Factors affecting mortality in burns: a single center studyKETAN VAGHOLKAR
Background: Burns injury continues to be the greatest challenge to the trauma surgeon. A multitude of factors determine the mortality in burns patients. The present study aims at identifying those factors which have a significant impact on mortality in burns patients.
Methods: A total 80 patients presenting with burns injury were studied prospectively. Various factors which included age, sex, aetiology, mode of injury, total body surface area which is burnt (BSA), duration of stay, time interval up to admission, pregnant state, inhalation injury, systemic complications, wound complications, and psychological impact were studied.
Results: The mean age was 24.07 years. 59 were females, 21 were males. 19 (23.75%) cases were suicidal in aetiology whereas the remaining 61(76.25%) were accidental. Flame injury was the most common mode of injury in 65 patients (81.25%). The mean BSA in the study was 53.5% whereas the mean BSA in those patients who expired was 71.4%. Mean duration of stay in hospital was 6.55 days whereas mean time interval between burns injury and admission to hospital was 101.33 minutes. All 12 pregnant women had spontaneous miscarriages with a mortality in 11 patients. Inhalation injury was seen in 49 patients (61%) with mortality of 42 (83.7%) patients. Systemic complications seen in 60 patients mortality and BSA was high in patients who had infection. 31 patients in the study had severe depression with a mortality of 91.32%. 50 out of the 80 patients studied expired.
Conclusions: Increased age, BSA, mode of injury, presence of inhalation injury, systemic complication, pregnant state, wound infection and depression had a significant impact on the mortality of burns patients.
Expert Recommendations for the Laboratory Diagnosis of Neuronal Ceroid Lipofuscinosis Type 2 (CLN2 disease): Diagnostic Algorithm and Best Practice Guidelines for a Timely Diagnosis
BOOSTING YOUR IMMUNITY During the COVID 19 PandemicLouis Cady, MD
In this presentation, presented as a live webinar on Monday, April 27th, Dr. Louis Cady of the Cady Wellness Institute reviewed practical, common-sense things that can be done to boost your immunity, with documentation from the peer-reviewed medical literature. Dr. Cady also reviews supplements and nutrients that are established in the peer-reviewed medical literature as having antiviral capabilities. These include Vitamins C,D, and E, Zinc, carotenoids and antioxidants, probiotics, the reishi mushroom, elderberry, cannabidiol (CBD - not marijuana or weed!).
Points presented are scrupulously documented from the medical literature. This presentation does not guarantee or represent that using ANY of these nutrients will "keep you from getting infected or dying" from COVID 19. They are presented for your thoughtful consideration.
Factors affecting mortality in burns: a single center studyKETAN VAGHOLKAR
Background: Burns injury continues to be the greatest challenge to the trauma surgeon. A multitude of factors determine the mortality in burns patients. The present study aims at identifying those factors which have a significant impact on mortality in burns patients.
Methods: A total 80 patients presenting with burns injury were studied prospectively. Various factors which included age, sex, aetiology, mode of injury, total body surface area which is burnt (BSA), duration of stay, time interval up to admission, pregnant state, inhalation injury, systemic complications, wound complications, and psychological impact were studied.
Results: The mean age was 24.07 years. 59 were females, 21 were males. 19 (23.75%) cases were suicidal in aetiology whereas the remaining 61(76.25%) were accidental. Flame injury was the most common mode of injury in 65 patients (81.25%). The mean BSA in the study was 53.5% whereas the mean BSA in those patients who expired was 71.4%. Mean duration of stay in hospital was 6.55 days whereas mean time interval between burns injury and admission to hospital was 101.33 minutes. All 12 pregnant women had spontaneous miscarriages with a mortality in 11 patients. Inhalation injury was seen in 49 patients (61%) with mortality of 42 (83.7%) patients. Systemic complications seen in 60 patients mortality and BSA was high in patients who had infection. 31 patients in the study had severe depression with a mortality of 91.32%. 50 out of the 80 patients studied expired.
Conclusions: Increased age, BSA, mode of injury, presence of inhalation injury, systemic complication, pregnant state, wound infection and depression had a significant impact on the mortality of burns patients.
Expert Recommendations for the Laboratory Diagnosis of Neuronal Ceroid Lipofuscinosis Type 2 (CLN2 disease): Diagnostic Algorithm and Best Practice Guidelines for a Timely Diagnosis
BOOSTING YOUR IMMUNITY During the COVID 19 PandemicLouis Cady, MD
In this presentation, presented as a live webinar on Monday, April 27th, Dr. Louis Cady of the Cady Wellness Institute reviewed practical, common-sense things that can be done to boost your immunity, with documentation from the peer-reviewed medical literature. Dr. Cady also reviews supplements and nutrients that are established in the peer-reviewed medical literature as having antiviral capabilities. These include Vitamins C,D, and E, Zinc, carotenoids and antioxidants, probiotics, the reishi mushroom, elderberry, cannabidiol (CBD - not marijuana or weed!).
Points presented are scrupulously documented from the medical literature. This presentation does not guarantee or represent that using ANY of these nutrients will "keep you from getting infected or dying" from COVID 19. They are presented for your thoughtful consideration.
