The document discusses druggability considerations for G protein-coupled receptors (GPCRs) and ion channels. It outlines challenges in central nervous system (CNS) drug development and the potential of beta-secretase (BACE) inhibitors for treating Alzheimer's disease. It also discusses the properties of BACE inhibitors and challenges in developing them, including achieving inhibition in the CNS. Finally, it provides examples of early BACE inhibitors that incorporated hydroxyethylamine (HEA) motifs and emerging methods to truncate the HEA.
This document discusses using surface-enhanced Raman spectroscopy (SERS) to detect chemical agents and their hydrolysis products in water at very low (part-per-billion) concentrations in less than 10 minutes. SERS provides high specificity and sensitivity to identify chemicals without false positives. The approach uses functionalized sol-gel SERS capillaries to extract and pre-concentrate samples for fast, on-site analysis at part-per-billion levels for chemicals like cyanide, thiodiglycol, and methyl phosphonic acid in under a minute. Future work involves continuous monitoring of water supplies using a SERS sensor connected to a flow system.
This document summarizes the optimization of an organocatalytic domino Michael-Aldol reaction to synthesize bispirooxindoles. Various cinchona alkaloid derivatives were evaluated as catalysts, with a trifunctional S-binaphthyl diamine catalyst (VIII) giving excellent diastereoselectivity and enantioselectivity. Reaction conditions such as temperature, solvent, and substrate scope were varied, demonstrating good yields and selectivity for a range of substrates. A different protecting group was also investigated, and bispirooxindoles were successfully deprotected to give the corresponding amines in high yields and selectivity.
Here's a shortly described presentation on molecular mechanism of drug action that I presented for my pharmacology course.
I tried to include everything related to this topic shortly including receptors, ion channels, carrier molecules & enzymes.
Hope it'll be helpful.
This document discusses cellular signalling and molecular mechanisms of drug action. It describes the different types of cell signalling including extracellular signals like hormones and intracellular signals like calcium and cyclic nucleotides. It also explains different receptor types like G-protein coupled receptors and ligand-gated ion channels. Additionally, it covers molecular mechanisms of drug action like receptor occupancy models and transducer mechanisms. Finally, it discusses ion channels involved in cellular signalling like sodium, calcium and potassium channels as well as their pharmacological modulation.
This document summarizes the concepts of agonists and antagonists in receptor activation and inhibition. It defines agonists as ligands that enhance receptor activity and antagonists as those that oppose agonist action and block receptor activation. The document compares the properties and types of agonists, including full, partial, and inverse agonists, and antagonists, including competitive, non-competitive, and irreversible antagonists. It discusses how agonists and antagonists regulate signaling pathways through their effects on receptor activation and inhibition.
The Mitsunobu reaction allows the conversion of alcohols to various functional groups using trialkyl/triaryl phosphine and dialkyl azodicarboxylate reagents. It proceeds via an oxidation-reduction mechanism. Common applications include esterification, etherification, and N-alkylation reactions. Recent advances have focused on replacing conventional reagents to improve selectivity and yields. The Mitsunobu reaction has been widely used in the synthesis of natural products and pharmaceuticals.
This document discusses purine and pyrimidine metabolism. It covers the biosynthesis of purines through 11 steps, degradation of purines to uric acid, medical conditions related to purine metabolism like Lesch-Nyhan and ADA deficiency, the causes and treatment of gout, and drugs used to treat gout like colchicine, probenecid, and allopurinol.
The document discusses factors that determine the biological activity of phosphodiesterase inhibitors. It finds that inhibitory activity mainly depends on bond stretch energy, geometric section, number of types of molecular associates, molecule surface area, sum of atomic volumes, and sum of free carbon atomic volumes and surfaces. Inhibitory activity is influenced by the molecule's geometry and ability to complementarily fit and strongly interact with the binding site. Virtual receptor modeling shows the most active structure occupying the receptor space most completely.
This document discusses using surface-enhanced Raman spectroscopy (SERS) to detect chemical agents and their hydrolysis products in water at very low (part-per-billion) concentrations in less than 10 minutes. SERS provides high specificity and sensitivity to identify chemicals without false positives. The approach uses functionalized sol-gel SERS capillaries to extract and pre-concentrate samples for fast, on-site analysis at part-per-billion levels for chemicals like cyanide, thiodiglycol, and methyl phosphonic acid in under a minute. Future work involves continuous monitoring of water supplies using a SERS sensor connected to a flow system.
This document summarizes the optimization of an organocatalytic domino Michael-Aldol reaction to synthesize bispirooxindoles. Various cinchona alkaloid derivatives were evaluated as catalysts, with a trifunctional S-binaphthyl diamine catalyst (VIII) giving excellent diastereoselectivity and enantioselectivity. Reaction conditions such as temperature, solvent, and substrate scope were varied, demonstrating good yields and selectivity for a range of substrates. A different protecting group was also investigated, and bispirooxindoles were successfully deprotected to give the corresponding amines in high yields and selectivity.
