Presentation on recent advances in Parkinsons disease. Tried to cover up new drugs as well as new devices like Duodopa set up. . i have tried to put a light on the established treatment of Parkinson's disease along with its mechanism of actions in circuit loops which will help to understand the topic in depth!
Non adrenergic non cholinergic transmission(nanc)Merlin Binu
Neurotransmitters other than Acetyl choline and NorAdrenaline of parasympathetic and sympathetic nervous system play important role in synaptic junction transmission. That neurotransmitters are called NANC.
This slideshare is about what is autocoid,and differences between harmone and autocoid and had expalined about an example which is an autocoid and also an chemical messenger.and it is also known as happy harmone.
5HT widely distributed in:
GIT enterochromaffin cells (90%)
myenteric plexus where it serves as a prokinetic agent
As a neurotransmitter in CNS
platelets where it diffuses inside from plasma by active transport, and is released at the site of damage after platelet aggregation,
In lungs, bone marrow, pineal gland (as a precursor of melatonin)
5- HT is then stored in 5-HT containing cells such as enterochromaffin cells and neurons as co-transmitter together with various peptide hormones such as somatostatin, vasoactive intestinal peptide and substance P
5-HT is stored within storage vesicles, and its uptake at the vesicular membrane by vesicular monoamine transporter (VMAT-2) is inhibited by reserpine.
Degradation occurs through oxidative deamination by MAO, to 5-hydroxyindole acetaldehyde followed by its oxidation to 5-hydroxyindole acetic acid (5-HIAA)
5- HIAA is excreted in urine
Gaddum and Picarelli (1957) classified 5-HT receptors into musculotropic (D type) and neurotropic (M type) on the basis of their blockade by Dibenzyline (phenoxybenzamine) and Morphine.
5- HT Receptors: there are seven main types (5-HT1, to 5- HT7) of serotonin receptors. Of these, 5-HT1, and 5- HT2, are subdivided further. With a total of 14 (types plus subtypes) receptors.
5-HT Receptors Location:5-HT, receptors are located mainly in CNS. They function as inhibitory presynaptic receptors (auto receptor) and belong to the family of G-protein coupled receptors linked to adenylate cyclase
5-HT1 : Auto receptors; inhibit serotonergic neural activity in brain.
5-HT1A—present in raphe nuclei and hippocampus; buspirone (antianxiety) may act through these receptors.
5-HT1D/1B—Constricts cranial blood vessels and inhibits release of inflammatory neuropeptides in them; sumatriptan (antimigraine) acts through these receptors.
5-HT2A : Previously D type receptor; most important post junctional receptor mediating direct actions of 5-HT like vascular and visceral smooth muscle contraction, platelet aggregation, neuronal activation in brain; ketanserin blocks these receptors.
5-HT3 : Previously M type receptor; depolarizes neurones by gating cation channels; elicits reflex effects of 5-HT—emesis, gut peristalsis, bradycardia, transient hypotension, apnoea, pain, itch; ondansetron (antiemetic) acts by blocking these receptors.
5-HT4 : Mediate intestinal secretion, augmentation of peristalsis. Renzapride (prokinetic) is a selective 5-HT4 agonist.Central Nervous System :5-HT is an important neurotransmitter in CNS
5-HT is involved in the regulation of mood, behaviour, sleep, depression, pain perception, sexual activity, thermoregulation
in the hypothalamic control of the release of pituitary hormones.
Presentation on recent advances in Parkinsons disease. Tried to cover up new drugs as well as new devices like Duodopa set up. . i have tried to put a light on the established treatment of Parkinson's disease along with its mechanism of actions in circuit loops which will help to understand the topic in depth!
Non adrenergic non cholinergic transmission(nanc)Merlin Binu
Neurotransmitters other than Acetyl choline and NorAdrenaline of parasympathetic and sympathetic nervous system play important role in synaptic junction transmission. That neurotransmitters are called NANC.
This slideshare is about what is autocoid,and differences between harmone and autocoid and had expalined about an example which is an autocoid and also an chemical messenger.and it is also known as happy harmone.
5HT widely distributed in:
GIT enterochromaffin cells (90%)
myenteric plexus where it serves as a prokinetic agent
As a neurotransmitter in CNS
platelets where it diffuses inside from plasma by active transport, and is released at the site of damage after platelet aggregation,
In lungs, bone marrow, pineal gland (as a precursor of melatonin)
5- HT is then stored in 5-HT containing cells such as enterochromaffin cells and neurons as co-transmitter together with various peptide hormones such as somatostatin, vasoactive intestinal peptide and substance P
5-HT is stored within storage vesicles, and its uptake at the vesicular membrane by vesicular monoamine transporter (VMAT-2) is inhibited by reserpine.