Journal Club: Genetic Predisposition to Schizophrenia Associated with Increas...Ashutosh Ratnam
Here's a Journal Club Presentation I made on the article 'Genetic Predisposition to Schizophrenia Associated with Increased Use of Cannabis' which appeared in the Nov 14 issue of Molecular Psychiatry. It explored the possibility of whether people with high genetic risk scores for Schizophrenia somehow had a propensity for cannabis, establishing a biological basis for 'reverse causality'.
Dr. Cady deconstructs some the medical literature about the use of nutrients - and the evidence of what happens in the presence of their insufficiency. Everything for decreased viral replication to decrease brain shrinkage is covered. The role of antioxidant and carotenoids, measured by the Pharmanex Biophotonic Scanner, is reviewed.
Please note - there is no representation that any nutrient or supplement can treat, prevent, mitigate, or cure any medical condition. It does seem, however, upon reflecting on the medical literature, that there seems to be a lot of evidence for therapeutic effect in the presence of good levels of nutrient, and harm to patients if they have insufficient levels.
Determining Prognosis in Cancer and Non-cancer DiagnosisVITAS Healthcare
This helps physicians, nurses, case managers and social workers understand the trajectories of dying from cancer and non-cancer diagnoses, including heart, lung, kidney and liver disease, stroke, HIV/AIDS, dementia and neurodegenerative diseases. Aided by a better grasp of the decline-related domains involved in poor prognosis, disease progression and disease end stages, attendees will be better positioned to identify patients and residents who are appropriate for hospice care.
Efficacy and safety of traditional Chinese medicine kidney-nourishing formula...LucyPi1
Abstract Objective: Finding an effective therapy against Alzheimer’s disease (AD) has been associate increasingly pressing issue and traditional Chinese medicine (TCM) is widespread in the prevention and treatment of AD in China. The aim of this study was to judge the efficaciousness and safety of TCM kidney-nourishing (the changes of pathological state of kidney deficiency by means of TCM treatment and so on) formula (TKNF) for AD in comparison with donepezil. Methods: The retrieval period of seven databases was from the establishment of each database to April 2019. Two authors independently identified randomized controlled trials (RCTs), fetched data and assessed bias risk. Comprehensive analysis process was conducted with review manager for eligible and appropriate RCTs. Results: A complete of 981 AD patients from 13 studies were enclosed. Meta-analysis of RCTs showed that there was no significant difference in the improvement of Alzheimer's disease assessment scale-cognitive subscale score between 2 groups in short term, but the effect of long-term treatment may exceed donepezil; there was a significant difference in the improvement of activities of daily living score between 2 groups; there was a significant difference in TCM curative efficacy between 2 groups with long-term treatment. There was no significant difference in the incidence of adverse events between 2 groups. The quality of the evidence was high or moderate. Conclusion: Compared with donepezil, TKNF was an effective drug for AD patients and the clinical application of TKNF was safe. TKNF's long-term benefits need more evidence to verify.
This presentation focusses on the importance of diagnostic biomarkers for Alzheimer's disease. MRI, amyloid PET and CSF biomarkers are discussed in detail.
Journal Club: Genetic Predisposition to Schizophrenia Associated with Increas...Ashutosh Ratnam
Here's a Journal Club Presentation I made on the article 'Genetic Predisposition to Schizophrenia Associated with Increased Use of Cannabis' which appeared in the Nov 14 issue of Molecular Psychiatry. It explored the possibility of whether people with high genetic risk scores for Schizophrenia somehow had a propensity for cannabis, establishing a biological basis for 'reverse causality'.
Dr. Cady deconstructs some the medical literature about the use of nutrients - and the evidence of what happens in the presence of their insufficiency. Everything for decreased viral replication to decrease brain shrinkage is covered. The role of antioxidant and carotenoids, measured by the Pharmanex Biophotonic Scanner, is reviewed.
Please note - there is no representation that any nutrient or supplement can treat, prevent, mitigate, or cure any medical condition. It does seem, however, upon reflecting on the medical literature, that there seems to be a lot of evidence for therapeutic effect in the presence of good levels of nutrient, and harm to patients if they have insufficient levels.
Determining Prognosis in Cancer and Non-cancer DiagnosisVITAS Healthcare
This helps physicians, nurses, case managers and social workers understand the trajectories of dying from cancer and non-cancer diagnoses, including heart, lung, kidney and liver disease, stroke, HIV/AIDS, dementia and neurodegenerative diseases. Aided by a better grasp of the decline-related domains involved in poor prognosis, disease progression and disease end stages, attendees will be better positioned to identify patients and residents who are appropriate for hospice care.