Here's a shortly described presentation on molecular mechanism of drug action that I presented for my pharmacology course.
I tried to include everything related to this topic shortly including receptors, ion channels, carrier molecules & enzymes.
Hope it'll be helpful.
This document discusses cellular signalling and molecular mechanisms of drug action. It describes the different types of cell signalling including extracellular signals like hormones and intracellular signals like calcium and cyclic nucleotides. It also explains different receptor types like G-protein coupled receptors and ligand-gated ion channels. Additionally, it covers molecular mechanisms of drug action like receptor occupancy models and transducer mechanisms. Finally, it discusses ion channels involved in cellular signalling like sodium, calcium and potassium channels as well as their pharmacological modulation.
This document summarizes the concepts of agonists and antagonists in receptor activation and inhibition. It defines agonists as ligands that enhance receptor activity and antagonists as those that oppose agonist action and block receptor activation. The document compares the properties and types of agonists, including full, partial, and inverse agonists, and antagonists, including competitive, non-competitive, and irreversible antagonists. It discusses how agonists and antagonists regulate signaling pathways through their effects on receptor activation and inhibition.
The Mitsunobu reaction allows the conversion of alcohols to various functional groups using trialkyl/triaryl phosphine and dialkyl azodicarboxylate reagents. It proceeds via an oxidation-reduction mechanism. Common applications include esterification, etherification, and N-alkylation reactions. Recent advances have focused on replacing conventional reagents to improve selectivity and yields. The Mitsunobu reaction has been widely used in the synthesis of natural products and pharmaceuticals.
This document discusses purine and pyrimidine metabolism. It covers the biosynthesis of purines through 11 steps, degradation of purines to uric acid, medical conditions related to purine metabolism like Lesch-Nyhan and ADA deficiency, the causes and treatment of gout, and drugs used to treat gout like colchicine, probenecid, and allopurinol.
The document discusses factors that determine the biological activity of phosphodiesterase inhibitors. It finds that inhibitory activity mainly depends on bond stretch energy, geometric section, number of types of molecular associates, molecule surface area, sum of atomic volumes, and sum of free carbon atomic volumes and surfaces. Inhibitory activity is influenced by the molecule's geometry and ability to complementarily fit and strongly interact with the binding site. Virtual receptor modeling shows the most active structure occupying the receptor space most completely.
This document provides an overview of DNA structure and the different forms it can take. It discusses the primary structures of DNA including nucleotides, nucleosides, and bases. It then describes the canonical B-DNA double helical structure proposed by Watson and Crick, including base pairing, base stacking, and the forces that stabilize the structure. Finally, it briefly discusses alternative A-form and Z-form double helical structures and their biological relevance.
Esta ha sido una de las conferencias que mas me ha gustado darla por lo moderno en el tratamiento de la DBM tipo 2 ,con el uso de la Linagliptina completamos el cuadro
This document summarizes the structure-activity relationships of inhibitors of plasminogen activator inhibitor-1 (PAI-1). PAI-1 regulates several cellular processes and its inhibition may help treat diseases associated with high PAI-1 levels like diabetes and atherosclerosis. The study synthesized sulfonimide- and ester-based inhibitors and evaluated their ability to inhibit PAI-1. Modifying groups like the gallate to protocatechuate or the carbamate side chain altered the inhibitors' potency, with certain modifications improving PAI-1 inhibition. The inhibitors showed IC50 values in the low micromolar range.
The big topic of the last few years, the use of small organic molecules to catalyse enantioselective transformations. This lecture will start with proline before moving on to some of MacMillan's contributions to this field and, finally, finish with hydrogen bond catalysts and Brønsted acids.
Self explanatory really, this lecture looks at chiral auxiliaries. We will concentrate on oxazolidinones in alkylations, aldol reaction and the Diels-Alder reaction. There will be a couple examples of other auxiliaries.
The Mannich reaction involves the condensation of an enolizable carbonyl compound, an aldehyde such as formaldehyde, and a primary or secondary amine. This results in an aminoalkylation and formation of a β-aminocarbonyl compound known as a Mannich base. Modifications using preformed Mannich bases and reactive substrates extend the scope and selectivity of the reaction. The Mannich reaction has wide applications in organic synthesis and for producing natural and medicinal compounds.
The document describes improvements made to the process for manufacturing the potential therapeutic compound ELN 296571. It summarizes the original multi-step synthesis route and key intermediate compound ELN 361973. The route was optimized to require fewer steps and produce ELN 361973 in higher yields and purity. Later, production of the important intermediate ELN 361973 was outsourced to improve the overall process.
