3. 3
INTRODUCTION
• Parkinson’s disease (PD) is a complex progressive
neurodegenerative disease characterized by tremor,
rigidity, and bradykinesia, with postural instability
appearing in some patients as the disease progresses.
• Parkinson’s disease (PD) is the second most
common neurodegenerative disease, affecting 1%
of the population over 55 years of age.
• PD is characterized by the loss of 50-70% of the
dopaminergic neurons in the substantia nigra, a
profound loss of dopamine (DA) in the striatum,
and the presence of intracytoplasmic inclusions
called Lewy bodies (LB)
4. FIG: 1 DOPAMINE LEVEL IN NORMAL AND PARKINSON’S
AFFECTED NEURON
5. ETIOLOGY
5
• Advancing age : above 60 years mostly seen while young onset disease is called a patients
develop Parkinson disease between 21- 40 years.
• Sex: male are more likely to get than female.
• Encephalitis infection in response to brain trauma, tumors etc.
• Family history: having one or more close relatives with the disease increase the rise of getting
• Low estrogen level: most menopausal women who do not use hormone replacement therapy
are more risk of getting the disease.
• Low level of vitamins: researchers was found that people with low level of vitamin B develop
severe Parkinson symptoms.
• Head trauma: trauma to the head, neck and upper cervical spine increase the chance of getting
Parkinson’s disease.
6. PATHOPHYSIOLOGY
Antipsychotic drug, encephalitis and other causes
Affects the substantia nigra
Destruction of dopamine producing neurons within the basal ganglia
Reduces the amount of available striatal dopamine (inhibitory effects)
There is increase in acetylcholine(excitatory effects)
Difficulty in controlling and initiating voluntary movements
6
7. SYMPTOMS
• Tremor – tremor, or shaking, usually begins in a
limbs, often your hand or fingers
• Slowed movement (bradykinesia)
• Rigid muscles
• Impaired posture and balance
• Loss of automatic movements
• Speech changes
7
13. 1 3
Immunotherapy for alpha-synucleinopathy
• alpha-synuclein is considered a key molecule in the neuronal death in PD.
• It is assumed that a-synuclein misfolds intracellularly and aggregates into toxic forms, enters
the extracellular space and is subsequently taken up by an adjacent neuronal structure –
leading to propagation of the toxic a-synuclein seeds
• There is some evidence that the CSF content of a-synuclein in exosomes correlates with the
disease phenotype and progression.
• Thus, active or passive immunotherapeutic strategies aim to reduce the level of extracellular
toxic a-synuclein aggregates and thus to limit its propagation.
14. 1 4
• FDA Approved safinamide as an Add-On Treatment for
Patients with Parkinson’s Disease experiencing “off”
episodes.
- Trade name = Xadago, Onstryv
• Mechanism of action –
• potent, selective, and reversible inhibitor of monoamine
oxidase B (MAO-B) with more than 1000-fold selectivity
over MAO-A.
• blockade of voltage-dependent Na+ and Ca2+ channels
and inhibition of glutamate release.
• Limitations of Use : XADAGO has not been shown to be
effective as monotherapy for the treatment of PD.
Safinamide
15. 1 5
Safinamide…
Dose –
- 50 mg administered orally once daily (at the same time of day), without regard to
meals.
- After two weeks, the dosage may be increased to 100 mg once daily, based on
individual need and tolerability.
- Daily dosages above 100 mg have not been shown to provide additional benefit,
and higher dosages increase the risk for adverse reactions.
- effective only in combination with levodopa/carbidopa
16. 1 6
Safinamide…
Pharmacokinetics –
• Absorbed quickly and nearly completely from the gut.
• There is no relevant first-pass metabolism, total bioavailability is 95%.
• Eliminated, mainly (>90%) in form of its metabolites, via the kidney, with an
elimination half-life of 20 to 30 hours.