Degradation occurs through oxidative deamination by MAO, to 5-hydroxyindole acetaldehyde followed by its oxidation to 5-hydroxyindole acetic acid (5-HIAA)
5- HIAA is excreted in urine
Gaddum and Picarelli (1957) classified 5-HT receptors into musculotropic (D type) and neurotropic (M type) on the basis of their blockade by Dibenzyline (phenoxybenzamine) and Morphine.
5- HT Receptors: there are seven main types (5-HT1, to 5- HT7) of serotonin receptors. Of these, 5-HT1, and 5- HT2, are subdivided further. With a total of 14 (types plus subtypes) receptors.
5-HT Receptors Location:5-HT, receptors are located mainly in CNS. They function as inhibitory presynaptic receptors (auto receptor) and belong to the family of G-protein coupled receptors linked to adenylate cyclase
5-HT1 : Auto receptors; inhibit serotonergic neural activity in brain.
5-HT1A—present in raphe nuclei and hippocampus; buspirone (antianxiety) may act through these receptors.
5-HT1D/1B—Constricts cranial blood vessels and inhibits release of inflammatory neuropeptides in them; sumatriptan (antimigraine) acts through these receptors.
5-HT2A : Previously D type receptor; most important post junctional receptor mediating direct actions of 5-HT like vascular and visceral smooth muscle contraction, platelet aggregation, neuronal activation in brain; ketanserin blocks these receptors.
5-HT3 : Previously M type receptor; depolarizes neurones by gating cation channels; elicits reflex effects of 5-HT—emesis, gut peristalsis, bradycardia, transient hypotension, apnoea, pain, itch; ondansetron (antiemetic) acts by blocking these receptors.
5-HT4 : Mediate intestinal secretion, augmentation of peristalsis. Renzapride (prokinetic) is a selective 5-HT4 agonist.Central Nervous System :5-HT is an important neurotransmitter in CNS
5-HT is involved in the regulation of mood, behaviour, sleep, depression, pain perception, sexual activity, thermoregulation
in the hypothalamic control of the release of pituitary hormones.
Safety pharmacology is a branch of pharmacology with its aim to predict the potential clinical risk profile of new chemical entities (NCEs).
It has the ability to predict the potential off-target drug effects on major organ systems which are associated with exposure in the therapeutic range and above.
As an essential part of the spectrum of drug discovery and development, safety pharmacology studies are generally conducted to determine the relative drug effect on main organs, including respiratory system, central nervous system, and cardiovascular system.Safety pharmacology is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials.
SP studies are described in the international conference on harmonization (ICH) S7A and S7B Guidelines.
Importance of guidelines in regulatory toxicity testingChander K Negi
Importance of Guidelines in Regulatory Toxicity studies
Guidelines are the consensus document accepted by a regulatory body
Prevent duplication of clinical trials in humans
Ensure SAFETY, EFFICACY and QUALITY of medicines
Minimize the use of animal testing without compromising safety and effectiveness
Safety pharmacology is a branch of pharmacology with its aim to predict the potential clinical risk profile of new chemical entities (NCEs).
It has the ability to predict the potential off-target drug effects on major organ systems which are associated with exposure in the therapeutic range and above.
As an essential part of the spectrum of drug discovery and development, safety pharmacology studies are generally conducted to determine the relative drug effect on main organs, including respiratory system, central nervous system, and cardiovascular system.Safety pharmacology is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials.
SP studies are described in the international conference on harmonization (ICH) S7A and S7B Guidelines.
Importance of guidelines in regulatory toxicity testingChander K Negi
Importance of Guidelines in Regulatory Toxicity studies
Guidelines are the consensus document accepted by a regulatory body
Prevent duplication of clinical trials in humans
Ensure SAFETY, EFFICACY and QUALITY of medicines
Minimize the use of animal testing without compromising safety and effectiveness
Alzheimer’s Association Holds 2017 Advocacy Forum in WashingtonBradley DiTeresi
Based in Kansas City, Bradley DiTeresi pursues a number business endeavors, including a real estate partnership with Casas Hof Constructatora e Inmobiliaria. In addition to his professional activities, Bradley DiTeresi supports a wide range of nonprofits, including the Alzheimer’s Association.
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.