Efficacy and safety of traditional Chinese medicine kidney-nourishing formula...LucyPi1
Abstract Objective: Finding an effective therapy against Alzheimer’s disease (AD) has been associate increasingly pressing issue and traditional Chinese medicine (TCM) is widespread in the prevention and treatment of AD in China. The aim of this study was to judge the efficaciousness and safety of TCM kidney-nourishing (the changes of pathological state of kidney deficiency by means of TCM treatment and so on) formula (TKNF) for AD in comparison with donepezil. Methods: The retrieval period of seven databases was from the establishment of each database to April 2019. Two authors independently identified randomized controlled trials (RCTs), fetched data and assessed bias risk. Comprehensive analysis process was conducted with review manager for eligible and appropriate RCTs. Results: A complete of 981 AD patients from 13 studies were enclosed. Meta-analysis of RCTs showed that there was no significant difference in the improvement of Alzheimer's disease assessment scale-cognitive subscale score between 2 groups in short term, but the effect of long-term treatment may exceed donepezil; there was a significant difference in the improvement of activities of daily living score between 2 groups; there was a significant difference in TCM curative efficacy between 2 groups with long-term treatment. There was no significant difference in the incidence of adverse events between 2 groups. The quality of the evidence was high or moderate. Conclusion: Compared with donepezil, TKNF was an effective drug for AD patients and the clinical application of TKNF was safe. TKNF's long-term benefits need more evidence to verify.
This presentation focusses on the importance of diagnostic biomarkers for Alzheimer's disease. MRI, amyloid PET and CSF biomarkers are discussed in detail.
Parkinson's disease is a brain disorder that progressively affects a person’s ability to control body movements, caused by a disorder of certain nerve cells in a part of the brain that produces dopamine, a chemical messenger the brain uses to help direct and control body movement.
Early diagnosis of Parkinson's disease gives you the best chance of a longer, healthier life. This presentation covers the information about biomarkers for Parkinson Diseases which include biological, physiological and imagine candidate / novel biomarkers.
DIRI with commercial available agents ,,,.pdfMOHITROCK1
review articles 7th semester b pharm final year
topic: Drug Induced Renal Injury (DIRI): Alarming indication towards the
catastrophic behavior of drugs
Materials and Methods of DIRI
Renal manifestations of recrea
Nephrotoxicity of Ciprofloxaci
Herbal Nephropathy (Cranberry)
B PHARM
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
Introduction:
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is an important biological process for modulating eukaryotic gene expression.
It is highly conserved process of posttranscriptional gene silencing by which double stranded RNA (dsRNA) causes sequence-specific degradation of mRNA sequences.
dsRNA-induced gene silencing (RNAi) is reported in a wide range of eukaryotes ranging from worms, insects, mammals and plants.
This process mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
What are small ncRNAs?
micro RNA (miRNA)
short interfering RNA (siRNA)
Properties of small non-coding RNA:
Involved in silencing mRNA transcripts.
Called “small” because they are usually only about 21-24 nucleotides long.
Synthesized by first cutting up longer precursor sequences (like the 61nt one that Lee discovered).
Silence an mRNA by base pairing with some sequence on the mRNA.
Discovery of siRNA?
The first small RNA:
In 1993 Rosalind Lee (Victor Ambros lab) was studying a non- coding gene in C. elegans, lin-4, that was involved in silencing of another gene, lin-14, at the appropriate time in the
development of the worm C. elegans.
Two small transcripts of lin-4 (22nt and 61nt) were found to be complementary to a sequence in the 3' UTR of lin-14.
Because lin-4 encoded no protein, she deduced that it must be these transcripts that are causing the silencing by RNA-RNA interactions.
Types of RNAi ( non coding RNA)
MiRNA
Length (23-25 nt)
Trans acting
Binds with target MRNA in mismatch
Translation inhibition
Si RNA
Length 21 nt.
Cis acting
Bind with target Mrna in perfect complementary sequence
Piwi-RNA
Length ; 25 to 36 nt.
Expressed in Germ Cells
Regulates trnasposomes activity
MECHANISM OF RNAI:
First the double-stranded RNA teams up with a protein complex named Dicer, which cuts the long RNA into short pieces.
Then another protein complex called RISC (RNA-induced silencing complex) discards one of the two RNA strands.
The RISC-docked, single-stranded RNA then pairs with the homologous mRNA and destroys it.
THE RISC COMPLEX:
RISC is large(>500kD) RNA multi- protein Binding complex which triggers MRNA degradation in response to MRNA
Unwinding of double stranded Si RNA by ATP independent Helicase
Active component of RISC is Ago proteins( ENDONUCLEASE) which cleave target MRNA.
DICER: endonuclease (RNase Family III)
Argonaute: Central Component of the RNA-Induced Silencing Complex (RISC)
One strand of the dsRNA produced by Dicer is retained in the RISC complex in association with Argonaute
ARGONAUTE PROTEIN :
1.PAZ(PIWI/Argonaute/ Zwille)- Recognition of target MRNA
2.PIWI (p-element induced wimpy Testis)- breaks Phosphodiester bond of mRNA.)RNAse H activity.
MiRNA:
The Double-stranded RNAs are naturally produced in eukaryotic cells during development, and they have a key role in regulating gene expression .