This document provides an overview of sexually transmitted infections (STIs) for clinicians. It discusses the most common bacterial, viral and parasitic STIs including their epidemiology, diagnosis and treatment recommendations. Screening and prevention strategies are also reviewed, including behavioral counseling, vaccination, condom use and expedited partner therapy. The impacts of STIs on women's reproductive health are highlighted.
This document discusses the differential diagnosis and management of vulvovaginal disorders. It begins by categorizing common conditions into infections (trichomoniasis, bacterial vaginosis, vulvovaginal candidiasis), skin conditions (fungal vulvitis, contact dermatitis, vulvar dermatoses), and psychogenic causes. It then provides detailed guidelines on evaluating, diagnosing, and treating specific infections like trichomoniasis, bacterial vaginosis, and vulvovaginal candidiasis. It also reviews vulvar conditions like lichen sclerosus, contact dermatitis, and classifications of vulvar dermatoses.
This document provides information about migraine in women. Some key points:
- Migraine is 3 times more common in women than men. Hormonally-associated migraines affect 12 million women in the US.
- Migraines are often associated with changes in hormone levels, such as during menstruation, pregnancy, use of oral contraceptives, and menopause.
- Diagnosis of migraine involves evaluating symptoms such as headache duration/intensity, nausea, light/sound sensitivity, visual/sensory disturbances (aura).
- Treatment involves both acute symptomatic relief and preventive medications, though choices are more limited during pregnancy/breastfeeding due to safety.
This document discusses 5 case studies involving GI disorders in women. The first case involves a 32-year-old woman with 5 years of diarrhea and abdominal pain. The next best step is reassurance without further testing, as her symptoms are consistent with irritable bowel syndrome. The second case involves a 38-year-old woman with vomiting after gastric bypass surgery, where an internal hernia is the most likely cause. The third case involves a pregnant woman referred for irritable bowel syndrome, where testing her for celiac disease is the next best step. The fourth case involves constipation, where pelvic floor dysfunction is the most likely diagnosis given her exam findings. The fifth case involves a 58-year-old woman with diarrhea
Here are my recommendations for the 56 year old woman with subclinical hypothyroidism:
1. Her diagnosis is subclinical hypothyroidism based on an elevated TSH of 7.1 and normal free T4.
2. Given her age (56), fatigue, and 3-4 lb weight gain, I would recommend a trial of levothyroxine therapy. Treatment is reasonable for patients with TSH >10 or positive thyroid antibodies, which she does not have data for. However, treatment may modestly improve her lipids and symptoms.
3. She should be monitored every 6 months with TSH checks to ensure her TSH is maintained between 0.5-2.0 and that she does not
The document announces the Women's Health 2012 Congress hosted by the NIH Office of Research on Women's Health. It will feature scientific poster awards for Women's Health and Sex Differences Research. The congress focuses on women's health issues and research.
The document discusses how the Affordable Care Act (ACA) aims to improve access to preventive health services for women by requiring new health plans to cover recommended preventive services without cost sharing. This includes services for cancer screening, chronic disease prevention and management, vaccinations, healthy behaviors counseling, pregnancy-related care, and reproductive health services. The new rules apply to new private health plans starting in 2010 and 2012, with some exemptions for grandfathered and religious plans. Implementation will consider factors like network restrictions, separate billing for visits and services, and ensuring adequate provider training and capacity.
The document summarizes the charge given by the Institute of Medicine to convene a committee of experts to review women's preventive health services and identify gaps. The committee was tasked with recommending services to be included in comprehensive national guidelines. After reviewing evidence, the committee made 8 recommendations, including screening for gestational diabetes, HPV testing, counseling on STIs and HIV, contraception services, lactation support, interpersonal violence screening, and annual well-woman visits.
This document summarizes key aspects of the Affordable Care Act (ACA) and how it benefits women's health and preventive care. It discusses how the ACA expands insurance coverage to over 34 million Americans, strengthens consumer protections, and requires insurers to cover preventive services for women at no additional cost. Specifically, it outlines services that must be covered for pregnant women, various cancer and disease screenings, counseling services, contraception and sterilization coverage, lactation support, and violence screening. It also notes that some existing "grandfathered" health plans are exempt from some ACA requirements but still must cover certain new benefits.
Dr. Iglesia has no conflicts of interest to disclose. The objectives of the document are to develop effective treatment plans, communicate treatment goals, minimize medication side effects, and describe new therapies for overactive bladder in women. Overactive bladder affects millions of Americans, especially women, and prevalence increases with age. New therapies aim to change stereotypes about overactive bladder and provide realistic information about prevalence and severity. Behavioral interventions like pelvic floor exercises and bladder training can be effective treatment approaches.
