
who have shown great support and patience during this difficult phase of my life.
To end this section, this is a quote that has kept me motivated:
Knowledge cannot be acquired when the body is in comfort. -‐ Yahya ibn Katheer
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Table of Contents
ACKNOWLEDGEMENTS .................................................................................. 2
LIST OF FIGURES ............................................................................................ 5
ABBREVIATION .............................................................................................. 5
ABSTRACT ..................................................................................................... 6
1.0 Introduction ............................................................................................ 8
1.1 What is Parkinson’s disease? ................................................................ 9
1.1.1 Pathology .......................................................................................... 10
1.2 Epidemiology ...................................................................................... 14
1.3 Symptoms of Parkinson’s disease ....................................................... 15
1.3.1 Non-‐motor symptoms ....................................................................... 15
1.3.2 Motor symptoms ............................................................................... 17
1.4 Treatments for Parkinson’s disease .................................................... 19
1.4.1 Levodopa ........................................................................................... 21
2.0 Aims & Objectives ................................................................................. 24
2.1 Aims ................................................................................................... 24
2.2 Objectives .......................................................................................... 24
3.0 Methodology ......................................................................................... 25
3.1 ResearchGate ..................................................................................... 26
3.2 ScienceDirect ...................................................................................... 26
3.3 Google Scholar ................................................................................... 26
3.4 PubMed ............................................................................................. 26
3.5 Regulated Webpages .......................................................................... 27
4.0 Results and Discussion ........................................................................... 28
4.1 MEDAs ............................................................................................... 31
4
4.2 LEDAs ................................................................................................. 33
4.3 How does QoL differ in MEDAs compared to LEDAs due to levodopa
treatment accessibility? ........................................................................... 35
5.0 Conclusion ............................................................................................. 36
5.1 Future Research ................................................................................. 37
6.0 References ............................................................................................. 38
5
LIST OF FIGURES Figure 1.1.1.1 The basal ganglia
Figure 1.1.1.2 Dopamine depletion in the substantia nigra throughout course of Parkinson’s
disease
Figure 1.1.1.3 Lewy bodies in the substantia nigra
Figure 1.3.2.1 Dopamine depletion affects motor functions of Parkinson’s disease patients
Figure 1.4.1.1 Chemical structure of levodopa
Figure 1.4.1.2 Mechanism of action for levodopa/carbidopa
Figure 4.0.1 Estimated increase in Parkinson’s disease incidences in various countries, 2005-‐
2030
Figure 4.0.2 Original SINEMET® formula
Figure 4.0.3 SINEMET® CR formula
Figure 4.1.1 Increase in death rates for Parkinson’s disease in the USA, 1973-‐2003
ABBREVIATION α-‐Syn – alpha-‐Synuclein
BBB – Blood brain barrier
BG – Basal ganglia
CR – Controlled release
HRQoL – Health Related Quality of Life
LEDA – Less Economically Developed Area
MEDA – More Economically Developed Area
PD – Parkinson’s disease
QoL – Quality of Life
SN – Substantia nigra
UK – United Kingdom
USA – United States of America
6
ABSTRACT Keywords: Parkinson’s disease, levodopa, SINEMET®, carbidopa, quality of life, dopamine.
Background
Quality of Life is a concept used by those within the medicinal field to diagnose and evaluate
treatments. Quality of Life in patients suffering from Parkinson’s disease is often measured
in the form of a questionnaire whereby the overall aim is to obtain how content the patient
is with their life whilst managing the disease. This project will investigate Quality of Life in
both more and less economically developed areas of the world by identifying any differing
levels of accessibility to treatment of Parkinson’s disease. The specific treatment that will be
focused on is levodopa, in particular the SINEMET® brand which is a combination of
levodopa and carbidopa.
Methodology
Several authentic databases were used to carry out this research: ResearchGate,
ScienceDirect, Google Scholar, PubMed and regulated governmental websites (NHS and
WHO).
Results and Discussion
This research has identified levodopa as being the most common medication used in the
treatment of Parkinson’s disease and is demanded worldwide due to its high success rate in
helping patients to manage their symptoms. More economically developed areas such as
the USA see high incidences of Parkinson’s disease but this is counteracted by the country’s
high expenditure towards related treatment. Less economically developed areas such as
India witness the country’s inability to provide modern medication due to an absence in
funds.
Conclusion
Results of this research conclude that economically developed areas suffer from a lack of
consistent patient care in terms of consultation visits and the delivery of medication, to the
extent where some pharmacies depend on charitable donations. Contrastingly, more
7
economically developed areas have a much greater advantage due to financial stability and
are able to put money towards research which enables them to determine the best
medication to treat Parkinson’s disease. Both of these situations effect patient Quality of
Life, the former positively and the latter negatively.
8
1.0 Introduction Quality of life (QoL) has been described as a multi-‐dimensional construct [1] with its three
main categories being physical, mental and social [1]. It is a concept that is widely known in
the more economically developed regions of the world where countries take great interest
in health related quality of life (HRQoL) whereby those within the medicinal field evaluate
the effect of an illness and treatment on a patient, a patient’s view on their own health
condition as well as their welfare and contentment with life [1]. Many neurodegenerative
disorders, including Parkinson’s disease (PD), have a range of both motor and non-‐motor
symptoms which affect the QoL of the patient. PD is commonly associated with complaints
such as falls and dementia which may in fact significantly affect the patients’ QoL as
opposed to the main signs of PD [2] (“tremor, bradykinesia, rigor and postural instability” [3]).
The implementation of measuring the QoL in patients has become very significant in
assessing the outcomes of treatments for PD and also helps with diagnosing and evaluating
the health situation of a patient over a duration of time. To access this information,
questionnaires are created so that the patient (ideally) or someone on their behalf can
complete it; the questionnaires used for PD are typically the Parkinson’s Disease
Questionnaire (PDQ-‐39) and the Parkinson’s Disease Quality of Life Questionnaire (PDQL) [1].