1. Parkinson’s
- Group 2A
Leana Sturch, Jasmine Blocksidge, Tom Filarowski,
Simran Bhardwaj, Ioannis Livanos & Laura Cowley
Pharmacology - Level 6
Sheffield Hallam University
Department of Biosciences & Chemistry
2. Initial consultation with patient
Patient history:
▶ 55 years old
▶ Father died at 70, having developed similar symptoms at 65
Symptoms:
▶ Stiffness
▶ Limb tremors (especially hands)
Observations:
▶ Walks with a shuffle
2
3. Provisional diagnosis
▶ Mrs. LN was sent to her local hospital to have an MRI scan which then provoked
her consultant to send her for further investigation using an [18F] dopa PET scan
and a [123I]β-CIT SPECT scan.
▶ Mrs. LN was diagnosed with early signs of Parkinson's disease and prescribed
selegiline (10mg daily) and cabergoline (1mg daily increased every week to a
maximum of 3mg per day - or until an optimum dosage for the patient was
reached).
3
4. PD: A brief summary
Figure 1 nigrostriatal pathway (Health Union, 2017).
4
▶ Progressive death of
dopaminergic neurons causing
a drop in dopamine (DA)
neurotransmission
▶ Lewy bodies are found in
surviving cells, this is due to
alpha-synucleinopathy
(misfolded alpha synuclein
protein) (Kravitz & Kreitzer, 2012)
(Lotharius & Brundin, 2002).
5. PD: Loss of dopaminergic neurons
5
Figure 2 Role of the substantia nigra
in PD (Whalen, 2015).
The inhibitory system (D2 receptors),
negatively regulates the release of ACh.
In PD there is an imbalance of
neurotransmitters resulting in an
irregular output signal and thus we
do not have normal controlled
movement pattern.
Loss of dopaminergic neurons
leads to an underexpression of DA.
Overexpression of ACh can be
dampened down by DA release in
the substantia nigra pars compacta
(SNpc).
The excitatory system (D1
receptors), positively regulates the
release of acetylcholine (ACh).
The system can restore balance
through several different drug
systems.
(DeMaagd & Philip, 2015; Whalen, 2015; Chaudhuri, Clough & Sethi, 2011)
6. PD: A brief summary
6
Possible causes
80-90% cases are
idiopathic
Associated risk factors
include:
● Head trauma
● Toxin exposure
● Oxidative stress
Some familial PD cases
exist
Genetic inheritance exists
and some genes
identified are:
● LRRK2, SNCA
● PARK7, PINK1, PRKN
(National Institute of
Health, 2018), (Schulte &
Gasser, 2011).
7. Further causes of PD
▶ Exogenous and/or endogenous toxins. (Miller, Gainetdinov, Levey
& Caron, 1999)
▶ Genetic risk (Billingsley, Bandres-Ciga, Saez-Atienzar & Singleton,
2018)
▶ Pesticides and metals on the aggregation of α-synuclein (Uversky,
Li, Bower & Fink, 2002)
▶ Free radical mediated damage (Kumar et al., 2012)
Diverse genetic, biological and environmental influences
7
8. Diagnosis
Often treatment with low doses of
levodopa-carbidopa will begin here if
suspicion of PD is strong and if symptoms
improve after weeks, this will confirm the
diagnosis (Frank, Parry & Rossiter, 2006).
8
9. Diagnosis - Specialised scans
Mrs LN went through each stage of the diagnosis process previously described and then had:
1. [18F]-dopa PET scan - allows the function of the dopaminergic pathways in the brain to be visualised
using a positron emitting analog of L-dopa (the precursor for DA) which is taken up through the blood-
brain barrier (BBB), to be metabolised by aromatic L-amino acid decarboxylase and stored in
intraneuronal vesicles until the neuron fires (Nanni, Fanti & Rubello, 2007) (Wahl & Namhias, 1996).
2. [123I]β-CIT SPECT scan - shows the loss of DA transporters associated with PD, allowing the stage of the
disease to be shown, as well as distinguishing PD from essential tremor within a patient exhibiting symptoms
of both (Seibyl et al., 1998) (Parkinson’s UK, 2014).
