A Presentation On
“To Study the Safety of Neurodegenerative Medication”
Presentation By: Submitted To:
VIPIN KUMAR DR.SASHI KUMAR SINGH
ENROLL No: 2020/1517 (ASISTANT PROFESSOR)
SHEKHAWATI INSTITUTE OF PHARMACY, SIKAR
AFFILIATED TO
RAJASTHAN UNIVERSITY OF HEALTH AND SCIENCE,
JAIPUR
List of content
1. Introduction
2. Literature review
3. Rationale Study
4. Objectives
5. Conclusion
6. Summary
7. References
INTRODUCTION
Neurodegenerative Disease
v Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of the structure and function of the
nervous system, particularly neurons in the brain and spinal cord. These conditions are chronic, often incurable, and lead to a gradual loss
of neurological function over time.
v
Common Neurodegenerative Diseases:
1. Alzheimer’s Disease (AD)
1. Most common cause of dementia.
2. Marked by memory loss, confusion, and cognitive decline.
3. Associated with accumulation of beta-amyloid plaques and tau tangles in the brain.
4.
2. Parkinson’s Disease (PD)
1. Affects movement control.
2. Symptoms include tremors, stiffness, bradykinesia (slowness of movement), and postural instability.
3. Caused by the loss of dopamine-producing neurons in the substantia nigra.
4.
3. Amyotrophic Lateral Sclerosis (ALS)
1. Also known as Lou Gehrig’s disease.
2. Involves the death of motor neurons, leading to muscle weakness and paralysis.
3.
4. Huntington’s Disease (HD)
1. A genetic disorder.
2. Characterized by motor dysfunction, psychiatric symptoms, and cognitive decline.
Commonly Used Neurodegenerative Medications
1. Alzheimer’s Disease
●
Medication ●
Class ●
Mechanism
●
Donepezil ●
Cholinesterase inhibitor ●
Increases acetylcholine in the brain
●
Rivastigmine ●
Cholinesterase inhibitor ●
Inhibits AChE and BuChE
●
Galantamine ●
Cholinesterase inhibitor ●
Enhances cholinergic function
●
Memantine ●
NMDA receptor antagonist ●
Blocks excess glutamate activity
2. Parkinson’s Disease
●
Medication ●
Class ●
Mechanism
●
Levodopa + Carbidopa ●
Dopamine precursor ●
Increases dopamine levels
●
Pramipexole ●
Dopamine agonist ●
Stimulates dopamine receptors
●
Ropinirole ●
Dopamine agonist ●
Mimics dopamine
●
Selegiline ●
MAO-B inhibitor ●
Inhibits dopamine breakdown
●
Entacapone ●
COMT inhibitor ●
Prolongs Levodopa effect
●
Amantadine ●
NMDA antagonist ●
Increases dopamine release
3. Amyotrophic Lateral Sclerosis (ALS)
●
Medication ●
Class ●
Mechanism
●
Riluzole ●
Glutamate release inhibitor ●
Reduces excitotoxicity
●
Edaravone ●
Free radical scavenger ●
Reduces oxidative stress
4. Huntington’s Disease
●
Medication ●
Class ●
Mechanism
●
Tetrabenazine ●
VMAT2 inhibitor ●
Reduces dopamine release
●
Similar to tetrabenazine with better
●
Deutetrabenazine ●
VMAT2 inhibitor
safety
●
Antipsychotics (e.g., Olanzapine) ●
Dopamine antagonists ●
Manage behavioral symptoms
Safety Parameters for Neurodegenerative Medications
1. Liver Function
2.
•Drugs like Riluzole, Donepezil can cause liver toxicity.
•
•Test: ALT, AST, Bilirubin.
•
•Action: Monitor regularly; adjust or stop if enzymes elevate.
2. Kidney Function
•Drugs like Memantine, Amantadine are renally excreted.
•
•Test: Serum Creatinine, eGFR.
•
•Action: Dose adjustment in renal impairment.
3. Cardiovascular Monitoring
•Drugs like Donepezil, Levodopa may cause bradycardia or hypotension.
•
•Test: ECG, BP, Pulse rate.
•
•Action: Monitor vitals; avoid in cardiac patients.
4. Neuropsychiatric Effects
•Drugs like Dopamine agonists, Tetrabenazine may cause hallucinations, depression.
•
•Monitoring: Behavior, mental status, mood changes.
•
•Action: Adjust dose or discontinue if severe.
5. Hematological Monitoring
•Drugs like Clozapine (off-label) can cause low WBC
•.
•Test: CBC with differential.
•
•Action: Stop drug if agranulocytosis risk is high.
6. Weight and Nutrition
•Drugs like Rivastigmine and Tetrabenazine may cause appetite loss and weight loss.
•
•Monitoring: Body weight, BMI, appetite.
•
•Action: Nutritional support if significant loss occurs.
7. Drug Interactions
•MAO-B inhibitors + SSRIs can lead to serotonin syndrome.
•
•Monitoring: Medication review, symptoms of toxicity.
•
•Action: Avoid dangerous combinations.
