"It is now time for a paradigm shift in the treatment of Type 2 diabetes by assessing the individual patient’s risk by determining the inflammatory status and develop drugs that not only sustain the beta cell function but can also be evaluated as a prophylactic therapy."
Treinamento sobre Marketing na Igreja apresentado no Conjubase 2012.
Conheça um pouco sobre como o marketingo pode ajudar a sua igreja ou o seu ministério a Crescer, descubra se o marketing é heroi ou vilão.
Predicting the successional stage in biological soil crust by physical, biophysiological measurements and in combination with molecular methods (DGGE 16S rRNA) and phospholipid fatty acid analysis (PLFA)
Treinamento sobre Marketing na Igreja apresentado no Conjubase 2012.
Conheça um pouco sobre como o marketingo pode ajudar a sua igreja ou o seu ministério a Crescer, descubra se o marketing é heroi ou vilão.
Predicting the successional stage in biological soil crust by physical, biophysiological measurements and in combination with molecular methods (DGGE 16S rRNA) and phospholipid fatty acid analysis (PLFA)
The CRISPR/Cas9 system has emerged as one of the leading tools for modifying the genomes of organisms ranging from E. coli to humans. In this presentation, we discuss various methods for generating the crRNA and tracrRNA components that are required for guiding the Cas9 endonuclease to genomic targets. You will also learn how to optimize a new 2-part CRISPR RNA system from IDT that offers multiple benefits over other technologies.
Dicas de Marketing e Comunicação para Igrejas. Veja como tornar a sua igreja mais relevante atrair mais membros. Com essas dicas a gestão da sua igreja vai ficar mais dinâmica e adaptada as novas mídias como Blogs, Facebook e muito mais.
The growing epidemic of type 2 diabetes is one of the leading causes of premature morbidity and mortality worldwide, mainly due to the micro- and macrovascular complications associated with the disease. A growing body of evidence suggests that although the risk of developing complications is greater with glucose levels beyond the established
The CRISPR/Cas9 system has emerged as one of the leading tools for modifying the genomes of organisms ranging from E. coli to humans. In this presentation, we discuss various methods for generating the crRNA and tracrRNA components that are required for guiding the Cas9 endonuclease to genomic targets. You will also learn how to optimize a new 2-part CRISPR RNA system from IDT that offers multiple benefits over other technologies.
Dicas de Marketing e Comunicação para Igrejas. Veja como tornar a sua igreja mais relevante atrair mais membros. Com essas dicas a gestão da sua igreja vai ficar mais dinâmica e adaptada as novas mídias como Blogs, Facebook e muito mais.
The growing epidemic of type 2 diabetes is one of the leading causes of premature morbidity and mortality worldwide, mainly due to the micro- and macrovascular complications associated with the disease. A growing body of evidence suggests that although the risk of developing complications is greater with glucose levels beyond the established
Systemic diseases, or conditions themselves do not cause periodontitis but alter host tissues to increase the progression of periodontal disease. Systemic diseases and conditions can influence the course of periodontitis or affect the periodontal supporting tissues independent of the presence of dental plaque. Most commonly affecting diseases are diabetes, neoplasms.
In Pakistan, the overall prevalence of dyslipidemia in adolescents aged 10–18 years is 21.7~25.2%; prevalence is reported to be two times higher (53.1~56.1%) in obese adolescents. However, few studies have been conducted on the relationship between height and blood lipid concentrations in children and adolescents The recent emphasis on treatment of the dyslipidemia of the metabolic syndrome (hypertriglyceridemia, reduced high-density lipoprotein, and increased small, dense low-density lipoprotein particle number) has compelled practitioners to consider lipid-lowering therapy in a greater number of their patients, as one in two individuals over age 50 has the metabolic syndrome. Individuals with the metabolic syndrome typically have normal low-density lipoprotein cholesterol levels, and current lipid-lowering guidelines may underestimate their cardiovascular risk. Two subgroups of patients with the metabolic syndrome are at particularly high risk for premature CAD. One, individuals with type 2 diabetes, accounts for 20-30% of early cardiovascular disease. The second, familial combined hyperlipidemia, accounts for an additional 10-20% of premature CAD. Familial combined hyperlipidemia is characterized by the metabolic syndrome in addition to a disproportionate elevation of apolipoprotein B levels. The measurement of fasting glucose and apolipoprotein B, in addition to the fasting lipid profile, can help to estimate CAD risk in patients with the metabolic syndrome. In this research we compared allopathic medication and medicinal herb in treating hyperlipidemia.