These questionnaires are used because they are reliable, easy to respond to and reproduce
and easy to interpret. They also provide an insight into which symptoms are considered by
patients to have the most effect on the QoL [2].
This study will look at the QoL in Parkinson’s disease patients living in less economically
developed areas (LEDAs) of the world in comparison to the more economically developed
areas (MEDAs) in order to weigh the differences of the value placed on the concept QoL.
The treatment that will be focused on and evaluated in terms of its effect on QoL is the
levodopa medication. Levodopa is commonly used to treat Parkinson’s disease symptoms
and most patients end up being treated with it. Levodopa has several side effects that are
counteracted through the use of other medication alongside it however, studies have also
found that after using levodopa for a long period of time other serious symptoms, such as
dyskinesia, may occur in patients [38]. This study aims to analyse how easy it is to obtain
9
this treatment in less economically developed countries versus more economically
developed countries and look at how QoL differs between patients with different levels of
treatment accessibility.
A hypothesis has been constructed for the results of this study: less financially able patients
have a different perspective of money and therefore the medication that is accessible to
them whilst patients who are financially able fully acknowledge the concept of QoL because
they have the means to access treatment. PD often has no known direct cause for its
symptoms, meaning that even more money and time needs to be spent by doctors in
gaining knowledge of the disorder in LEDAs. Due to patients’ unpredictable responses to
drugs and surgery [7] this study will investigate, amongst other matters, whether the medical
profession is willing to jeopardise the QoL of patients who do not have the support to invest
in adequate care.
1.1 What is Parkinson’s disease?
PD has been said to be the most widespread serious movement disorder in the world [7]
currently affecting around 6 million people worldwide [23]. It is expected that the social and
financial drain upon communities due to the disease will only become greater as populaces
age [4]. James Parkinson is attributed to discovering PD since he constructed a detailed
written study titled An Essay on the Shaking Palsy, in 1817 [7]. In this monograph he
described a neurological disease which comprised of a resting tremor and a peculiar form of
motor disability [7]. After reading this paper, Jean-‐Martin Chacot, said to be the father of
neurology, suggested that the described syndrome should be called Maladie de Parkinson
(Parkinson’s Disease [6]).It is worth mentioning that Dániel Bereczki, a professor of
neurology, provided evidence of a much earlier source that describes the main symptoms of
PD. Ferenc Pápai Páriz was a Hungarian physician whose medical text book Pax Corporis
(Peace of the Body) was published in 1690, in this book Páriz conveys his findings of a
progressive neurological disorder mainly affecting those old in age. His description fits that
of which we use today to define PD, with detailed descriptions of the tremor, bradykinesia,
rigor and postural instability and he even proposes that the disease starts in the brain.
10
Bereckzi notes that Ferenc’s pages on what we now know to be PD is not as detailed as
Parkinson’s essay, however it provided the distinct traits of PD 130 years prior [3].
1.1.1 Pathology
Research is fundamental for the advancement of knowledge and treatment for any illness,
and fortunately the communication standards of the 1600s compared with the 2000s has
witnessed a vast improvement. Technology allows us to share knowledge globally and has
also enabled us to gain a better understanding of conditions such as PD. Today we know
that PD is a neurodegenerative condition [11] that affects movement as a result of
diminishing nerve cells in the substantia nigra (SN), an area within the midbrain, as well as in
other parts of the brain. The SN is a vast group of pigmented neurons [12] that have a huge
factor in controlling a person’s thought and movement [10]. It comprises of two sections; the
pars reticulata and the pars compacta. The pars compacta is a crucial part as its cells contain
melanin, enabling the synthesis of dopamine which is then sent to either one of two
components of the basal ganglia (BG) contributing to the management of the motor system:
the caudate nucleus or the putamen (Figure 1.1.1.1). These two components along with the
globus pallidus [12] and the amygdala [15] make up the striatum.
11
Figure 1.1.1.1 Diagram of the basal ganglia which is made up from numerous brain
structures, together contributing to the control of movement in the body. The areas labelled
are all affected by Parkinson’s disease as the disease progresses. [15] [Accessed: January 17th
2016]
The BG is essentially a great mass of nerve cells (nuclei), part of which is the striatum [15].
The basal ganglia is responsible for all gross motor actions such as running and swimming [15]. Damage to this part of the brain can result in movement difficulty, stiffness and
clumsiness or as seen in PD, an individual may also suffer from a tremor [15], therefore
making the basal ganglia highly significant in the context of PD. The loss of nerve cells in a
patient with PD causes a decrease in the production of a chemical named dopamine. These
dopamine neurons allow for a pathway to be formed to the striatum so that signals can be
sent [10]. As dopamine is responsible for bodily functions, its reduction (Figure 1.1.1.2)
results in the “denervation” [14] of the striatum, thus leading to a continuous malfunctioning
of the motor system (area involved in movement) which only worsens with age as there is
no current cure for the disease [14].
12
Figure 1.1.1.2 Diagram showing dopamine depletion in the substantia nigra throughout the
course of Parkinson’s disease. The high and low dopamine indicator on the right of the
diagram shows that higher levels of dopamine is represented in the red and orange colours.
Month 22 (post diagnosis) to month 46 show a blue colour which represents low levels of
dopamine, therefore indicating the continuous decrease in dopamine as the disease
progresses. [29] [Accessed: January 17th 2016]
Findings also show that as well as dying cells, the cells that are left behind in regions of the
brain specific to memory and muscle movement contain deposits of an abnormal protein [30]
named Lewy bodies (Figure 1.1.1.3). The reason for their abnormality is mainly due to two
factors: firstly, the structure of these proteins is very atypical in respect to the way they fold [44] and secondly, they contain numerous proteins such as alpha-‐Synuclein (α-‐Syn), ubiquitin, [41] neurofilament, alpha B crystalline [42] and Tau [43]. Another factor that adds to the
abnormality of Lewy bodies is that they are sometimes found surrounded by neurofibrillary
tangles [43]. It has been proposed that the affect Lewy bodies have on the cells is a possible
interference with chemical communications between brain cells [30].
