ABDERAZAK BOUZIANE PROJECT

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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.

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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

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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

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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

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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

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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.

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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

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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.

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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.

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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].

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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].

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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:

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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

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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].

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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

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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

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(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

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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].

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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

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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).

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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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