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
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
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
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.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
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
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
It is time for a paradigm shift in the treatment of type 2 diabetes (2)
1. 1
“Get Real and Get It Right” with Type 2 diabetes: It Is Time For
A Paradigm Shift
TriGlytzaÔ: A Potential Gamechanger for Type 2 diabetes Patients
Ravi Kumar, Ph.D. Founder and CEO, ARKAY Therapeutics
Mission Statement: Develop Clinically Superior Yet Affordable Innovative Products
That Provide Sustained Glycemic Control For Type 2 diabetes Patients Worldwide.
Executive Summary
ARKAY Therapeutics is a privately-held clinical stage biopharmaceutical company located
in East Windsor, NJ. Type 2 diabetes, a leading cause of death worldwide is an
independent risk factor for a variety of diseases including: cardiovascular disease, several
types of cancers and neurological disorders. Type 2 diabetes continues to be an unmet
medical need because the currently marketed treatment options do not adequately treat
the underlying multidimensional pathophysiology. In real-world clinical practice in the
United States, the first-line of therapy, second and third add-on drugs failed in almost 50%
of the newly diagnosed patients between 2006 and 2016. These drugs were approved for
treating primarily the symptoms as indicated by reductions in the HbA1c levels and not for
mitigating the underlying pathophysiology of progressive deterioration of pancreatic beta
cell function. They are inadequate in filling one of the most important clinical gaps in the
Type 2 diabetes space: sustained glycemic control with a focus on preventing pancreatic
beta cell failure and decreasing insulin resistance. To fill this important gap, ARKAY
Therapeutics is developing an innovative, rationalized and patient-centric product called
RK-01 or TriGlytzaÔ. It is custom-designed and formulated to target multiple distinct and
overlapping pro-inflammatory signaling pathways along the RAS-IL1b-Cox2-PGE2-EP3
axis that contribute to progressive deterioration of beta cell function and insulin resistance,
the core defects in all patients. The scientific rationale and the product concept are
supported by the results obtained from translational animal models as well as controlled
clinical studies. They have been endorsed by leading experts in the diabetes and
cardiovascular disease space. ARKAY is currently raising capital for an FDA-approved
clinical study (ClincialTrials.gov ID: NCT03686657) to evaluate the superiority of RK-01
prototype over Metformin, the current standard of care in newly diagnosed drug naïve and
obese Type 2 diabetes patients with inadequate glycemic control with Metformin
monotherapy. TriGlytzaÔ represents a paradigm shift in the clinical management of Type
2 diabetes and it is a potentially disruptive product.
Scientific Rationale and The Product Concept
The march of diabetes has been relentless. Diabetes patient population has almost
doubled between 1980 and 2014 worldwide (Statista). It is not showing any signs of
slowing down. Over 90% of diabetes patients have Type 2 diabetes which is characterized
by insulin resistance and pancreatic beta cell dysfunction. There are over 26 million Type
2 diabetes patients in the United States alone and it is expected to grow to over 40 million
by 2040 (IDF, Facts and Figures). Over 1.3 million people are diagnosed with Type 2
diabetes every year in the United States alone. The prevalence of prediabetes is three
times that of Type 2 diabetes. A Third of the U.S. population or over 86 million people
have prediabetes. The Type 2 diabetes population is expected to double to over 600
2. 2
million worldwide by 2045 (Figure 1). The current global economic burden is over $2.3T.
Diabetes along with the cardiovascular diseases is the third leading cause of death in the
United States (ADA, CDC, Biovision). The global Type 2 diabetes market is expected to
grow from $20.4B to over $58.7B in 2025 (FiercePharma). The burden of Type 2 diabetes
or the risk of incidence for cancers such as breast, rectum, pancreas, liver and gall bladder
is over 35% because it is an independent risk factor (Zhao, X-B. et al. 2016; Ballatori, P.
et al. 2017). Recent publications have highlighted the risk of developing diseases such as
Alzheimer’s disease, Parkinson’s disease and depression in diabetes patients. The link
between insulin resistance of the brain cells and Alzheimer’s disease is so strong that
some have proposed classifying it as Type 3 diabetes (Kandimalla, R. et al. 2017).
The current treatment guidelines and algorithms of AACE, ADA and EASD provide an
extremely valuable tool and a roadmap for treating diabetes patients but unfortunately,
they are designed to fail in real-world clinical practice due to the complex dynamic among
patients, healthcare providers (HCPs) and the Health Care System (HCS) barriers.