13
Figure 1.1.1.3 Image showing a number of Lewy bodies within the same neuron, inside the
substantia nigra. [32] [Accessed: January 12th 2016]
The primary importance of Lewy bodies in the diagnosis of PD was abrogated in the 20th
century when it was discovered that Lewy bodies were present in some individuals with no
neurological problems and were not present in some patients with PD [33]. However, it is still
a requirement that Lewy bodies be identified in the residual nigral neurons in order to
diagnose PD [17]. The main component of Lewy bodies is called α-‐Syn and their pathology is
not just found in the brain. Their effects can be seen in the autonomic nervous system in
relation to the heart muscle, the intestinal tract muscles and the prostate gland [16]. In
regards to the intestinal tract muscles, impairment occurs as well as a change in
coordination and other problems, or patients may find they develop a symptom where they
have difficulty swallowing. Some patients unfortunately suffer from both ailments as a
result of the α-‐Syn’s effect on the body [17].
Braak and colleagues describe the stages of PD pathology [18] which also shows the
pathology of α-‐Syn in relation to its appearance and effect on the body, providing a better
understanding of the occurrence of symptoms in PD patients:
14
Braak Stage 1: [Early PD and before occurrence of motor symptoms] Impairment of sense of
smell and of the autonomic nervous system (especially concerning the stomach and
intestines).
Braak Stage 2: [Early PD] Deposits of Lewy bodies found in numerous nuclei within the
medulla (part of the brainstem) possibly causing the initiation of malfunctions in the rapid
eye movement (REM) phase of sleep and other apparent conditions in early PD.
Braak Stages 3-‐4: [Motor phases of PD] Lewy bodies are now visible in the SN (the first area
of the brain where neuronal cell loss occurs [28]) and movement disorders are now a
significant aspect of PD in the patient.
Braak Stages 5-‐6: [Advanced PD] Lewy bodies are now deposited in the neocortex. (The
neocortex is part of the cerebral cortex which contains many neurons and is connected to
functions such as the senses, movement and thought processing [28]).
1.2 Epidemiology
Around 0.3% of the general population in MEDAs are affected by PD with an approximate
1% of the affected population being over the age of 60 years [4] and 3-‐5% being 85 years and
above [21]. Looking at the development of PD in correlation to age, 17.4 patients in 100 000
are between 50 and 59 years old whereas 93.1 patients in 100 000 are between 70 and 79
years old [6]. The average age for the onset of PD is said to be 60 years [6] or early to mid-‐60s [7] and the average life expectancy from being diagnosed with the disease until the patient
dies is 15 years [6]. Around 5-‐10% of PD patients have young onset PD where symptoms can
become apparent as young as 21 years or as old as 50 years [7].
As well as the major factor of age playing in the likelihood of developing PD, gender also has
its part; men are 1.5% more likely than women to develop PD [7]. Some other interesting
statistics regarding PD show that women post-‐menopause (and not on hormone
replacement) with a low daily intake of caffeine appear to be around 2.5% more at risk of
developing PD. Additionally, those who have never smoked are twice as likely to develop PD
15
than those who have smoked [6]. Ethnicity does not appear to be a factor of developing the
disease [7], however studies continue to be carried out amongst some groups of people in
order to get a better understanding of familial (gene related) PD.
In the past PD was often only linked to the deficiency in dopamine which leads to
movement disorders. However, later discoveries have looked into what causes the cell loss
in the beginning. The exact cause of PD itself still remains unknown although it has been
stated that it is a possible result of an environmental factor (such as pesticides and tobacco [25]), a genetic factor or both factors together [20]. More recent studies of PD focus on the
genetic impact on developing PD because proof for the disease being caused or triggered by
environmental factors is few [6]. In fact, studies have shown that in some cases there are
definite genetic mutations (six different genes have been identified [22]) causing PD which in
turn suggests that PD is in effect a multi-‐system brain disease. This can potentially lead to a
new outlook on the treatment of familial forms of PD [2].
1.3 Symptoms of Parkinson’s disease
All symptoms of PD cannot be cured but can be controlled by medication. Medication helps
to provide a certain amount of relief for patients by reducing some symptoms of the
disease, providing a better quality of life. The symptoms of PD, as opposed to the disease
itself, are what cause patients to die. The exact cause of death is not easy to recognise in
many cases but the most documented cause is pneumonia [6].
1.3.1 Non-‐motor symptoms
During the early stages of PD, patients may find that they suffer from non-‐motor complaints
such as depression, constipation and sleep disorders [26]. Unfortunately, many of these
symptoms lead to a misdiagnosis as they suggest conditions other than PD when motor
symptoms are not apparent or very elusive [23]. A reliable biomarker for PD or a diagnostic
assessment that is easy to implement are still yet to be found [4], so PD continues to be
described as an “enigmatic” [7] or “sporadic” [6] disease. Because of the difficulty with
clinically diagnosing PD in its beginning stages [4], it has been recommended that screening
non-‐motor symptoms may actually help by providing an early preclinical diagnosis of PD [27].
16
According to Schrag and colleagues, depression is the main cause of decrease in QoL and
affects 40-‐60% of PD patients [1]. Depression affects QoL through many aspects such as
causing cognitive impairment to worsen and putting a financial strain on patients due to a
higher need for health care [39]. Depression in PD is such a problematic symptom as it can
even cause sleep disorders to develop in the patient [21]. Other findings show that
depression can also significantly impact on motor symptoms [39] and the effect of treatment
for motor symptoms such as deep brain stimulation [34]. These studies have only been
carried out on a small scale so more research is needed but it shows the effects of
depression in PD is not yet fully understood, particularly seeing as depression without PD is
already a complex condition; its effect in PD may be even more critical than it is currently
thought to be [35].