The document discusses cervical cancer screening guidelines and strategies, comparing the use of Pap tests, HPV tests, and primary HPV screening. It provides information on the epidemiology of HPV and progression to cervical cancer, as well as data from studies showing that primary HPV screening can detect more high-grade cervical lesions than cytology alone.
The document discusses depression in women and improving outcomes. Major depression has a significant public health impact and is the leading cause of disability among women worldwide. Women experience depression rates 1.5-2.5 times higher than men ages 15-54. Key ways to improve outcomes include considering differential diagnoses, treating to remission, measuring symptom improvement, using evidence-based interventions personalized to the individual woman, and providing self-help resources.
This document discusses strategies for managing obesity in women. It notes that obesity is influenced by multiple factors including genetics, environment, diet, physical activity, and life events. Key life events that can influence weight gain include pregnancy, menopause, and aging. Maternal obesity increases health risks for both mother and child during pregnancy and the child's future obesity risk. Abdominal obesity, as measured by waist circumference, is a better predictor of health risks than BMI alone. Managing obesity requires addressing its underlying causes through lifestyle changes.
This document is an in memoriam for Trudy L Bush, a professor of epidemiology and preventive medicine at the University of Maryland who passed away in 2001. It summarizes her landmark research on the effects of hormones on various body systems, her trailblazing leadership in the field of women's health, and her tireless commitment to medical education relating to women's health and menopause. The document honors her memory with an annual lecture series.
Evidence based management of cardiovascular disease in women plmiami
1. Evidence Based Management of Cardiovascular Disease in Women discusses the leading causes of death in Americans and how cardiovascular disease is the number one killer of women.
2. The document reviews gender differences in atherosclerosis, such as plaque erosion being more common in women than plaque rupture seen in men, making diagnosis of cardiovascular disease more difficult in women.
3. Prevention strategies discussed include reducing atherosclerosis, preventing plaque rupture and erosion, limiting thrombosis, and recognizing the presence of cardiovascular disease in women.
This document provides an overview of DNA structure and the different forms it can take. It discusses the primary structures of DNA including nucleotides, nucleosides, and bases. It then describes the canonical B-DNA double helical structure proposed by Watson and Crick, including base pairing, base stacking, and the forces that stabilize the structure. Finally, it briefly discusses alternative A-form and Z-form double helical structures and their biological relevance.
Esta ha sido una de las conferencias que mas me ha gustado darla por lo moderno en el tratamiento de la DBM tipo 2 ,con el uso de la Linagliptina completamos el cuadro
This document summarizes the structure-activity relationships of inhibitors of plasminogen activator inhibitor-1 (PAI-1). PAI-1 regulates several cellular processes and its inhibition may help treat diseases associated with high PAI-1 levels like diabetes and atherosclerosis. The study synthesized sulfonimide- and ester-based inhibitors and evaluated their ability to inhibit PAI-1. Modifying groups like the gallate to protocatechuate or the carbamate side chain altered the inhibitors' potency, with certain modifications improving PAI-1 inhibition. The inhibitors showed IC50 values in the low micromolar range.
The big topic of the last few years, the use of small organic molecules to catalyse enantioselective transformations. This lecture will start with proline before moving on to some of MacMillan's contributions to this field and, finally, finish with hydrogen bond catalysts and Brønsted acids.
Self explanatory really, this lecture looks at chiral auxiliaries. We will concentrate on oxazolidinones in alkylations, aldol reaction and the Diels-Alder reaction. There will be a couple examples of other auxiliaries.
The Mannich reaction involves the condensation of an enolizable carbonyl compound, an aldehyde such as formaldehyde, and a primary or secondary amine. This results in an aminoalkylation and formation of a β-aminocarbonyl compound known as a Mannich base. Modifications using preformed Mannich bases and reactive substrates extend the scope and selectivity of the reaction. The Mannich reaction has wide applications in organic synthesis and for producing natural and medicinal compounds.
The document describes improvements made to the process for manufacturing the potential therapeutic compound ELN 296571. It summarizes the original multi-step synthesis route and key intermediate compound ELN 361973. The route was optimized to require fewer steps and produce ELN 361973 in higher yields and purity. Later, production of the important intermediate ELN 361973 was outsourced to improve the overall process.
This document provides an overview of sexually transmitted infections (STIs) for clinicians. It discusses the most common bacterial, viral and parasitic STIs including their epidemiology, diagnosis and treatment recommendations. Screening and prevention strategies are also reviewed, including behavioral counseling, vaccination, condom use and expedited partner therapy. The impacts of STIs on women's reproductive health are highlighted.