Yoga and Mindfulness on the Rise among Office WorkersGreg Gerkens
The recipient of two advanced study certificates, Greg Gerkens has over a decade of experience as a teacher and administrator working with children requiring extra assistance in the classroom. When he isn't assisting students in reaching their academic goals, Greg Gerkens lives an active lifestyle that includes yoga.
Definition
Statistics of AD
A brief introduction
Signs and symptoms of AD
NMDA receptors
Classification
Causes
Risk Factors
Pathophysiology
AD… The great unknown
Treatment Options
Future Trends
Where does the creative thought come from? Is it magic? Is the creative skill a genetic gift for only a few? We all are creative, it is our ability of expressing your creativity that may vary.
Creativity needs a method and the right conditions. Just create the right condition and remove the ugly limits that prevent us from being as creative as we can be.
I'll cover also the design topic of the difference between empty and negative space still from a creative point of view.
Early-onset Alzheimer's disease occurs in people age 30 to 60.
Rare, representing less than 5 percent of all people who have Alzheimer's Inherited type known as familial Alzheimer's disease (FAD). It caused by mutations in at least 3 genes ( these Mutations increase the production of a Aβ42) :Most cases of Alzheimer's are the late-onset form, which develops after age 60.
The causes include a combination of genetic, environmental, and lifestyle factors .
the increase risk is related to the apolipoprotein E (APOE) found gene on chromosome 19.
APOE contains the instructions for making a protein that helps carry cholesterol and other types of fat in the bloodstream. APOE comes in different forms, or alleles. Three forms—APOE ε2, APOE ε3, and APOE ε4—occur most frequently.
APOE ε2 is relatively rare and may provide some protection against the disease.
If Alzheimer's disease occurs in a person with this allele, it develops later in life than it would in someone with the APOE ε4 gene.
A presentation about Alzheimer's disease, it's definition, it's etiology, its mechanism of development as well as actual treatment and developing treatments.
Alzheimer's disease is a progressive disorder that causes brain cells to waste away (degenerate) and die. Alzheimer's disease is the most common cause of dementia — a continuous decline in thinking, behavioral and social skills that disrupts a person's ability to function independently.
Symptoms: Amnesia; Dementia
Diseases or conditions caused: Dementia
Pathophysiology
Pathology
BPharm 2nd Semester
MPharm
Therapeutics
MBBS
Alzheimer's disease is a neurodegenerative disorder with severe dementia. Due to the accumulation of Beta-Amyloid proteins acetyl-choline producing neurons are getting degenerated. Alzheimer's disease is one of the most devastating brain disorders of elderly humans. It is an under-treated and under-recognized disease that is becoming a major public health problem.
the feathers of the disease and It is histology
For downloading the presentation, more presentations , infographics and blogs visit :
studyscienceblog.wordpress.com
Alzheimer's is the most common form of dementia, a general term for memory loss and other intellectual abilities serious enough to interfere with daily life. Alzheimer's disease accounts for 60 to 80 percent of dementia cases.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
3. Alzheimer’s disease is defined as
premature aging of the brain, usually
beginning in mid-adult life and
progressing rapidly to extreme loss of
mental powers—similar to that seen in
very, very old age.
Introduction
4. In Alzheimer’s disease, there is loss of
neurons in that part of the limbic
pathway that drives the memory
process.
Loss of this memory function is
devastating.
5. It is a progressive and fatal
neurodegenerative disorder that results in
impairment of the person’s ability to
perform activities of daily living as well as
a variety of neuropsychiatric symptoms
and behavioral disturbances in the later
stages of the disease.
6. Approximately 10% of all person over
the age of 70 years have significant
memory loss, and in more than half
(60-70%) the cause is Alzheimer’s
disease
7. In 1906, Dr. Alois Alzheimer,
specifically identified a collection of
brain cell abnormalities as a disease.
History
8. The disease was first described as a
distinctive disease by Emil
Kraepelin after suppressing some
of the clinical (delusions and
hallucinations) and pathological
features (arteriosclerotic changes)
contained in the original report of
Auguste D.
9. In the 1960s, scientists discovered a link
between cognitive decline and the
number of plaques and tangles in the
brain.
Emil Kraepelin
10. The medical community then formally
recognized Alzheimer's as a disease and
not a normal part of aging.
12. Stages of Alzheimer's disease
A) Effects of ageing on memory but not AD
i) Forgetting things occasionally
ii) Misplacing items sometimes
iii) Minor short-term memory loss
iv) Forgetting that memory lapses
happened.