Multiple factors contribute to the clinical inertia that occurs after the failure of Metformin,
the current first line of therapy as a result of the delay in the treatment intensification which
prevents patients from reaching their target goals for HbA1c levels (Okemah, O. et al.
2018). HbA1c is the surrogate marker and a measure of blood glucose levels. Failure to
meet patient-specific HbA1c goals put patients on a certain path to diabetes-related
microvascular complications such as retinopathy, neuropathy and nephropathy,
macrovascular complications such as stroke, peripheral artery disease (PAD), Coronary
Artery Disease (CAD). Inadequate glycemic control is responsible for over 200,000 cases
of diabetes-related complications per year in North America alone (Strain, W.D. et al.
2014). The currently marketed treatment options have focused on changing the hepatic
glucose output, insulin sensitization, direct stimulation of beta cells, or reducing the
glucose reabsorption in the kidneys. In real world clinical practice, a study that examined
trends and intensification in the use of antidiabetes drugs in over 1,023,340 adults
between 2006 and 2016 in the United States reported that the proportion of patients using
Metformin as the first-line of therapy increased from 60% in 2005 to 77% in 2016 and
antidiabetes drugs failed in almost 50% of the newly diagnosed patients (Montvida, O. et
al. 2018). In patients prescribed Metformin as the first-line of therapy, 48% initiated a
second add-on treatment at a mean HbA1c of 8.4%. Among the 78% of patients who had
at least 1-year follow-up after starting a second antidiabetes medication, 52% were
prescribed a third agent. The discontinuation rates in the first year were highest among
SGLT2 inhibitors (25%), followed by TZDs (21%), GLP-1 receptor agonists (21%) and
DPP-IV inhibitors (18%). Failure occurs because they were designed to treat and
approved based primarily on their ability to treat the symptoms such as HbA1c and not for
mitigating the underlying pathophysiology of progressive deterioration of pancreatic beta
cell function, the core defect in all patients. Beta cells in the Pancreas have an inherent
capacity for compensating for elevated blood glucose levels or hyperglycemia and insulin
resistance by secreting required amount of insulin. In spite of therapy with the current
treatment options, beta cell mass progressively decreases and their function continues to
deteriorate compromising their ability to compensate for hyperglycemia and insulin
resistance. Patients gradually reach a state of insulin dependence, a stage at which insulin
therapy becomes the only treatment option and at this stage Type 2 diabetes becomes
indistinguishable from Type 1 diabetes. It is important to note that the progressive nature
3. 3
of Type 2 diabetes is not due to an increase in insulin resistance but rather due to
progressive decline in beta cell function. Based on the results from numerous clinical
studies (Vanik, A.I. 2004), it is now time for a paradigm shift in the treatment of Type 2
diabetes by assessing the individual patient’s risk by determining the inflammatory status
and develop drugs that not only sustain the beta cell function but can also be evaluated
as a prophylactic therapy.
Source: IDF.ORG
Figure 1: Global diabetes emergency due to the unrelenting march of diabetes. Number
of people with diabetes worldwide and per region, 2017 vs. 2045 (Ages 20-79 years).
Source: IDF
Type 2 diabetes is a progressive inflammatory disease and inflammation is central to the
pathophysiology (Vinik, A.I. 2004; Skyler, J.S. et al. 2017). It has a multifactorial and
multidimensional pathophysiology but the unifying pro-inflammatory signaling pathways
that originate from a variety of clinically relevant tissues along the RAS-IL1b-Cox2-PGE2-
EP3 axis (Figure 2) contribute to progressive deterioration of pancreatic beta cell function,
the core defect or the “final common denominator” (Schwartz, S. et al. 2016). Pro-
inflammatory signals originating from multiple clinically relevant cell types and tissues due
to the multifactorial pathophysiology trigger apoptosis or programmed cell death of beta
cells and degrade their capacity to respond adequately to the elevated blood glucose
levels (Figure 3 and 4). Pro-inflammatory signals contribute to the pathophysiology of
diabetes complications as well (Skyler, J.S. et al. 2017). From a clinical perspective, it is
important to note that over 85% of Type 2 diabetes patients have high blood pressure
(ADA, Facts and Figures) and over 47% of the adults with Type 2 diabetes also have
arthritis as a coexisting condition (arthritis.org). Activation of Renin-Angiotensin System
4. 4
or RAS and Cyclooxygenase-2 or Cox-2-mediated cascade of signaling pathways
contribute to high blood pressure and arthritis or degenerative joint disease, respectively.