Litetature review
v Deborah A. Burton et al. (2000) Department of Anaesthesia, St George’s Hospital Medical School, University of London, Jenner
Wing, Cranmer Terrace, London, SW17 ORE, England, Neurodegenerative diseases are increasingly common in elderly patients,
who present a particular anaesthetic challenge. The majority of people over the age of 70 years have some degree of cerebral
atrophy. The pathogenesis of neurodegenerative diseases is due to alterations in the transport, degradation and aggregation of
proteins. Alterations in physiology that occur with advancing age affect both the pharmacokinetics and pharmacodynamics of
drugs used in the elderly. Changes in pharmacokinetics result in either increased or reduced drug concentrations depending on the
variable contributions of absorption, metabolism and elimination.
v
v Jia Liu & Lu-ning Wang et al. (2017) The efficacy and safety of riluzole for neurodegenerative movement disorders: a systematic
review with meta-analysis, Neurodegenerative movement disorders mainly include Parkinson’s disease, atypical parkinsonisms,
Huntington disease, and hereditary ataxia. Riluzole is the only drug approved by the US Food and Drug Administration for
amyotrophic lateral sclerosis. The neuroprotective effects of riluzole have been observed in experimental models of
neurodegenerative movement disorders. In this paper, we aimed to systematically analyze the efficacy and safety of riluzole for
patients with neurodegenerative movement disorder. We searched the electronic databases such as PubMed, EMBASE, CINAHL,
Cochrane Library and China National Knowledge Infrastructure until June 2017 for the eligible randomized controlled trials, as
well as the unpublished and ongoing trials. For continuous data, we calculated standardized mean differences with 95% confidence
intervals if studies did not use the same scales to measure outcomes. For dichotomous data, we calculated risk differences if a trial
reported no adverse events or dropouts. We pooled the results using a random-effects model.
v
v Susan Hall et al. (2024) The neurodegenerative hypothesis of depression and the influence of antidepressant medications, Depression
is a complex neurological disease that holds many theories on its aetiology and pathophysiology. The monoamine strategy of
treating depression with medications to increase levels of monoamines in the (extra)synapse, primarily through the inhibition of
monoamine transporters, does not always work, as seen in patients that lack a response to multiple anti-depressant exposures, as
well as a lack of depressive symptoms in healthy volunteers exposed to monoamine reduction. Depression is increasingly being
understood not as a single condition, but as a complex interplay of adaptations in various systems, including inflammatory
responses and neurotransmission pathways in the brain. This understanding has led to the development of the neurodegenerative
hypothesis of depression. This hypothesis, which is gaining widespread acceptance posits that both oxidative stress and
inflammation play significant roles in the pathophysiology of depression. This article is a review of the literature focused on
neuroinflammation in depression, as well as summarised studies of anti-inflammatory and antioxidant effects of antidepressants.
v
v Peter T Lansbury Jr. et al. (2004) Back to the future: the 'old-fashioned' way to new medications for neurodegeneration, Despite
the increasing prevalence of Alzheimer's disease, Parkinson's disease and less common neurodegenerative diseases—and despite
the large amount of primary research that has been carried out into the causes and pathogenic features of these conditions—
progress toward effective treatments has been remarkably slow. Why is this, and what can be done to accelerate it? There are a
number of obstacles to effective drug discovery for neurodegeneration, but by considering these problems it is possible to identify
lessons for the future.
v
v Floyd E. Bloom, MD; John F, et al, (2005) Mouse Models of Human Neurodegenerative Disorder Requirements for Medication
Development, Central nervous system diseases constitute a major target for drug development. Transgenic mouse models, in which
genes identified in familial forms of human brain diseases are expressed in mouse neurons and glia, offer opportunities to detect
and follow pathologic progression and provide potential biomarkers by which to assess therapeutic interventions. Evidence for
Alzheimer disease suggests some starting requirements for the experimental data that could enhance the likelihood of developing
medications in these mouse models that would also be effective in humans.
v
v Jeffrey L. Cummings & Kate Zhong et al. (2006) Treatments for behavioural disorders in neurodegenerative diseases: drug
development strategies, Neuropsychiatric symptoms and behavioural alterations are common in neurodegenerative diseases, and
effective treatment of these changes represents an important unmet public health need. Imaging, neuropathological,
neurotransmitter and molecular genetic studies increasingly identify specific mechanisms that mediate behavioural changes in
neurodegenerative disorders and provide a platform for seeking effective therapeutic interventions. Measuring behavioural
outcomes in clinical trials of antidementia agents represents an important means of evaluating treatment effectiveness, and clinical
trial methodologies and behavioural instrumentation are evolving to facilitate drug development in this important therapeutic target
area.
v
v Rosa L. Drijgers; Pauline Aalten, et al. (2009) Pharmacological Treatment of Apathy in Neurodegenerative Diseases: A Systematic
Review, To evaluate the efficacy of pharmacological treatment of apathy in patients with neurodegenerative diseases. Methods:
Systematic review of studies assessing the effects of pharmacological treatment on apathy in neurodegenerative diseases. Results:
Thirty-five studies were included: 2 meta-analyses, 13 randomized controlled trials (RCTs), 14 open-label studies, 5 case series,
and 1 single case study. Eight studies included apathy as a primary outcome. A cholinesterase inhibitor was investigated in 24
studies, methylphenidate in 5, and other medications in 6 studies. Most RCTs of cholinesterase inhibitors reported a small but
statistically significant improvement of apathetic symptoms. Conclusions: Although some medications are promising candidates
for further study, there is as yet insufficient evidence that pharmacological treatment improves apathetic symptoms in patients with
neurodegenerative disease. Large-scale, placebo-controlled RCTs with apathy as a primary outcome measure are needed to
establish the potential benefit of pharmacological treatment of apathy.