Clinical Features
13. B) Early stage Alzheimer's
i) Absent-mindedness
ii) Forgetting appointments
iii) Slight changes seen by close loved
ones
iv) Some confusion in situations outside
the familiar
14. C) Middle stage Alzheimer's
i) Deeper difficulty remembering
recently learned information
ii) Deepening confusion in many
circumstances
iii) Speech impairment
iv) Repeatedly initiating the same
conversation
15. D) Late stage Alzheimer's
i) More aggressive or passive
ii) Some loss of self-awareness
iii) Debilitating cognitive deficit
iv) More abusive, anxious, or
paranoid
16.
17. a) Genetics
b) Cholinergic hypothesis
c) Amyloid hypothesis
d) Tau hypothesis
e) Other hypothesis
Pathophysiology
18. Genetic factors play an important role
and about 15% of cases are familial.
Familial cases fall into two main groups:
early-onset disease with autosomal
dominant inheritance and a later-onset
group whose inheritance is polygenic.
Genetics
19. Mutations in several genes have been
described. The inheritance of one of the
alleles of apolipoprotein ε (apo ε4) is
associated with an increased risk of
developing the disease (2–4 times higher
in heterozygotes and 6–8 times in
homozygotes).
20. Most of autosomal dominant familial AD
can be attributed to mutations in one of
three genes: those encoding amyloid
precursor protein (APP) and presenilins 1
and 2.
21. The oldest, on which most currently
available drug therapies are based,
is cholinergic hypothesis, which proposes
that AD is caused by reduced synthesis of
theneurotransmitter acetylcholine.
Cholinergic hypothesis
22. The cholinergic hypothesis has not
maintained widespread support, largely
because medications intended to treat
acetylcholine deficiency have not been
very effective.
23. Amyloid hypothesis
In 1991, the amyloid hypothesis postulated
that extracellular amyloid beta (Aβ)
deposits are the fundamental cause of the
disease.
24. Support for this postulate comes from the
location of the gene for the amyloid
precursor protein (APP) on chromosome
21, together with the fact that people
with trisomy 21 (Down Syndrome) who
have an extra gene copy almost universally
exhibit AD by 40 years of age.
25. In 2009, this theory was updated,
suggesting that a close relative of the beta-
amyloid protein, and not necessarily the
beta-amyloid itself, may be a major
culprit in the disease.
26. N-APP, a fragment of APP from the
peptide's N-terminus, is adjacent to beta-
amyloid and is cleaved from APP by one of
the same enzymes.
27. N-APP triggers the self-destruct pathway
by binding to a neuronal receptor called
death receptor 6 (DR6), also known as
(TNFRSF21).
28. DR6 is highly expressed in the human
brain regions most affected by
Alzheimer's, so it is possible that the N-
APP/DR6 pathway might be hijacked in
the ageing brain to cause damage.
29.
30.
31.
32. Exactly how disturbances of
production and aggregation of the
beta-amyloid peptide gives rise to
the pathology of AD is not known.
33. The amyloid hypothesis traditionally
points to the accumulation of beta
amyloid peptides as the central event
triggering neuron degeneration.
34. Accumulation of aggregated
amyloid fibrils, which are believed
to be the toxic form of the protein
responsible for disrupting the
cell's calcium ion homeostasis,
induces programmed cell
death (apoptosis).
36. Other hypothesis
Herpes simplex virus type 1 has been
proposed to play a causative role in people
carrying the susceptible versions of the
apoE gene.
37. Some studies have shown an increased risk
of developing AD with environmental
factors such as the intake of metals,
particularly alluminium.
39. There is tentative evidence that
exposure to air pollution may be a
contributing factor to the
development of Alzheimer's disease.
40. Biochemistry
Alzheimer's disease has been identified as
a protein misfolding disease (proteopathy),
caused by plaque accumulation of
abnormally folded amyloid beta protein,
and tau protein in the brain.
41. APP is critical to neuron growth,
survival and post-injury repair.
42.
43. Plaques are made up of small peptides,
39–43 amino acids in length,
called amyloid beta (Aβ). Aβ is a
fragment from the larger amyloid
precursor protein (APP).
44. APP is a transmembrane protein that
penetrates through the neuron's
membrane.
45. In Alzheimer's disease, an unknown enzyme
in a proteolytic process causes APP to be
divided into smaller fragments.
46. One of these fragments gives rise to fibrils
of amyloid beta, which then form clumps
that deposit outside neurons in dense
formations known as senile plaques.
47. Alzheimer's disease is usually diagnosed
based on the person's medical history,
history from relatives, and behavioural
observations.
Diagnosis
48. Advanced medical imaging with
a) CT
b) MRI
c) SPECT
d) PET, can be used to help exclude
other cerebral pathology or
subtypes of dementia.