Activation of RAS in the context of pancreatic beta cells has nothing to do with high blood
pressure but it is in fact pro-inflammatory. It contributes along with Cox-2 mediated
elevation in PGE2 to reduction in the beta cell mass and progressive deterioration of beta
cell function. The dose-dependent elevation in PGE2 levels and reduction in the beta cells
ratio/islet (Oshima, H. et al. 2006) in a transgenic mouse model (Figure 5) is supported by
an increased production of PGE2 isolated from islets obtained from donors with Type 2
diabetes patients compared to non-diabetic donors (Kimple, M.E. et al. 2013).
Figure 2: Pro-inflammatory pathophysiology of Type 2 diabetes: RAS-IL1b-Cox2-PGE2-
EP3 axis
Furthermore, a cross-sectional view of an initial cohort study data revealed that PGE2
levels, a potent inhibitor of insulin secretion, predicted lack of effectiveness of GLP-1
analogs and DPP-IV inhibitors in Type 2 diabetes patients (Fenske, R. et al. 2017). The
clinical significance of PGE2 is further supported by suppression of GLP-1 mediated
insulin secretion by PGE2 analog Sulprostone (EP3 agonist) and it was overcome by an
EP3-specific antagonist, L-798106 (Kimple, M.E. et al. 2013). Therefore, for efficient
clinical management, an innovative and rationalized drug combination such as TriGlytzaÔ
that can provide sustained glycemic control with a focus on preventing beta cell failure,
decreasing insulin resistance, preventing or delaying insulin therapy and delaying or
preventing diabetes complications in the context of comorbidities such as high blood
5. 5
pressure and a coexisting condition such as arthritis is essential and it makes perfect
clinical sense.
Source: Skyler, J.S. et al. 2017
Figure 3: Multidimensional and multifactorial pathophysiology of Diabetes
6. 6
Metformin is the “Gold Standard” and the current standard of care for Type 2 diabetes
patients. It also is the current first line of therapy. Metformin’s efficacy is insulin dependent
and it becomes ineffective as beta cell function deteriorates to a state of insulin
Source: Schwartz, S. et al. 2016
Figure 4: b-cell-centric construct: Targeted therapies for preserving beta cells and
decreasing insulin resistance.
insufficiency in spite of therapy. It is an off-patent drug and it is highly affordable world-
wide. All the drugs that have been approved for Type 2 diabetes were approved as an
add-on drug to Metformin because they were evaluated in patients on Metformin
background. Therefore, it makes not only the clinical sense but more importantly, an
economic sense to develop a product that sustains the efficacy of Metformin and is also
affordable worldwide. In real-world clinical practice, it is not just the clinical superiority that
matters but what patients can afford and what they are willing to take matters more. There
is no doubt that some great new drugs have reached the market in recent years such as
GLP-1s e.g. Novo Nordisk’s Victoza, SGLT2 inhibitors e.g. Eli Lilly/Boehringer Ingelheim’s
Jardiance and DPP4 inhibitors e.g. Merck’s Januvia. Some of these drugs have
differentiated themselves by not only lowering blood glucose levels but more importantly
by reducing the risk of cardiovascular disease. But unfortunately, these drugs and the
mechanisms they target do not have an inherent anti-inflammatory capacity to maintain
or restore beta cell function long term. They do appear to improve the beta cell function
short term indirectly due to reduction in the stress on the beta cells as a consequence of
lowering of the blood glucose levels. It is not sustainable as indicated by the failure of the
7. 7
second and third add-on drugs in real-world clinical practice in almost 50% of the patients
in the United States (Montvida, O. et al. 2018).
Source: Oshima, H. et al. 2006
Figure 5: Fluorescence immunostaining of the islets for insulin (b-cell; Green) and
glucagon (a-cell;red). Shown are results of two islets from each for the wild-type (A), RIP-
8. 8
C2 (Cox2)mE(mPGES) (Tg/–) mice (B), RIP-C2mE (Tg/Tg) mice (C). Scale bars, 100 µm.
Shown in the bottom panel ratio of b-cells (D) and a-cells (E) to the total islet cells (mean
±S.E.) *, p<0.05.
To fill this clinically important gap, ARKAY Therapeutics is developing a uniquely
formulated proprietary product, RK-01 or TriGlytzaÔ by using a dual combination of
Celecoxib, a Cox-2 inhibitor and Valsartan, an Angiotensin II Type 1 receptor blocker
which is also a RAS blocker as an add-on or as an adjunctive therapy to Metformin.