This document discusses the differential diagnosis and management of vulvovaginal disorders. It begins by categorizing common conditions into infections (trichomoniasis, bacterial vaginosis, vulvovaginal candidiasis), skin conditions (fungal vulvitis, contact dermatitis, vulvar dermatoses), and psychogenic causes. It then provides detailed guidelines on evaluating, diagnosing, and treating specific infections like trichomoniasis, bacterial vaginosis, and vulvovaginal candidiasis. It also reviews vulvar conditions like lichen sclerosus, contact dermatitis, and classifications of vulvar dermatoses.
This document provides information about migraine in women. Some key points:
- Migraine is 3 times more common in women than men. Hormonally-associated migraines affect 12 million women in the US.
- Migraines are often associated with changes in hormone levels, such as during menstruation, pregnancy, use of oral contraceptives, and menopause.
- Diagnosis of migraine involves evaluating symptoms such as headache duration/intensity, nausea, light/sound sensitivity, visual/sensory disturbances (aura).
- Treatment involves both acute symptomatic relief and preventive medications, though choices are more limited during pregnancy/breastfeeding due to safety.
This document discusses 5 case studies involving GI disorders in women. The first case involves a 32-year-old woman with 5 years of diarrhea and abdominal pain. The next best step is reassurance without further testing, as her symptoms are consistent with irritable bowel syndrome. The second case involves a 38-year-old woman with vomiting after gastric bypass surgery, where an internal hernia is the most likely cause. The third case involves a pregnant woman referred for irritable bowel syndrome, where testing her for celiac disease is the next best step. The fourth case involves constipation, where pelvic floor dysfunction is the most likely diagnosis given her exam findings. The fifth case involves a 58-year-old woman with diarrhea
Here are my recommendations for the 56 year old woman with subclinical hypothyroidism:
1. Her diagnosis is subclinical hypothyroidism based on an elevated TSH of 7.1 and normal free T4.
2. Given her age (56), fatigue, and 3-4 lb weight gain, I would recommend a trial of levothyroxine therapy. Treatment is reasonable for patients with TSH >10 or positive thyroid antibodies, which she does not have data for. However, treatment may modestly improve her lipids and symptoms.
3. She should be monitored every 6 months with TSH checks to ensure her TSH is maintained between 0.5-2.0 and that she does not
The document announces the Women's Health 2012 Congress hosted by the NIH Office of Research on Women's Health. It will feature scientific poster awards for Women's Health and Sex Differences Research. The congress focuses on women's health issues and research.
The document discusses how the Affordable Care Act (ACA) aims to improve access to preventive health services for women by requiring new health plans to cover recommended preventive services without cost sharing. This includes services for cancer screening, chronic disease prevention and management, vaccinations, healthy behaviors counseling, pregnancy-related care, and reproductive health services. The new rules apply to new private health plans starting in 2010 and 2012, with some exemptions for grandfathered and religious plans. Implementation will consider factors like network restrictions, separate billing for visits and services, and ensuring adequate provider training and capacity.
The document summarizes the charge given by the Institute of Medicine to convene a committee of experts to review women's preventive health services and identify gaps. The committee was tasked with recommending services to be included in comprehensive national guidelines. After reviewing evidence, the committee made 8 recommendations, including screening for gestational diabetes, HPV testing, counseling on STIs and HIV, contraception services, lactation support, interpersonal violence screening, and annual well-woman visits.
This document summarizes key aspects of the Affordable Care Act (ACA) and how it benefits women's health and preventive care. It discusses how the ACA expands insurance coverage to over 34 million Americans, strengthens consumer protections, and requires insurers to cover preventive services for women at no additional cost. Specifically, it outlines services that must be covered for pregnant women, various cancer and disease screenings, counseling services, contraception and sterilization coverage, lactation support, and violence screening. It also notes that some existing "grandfathered" health plans are exempt from some ACA requirements but still must cover certain new benefits.
Dr. Iglesia has no conflicts of interest to disclose. The objectives of the document are to develop effective treatment plans, communicate treatment goals, minimize medication side effects, and describe new therapies for overactive bladder in women. Overactive bladder affects millions of Americans, especially women, and prevalence increases with age. New therapies aim to change stereotypes about overactive bladder and provide realistic information about prevalence and severity. Behavioral interventions like pelvic floor exercises and bladder training can be effective treatment approaches.
The document discusses cervical cancer screening guidelines and strategies, comparing the use of Pap tests, HPV tests, and primary HPV screening. It provides information on the epidemiology of HPV and progression to cervical cancer, as well as data from studies showing that primary HPV screening can detect more high-grade cervical lesions than cytology alone.
The document discusses depression in women and improving outcomes. Major depression has a significant public health impact and is the leading cause of disability among women worldwide. Women experience depression rates 1.5-2.5 times higher than men ages 15-54. Key ways to improve outcomes include considering differential diagnoses, treating to remission, measuring symptom improvement, using evidence-based interventions personalized to the individual woman, and providing self-help resources.