49. The diagnosis can be confirmed with very
high accuracy post-mortem when brain
material is available and can be
examined histologically.
58. Local and national support groups, such
as the Alzheimer's Association and the
Family Caregiver Alliance, are valuable
resources. Internet access to these resources
has become available to clinicians and
families in recent years.
60. Tacrine: It is the first centrally acting anti-ChE
to be introduced for AD.
In clinical trials tacrine produced significant
improvement in memory, attention, praxis,
reason and language.
However, it does not alter the course of
underlying disease process.
Frequent side effects and hepatotoxicity have
restricted its use.
61. Donepezil (1996): This is a cerebroselective and
reversible anti-AChE drug.
The benefit is ascribed to elevation of ACh level in the
cortex, especially in the surviving neurones that project
from basal forebrain to cerebral cortex and hippocampus.
Because of long t½ (~70 hr), donepezil is administered once
daily at bed time; a distinct advantage over rivastigmine
and galantamine which need twice daily dosing. Moreover,
it can be used even in relatively severe case of AD.
Donepezil is generally well tolerated and is not hepatotoxic.
Dose: 5 mg OD HS (max 10 mg OD)
62. Rivastigmine (2000): This carbamate derivative of
physostigmine inhibits both AChE and BuChE.
The carbamyl residue introduced by rivastigmine into
AChE molecule dissociates slowly resulting in inhibition
of cerebral AChE for upto 10 hours despite the 2 hr
plasma t½ of the drug.
Rivastigmine is indicated in mild to moderate cases of
AD, but not in advanced disease.
Dose: Initially 1.5 mg BD, increase every 2 weeks by 1.5
mg/day upto 6 mg/BD
63. Galantamine (2001): It is a natural alkaloid
which selectively inhibits cerebral AChE and
has some direct agonistic action on nicotinic
receptors as well.
It is well tolerated, but needs twice daily
dosing.
Dose: 4 mg BD (max 12 mg BD)
64. N-methyl-D-aspartate receptor
(NMDA) antagonist.
a) Memantine: It appears to restore the
function of damaged nerve cells and
reduce abnormal excitatory signals by the
modulation of the NMDA receptor
activity.
65. It is indicated in moderate-to-severe AD,
either to replace anti-AChEs or to
supplement them.
Dose: Initially 5 mg OD, increase
gradually upto 10 mg BD; stop if no
clinical benefit in 6 months.
66.
67. Piracetam : This cyclic GABA derivative has no
GABA like activity and has been called ‘nootropic’
meaning a drug that selectively improves efficiency of
higher telencephalic integrative activities.
Piracetam is not a vasodilator, does not affect
total/regional CBF, but may reduce blood viscosity. In
India and some other countries it has been promoted
for cognitive impairment and dementia in the elderly as
well as for mental retardation in children for over 30
years.
68. Side effects are minor: gastric discomfort,
nervousness, excitement, insomnia, dizziness and
skin rash.
Dose: 0.8–1 g TDS oral; children 20 mg/kg BD–
TDS; 1–3 g i.m. 6 hourly in stroke/head injury.
69. Pyritinol (Pyrithioxine) : It consists of two
pyridoxine molecules joined through a disulfide bridge,
but has no vit B6 activity.
It is claimed to activate cerebral metabolism by
selectively increasing glucose transport across blood-
brain barrier and improving regional blood flow in
ischaemic brain areas.
It has been promoted for: Sequelae of cerebrovascular
accidents, head injury, prolonged anaesthesia. Infants
and children with developmental disorders of CNS,
delayed milestones. Concentration and memory defects,
senility, organic brain syndromes.
However, therapeutic benefit, if any, is uncertain.
70. Dose: 100–200 mg TDS, children 50–100 mg TDS
orally; 200–400 mg every 4–6 hours (max. 1 g/day) has
been given i.v. for recovery from cerebral hypoxia due
to cardiac arrest, anaesthesia, brain operations and
stroke.
Side effects: Only mild g.i. upset was noted initially.
Later skin rashes, itching and taste disturbances.
It has been withdrawn in some countries.
71. Dihydroergotoxine (Codergocrine): It is a
semisynthetic ergot alkaloid having α adrenergic
blocking property; claimed to increase cerebral blood
flow selectively.
Dose of 1.0–1.5 mg TDS oral/sublingual or 0.3 mg i.m.
OD, it has been recommended for MCI and dementia.
Therapeutic value is not established.
72. Citicoline: It is a compound derived from choline and
cytidine, that is involved in biosynthesis of lecithin.