Celecoxib or CelebrexÒ is currently approved for treating Arthritis and Valsartan or
DiovanÒ is currently approved as an anti-hypertensive drug. They both are being
repurposed for treating Type 2 diabetes. Results from the controlled clinical studies with
Type 2 diabetes patients (El-Bahrawy, H. et al. 2017; Gonazalez-Ortiz, M. et al. 2005;
Goossens, G.H. et al. 2012; Mendez del Villar, et al. 2017; Pscherer, S. et al. 2010;
Ramos-Zavala, M. et al. 2011; van der Zijl, N.R. et al. 2011) as well as from appropriate
animal models (Fujita, H. et al. 2007; Cole, B.K. et. Al. 2010; Kumar, R. ADA Conference
2016 and Diabetes 2016; Lu, C.H. et al. 2016) have shown that they improve beta cell
function, first and second phase of insulin secretion, lower HbA1c levels, improve insulin
sensitivity, inflammatory, lipid and atherogenic parameters. ARKAY has adopted a
505(b)(2) regulatory strategy for the clinical development of the commercial proprietary
formulation of TriGlytzaÔ. This strategy reduces the cost and the time of development
and enables competitive pricing worldwide. The cost of development is expected to be
only a fraction i.e. about 20% or $200M vs. >$1B compared to the development of a new
molecular entity or NCE. ARKAY has mitigated the risk to a great extent because there is
already human proof-of-concept (PoC) from controlled clinical studies and the component
drugs have a track record of safety for chronic use in the Type 2 diabetes space. Unlike
the currently marketed treatment options which treat Type 2 diabetes in isolation,
TriGlytzaÔ is custom-designed to treat the disease in the context of comorbidities and
coexisting conditions. The clinical study protocol is designed with unique sets of patient
populations, primary and secondary outcome measures that would help TriGlytzaÔ to
differentiate from currently marketed drugs and facilitate unique labeling upon approval
by the FDA (Kumar, R. 2018, ClinicalTrials.gov ID: NCT03686657).
The U.S. FDA has approved or cleared the ARKAY’s IND (Investigational New Drug)
application for evaluating the superiority of TriGlytzaÔ over Metformin in drug naïve newly
diagnosed and obese Type 2 diabetes patients with inadequate glycemic control with
Metformin monotherapy, ClinicalTrials.gov ID: NCT03686657. The U.S. patent office
(USPTO) has issued ARKAY a patent, US 9,839,644 which protects the formulations and
the method used for TriGlytzaÔ. ARKAY has also filed a continuation patent application
which protects additional adjunctive or add-on formulations of RK-01 to drugs such as
GLP-1s, SGLT2 inhibitors and DPP-IV inhibitors. The pipeline of ARKAY also includes
repurposing of RK-01 for orphan diseases such as NASH (Non-alcoholic Steatohepatitis)
and PCOS (Polycystic Ovarian Syndrome). ARKAY Therapeutics was recently
announced as a finalist for the CARE (Clinical and Research Excellence) award. The
winners will be announced at an award ceremony event on May 2nd
in Boston, MA. Based
on the results obtained from controlled clinical studies with the component drugs, we
expect TriGlytzaÔ to prevent Metformin failure by maintaining a state of insulin sufficiency
9. 9
and mitigate the clinical inertia. Our long term goal is to replace Metformin with TriGlytzaÔ
as the first line of therapy. It will also be evaluated for reducing the risk of developing Type
2 diabetes in prediabetes patients in a future clinical trial.
The scientific rationale and the product concept have been endorsed by leading
endocrinologists and experts in the metabolic and cardiovascular disease space; some of
them have joined ARKAY’s management team, the board and the scientific advisory
committee. One of them is Stan Schwartz, MD, a renowned endocrinologist, and expert
in cardiometabolic syndrome and an Emeritus Associate Clinical Professor, University of
Pennsylvania. Dr. Schwartz developed the pancreatic ‘beta-cell-concept’ for reclassifying
diabetes as well as for efficient clinical management of diabetes by stratifying patients
based on the defects and mechanisms that contribute to beta cell dysfunction. Beta cell
dysfunction is the core defect or the common denominator in all patients irrespective of
what the contributing or risk factors are in each individual patient. Dr. Schwartz has not
only invested in ARKAY Therapeutics but also has joined the management team as the
Chief Medical Advisor. Robert Busch, MD, Albany Medical College, Albany, NY, a
renowned endocrinologist and a diabetes expert has graciously volunteered to be the
principal Investigator (PI) on the clinical study. Dr. Busch has served as a PI in over 40
clinical trials.