Anxiety is another prevalent disorder amongst PD patients [21] and 20-‐46% of patients are
said to suffer from it, with other findings claiming the percentage of patients to be 75%.
Anxiety is an important symptom that may be overlooked, however it has a huge effect on a
patient’s cognition. This symptom affects a patient’s QoL through causing lack of motivation
and aggravating other PD linked symptoms. Anxiety can also lead patients to refuse
treatment which no doubt will affect the QoL of life they continue to lead as PD progresses [1].
Sleep disorders are a highly significant non-‐motor symptom of PD [21] as they greatly affect a
patient’s QoL due to their overwhelming and potentially dangerous nature. Sleep disorders
that occur early in PD have been linked to an interference with dopamine signals within the
central nervous system. This symptom can come about in the form of sleeping too much
during the day which can consequently lead to serious accidents such as car crashes or the
inability to function socially. These factors considerably decrease a patient’s QoL [1].
Fatigue is a symptom of PD that also inhibits patients from leading a higher QoL whilst it is
still a problem that is being misjudged. PDQ-‐39 studies gathering information on HRQoL
show that 1 in 3 patients deem fatigue to be the most debilitating symptom of PD. Hitten et
al. found that extreme fatigue was present in 48% of PD patients. It has also been stated
17
that measuring the impact of fatigue is as important as measuring cognitive impairment
(which affects 40-‐65% of PD patients) and depression with regards to symptoms that affect
QoL the most. The fatigue experienced by PD patients is similar to the typical tremor in the
sense that it too is uncontrollable. This symptom can affect patients in numerous ways
whether it’s causing energy loss or weakness in the muscles. Fatigue is a serious symptom
and is one of many non-‐motor symptoms that show the disabling effects of PD are not only
directly connected to movement and can appear years prior to a diagnosis [1].
Non-‐motor symptoms such as dementia [24] and dysautonomia (a range of conditions caused
by failure of the autonomic nervous system) tend to appear more in the late stages of PD [5]
although it is still known for cognitive impairment to become present in early PD [21].
Dementia is a symptom that is often linked to PD and is estimated to affect around 30% [31]
of PD patients, with much higher incidence rates having been reported [39]. Cognitive
impairment increases with PD so the symptoms of patients who develop dementia as well
as cognitive impairment are much more severe than in non-‐demented patients [21]. PD
patients are more at risk of developing dementia as they get older and are also more at risk
if they suffer from slight cognitive impairment and if particular symptoms (such as postural
instability) are severe [39]. Dementia in PD has a great influence on the QoL of the patient
and caregiver; alongside it being financially draining it increases the likelihood of the patient
moving to a nursing home and also increases the time they spend in hospital [31]. There are
many other non-‐motor symptoms associated with PD such as issues dealing with emotion,
coordination and speech difficulties, balancing problems and general pain in the body, that
all affect a patient’s QoL tremendously although many a time are underestimated [1].
1.3.2 Motor symptoms
Common motor disorders associated with PD are a tremor, postural instability (some
definitions replace this with bradykinesia – a term for slowed movements – or add it in as an
additional PD feature) [40] and rigidity [20], by the time these are found in a patient a correct
clinical diagnosis of PD is usually issued [21] although not all of these symptoms are
necessarily present at the time of diagnosis. Motor symptoms gradually deteriorate further
as PD progresses in the patient, due to the continuous depletion of dopaminergic neurons
18
(Figure 1.3.2.1) and it has been found that PD advances slower in patients whose main
motor symptom is the tremor. Due to the severity of the cell loss in the substantia nigra, PD
in patients with bradykinesia and rigidity as dominant symptoms advances much faster [40].
QoL is greatly affected by motor symptoms as they have a disabling effect on patients and
make it difficult to carry out everyday tasks.
Figure 1.3.2.1 Diagram showing how gradual loss of dopaminergic neurons affects
Parkinson’s disease patients’ motor functions [15]. [Accessed: February 7th 2016]
Falls are a common motor symptom affecting many PD patients in varying ways. Some
patients find themselves tripping indoors, whilst others mainly whilst outdoors and other
patients suffer from falls due to an unexpected balance loss. Falls are more likely to occur in
PD patients who are older, have suffered from the disease for a long period of time; are
currently in the more advanced stages of the disease; are suffering from autonomic
19
impairment or; are suffering from postural instability. PD patients who have higher
incidence rates of problems balancing whilst standing, motor complaints and changes to the
brain are found to be the ones who suffer from falls. These falls greatly affect patients’ QoL
as they often lead to bruising of soft tissue and sometimes lead to fractures in the body [36].
Gait impairment is another very common motor symptom in PD which concerns the walking
of the patient, it is so prevalent amongst PD patients that it is sometimes included among
the cardinal signs of the disease. Some patients experience this symptom in a continuous
manner whilst others experience it in episodes where their gait freezes. The former type of
gait impairment is more related to the timing of movements whilst walking such as reduced
speed, arm swinging and step length. The latter type of gait impairment typically appears in
advanced stages of PD and manifests as pausing whilst turning, difficulty upon starting to
move and “freezing” episodes in smaller areas such as entranceways. Gait impairment
affects QoL significantly as walking is a task performed daily. This symptom has been linked
to falls, emphasising its disabling nature due to its aggravation of pre-‐existing motor
symptoms. It has also been found that gait impairment may be influenced by non-‐motor
symptoms relating to cognition and vision [37]. It is fair to say that both motor and non-‐
motor symptoms alike have a substantial effect on the QoL of PD patients. The symptoms in
PD require a great amount of understanding as they tend to be complex within themselves
yet on top of this studies show links between symptoms proving that symptoms can
influence each other for the worse.