9
10. Biochemical defects associated with PD
▶ Until symptoms such as dyskinesia become noticeable to a patient, they are unlikely to present
themselves for medical intervention, at which point there has often been irreversible damage done to
the SNpc
▶ This makes biochemical diagnosis of PD extremely difficult, as often these clinical symptoms will not
become present until approximately 50% of the dopaminergic receptor cells in the SNpc are lost (a
process which can take up to around 5 years) (Michell, Lewis, Fltynie & Barker, 2004)
▶ Adler et al. (2014) found that diagnosis of possible PD was only clinically correct (neuropathologically) in
53% of patients with under 5 years of disease progression, but this statistic increases to 88% after 5 years
have passed
10
11. Role of glial reaction in PD
11
↑ pro-inflammatory cytokines (e.g. TNF-α, IL-1β) in
brain/CSF
Caspase-6/-8 activation
Stimulate nitric oxide
production in glial cells (↑OS)
Apoptosis of DA cells of SNpc The role of glial reaction and
inflammation in Parkinson’s disease
(created using information from
Hirsch et al., 2003)
12. The role of oxidative stress (OS) in PD
▶ OS is thought to be involved in a cascade of biochemical alterations which occur in dopaminergic cell
death, and thus PD - BUT, at what point OS becomes involved is a point of contention
▶ Increased levels of basal OS are found in the SNpc of PD patients
▶ It has also been suggested that L-dopa (used for symptomatic treatment of dyskinesia) may increase the
oxidative load further
▶ The metabolism of DA by monoamine oxidases (MOA) in the SNpc also contributes to OS due to the
byproduct of this reaction, hydrogen peroxide (H2O2)
(Jenner, 2003)
12
13. DA metabolism itself causes OS
▶ Not only does DA breakdown generate reactive
oxygen species (ROS), it can also auto-oxidise as it
is unstable
▶ DA quinones (DAQ) are also produced by DA
breakdown
▶ DAQ are highly reactive, and able to irreversibly
conjugate with cysteine residues on proteins,
promoting misfolding - often leading to
inactivation and sometimes aggregation
▶ If DAQ conjugate with α-synuclein, then α-
synuclein toxicity can be enhanced
▶ Further ROS can also be created by redox cycling
undergone by DAQ and their conjugated proteins
▶ How cytotoxic DAQ are depends on the genetic
basis of the PD sufferer
13
Fig 3. Positive feedback loops which contribute to decreased GSH and thus increase
vulnerability of the dopaminergic neuron (Zhou, Selvaratnam, Chao, Lim & Tan, 2016)
14. Mitochondrial Dysfunction
▶ Genetic disorder which occurs when the
mitochondria of the cell fail to produce enough
energy for cell or organ function.
▶ Mitochondria have a central role in ageing-
related neurodegenerative diseases.
▶ A cure for mitochondrial disease could impact
cures for Autism, Parkinson’s, Alzheimer’s and
Muscular Dystrophy.
14
(Nicolson, 2014), ("What is Mitochondrial Disease? - UMDF", 2018)
Fig 4. The influence of mitochondrial dysfunction on several diseases.
("Related Diseases - Foundation for Mitochondrial Medicine", 2018)
15. Mitochondrial Dysfunction in PD
▶ Defective mitochondrial function and
increased OS have been demonstrated as
having an important role in PD
pathogenesis.
▶ Pathogenic mutations in genes directly
linked to mitochondrial dysfunction.
▶ Characterized by the generation of ROS.
15
Fig 5. Representative pathways of mitochondrial
dysfunction involved in Parkinson’s disease
pathophysiology (Park, Davis & Sue, 2018)
(Moon & Paek, 2015; Nicolson, 2014)
16. Non-motor symptoms of PD
These symptoms include:
▶ Depression
▶ Dementia
▶ Sleep disorders
▶ Bowel and bladder problems
▶ Fatigue
▶ Apathy
▶ Autonomic dysfunction
16
Fig 6. Diagram of symptoms related to PD. (Todorova, Jenner & Ray Chaudhuri, 2014)
17. Non-motor symptoms of PD
▶ The presence of nonmotor symptoms supports neuronal loss in non-dopaminergic areas as well.
(DeMaagd & Philip, 2015)
▶ Clinicians frequently overlook these symptoms as shown by an international survey in 2010 which
showed that up to 62% of PD patients do not declare symptoms such as apathy, pain, sexual
difficulty, bowel incontinence or sleep disorder. (Chaudhuri et al., 2010)
▶ Jellinger (2011) stated that Parkinson's can no longer be considered a complex motor disorder
characterised by extrapyramidal symptoms, but as a progressive multisystem disease
17
18. Potential Biomarkers of PD
▶ 3, 4-Dihydroxyphenylacetaldehyde (DOPAL), a toxic metabolite of DA
▶ Leads to the destruction of DA terminals
▶ Contributing factor to DA deficiency associated with PD
▶ Cerebrospinal fluid (CSF) levels of a-synuclein may be decreased
▶ Conflicting evidence of this
18
(Goldstein et al., 2013; Kapur et al., 2000)
19. The future of PD diagnosis
▶ Recent research has proposed links between gut problems years
before development of lewy bodies and hypokinesia in PD patients
▶ PD sufferers are found to have lower levels of butyrate, meaning that
the permeability of the BBB is increased as tight junction formation is
hindered (Houser & Tansey, 2017)
▶ Prevotella bacteria (which produce mucin) are found much less
abundantly in the guts of PD patients, increasing the permeability of
the intestinal wall, promoting widespread inflammation
▶ Although more research is needed to firmly link these symptoms,
microbiota phenotype may be a future biomarker to be used before
severe disease progression (Scheperjans et al, 2015)