• The pharmacokinetics of safinamide is not influenced by race and sex
17. 1 7
Safinamide…
Side effects:
1] Severe hypertension
2] serotonin syndrome
3] Falling Asleep During Activities of Daily Living
4] dyskinesia
5] hallucinations
6] Retinal degeneration and loss of photoreceptor cells
7] psychotic behaviour
18. ISTRADEFYLLIN
E
1 8
• FDA approved drug as an adjunctive treatment to
levodopa/carbidopa in adult patients with
Parkinson’s disease (PD) experiencing “off”
episodes.
• Trade name – Nourianz
• Dosing Information-
• The recommended dosage is 20 mg administered
orally once daily.
• The dosage may be increased to a maximum of
40 mg once daily, based on individual need and
tolerability.
• NOURIANZ can be taken with or without food
19. 1 9
Mechanism of action –
• an adenosine receptor antagonist
• Adenosine A2A receptors are selectively located in GABAergic cell
bodies and terminals of indirect striatopallidial pathway
• Adenosine is functionally linked to D2 receptors & enhances GABA
release which contributes to over activity of indirect pathway [which
is the underlying mechanism of PD]
• Adenosine antagonist improve symptoms by acting on indirect
pathway allowing D1 mediated direct pathway.
25. 2 5
Parkinson’s Disease Emerging Drugs
1) Tavapadon
Company/Sponsor : Cerevel Therapeutics
Tavapadon is a selective dopamine D1/D5 partial agonist that Cerevel is developing for
the treatment of early- and late-stage Parkinson’s disease.
Cerevel initiated a registration-directed Phase 3 program for tavapadon beginning in
January 2020, which includes two trials in early-stage Parkinson’s, known as TEMPO-1
and TEMPO-2, one trial in late-stage Parkinson’s, known as TEMPO-3, and an open-
label safety extension trial, known as TEMPO-4. Initial data from the Phase 3 program
are expected to be available beginning in the first half of 2023.
26. 2 6
2) Prasinezumab
Company/Sponsor : Roche
Prasinezumab (RG7935) is a monoclonal antibody targeting alpha-synuclein, a protein
that may misfold and be involved in the pathogenesis of Parkinson's disease. It has been
tested in preclinical models of synuclein-related disease and has shown a reduction of
neurodegeneration. A phase II clinical trial is evaluating prasinezumab for the treatment of
patients with Parkinson's disease.
27. 2 7
3) AXO-Lenti-PD
Company/Sponsor : Sio Gene Therapies
AXO-Lenti-PD is the only investigational gene therapy for Parkinson’s disease that
delivers the three key genes (TH, CH1, and AADC) required for endogenous
dopamine synthesis in a single lentiviral vector. The goal of this one-time infusion
is to restore steady, tonic levels of dopamine, potentially reducing the need for daily
L-dopa medication while stabilizing the disease to provide long-lasting benefits.
AXO-Lenti-PD has been optimized from ProSavin, an earlier gene therapy for the
treatment of Parkinson’s disease. Currently, it is in the Phase II stage of clinical
trial evaluation.
28. SUMMARY
2 8
• Pharmacological treatment of PD should be tailored to the individual patient.
• In most patients levodopa with carbidopa still forms the mainstay therapy. But
with the association of multiple newer targets and pathways in the pathology of
PD, many novel agents acting via non dopaminergic pathways are under various
stages of clinical trials and showing good results which could be further exploited.
• Still no drug can alter the pathology of Parkinson's disease, all drugs act
symptomatically
• Stem cell therapy and gene therapy can be future prospects for regenerative
medicine to treat PD
29. 2 9
• Kevin, Gary, Marco, Leah, et al. Parkinson’s Disease Drug Therapies in the Clinical Trial
Pipeline. Journal of Parkinson’s Disease 2022;12:1073–1082
• DelveInsight Business Research LLP. Parkinson’s Disease Pipeline Offers Promising New
Options for Treatment. January 17, 2022 20:00
• Kanaan NM, Manfredsson FP: Loss of Functional Alpha-Synuclein: A Toxic Event in
Parkinson’s Disease. J Parkinsons Dis. 2012; 2(4): 249–67.
• Goodman Gillman’ The pharmacological basics of therapeutics, 13th ed. by Laurence L.
Brunton, Randa Hilal-Dandan, Björn C. Knollmann. McGRAW-HILL Publisher.
References