1.4 Treatments for Parkinson’s disease
As there is no known cure for PD, treatment is not aimed to cure patients from the disease
rather it is aimed to enhance patients’ QoL [1]. There are several methods used to treat PD
symptoms including medicinal drugs, surgery and supportive therapies [46]. A common
surgical procedure used to treat motor symptoms in PD is deep brain stimulation, this
involves inserting a pulse maker into the chest. Wires placed under the skin are connected
to the pulse maker and inserted into specific brain areas. A very small electric current
produced from the pulse maker runs through the wires and stimulates the PD affected brain
areas [46].
20
The purpose of medication in PD is to improve the main symptoms such as tremors and
other problems with motor functioning, these medications can be split into three
categories. The first category is medication that increases dopamine levels in the brain [45],
also known as dopamine-‐replacement therapy. This type of treatment is usually very helpful [9] in lessening the effects of motor symptoms [40] and temporarily reversing behaviour and
mood changes that may have occurred in patients [9]. Constant use of dopamine treatment
may even eliminate or decrease non-‐motor fluctuations in PD [18]. The main medication used
for PD is levodopa, this will be discussed further in 1.4.1.
The second category of medication are those that impact on neurotransmitters within the
body (besides dopamine) to lessen PD symptoms [45], such as dopamine agonists and
monoamine oxidase-‐B inhibitors. Dopamine agonists behave similarly to levodopa in
substituting the loss of dopamine in the brain. This treatment has less of an effect than
levodopa but also lacks some of its side effects. Dopamine agonists are usually taken in
tablet form but apomorphine (a type of agonist) can be injected under the skin. Sometimes
dopamine agonists can be taken at the same time as levodopa medication in order to
reduce the levodopa uptake into the blood brain barrier (BBB), which lessens its side effects
in the patient. The side effects caused by dopamine agonists when taken by themselves
include nausea, vomiting, tiredness dizziness, hallucinations, confusion and less commonly,
compulsive behavior and extremely increased libido. Similarly to dopamine agonists,
monoamine oxidase-‐B inhibitors are used to treat symptoms in early PD however, the
inhibitors work by blocking the effect of monoamine oxidase-‐B which is a chemical in the
brain that eradicates dopamine. Again, the effect these inhibitors have on treating
symptoms tend to be lower than the effect of levodopa so they can be taken in combination
or combined with dopamine agonists instead. The side effects caused by the inhibitors alone
include nausea, headache and abdominal pain [46].
The third category is medications that help regulate non-‐motor symptoms [45]. Non-‐motor
symptoms vary and many have their own specific medication to treat that particular
symptom for example, clonazepam is often used to treat insomnia and rapid eye movement
behavior disorders and clozapine is often used to treat psychosis and hallucinations [6].
Supportive therapies are usually used to treat non-‐motor symptoms as they also increase
21
patients’ QoL and help them to cope better with the disease. Speech and language
therapists can help patients who have developed problems speaking and swallowing by
teaching them specific exercises. Exercise of the body is also recommended to treat many
symptoms from depression and anxiety to urinary incontinence [46]. Treatments can even
come in the form of sleep techniques or diet changes, for example patients suffering from
orthostatic hypotension may be advised to increase their water and salt intake [6].
1.4.1 Levodopa
Levodopa, also known as L-‐dopa, is an amino acid [48] that can be found naturally in animals
and plants [45]. It is an official symptomatic treatment [47] that is converted to dopamine in
the brain’s nerve cells [46], in order to increase dopamine levels. This is the most common
medication used to treat PD and it represents 1/3 of global sales in the PD market. During
the early stages of PD some patients briefly forget that they are suffering from PD due to
the high effect levodopa has on treating their symptoms enabling them to continue living a
productive lifestyle for a while. QoL is increased because levodopa greatly aids in reducing
bradykinesia, rigidity, balancing problems and other non-‐motor symptoms. For many
patients this means being able to continue working and carrying out daily activities with
ease [45].
The chemical structure of levodopa is (S)-‐2-‐Amino-‐3-‐(3,4-‐dihydroxyphenyl)propanoic acid
[49] (Figure 1.4.1.1).
22
Figure 1.4.1.1 A diagram showing the chemical structure of levodopa [47]. [Accessed: March
15th 2016]
Levodopa is used to treat PD symptoms because it has the ability to cross the BBB whilst
dopamine does not [47]. Levodopa is usually administered in the form of a tablet or liquid
and is often taken in combination with another chemical named carbidopa. Carbidopa stops
the levodopa from breaking down in the blood stream, allowing it to continue past the BBB [46] whilst not crossing the BBB itself [47] (Figure 1.4.1.2). Carbidopa has other benefits for the
patient when taken with levodopa such as decreasing the dose of levodopa needed [45] and
lessening the intensity of gastrointestinal (e.g. nausea) and cardiovascular (e.g. orthostatic
hypotension) side effects caused by levodopa based medication [48]. Carbidopa itself has no
known side effects on patients [47].
Figure 1.4.1.2 A diagram showing the mechanism of action for levodopa and carbidopa [47].
[Accessed March 15th 2016]
Although levodopa can be seen through many clinical studies to be a successful method of
treating PD symptoms [40], it also has associated downfalls. Studies have shown that
23
bradykinesia and rigidity respond the best to dopamine medication and DBS, followed by
tremor. However, postural instability is generally unresponsive to dopamine replacement
therapy. This is a great downfall of levodopa based medication as falls and gait problems
linked to postural instability significantly impact on patients’ QoL [40]. In addition to this,
levodopa treatment also has many side effects some being another cause for substantial
decrease in patient QoL. Some of these side effects include nausea, vomiting, low blood
pressure, restlessness, drowsiness and sudden sleep onset [45]. As PD progresses, nerve cells
continue to be lost and this is linked to a gradual decrease in the effect of levodopa as there
are less cells in the brain to absorb it [46]. Studies show that higher doses and long-‐term use
of levodopa can cause dyskinesia (“involuntary body movements”) to occur which can have
a disabling effect on the patient as they have less control over their actions. Higher
dopamine dosage is also said to be the cause of patients developing symptoms such as
hallucinations, confusion and periods of time where response to medication is either very
low or non-‐existent [40].