Citicoline is believed to improve cerebral function by
increasing blood flow to the brain and enhancing
cerebral metabolism.
In the absence of effective medicines and under
promotional pressure, citicoline is being commonly
prescribed for impaired brain function due to ischaemic
stroke, parkinsonism, head injury, etc.
Dose: 0.5–1 g/day i.m. or i.v. inj, 200–600 mg/day oral in
divided doses.
73. Ginkgo biloba: The dried extract of this Chinese
plant contains a mixture of ginkgoflavon glycosides,
which have PAF antagonistic action.
Since PAF has been implicated in cerebral thrombosis
and infarcts, it is professed that G. biloba will prevent
cerebral impairment in cerebrovascular insufficiency.
It has been promoted for a variety of cognitive and
behavioural disorders in the elderly.
Dose: 40–80 mg TDS for a minimum period of 4
weeks.
74. Piribedil: It is a dopaminergic agonist claimed to
improve memory, concentration, vigilance, giddiness and
tinnitus in the elderly due to circulatory insufficiency.
Benefit is unsubstantiated.
Minor efficacy in parkinsonism has also been reported.
Side effects are mild g.i. complaints.
Dose: 50 mg OD, BD.
77. 1) Cholinesterase inhibitor
a) Phenserine: Phenserin treatments
increased cognition and regional cerebral
metabolic rate for glucose in AD patients.
b) Dimebon: A cholinesterase inhibitor and also
a NMDA-antagonist, showed improved cognitive
and self-service functions while diminishing the
psychopathic symptoms in AD patients.
78. c) Huperzine A: A Chinese herb with
reversibly and selectively acetylcholinesterase
inhibition activity, displayed good
pharmacokinetics with a rapid absorption and
a wide distribution in the body at a low to
moderate rate of elimination.
Clinical trials have shown its cognitive
enhancement in AD at a dose of 0.4 mg and
seems to be a potential treatment option for
AD.
79. d) Ladostigil : A multimodal drug, combined
neuroprotective effects with monoamine oxidase
(MAO) -A and -B and cholinesterase inhibitory
activities in a single molecule, was tested and now
in Phase II clinical trial.
e) PMS777: A new cholinesterase inhibitor
with anti-PAF activity is also in clinical trial
80. a) β-secretase inhibitors:
i) BACE (β- site APP cleaving enzyme): Lateral
ventricular injection of this inhibitor led to a
significant dose- and time-dependent lowering of
brain Aβ40 and Aβ42, a robust decreased sAPPβ
and an increased sAPPα secretion.
ii) KMI-429: Injection of this inhibitor into the
hippocampus of APP transgenic mice reduced Aβ
production.
2) Aβ-targeting strategies
81. iii) GSK188909: Oral administration of this
non-peptidic BACE1 inhibitor results in a
significant reduction in the level of Aβ40 and
Aβ42 in the brain of transgenic mice.
83. c) α-secretase activators/modulators
Since α-secretase and β-secretase compete
for the same substrate of APP, upregulation of
α-secretase activity may decrease the amount of
APP available for β-secretase, and thus decrease
Aβ secretion and have therapeutic potential.
84. Many studies had indicated that members of
the adamalysin family of proteins, mainly
ADAM(A Disintegrin And Metalloproteinase)
10, ADAM 17 and ADAM 9, fulfill some of the
criteria required of α-secretase.
i) Deprenyl: A neuroprotective agent used to
slow AD progress, was shown to increase α-
secretase activity by promoting ADAM10 and
PKCα/ε translocation
85. d)M1 muscarinic agonists
M1 muscarinic receptors play a role in an
apparent linkage of three major hallmarks of
AD: Aβ peptide; tau hyperphosphorylation and
loss of cholinergic function conductive to
cognitive impairments.
86. i) Talsaclidine: It is a functionally selective
muscarinic M1 agonist that stimulates non-
amyloidogenic α-secretase processing in vitro.
In a double-blind, placebo-controlled, and
randomized clinical study in AD patients,
treatment with talsaclidine decreased CSF Aβ
about 20% as compared with the baseline,
suggesting its therapeutic potential.
87. ii) AF102B: another M1 agonist, also decreased
CSF Aβ of AD patients.
iii) AF267B: On clinical trial.
88. e) Aβ-aggregation inhibitor
i) iAβ5p: This is the first drug was a β-sheet
breaker, which showed that intra hippocampal
injection of it resulted in improved spatial
memory and decreased amyloid plaque deposits.
ii) Tramiprosate: It is a compound that binds
to soluble Aβ and inhibits the formation of
neurotoxic aggregates that lead to amyloid
plaque deposition in the brain.