This document discusses strategies for managing obesity in women. It notes that obesity is influenced by multiple factors including genetics, environment, diet, physical activity, and life events. Key life events that can influence weight gain include pregnancy, menopause, and aging. Maternal obesity increases health risks for both mother and child during pregnancy and the child's future obesity risk. Abdominal obesity, as measured by waist circumference, is a better predictor of health risks than BMI alone. Managing obesity requires addressing its underlying causes through lifestyle changes.
This document is an in memoriam for Trudy L Bush, a professor of epidemiology and preventive medicine at the University of Maryland who passed away in 2001. It summarizes her landmark research on the effects of hormones on various body systems, her trailblazing leadership in the field of women's health, and her tireless commitment to medical education relating to women's health and menopause. The document honors her memory with an annual lecture series.
Evidence based management of cardiovascular disease in women plmiami
1. Evidence Based Management of Cardiovascular Disease in Women discusses the leading causes of death in Americans and how cardiovascular disease is the number one killer of women.
2. The document reviews gender differences in atherosclerosis, such as plaque erosion being more common in women than plaque rupture seen in men, making diagnosis of cardiovascular disease more difficult in women.
3. Prevention strategies discussed include reducing atherosclerosis, preventing plaque rupture and erosion, limiting thrombosis, and recognizing the presence of cardiovascular disease in women.
This document discusses care of cancer survivors and outlines the following key points in 3 sentences:
1) Approximately 3% of the population are cancer survivors, with many being elderly and having multiple comorbidities. 2) Both cancer-related and general medical needs must be addressed in cancer survivors, including surveillance for recurrence, late effects of treatment, and new primary cancers as well as screening and management of comorbidities. 3) The role of primary care physicians in providing ongoing care for cancer survivors along with survivorship care plans is reviewed.
This document discusses factors that influence peak bone mass attained during adolescence and young adulthood. It notes that genetics account for 80% of variability in peak bone mass, and lists several genes associated with bone mineral density and fracture risk. Nutrition, physical activity, body composition, endocrine status like age of menarche, and use of birth control also impact peak bone mass. Regular weight-bearing exercise and adequate calcium, vitamin D, and protein intake during growth can help increase bone mass accrual and attain a higher peak.
This document summarizes best practices in lesbian health based on a presentation by Dr. Patricia Robertson. It finds that lesbians have higher rates of smoking, childhood abuse, obesity, and certain STIs. They have lower rates of Pap smears and mammograms due to cost and prior adverse experiences. The document recommends screening lesbians appropriately, discussing family planning options, ensuring legal protections for partners, and advocating for lesbian health in the community. Providers should encourage disclosure of sexual orientation to provide culturally competent care.
Lee P. Shulman is the Anna Ross Lapham Professor of Obstetrics and Gynecology and Chief of the Division of Clinical Genetics at Northwestern University. He discloses advisory roles and speaking engagements with several genetic testing companies. His research focuses on inherited cancer risk assessment and genetic testing for hereditary cancer syndromes. He provides an overview of the genetics of cancer including tumor suppressor genes and oncogenes, as well as specific hereditary cancer syndromes like BRCA1/2, Lynch syndrome, and Cowden syndrome that increase cancer risk, especially for women's cancers.
This document summarizes evidence-based care of women with rheumatoid arthritis (RA). It discusses that RA is a chronic inflammatory disorder that principally affects the synovial joints. It is characterized by a proliferative response in the synovium leading to bone and cartilage destruction. The document reviews who is affected by RA, common articular features, characteristic deformities, and extra-articular manifestations. It also discusses the natural history of RA and whether there are any gender differences. Current management approaches from 2012 are presented, including early diagnosis, prompt initiation of traditional DMARDs, and appropriate use of biological DMARDs.
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Unlock the full potential of the MECE (Mutually Exclusive, Collectively Exhaustive) Principle with this comprehensive PowerPoint deck. Designed to enhance your analytical skills and strategic decision-making, this presentation guides you through the fundamental concepts, advanced techniques, and practical applications of the MECE framework, ensuring you can apply it effectively in various business contexts.
The MECE Principle, developed by Barbara Minto, an ex-consultant at McKinsey, is a foundational tool for structured thinking. Minto is also renowned for the Minto Pyramid Principle, which emphasizes the importance of logical structuring in writing and presenting ideas. This presentation includes a clear explanation of the MECE principle and its significance. It offers a detailed exploration of MECE concepts and categories, highlighting how to create mutually exclusive and collectively exhaustive segments. You will learn to combine MECE with other powerful business frameworks like SWOT, Porter's Five Forces, and BCG Matrix. Discover sophisticated methods for applying MECE in complex scenarios and enhancing your problem-solving abilities. The deck also provides a step-by-step guide to performing thorough and structured MECE analyses, ensuring no aspect is overlooked. Insider tips are included to help you avoid common mistakes and optimize your MECE applications.