24
2.0 Aims & Objectives 2.1 Aims The aim of this project is to ascertain how more economically developed areas perceive
Parkinson’s disease treatment with reference to the Quality of Life of patients in the region
in comparison to the less economically developed areas. The treatment focused on in this
study will be the levodopa/carbidopa combined medication, specifically the SINEMET®
brand.
2.2 Objectives A systematic review will be carried out on journals, books and regulated webpages in order
to identify what Parkinson’s disease is and how patient Quality of Life is being approached.
This will entail exploring treatments of Parkinson’s disease, specifically levodopa, and
investigating the access that countries in the more and less economically developed regions
of the world have to this treatment. Several areas will be focused on in this project including
the economical and pharmaceutical standpoints which will provide evidence to display how
Quality of Life is portrayed with regards to Parkinson’s disease.
25
3.0 Methodology This project will take a systematic review approach in order to focus on the impact of
Parkinson’s disease worldwide, allowing for the research of studies pertaining to Parkinson’s
disease in the more and less economically developed regions with brief exploration into the
economic factors regarding treatment in Parkinson’s disease. This will allow for the
interpreting of trends concerning poor and rich countries experiencing Parkinson’s disease
and how quality of life is affected. Throughout the project there has been several changes to
the title in order to specify the inclusion and exclusion criteria therefore making the
research obtained more specific.
In obtaining the research for this project information had to be reliable and accurate: this
was ensured by reviewing the research and the authors as well as checking whether
information had been subject to academic review. Additionally, data was only taken from
journals, text books and health regulated websites. Several database libraries were used to
gather secondary data, examples of these include; Research Gate, Science Direct, PubMed
and Google Scholar. As the database libraries produce large results with a variety of articles,
journals and reviews, filters had to be used in order to attain the information needed for the
project while eliminating irrelevant research. This was done by conducting advanced
searches whereby inclusion criteria were emplaced, keeping only the journals associated
with the sector of Parkinson’s disease that was being researched along with an exclusion
criterion to disregard all journals pre 1990.
To evaluate journals required a brief assessment of how reliable results were, this was
achieved by comparing several journals of a similar nature. Secondly, journals would be
checked for the specific key words (mentioned in the abstract) and if these search terms
were present in the journal this indicated that a sufficient amount of the journal was based
on what this study required. The following searches to be carried out for this study include
information on levodopa and its accessibility in MEDAs and LEDAs, specifically the
SINEMET® brand; funding that goes toward the treatment of PD in MEDAs and LEDAs; PD
treatment; and case studies to evaluate any occurring trends.
26
3.1 ResearchGate As some information was still under review and research, research gate is a reliable social
network database that allows access to published papers directly from the researcher, along
with the ability to ask questions regarding any published papers, reviews or articles. This
database also has filters in order to specify what was needed for the project.
3.2 ScienceDirect A scientific library with a broad range of journals, articles and journal reviews and was easily
accessed via institution login using the Kingston University account details. The search
engine was used to search for ‘Parkinson’s Disease’ which showed a total number of
130,000 + articles, however when the search was refined to a more specific title and only
using journals this provided a result of 8,774 journals. Each result had the summary of the
article in addition to the abstract and any important pictures. This ensured that only useful
journals were selected, and with the recommendation of similar journals the search was
made much easier.
3.3 Google Scholar
This database does not require a specific login as it is open to the public however, some of
the journals it presented would either require a specific login or were inaccessible without
being purchased. Initial research for ‘Parkinson’s Disease’ presented a result of 534,000
results which was later refined to ‘Parkinson’s Disease in the more economically developed
regions’ which displayed 19,900 results. Throughout the project the title was further
narrowed which in turn meant the number of results was much lower as the articles were
more specific. Most of the articles obtained from Google Scholar were used for background
knowledge of the topic.
3.4 PubMed Access to PubMed was via the Kingston university database known as iCat. Login through
the university allowed full access of the publications present on the database, filters were
also present in order to research specific journals. Similarly to ScienceDirect, PubMed
27
displayed both journal summary and abstract which made it easier to disregard any
information that was not needed. Most journals found in other databases, such as Goggle
Scholar, that required payment could be accessed via PubMed due to the university login
which made it very useful.
3.5 Regulated Webpages Some basic information was needed throughout the project such as simple statistics and
definitions as this information was not present in journals. These were gathered from
regulated webpages that are constantly updated such as NHS and WHO.
28
4.0 Results and Discussion Levodopa is described as the gold standard treatment for PD [50] due to its successful record
in treating motor symptoms. It is a much needed treatment and its necessity worldwide is
implied through the global market sales for PD medication. The global market size of PD
from 2006-‐2007 was $3.7 billion which increased to $4 billion in the years 2009-‐2010. This
suggests that the incidences of PD are increasing and therefore so is the requirement for
medication [47]. Even though new PD drugs and therapies keep appearing on the market,
levodopa has remained at the top and continues to be the main medication used for PD
treatment. This shows that although it is not a cure, levodopa is efficient and its success in
treating symptoms is still highly valued [50].
29
Figure 4.0.1 A graph showing an increase in Parkinson’s disease incidences in various
countries worldwide, with a focus on the year 2005 and the use of reliable international
databases to provide an accurate estimate on the projected amount of patients that will
have Parkinson’s disease by the year 2030. The term “PwPs” is an abbreviation for People
30
with Parkinson’s. The word “estimate” is used after 2005 because information was not
available for particular countries so data from neighbouring countries was used instead [51].