Ravi Kumar, Ph.D. the founder and CEO of ARKAY Therapeutics obtained M.S. and Ph.D.
in Molecular and Cell Biology from New York University. He has the subject matter
expertise in the metabolic, cardiovascular and chronic inflammatory disease space. Dr.
Kumar has over 30 years of academic and pharmaceutical industry experience which
includes The Cleveland Clinic Foundation, Pharmacia and Pfizer. He comes from a family
of diabetes patients, knows first-hand the limitations of the currently marketed treatment
options and the devastating consequences of diabetes-related complications.
The investment community, angel investors and venture capitalist firms alike are currently
focused so much on investing in the immuno-oncology space with a herd mentality and
have chosen to ignore the diabetes space. There are pharma companies and VC firms
who find ARKAY’s product concept “not innovative enough” because it is a combination
of repurposed pre-approved drugs. In the real-word, patients don’t care if the medicine
they are taking is innovative, new molecules or preapproved drugs; they just want a
sustainable and an affordable solution. Large pharma companies historically have used
at least $1B potential revenue threshold as a criterion to consider a new idea for a potential
investment or a partnership. The choice with TriGlytzaÔ is simple and straight forward:
an expensively priced innovative product developed from a NCE that can generate $1B
per year revenue for short term glycemic control with a small market share or a
competitively-priced patient-centric product that can provide sustained glycemic control
which can also generate equivalent or better revenue stream with a larger market share
with a positive impact on the lives of Type 2 diabetes patients worldwide. The 3-years
exclusivity from the 505(b)(2) regulatory strategy along with exclusivity from the issued
patent are expected to prevent competition from generic drugs until the patent expiration
in September 2034 which makes the revenue potential of TriGlytzaÔ comparable to a
drug developed from a NCE. In the prevailing environment, It has become increasingly
10. 10
difficult to raise capital for ARKAY’s clinical study to bring this very important patient-
centric product to the Type 2 diabetes patients. TriGlytzaÔ provides not only a superior
clinical solution but more importantly an affordable solution. Therefore, we are reaching
out to the global investment community to raise at least $10M for the human proof-of-
concept study with TriGlytzaÔ prototype. Multiple pharma companies in the diabetes
space have already expressed interest in partnering with ARKAY for the commercial
development after the completion of the human PoC study.
Conclusions
Pharmaceutical industry needs to explore Think-out-side-the-box approaches to address
the challenges of the real-world clinical practice: sustained glycemic control, preventing
clinical inertia, affordability and diabetes complications. It is now time for a paradigm shift
in the clinical management of Type 2 diabetes. Targeting the underlying pathophysiology
of multidimensional pro-inflammatory signaling cascade of events with a rationalized
combination product such as TriGlytzaÔ which is custom-designed to prevent beta cell
failure and decrease insulin resistance makes not only clinical sense and more importantly
an economic sense for Type 2 diabetes worldwide.
Please visit www.arkaytherapeutics.com for more information on the scientific rationale,
the product concept, the management team, board members and the scientific advisors.
Please contact ravi.kumar@arkaytherapeutics.com for the non-confidential business
plan.
Please feel free to share this article with your friends and family via LinkedIn and
other social media.
Glossary:
ADA: American Diabetes Association; AACE: American Association of Clinical
Endocrinologists; AngII: Angiotensin II; CARE: Clinical and Research Excellence; CDC:
Center for Disease Control; Cox-2: Cyclooxygenase-2; DPP-IV: Dipeptidyl Peptidase-IV;
EASD: European Association for the Study of Diabetes; FDA: Food and Drug Authority;
GLP-1: Glucagon-like Peptide-1; HbA1c: Hemoglobin A1c; IDF: International Diabetes
Federation; IL-1b: Interleukin-1b; NASH: Non-alcoholic Steatohepatitis; NFkB: Nuclear
Factor kB; PCOS: Polycystic Ovarian Syndrome; PGE2: Prostaglandin E2; PGH2:
Prostaglandin H2; PoC: Proof-of-concept; RAS: Renin-Angiotensin System; SGLT2:
Sodium Glucose Transporter-2; USPTO: United States Patent and Trademark Office
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