19
Gut microbiota and increased systemic
inflammation in PD (Houser & Tansey, 2017)
20. Future of PD diagnosis
▶ Novel method of detecting both PD and Alzheimer's
disease
▶ GC-MS measures volatile organic compounds (VOC’s)
present in breath
▶ 24 VOC’s were analysed, relationships between them
and the diseases were detected
▶ Would lead to earlier stage detection and definitive
diagnosis
20
(Tisch et al., 2013)
Figure shows the identifiable groupings between patients
who are normal, or who have PD, or Alzheimer's Disease
21. Selegiline
▶ Selegiline is protective treatment used to treat early stage PD
▶ Dose: 10 mg/day
▶ Rapidly absorbed through the GI tract
▶ Bioavailability of oral administration: 10%
▶ Predominantly excreted in urine, undergoes significant metabolism in
the liver. Metabolites include:
▶ Desmethylselegiline
▶ Methamphetamine
▶ Amphetamine
Selegiline
Image taken from drugbank.ca
21
(Mahmood, 1997)
22. Mechanism of action - Selegiline
▶ Easily crosses BBB
▶ Selectively inhibits MAO-B enzyme
▶ Selegiline stops the reuptake of DA,
which leads to an increase in DA
concentration
▶ Usually taken alongside Levodopa
22
Adapted from: Complexity of dopamine metabolism, (Meiser et al., 2013)(Mahmood, 1997)
23. Cabergoline
▶ Synthetic ergoline DA agonist
▶ Administered orally once daily (usually in the morning)
▶ High affinity for D2 receptors (subtypes D2 & D3 - inhibitory), but
also binds D1 receptors (stimulatory) and with lower affinity to 5-HT
receptors (sometimes causing psychotic effects)
▶ If taken orally, reaches peak plasma concentration after 2-3 hours
(not strongly bound to human plasma - approx 40%)
▶ Absolute bioavailability is unknown
▶ Hepatic metabolism, excreted mostly in faeces
▶ Estimated elimination half-life = 63-109 hours
(Del Dotto & Bonuccelli, 2003) Cabergoline
Image taken from drugbank.ca
23
24. Additional effects of cabergoline
▶ Development of motor complications is significantly delayed in patients treated solely with
cabergoline when compared with those taking Levodopa (Rinne et al., 1998)
▶ Cabergoline reduces DA turnover, thus reducing the production of its cytotoxic metabolites
(Finotti, Castagna, Moretti & Marzatico, 2000)
▶ Lipid peroxidation is reduced significantly after multiple cabergoline administrations, meaning
overall levels of OS in the SNpc are reduced, potentially providing a means by which to delay
further progression of PD (Finotti, Castagna, Moretti & Marzatico, 2000)
24
25. Cabergoline
▶ Binds to D2 with high affinity
▶ Mimics DA
How they both achieve the same
result.
Selegiline
▶ Inhibits MAO-B
▶ Decreases breakdown of DA
▶ Neuroprotective potential
25
Selegiline
(Image taken from
drugbank.ca)
Cabergoline
(Image taken from
drugbank.ca)
26. What is the rationale for prescribing
levodopa?
Dopamine = Onset of PD
Dopamine BBB
Levodopa Dopamine
Effective treatment for symptoms such as Stiffness Slowness of
movement
26
To get the most out of levodopa, it must be prescribed simultaneously to other drugs (Korczyn,
2018).
27. What is the rationale for prescribing
levodopa?
▶ Levodopa is absorbed in the duodenum
▶ Levodopa is a naturally occurring amino acid that can be synthesized in the human body
(LeWitt, 2014)
▶ Levodopa is rapidly taken up by dopaminergic neurons and converted to DA
▶ It is not converted to epinephrine and norepinephrine because dopaminergic neurons lack the
enzyme dopamine β-hydroxylase (DBH).
▶ DA is metabolized to homovanillic acid (HVA) by the enzymes monoamine oxidases (MAO)
and by catechol-O-methyltransferase (COMT)
▶ CSF HVA concentration shows a significant positive correlation with levodopa doses (Deleu,
Northway & Hanssens, 2002)
27
28. What is the rationale for prescribing
levodopa?
▶ About 80% of patients show improvement in conditions like rigidity
and bradykinesia, the other 20% have their normal motor function
restored
▶ Levodopa is also metabolized in the peripheral nervous system (PNS)
causing severe side effects
▶ Treatment with levodopa for an extensive period of time causes
patients to develop psychiatric and motor complications
▶ Half of the patients after 5-10 years of treatment, begin to develop
dyskinesia (involuntary movements), bradykinesia, rigidity, end-of
dose deterioration (fluctuations between mobility and immobility),
cramps, tremors and muscle stiffness (Davie, 2008)
28
Image taken from drugbank.ca
29. What is the rationale for prescribing
levodopa?
▶ Irregular absorption and rapid catabolism are the basis for
many of the problems associated with its chronic use
▶ The underlying cause of drug-induced dyskinesia is the
irregular/inconsistent stimulation of DA receptors in the
striatum due to the short half-life of DA (60 minutes)
▶ The therapeutic effectiveness of levodopa decreases as the
disease progresses
▶ Levodopa action relies on the presence of functional
dopaminergic neurons
▶ The greater the neuronal loss at the introduction of levodopa
the sooner the side effects are observed (Davie, 2008)
29
Image taken from drugbank.ca
30. Why is it important to prescribe
carbidopa at the same time as levodopa?
▶ Absence/little DA in the brain is thought to be the main cause of PD
▶ Therefore levodopa → DA in the brain - helps in controlling movement and tremors but can
only be done so if carbidopa is present to stop it breaking down in the bloodstream
(Margolesky & Singer, 2017).