89. f) Immunotherapy
Passive immunotherapy in AD patients with
repeated intravenous administration of human
immunoglobulin against Aβ peptide resulted in
stopped cognitive decline and slight
improvement in functional scores.
i) LY2062430: On Phase I and II clinical trials.
90. ii) Bapineuzumab: After a phase II,
multicenter, randomized, double-blind,
placebo-controlled clinical trials it shows
decreased total and phosphorylated tau levels
in CSF without affecting Aβ level.
91. iii) AN1792A: Randomized, double-blind,
placebo controlled, phase II clinical trial with
this synthetic Aβ peptide in patients with mild to
moderate AD was initiated, but the trial was
later discontinued because of approximately 6%
of the immunized AD patients(18/300) developed
meningoencephalitis.
93. vi) Imatinib: A tyrosine kinase inhibitor, was
shown to elevate AICD ( APP intracellular
domain) in H4 human neuroglioma cells, and
this was accompanied by concomitant increases
of NEP protein, mRNA levels, and activity.
vii) Valproic acid: A widely used drug in the
treatment of epilepsy, was capable of up-
regulating NEP expression, seen in
experimental rats.
94. Estrogen and green tea all could increase
NEP activity and suggest their potential in
AD treatment but there is a long way before
their final clinical application.
95. h) Apolipoprotein E (ApoE) promotes Aβ
clearance
The lipidated ApoE activates microglia and/or
astrocyte to degrade Aβ. It decreased brain
amyloid plaque burden and improved behavior
functions in AD transgenic mice.
Bexarotene: Is a nuclear receptor modulator
and ApoE activator, whether it is effective in
AD prevention needs to be explored clinically.
96. i) Drugs influencing Aβ blood–brain
barrier transport
The receptor for advanced glycation end
products (RAGE) resides in the blood vessel
wall cells and transport Aβ across the blood
brain barrier from systemic circulation to
facilitate their accumulation in brain.
97. In contrast to RAGE, low-density lipoprotein
receptor-related protein-1 (LRP-1) mediates
transport of Aβ peptide out of brain.
Thus inhibition of RAGE and/or activation of
LRP-1 may be a therapeutic target for AD, but
there are no clinical data available at present.
98. 3) Drugs development based on the
metals hypothesis:
There is increasing evidence that metal (mainly
Cu, Zn and Fe) metabolism is involved in the
major phthophysiological events of AD: APP
processing and tau hyperphosphorylation.
Several chelators of Zn/Cu have been shown to
inhibit Aβ aggregation in vitro and in vivo.
99. A phase II clinical trial with clioquinol, a
metal-protein-attenuating compound that
inhibits zinc and copper ions from binding to
Aβ, led to improved cognitive function,
decreased plasma Aβ42 level and zinc
concentration as compared with control group.
100. Other metal chelators includs XH1, DP-109,
PBT2.
PBT2 was an orally available, second generation
8-OH quinoline derivative of clioquinol, and is
advancing as a disease-modifying candidate
drug for Alzheimer’s disease.
101. 4) HMG-CoA reductase inhibitors
(the “statins”):
Clinical trial with atorvastatin for 1 year
provides some clinical benefit in AD patients.
Treatment with lovastatin resulted in decreased
plasma Aβ level.
102. 5) Monoamine oxidase inhibitors
MAO inhibitor deprenyl is an anti-Parkinson
drug used to inhibit dopamine degradation in the
brain. Also as a neuroprotective agent, deprenyl
has been used to slow the progress of
neurodegenerative diseases such as AD for many
years.
103. Rasagiline: Another MAO-B inhibitor is a
bifunctional molecule which also has
acetylcholinesterase inhibition activity.
104. 6)Treatments based on tau pathology
a) Prevention of phosphorylation of tau
b) Prevention of the aggregation of tau
c) Prevention the misfolding of tau
d) Tau immunotherapy
105. Protein phosphatase (PP)-2A: It may increase
dephosphorylation of tau. PP-2A also inhibits
kinases such as MAPK (mitogen activated
protein kinase), which phosphorylate tau.
a) Prevention of phosphorylation of tau
106. Cyclin-dependent kinase-5 (CDK5): It is a
kinase suggested to phosphorylate tau in AD.
Transgenic mice in which CDK5 activity is
activated (by overexpression of the p25
activator) in adult brain show evidence of a
striking neurodegeneration with some tau
pathology.