[Accessed: March 28th 2016]
The increase in PD incidences includes both MEDAs and LEDAs (Figure 4.0.1) leading this
study to focus on whether or not PD patients in all countries have easy access to levodopa
treatment which has been proven to be the best medication for treating PD symptoms and
improving QoL [52]. A popular brand of levodopa called SINEMET® (carbidopa and levodopa
combination) which is used worldwide was approved in 1975. This particular medication
ensures that 5-‐10% of levodopa passes the BBB as opposed to the 1% that passes when
levodopa is taken alone. It also reduces the daily intake of levodopa needed by patients for
effective treatment from 4000mg to 700mg. This allows for a reduction in the side effects
that impact on the peripheral nervous system [47]. SINEMET® is administered in the form of a
tablet which was originally only available as non-‐controlled release (Figure 4.0.2) until a
controlled release (CR) formula (Figure 4.0.3) was produced in 1991 [47].
Figure 4.0.2 An image of original SINEMET® formula (package) [53]. [Accessed March 28th
2016]
31
Figure 4.0.3 An image of SINEMET® in controlled release form (package) [54]. [Accessed
March 28th 2016]
4.1 MEDAs An increase in PD incidences in MEDAs (e.g. USA) has also seen an increase in death rates
(Figure 4.1.1). Recorded statistics of PD increase suggests that the requirement for levodopa
has also risen. Due to the progressive nature of PD and its cause being unknown, the ability
to treat patients with efficient medication, such as levodopa, and reduce symptoms may
help to lower death rates as more time can be spent finding an actual cure for the disease.
This is because patients who are successfully treated, have an increased QoL and provide
statistical information that can aid researchers’ future work.
32
Figure 4.1.1 A graph showing an increase in death rates for Parkinson’s disease in the United
States from 1973 to 2003 [55]. [Accessed March 28th 2016]
In 2012 $1.15 billion was spent towards PD treatment in the USA and this figure is expected
to increase to $2.33 billion dollars by 2022 [56]. This is a $1.18 billion increase over ten years
which not only reinforces the fact that PD incidences are becoming more frequent in the
USA but also suggests that the USA is spending more money towards PD therapies indicating
their concern for QoL. The increase in death rates shown in Figure 4.1.1 can be linked to the
increase in USA’s spending toward PD treatment as an answer for the issue of mortality rate
is sought. The approximate cost of SINEMET® therapy course in the USA is $1195 per annum
whilst the cost of SINEMET® CR is slightly more at $1716 per annum [56]. As this is one of the
main current therapies used in the USA, this indicates that not only can it be afforded by
patients but it can also be easily accessed within the USA. This again reinstates that the
USA’s health care system has a concern for patient QoL as it has allowed patients to access
this gold standard therapy. There are several case studies that signify the value of
SINEMET®, showing how this medication has improved PD symptoms.
33
Case Study 1 MEDA; Clinical Neuroscience Programme, Sini Hospital, Detroit, Michigan:
This study was a double-‐blind study, meaning that both the patients and the administrators
had no knowledge of the medication being tested in the trial. The study was conducted over
8 weeks and 19 PD patients with noticeable dose by dose fluctuations took part [57]. The
study aimed to compare the effects of SINEMET® 25/100mg and SINEMET® CR 50/200mg
and results showed that most patients taking SINEMET® CR had an improvement in
symptoms within hours [57]. SINEMET® CR increased the bioavailability for levodopa and
allowed the effect of levodopa to last longer, therefore providing substantial symptom
improvement for the majority of patients in the study [57]. This case study proves that the
USA have access to both forms of SINEMET® and are able to conduct clinical trials with
them, showing how their financial status positively affects their accessibility to different
types of drugs.
Case Study 2 MEDA; Hospital General Universitario Gregorio Marañón, Madrid, Spain: This
study consisted 450 PD patients, of which 299 experienced motor complications (group A)
and the remaining 151 showed stable motor response (group B) [58]. All of these patients
were previously taking standard levodopa treatment and a conversion to SINEMET® CR was
performed in this study. Drastic improvements were seen over the duration of the study.
Negative effects of the conversion were either mild or moderate and only 10% of patients
discontinued use of SINEMET® CR due to side effects [58]. 81% of group A and 73.8% of group
B preferred SINEMET® CR over the regular levodopa treatment, indicating an overall
decrease in symptoms [58]. An improvement in QoL can be seen particularly from the results
of group A as this group of patients suffered from motor dysfunction prior to the
conversion.
4.2 LEDAs As opposed to MEDAs, LEDAs are less fortunate in being able to distinguish between
diseases until their later stages, by which time treatment is not as efficient [59]. Although
there is an expected increase in PD incidences over several LEDAs such as India, Indonesia
and Brazil as shown in Figure 4.0.1, this does not necessarily mean that PD is the prioritised
disease focused on in that country. For example, in sub-‐Saharan Africa HIV, AIDS and
34
malaria are the most prominent diseases with high incidence rates meaning that funding
and time for research is prioritised here and not dedicated to other diseases [59]. This is
further reinforced through case studies that have taken place in LEDAs.
Case Study 1 LEDA; Tanzania
This case study is a review of the PD medication of a 55-‐year-‐old male patient who was
diagnosed with PD 5 years prior. Due to the tremor he had developed he had to take 125mg
of careldopa once a day and his neurologist also prescribed co-‐careldopa TDS which was
unaffordable by the patient [60]. After his neurologist left the country, the patient saw a
different consultant upon each visit to the clinic. The patient began taking several different
medications at different doses due to local pharmacies’ financial inability to constantly
restock co-‐careldopa. Instead the pharmacies were dependent on inconsistent charitable
donations which always had varying dosage preparations [60]. This case study shows the lack
of consistency in both patient care and medication dosage that may be experienced in
LEDAs.