▶ Situated in the mucosa of both the intestine and the liver, around 70% of levodopa that is
administered is metabolized by aromatic amino acid decarboxylase (AADC). The suppression
of levodopa metabolism will allow more levodopa to enter the brain (crossing the BBB) and be
converted to DA, helping alleviate the symptoms of PD (Waters & Henchcliffe, 2002).
▶ Taking carbidopa in addition to levodopa reduces side effects of high levodopa levels such as
vomiting and nausea as carbidopa is a peripheral AADC inhibitor, therefore preventing
levodopa being broken down.
Carbidopa (alone)→ Carbidopa + Levodopa →
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31. Why is it important to prescribe
carbidopa at the same time as
levodopa?
▶ When it is combined with carbidopa it reduces the amount of dose
needed by 10-fold.
▶ There is:
peripheral side effects and
motor function
▶ Carbidopa is aromatic amino acid decarboxylase (AADC) inhibitor
which stops the conversion of levodopa to DA increasing its
bioavailability in the CNS. (Korczyn, 2018)
31
Image taken from:
http://tmedweb.tulane.edu
32. Why is it important to prescribe
carbidopa at the same time as levodopa?
▶ After 3 years of therapy, motor complications develop less frequently in patients treated with
carbidopa than in patients treated only with levodopa
▶ Decarboxylation takes place in the brain since, decarboxylase inhibitors cannot penetrate the BBB
▶ The half life of carbidopa-levodopa is 90 minutes
▶ Carbidopa-levodopa is taken orally as tablets and the most common combinations are 25-100 mg
(1:4 ratio) and 10-100mg (1:10 ratio) (Korczyn, 2018) (SINEMET®)
32
33. What was the rationale for prescribing
entacapone?
Entacapone (alone) →
Carbidopa + Levodopa + Entacapone = Levodopa Dopamine
Effective treatment for symptoms such as Tremors
Muscular spas
Stiffness of bon
Poor muscular
control
(Waters & Henchcliffe, 2002)
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34. What was the rationale for prescribing
entacapone?
▶ Entacapone is a reversible inhibitor of the enzyme catechol-O-
methyltransferase (COMT)
▶ COMT converts levodopa to 3-O-Methyldopa in the body but
also in the brain reducing the bioavailability of levodopa
▶ The peak plasma concentration of entacapone is 1 hour and
only 2% is available for distribution because the rest of it binds to
albumin
▶ Despite the reduced availability, the addition of entacapone in
the carbidopa-levodopa treatment increases the plasma half-life
of levodopa by approximately 45% after each dose (Davie, 2008)
▶ Inhibition of both enzymes (AADC and COMT) increases the half-
life of levodopa by 85%, compared with a conventional
levodopa (Brooks, 2008)
34
Image taken from drugbank.ca
35. What was the rationale for prescribing
entacapone
▶ Entacapone does not cross the BBB therefore, it only prevents COMT from metabolizing
levodopa in the periphery
▶ Entacapone is given in patients with a late stage PD especially when the orally-dosed
levodopa is becoming progressively shorter, eliminating the early end-of-dose/wearing-off
effects
▶ Entacapone counteracts the fluctuations in plasma concentration of levodopa thus, the levels
remain longer within the therapeutic range increasing the benefits of each levodopa dose
▶ This produces a prolonged stimulation of the dopaminergic neurons in the brain which
subsequently improves motor function.
▶ Carbidopa-levodopa-entacapone is supplied as tablets, with various strengths
▶ Entacapone concentration remains constant in all tablets at 200 mg (optimal dose),
carbidopa-levodopa is supplied at 1:4 ratio and the concentration can range from 12.5-50 mg
to 50-200 mg (Deleu, Northway & Hanssens, 2002) (STALEVO®)
35
36. What was the rationale for prescribing
entacapone?
36
L.C.E. significantly
increase levodopa
delivery and storage in
the striatum by up to 50%
in PD patients, compared
with L.C. (Sawle et al.,
1994).
Plasma levodopa levels
(troughs) are significantly
higher in L.C.E. treatment
compared to an
equivalent L.C. dose
(Brooks, 2008)
37. Haloperidol
▶ Blocks receptors for DA neurotransmitters so nerves cannot be activated by DA-
receptor binding and a signal cannot be produced
▶ Antipsychotic drug that decreases excitement in the brain (Haloperidol - FDA
prescribing information, side effects and uses, 2018)
▶ Used to treat psychotic disorders such as:
▶ Schizophrenia
▶ Control motor (movement)/verbal tics
▶ Severe behavior problems in children
37
Image taken from drugbank.ca
38. Chlorpromazine
▶ Antipsychotic drug belonging to the class of drugs called phenothiazine
antipsychotics.
▶ It is aimed to restore the balance of certain natural substances in the brain.
▶ Used to treat disorders such as:
▶ Schizophrenia
▶ Manic phase of bipolar disorder
▶ Severe behaviour problems in children
38
Image taken from drugbank.ca
39. Why were haloperidol and
chlorpromazine not good ideas?