107. As report, inhibitors of CDK5 appear
to have some influence on the
development of pathology in some tau
transgenic mice. There are as yet no
reports of the use of CDK5 inhibitors in
humans.
108. Glycogen synthase kinase (GSK)-3β: It has
also been suggested as a drug target to
inhibit tangle formation.
This kinase is blocked by
Lithium,
The M1 muscarinic agonist AF267B,
Propentofylline (PPF) and
SRN-003-556.
109. Recent studies using cell models have
demonstrated that certain drug inhibitors
are able to prevent tau protein
aggregation and even dissolve the
developed aggregates, which include-
b) Prevention of the aggregation of tau
111. c) Prevention the misfolding of tau
i) Chaperones: The results from a study
by Dou and colleagues suggested that
increasing the activation of molecular
chaperones might prevent the misfolding of
tau, which would then reduce the
development of NFTs.
112. ii) Heat shock proteins: They have been
shown to activate chaperones that prevent
misfolding and even promote tau binding
with microtubules.
113. 7) Non-steroidal anti-inflammatory
drugs (NSAIDs)
More than 20 epidemiological studies,
some with a follow-up design and a good
estimation of NSAIDs use via prescription
data from pharmacies have suggested that
the prolonged intake of NSAIDs may be
associated with a reduced incidence of AD.
114. 8) Estrogens
Merlo et al. reported that estrogen can
activate matrix metalloproteinases-2 and −9
to increase beta amyloid degradation.
115. 9)Nicotine
Published studies in humans have reported the
effects of intravenous or subcutaneous nicotine
administration on people with AD.
Significant improvements were reported in
several cognitive tasks such as free recall,
visual attention and perception and in mood
although not on memory.
116. 10) Melatonin
In AD patients, melatonin
supplementation has been suggested to
improve circadian rhythmicity, and to
produce beneficial effects on memory.
117. 11) Cell transplantation and gene
therapy
In AD rat model, transplantation of cholinergic-
rich tissue or peripheral cholinergic neurons
ameliorates abnormal behavior and cognitive
function. But no clinical trials in AD patients
have been initiated with this method.
118. a) Endogenous nerve growth factor (NGF):
NGF administration rescues neurons
from injury-induced cell damage and leads
to associated memory improvements and
thus NGF is good for gene therapy.
119. b) Besides NGF, another candidate for gene
therapy is Aβ-degrading enzymes and the
animal experiments are also positive. Clinical
trials are not being initiated yet.
120. 12) Other pharmacological therapies
in clinical AD trails
a) Docosa-hexaenoic acid (DHA):
DHA is the most abundant omega 3 fatty acid
in the brain. Data from animal models support
the hypothesis that DHA maybe an effective
treatment for AD by means of antiamyloid,
antioxidant, and neuroprotective mechanisms.
121. b) Clioquinol: Metal chelation using
clioquinol has been reported in a pilot
study with 36 patients with AD to reduce
the rate of cognitive loss in a double-blind,
placebo-controlled, phase 2 clinical trial.
122. c) Resveratrol: Resveratrol, a red wine
polyphenol, recent studies on red wine
bioactive compounds suggest that
resveratrol modulates multiple mechanisms
of AD pathology.
123. Exert its neuroprotective role through
inhibition of Aβ aggregation, by
scavenging oxidants and exerting anti
inflammatory activities.
124. Vaccines
AN-1792: Phase I studies of AN-1792 in humans
indicated that the vaccine was well tolerated, and
a portion of the patients developed amyloid
antibodies. As a result of these findings, a
multicenter Phase IIa study in patients with mild-
to-moderate Alzheimer’s disease was initiated.
125. Passive immunization: By using antibodies
to Aβ4-10.
Intravenous immunoglobulin (IVIg):
Initial results suggest that IVIg infusion
may have long-term benefits for the
treatment of cognitive decline in
Alzheimer’s disease.149 A Phase II study is
currently underway.150
126. The ultimate goal for Alzheimer’s disease
pharmacotherapy is not merely to
ameliorate symptoms, but to alter the onset
or progression of the disease.
Conclusion
127. There are four drugs (donepezil,
galantamine, rivastigmine, and
memantine) currently approved for the
treatment of Alzheimer’s disease, but the
numerous complex and interrelated
biochemical pathways underlying
neurodegeneration in Alzheimer’s disease
provide numerous potential targets for
therapeutic intervention.
128. Several investigational compounds have
demonstrated potential as therapeutic or
preventive therapies and merit additional
study. Gradual elucidation of the exact
mechanisms of neurodegeneration will
result in increasingly focused drug
development efforts.
129.
130.
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