Case Study 2 LEDA; Kerala, South India
A male patient was diagnosed with PD at 26 years of age and due to neurology being in its
infancy in India at the time, he had to search for a long time before finding a neurologist to
diagnose him [61]. The neurologist advised that he could only control his tremors with
medication however, the required drugs were not accessible in India during that period and
had to be imported from the USA [61]. This importation did not just mean a delay in receiving
his treatment but it was also a costly procedure for the country and the medication was
expensive for the patient. The patient felt that there was a lack of help from the public
health system in terms of financial support and obtaining medication as patients were only
given access to old PD medication [61]. This case shows another situation where accessibility
to modern, efficient medication is low and patients suffer as a result.
35
4.3 How does QoL differ in MEDAs compared to LEDAs due to
levodopa treatment accessibility? The huge difference between MEDAs and LEDAs in regards to QoL is evident in the quality of
medication and the concern that health care systems express towards QoL through the way
they care for their patients. The financial status of MEDAs provides them with easy access to
modern medication and other resources. Both MEDA case studies portray the importance of
financial ability in treating PD as both the USA and Spain have the funding to conduct trials.
This means that they are able to evaluate which treatment is essential for specific groups of
patients therefore providing the best medication possible to help patients manage their PD
symptoms [60]. However, what the results indicate for LEDAs is that there appears to be
either a lack of concern towards QoL in patients [60] or concern is directed to diseases other
than PD because these diseases are more manifest throughout the country, such as HIV and
AIDS in sub-‐Saharan Africa [59]. LEDAs tend to witness a lack of consistency in medical supply
due to a shortage in finance which subsequently leads to patients receiving inconsistent
care during the course of their PD treatment [60]. Additionally, financial shortage also leads
to a growth in counterfeit drug usage as these are a cheaper alternative that patients in
LEDAs can afford [60]. This alternative risks the health of patients as counterfeit drugs
contain other ingredients that may be irrelevant to PD, they are not regulated and dosages
may be life-‐threatening in the long run [60], again affecting QoL.
36
5.0 Conclusion This study has identified the main factors of PD with a focus on its treatments and their
accessibility in MEDAs and LEDAs in order to gain an understanding on differing perceptions
of QoL. The manner in which QoL is acknowleged in LEDAs remains inconclusive as this
study has been unable to identify whether the apparent lack of concern for PD treatment is
due to disinterest or due to countries needs to prioritise the treatment of other diseases.
Also, it should be noted that PD is one of many prevalent diseases, and although it is
becoming more widespread it is not the most manifest disease in all countries. This in turn
means that it not possible for one small scale study, such as this project, to base the
perception of QoL in all LEDAs on how accessible PD treatment is in these regions.
Moreover, due to a relatively small time scale in which to complete the project as well as
being unable to access purchase-‐only journals, this study was conducted with limited
resources meaning that only a basic understanding can be gathered for certain aspects of
the investigation. In addition to these factors, only a small amount of data regarding PD in
LEDAs could be found whereas information on PD in MEDAs was very easily accessible,
particularly the USA. The only problem encountered in this area was finding reliable case
studies based in the UK, as although statistics in other forms agreed with the rest of the
project’s results, case studies in this region were difficult to come by. The overall ease in
researching PD in MEDAs emphasises the point made in this study as it is likely that financial
stability has enabled MEDAs to carry out many clinical trials, therefore gathering an
abundant of information and thus being in a position to provide this research to the public.
This is not the case with LEDAs where finance is low, research struggles to be funded for and
medical care is of a poorer quality.
Researching levodopa has shown the high status it has held in the PD treatment market for
over 40 years, as the demand for it is high across both MEDAs and LEDAs and high
expenditure increase towards levodopa treatment can be seen in MEDAs. The importance
given to levodopa based medication is due to its high success rate in treating motor
symptoms in PD patients, particularly during the early stages of the disease. Studies show its
significant impact on patient QoL which is a vital aspect in diagnosing PD and evaluating the
results of treatments. An unexpected aspect of this research affecting QoL which became
37
apparent towards the end of the study was the use of counterfeit drugs in LEDAs. The use of
these drugs as an affordable alternative for patients who cannot afford the likes of levodopa
or even cheaper, but regulated, medication provided locally (whether infrequent or not) is a
huge risk to the life of the patient. This is a crisis that questions the morality of health care
systems worldwide and even the global concept of QoL as it appears unethical that
countries such as the USA and Spain are able to not only provide medication at a price more
suitable for patients in their country, but they are also able to conduct many clinical studies
as funding for research exists. On the other hand, countries such as Tanzania and India
witness a lack of health care available, particularly as neurologists are not in abundance, and
deficiency in appropriate PD medication consequently leading to a decrease in QoL.
5.1 Future Research Future investigation for the ideal treatment is currently being conducted. As
levodopa/carbidopa treatment continues to be regarded as the gold standard therapy and
the most efficient worldwide it still has downfalls such as the levodopa effects wearing off
and the development of symptoms such as dyskinesia which overtime can have an effect on
the Quality of Life of PD patients [62]. Current research being undertaken in MEDAs (e.g. UK
and USA) show that funding is being invested into developing a new form of levodopa which
is to be taken with carbidopa alongside another drug called Entacapone [63]. Entacapone has
been shown to improve mobility and to enhance daily activities which in turn results in a
better Quality of Life for the patient [63]. With MEDAs progressing in the development of
new treatments for PD in comparison to LEDAs such as Tanzania and India, investigation
should be carried out as to how to support funding for treatment in these regions and also
to search for possible ways to allow LEDAs to access unused PD medication that MEDAs
might possess and not use.
38
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