▶ Treatment = Carbidopa + Levodopa + Entacapone →
▶ Work against goal of increasing DA= haloperidol and chlorpromazine →
▶ This is the opposite of what we want to achieve in order to better the symptoms of
PD, therefore making the disease worse and more progressive
▶ DA is an excitatory neurotransmitter that is a major motivational component of
reward - motivated behaviour but these two drugs do the opposite and since they
decrease excitement, they also decrease DA in the brain.
▶ This makes PD worse when working together as they work against what is trying the
be achieved.
39
40. Why were haloperidol and
chlorpromazine not good ideas?
▶ Both drugs are antagonists of D1, D2 and 5-HT2A (5-hydroxytryptamine/serotonin) receptors,
causing the reduction of the available DA in the brain
▶ About 80% of D2 receptors have to be blocked in order for antipsychotic effects to take place
▶ In schizophrenic patients there is an excess amount of DA in the CNS and by blocking the D2
receptors in the mesolimbic pathway the positive symptoms of schizophrenia will be relieved
▶ Antipsychotic drugs also inhibit D2 receptors in the nigrostriatal pathway
▶ The main disadvantage of the typical antipsychotic drugs is that they cause extrapyramidal
symptoms (EPS) due to the inhibition of all D2 receptors
▶ EPS: acute dyskinesias, acute dystonia (continuous muscle contractions) and akathisia (motor
restlessness) (Meltzer & McGurk, 1999)
▶ In PD patients the level of DA is already extremely low, so it is very important not to block the
little DA function that remains, causing even more severe symptoms
40
41. What was the rationale for removing
cabergoline and substituting quetiapine?
▶ As mentioned previously, cabergoline has long half-life so it
can be administered once a day
▶ Cabergoline effectively reduces akinesia (impairment of
voluntary movement) in the night and dyskinesia in the
morning
▶ Cabergoline has beneficial effects on PD symptoms however,
it has several side effects and the most severe are chest pain,
nausea, vomiting, shortness of breath, hallucinations, mood
changes and vision problems. (Curran & Perry, 2004)
▶ Mrs. LN was indeed suffering from visual and auditory
hallucinations therefore, cabergoline was substituted with
quetiapine
41
Image taken from drugbank.ca
42. Quetiapine
▶ Quetiapine is used to treat the psychosis associated with PD, seen later in the
disease at advanced stages
▶ Psychosis is increased in patients treated with DA agonists and levodopa
▶ One method of treatment is to reduce the dose of other medications treating PD
▶ Classed as an ‘atypical’ (second generation) antipsychotic drug
42
Image taken from drugbank.ca(Kapur et al., 2000)
43. Quetiapine
▶ Dose: 25 - 50 mg per day
▶ Bioavailability of oral administration: 100%
▶ Predominantly excreted in urine, undergoes significant metabolism in the liver at
CYP3A4
▶ Strong antagonist of the 5-HT2 receptors
▶ Half-life of 53 to 64 hours
▶ Weak antagonist of the D2 receptors
▶ Half-life of 8 to 10 hours
▶ Also binds to other receptors such as Histamine1
43
Image taken from drugbank.ca(Shotbolt et al., 2010; Kapur et al., 2000)
44. Mechanism of action, Quetiapine
▶ Mechanism of action of antipsychotic drugs is unknown however it is thought that they work by:
5-HT2
▶ inhibiting serotonin receptor leads to decreased amounts of serotonin released, therefore increasing
DA levels
▶ Thought that this may enhance antipsychotic drug, and delay development of EPS - not necessary
▶ Quetiapine binds more favourably to this receptor which is unusual for a antipsychotic
D2
▶ Receptor where it is thought the antipsychotic drugs produce their main effect
▶ However blocking too much (more than 70 - 80 %) of this receptor has a negative effect
▶ Fast dissociation from receptor
44
(Kapur et al., 2000; Rang et al., 2006)
45. Mechanism of action - Quetiapine
▶ Quetiapine reduces the EPS
▶ Quetiapine binds more loosely than DA, to the
D2 receptors
▶ Haloperidol and chlorpromazine bind more
tightly than DA to the D2 receptors
▶ The occupancy of D2 by quetiapine rapidly falls
off within 24 hours and there is no occupancy
after 48 hours
▶ In contrast, haloperidol maintains a constant D2
occupancy for over 24 hours and can occupy
D2 for days
45
46. Mechanism of action - Quetiapine
▶ The prediction of which antipsychotic drugs will or will not cause EPS, is known as the ‘fast-off
D2’ theory
▶ Quetiapine dissociates from D2, 100 times faster than the typical drugs (haloperidol and
chlorpromazine)
▶ Typical drugs dissociate from D2 receptor in about 30 minutes whereas, quetiapine dissociates
in the less than a minute
▶ However, after withdrawal, psychotic relapses of patients on quetiapine occur sooner
compared to the typical drugs
▶ The rapid dissociation and the low affinity are beneficial for PD patients since, it allows normal
DA transmission within the neurons (Seeman, 2002)
46