The presentation features illustrative examples from various industries to show MECE in action, providing practical insights and inspiration. It includes engaging group activities designed for the practice of the MECE principle, fostering collaborative learning and application. Key takeaways and success factors for mastering the MECE principle and applying it in your professional work are also covered.
The MECE Principle presentation is meticulously designed to provide you with all the tools and knowledge you need to master the MECE principle. Whether you're a business analyst, manager, or strategist, this presentation will empower you to deliver insightful and actionable analysis, drive better decision-making, and achieve outstanding results.
LEARNING OBJECTIVES:
1. Understand the MECE Principle
2. Improve Analytical Skills
3. Apply MECE Framework
4. Enhance Decision-Making
5. Optimize Resource Allocation
6. Facilitate Strategic Planning
SATTA MATKA DPBOSS KALYAN MATKA RESULTS KALYAN CHART KALYAN MATKA MATKA RESULT KALYAN MATKA TIPS SATTA MATKA MATKA COM MATKA PANA JODI TODAY BATTA SATKA MATKA PATTI JODI NUMBER MATKA RESULTS MATKA CHART MATKA JODI SATTA COM INDIA SATTA MATKA MATKA TIPS MATKA WAPKA ALL MATKA RESULT LIVE ONLINE MATKA RESULT KALYAN MATKA RESULT DPBOSS MATKA 143 MAIN MATKA KALYAN MATKA RESULTS KALYAN CHART
➒➌➎➏➑➐➋➑➐➐ Satta Matka Dpboss Matka Guessing Indian Matka
KALYAN MATKA | MATKA RESULT | KALYAN MATKA TIPS | SATTA MATKA | MATKA.COM | MATKA PANA JODI TODAY | BATTA SATKA | MATKA PATTI JODI NUMBER | MATKA RESULTS | MATKA CHART | MATKA JODI | SATTA COM | FULL RATE GAME | MATKA GAME | MATKA WAPKA | ALL MATKA RESULT LIVE ONLINE | MATKA RESULT | KALYAN MATKA RESULT | DPBOSS MATKA 143 | MAIN MATKA
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1. Druggability Considerations for GPCRs
and Ion Channels
Shaun R. Stauffer
6th Drug Discovery for Neurodegeneration Conference
February 12-14, 2012
2. Outline
1. CNS drug development statistics and the hope for BACE inhibitors
2. Druggability considerations for GPCRs
Orthosteric versus Allosteric Approaches
M1/M4 PAMs- receptor reserve and probe dependence
mGluR5 PAMs- ‘mode switching’ and allosteric agonism
3. Summary and Outlook
3. CNS drug development challenges
Tremendous need: neurological and psychiatric conditions account for 13% of the global burden of
disease
CNS drugs spend 8.1 yrs in human testing, more than 2 yrs longer than average for all agents
Regulatory approval of CNS drugs takes longer- 1.8 yrs vs1.2 yrs for all drugs
8.2% of CNS drug candidates that begin human testing will reach marketplace vs. 15 % for drugs
overall
46% of CNS candidates succeed in late-stage (phase III) trials, compared with 66% for all drugs
Evaluation of clinical improvement more difficult- schizophrenic episodes or cognitive
improvement in Alzheimer‟s patients more variable and require outcomes trials for therapies aimed
at disease modification
New coalitions emerging to bring government agencies, drug companies and patient advocacy
groups together, to develop a standardized clinical trials database to allow researchers to design
more efficient studies for new treatments and share the risk for development.
A Dearth of New Meds: Drugs to treat neuropsychiatric disorders have become too risky for Big Pharma.
K. I. Kaitin, C. P. Milne Scientific American, Aug. 2011.
4. Amyloid Precursor Protein (APP) Proteolysis:
A Fork in the Road
• -Secretase pathway – Predominant, sAPP neurotrophic (non-amyloidogenic)
• -Secretase pathway – Minor, normal in development/repair and pathologic
(A ) roles (oligomerization, “amyloidogenic”)
-secretase -secretase -secretase
VKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK
LVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK
A 1-40 (major)
sAPP A 1-42 (minor)
sAPP
Inhibition of -secretase (BACE) should impede the production
of the peptide A , hence slowing the progress of Alzheimer‟s
disease
5. BACE Active Site Properties
• Membrane associated aspartyl protease within pepsin family
• First cloned and purified in 1999
• Large, open, hydrophilic cleft
• Complementary binding to extended -strand inhibitor/substrate to achieve potency
P2
P1'
NH2
CO2H CO2H
O
H O H OH Me H O H
N N N N CO2H ~1 nM BACE-1
H2N N N
O H O Me O Me H O
Me Me
Me
P3 P1
L. Hong, J. Tang et al, Science 2000, 290, 150
7. BACE Inhibitor Challenges
• Best known inhibitory motifs are Transition State Analogues (TSA‟s)
• Problem: TSA‟s historically have poor brain penetration (Ritonavir®),
CYP inhibition and poor oral bioavailability (Renin inhibitors)
P2
P1'
NH2
CO2H CO2H
O
H O H OH Me H O H
N N N N CO2H ~1 nM BACE-1
H2N N N
O H O Me O Me H O
Me Me
Me
P3 P1
L. Hong, J. Tang et al, Science 2000, 290, 150
How can we achieve BACE inhibition in the CNS?