Rationale for Safety Studies in Neurodegenerative Medications
Safety pharmacology aims to identify and characterize potential adverse effects of new drugs on vital physiological functions before they are
administered to humans. This is particularly important for neurodegenerative diseases, where patients often have comorbidities and may be
more susceptible to side effects. Key reasons for conducting safety studies include:
• Patient Vulnerability: Individuals with neurodegenerative diseases like Alzheimer's or Parkinson's are often elderly and may have
multiple health issues, increasing the risk of adverse drug reactions
•
• Complex Disease Mechanisms: These diseases involve intricate pathways, making it challenging to predict how a new drug might
interact within the body.
•
• Regulatory Requirements: Regulatory agencies mandate thorough safety evaluations to ensure that the benefits of a new therapy
outweigh its risks.
Objectives
§ To identify prescription medications associated with a lower risk of three neurodegenerative diseases: Parkinson disease, Alzheimer
disease, and amyotrophic lateral sclerosis.
§
§ The objective of this study was to determine the safety, tolerability, and feasibility of plasma infusions in people with PD.
§
§ To assess the modification of the form of medication and evaluate staff observance of good clinical practices.
§
§ This involves assessing the drug's effects on vital systems, including the central nervous, cardiovascular, and respiratory systems, to
identify any undesirable pharmacodynamic effects.
§
§ Independent groups that periodically review accumulating trial data to identify any safety concerns or efficacy trends, with the authority to
recommend modifications or termination of the study.
§
CONCLUSION
Assignment to active treatment was not beneficial for any of the indications examined and may have been slightly disadvantageous for
patients with Alzheimer disease. Our findings suggest that patients with neurodegenerative diseases are not, on the whole, harmed by
assignment to placebo when participating in trials.
Through an MR approach, our study systematically screened the potential causal associations between clinical medications and major NDs,
indicating negative causal associations between immunosuppressants, antihypertensives, and thyroid preparations and AD risk, negative
causal associations between immunosuppressants, glucocorticoids, and thyroid preparations and PD risk, and positive causal associations
between HMG CoA reductase inhibitors, antithrombotic agents, and salicylic acid derivatives and ALS risk. This work provides us with a
whole understanding of the relationship between medications and NDs. In addition to clarifying the nature and mechanisms of
neurodegenerative diseases, this work also helps with drug repositioning and clinical management for ND patients.
Summary
§ Neurodegenerative medications are used to manage progressive disorders such as Alzheimer’s disease, Parkinson’s disease,
Huntington’s disease, and amyotrophic lateral sclerosis (ALS). These drugs aim to alleviate symptoms, slow disease progression,
and improve the quality of life. However, due to the chronic nature of these diseases and the elderly population they affect,
medication safety is a critical concern.
§
§ Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis
(ALS) are progressive and debilitating. Pharmacological treatments for these conditions aim to slow disease progression, manage
symptoms, and improve patient quality of life. However, the safety of these medications is a crucial concern due to the chronic
nature of treatment, age-related vulnerabilities, and the high prevalence of comorbidities in affected populations.
References
v Karen L Steinmetz & Edward G Spack, et al.(2009) The basics of preclinical drug development for neurodegenerative disease
indications.
v
v Deborah A. Burton, Grainne Nicholson & George M. Hall (2004), Anaesthesia in Elderly Patients with Neurodegenerative
Disorders.
v
v Yizhe Song,Brad A. Racette,Alejandra Camacho-Soto,Susan Searles Nielsen ,(2013) Biologic targets of prescription medications
and risk of neurodegenerative disease in United States Medicare beneficiaries.
v
v Jeffrey Cummings, MD, ScD(HC)1; Krista Lanctot, PhD2; George Grossberg, MD3; et al. (2024), Progress in Pharmacologic
Management of Neuropsychiatric Syndromes in Neurodegenerative Disorders a review.
v
v Raman Malhotra MD & Alon Y. Avidan MD, MPH, (2012), Neurodegenerative Disease and REM Behavior Disorder.
v
v Gus Alva galva@atpcr.com, Wiesław J. Cubała, […], and Sanjeev Pathak,(2924), Safety Profile of Pimavanserin Therapy in Elderly
Patients with Neurodegenerative Disease-Related Neuropsychiatric Symptoms: A Phase 3B Study
THANK YOU
ALL