Average properties of marketed CNS drugs:
small, rigid, Pgp <2.5, LogP >2, MW ~320; HBD ~1, HBA ~2, PSA ~41
K.M. Mahar Doan, J.W. Polli, et al. J. Pharmacol. Exp. Ther., 2002, 1029-1037
8. Aspartyl Protease Transition State Analogues
HHO OHP1' H O
N N
N
O P1 H O P2'
transition state
H OH P1' H OH P1' H NH2 P1' H OH O
N N N N
n
O P1 O O P1 OH O O P1 O O P1
hydroxyethylene (HE) di-hydroxyethylene (DHE) aminoethylene (AE) statine-based
H NH2 O OH H O H OH P1' O H P1'
H
N N N N P N
n N
O H
O P1 O P1 P1' O P1 P1 ' O P1 O
aminostatine (AS) hydroxyethyamine (HEA) phospinate-based reduced amide (RA)
Rich, D. J. Med.Chem., 2002,45, 541.; Greenlee, W. J. J. Med. Res. Rev. 10, 173, (1990)
9. Merck-Neogenesis Collaboration
• Screening a 5 million member compound library yields a single lead
P2 Opt.
O O
S
N
N O P1 /TSA Opt.
O O
OH H
O O NH HN N
O P1 '
NH NH HEA incorporation
Rich, D. et al P3
NH2 JMC 2002, 45, 541 P1
1
2 BACE-1 IC50 = 10 nM
BACE-1 IC50 = 25,000 nM
MW 506 MW 578
3 HBD P3 + P1 amides
4 HBA PGP P2 sulfonamide
substrate HEA
Coburn et al, J. Med. Chem., 2004, 47, 6117 V. John et al, J. Med Chem., 2004, 47, 158 (Elan)
Stachel et al, J. Med. Chem., 2004, 47, 6447 S. Kaldor et al, Bioorg. Med. Chem. Lett., 1995, 5, 721 (HIV)
10. X-Ray of HydroxyEthylAmine (HEA)
P2
O O
S
N
O O
OH H
Ph NH HN N
Ph
P3 P1'
P1
2
S1, S3
hydrophobic
regions:
S1, S3 and S2’
S2’
11. Emerging Chemical Methods Enables
Truncation of HEA
O O
S O O
N S
N
1) Rh(acac)(C2H4)2 / rac-BINAP
F O O
O F O O
NH HN (HO)2B
O N NH HN
OH
R
2) LiBH4
Ar
35 / 48 successfully isolated
Cl
Ar =
+ meta
F N isomer
HO2C
F H
HN F N
S O
O
4
IC50 = 28 nM
12. SAR: Alkyl Branch and P1
Stauffer, S. R. et al. Bioorg. Med. Chem. Lett., 2007, 17, 1788.
13. Origin of P3 Potency Enhancement?
• New H-bonding manifold for aminopyridine?
• 10s loop conformational change (S3 pocket, residues 9-14)?
Apo BACE-1,10s dynamics: J. Yon, et al. J. Mol. Biol. (2004) 343, 407.
Renin S3sp: J. Rahuel, et al. Chem. Biol., 2000, 493.
McGaughey, G. B. et al. Bioorg. Med. Chem. Lett., 2007, 17, 1117.
Stauffer, S. R. et al. Bioorg. Med. Chem. Lett., 2007, 17, 1788.
14. Pocket Collapses via Ligand-Dependent Conformational Change
Ser10
Thr232
G. McGaughey
16. Fast forward: Carbinamines, Spiropiperidines, and Acyl Amidines
O O
S
N
N
N X
Ph
Low CNS penetration 0.05 b/pIC50 = 330 nM IC50 = 0.4 nM
BACE-1 BACE-1 fragment-based discovery
sAPP _NF IC50 = 4200 nM ICMK-8931 entering PhII
sAPP _NF 50 = 40 nM
PSA >100 P-gp ratio(h) = 2, Papp =reduction in HV
robust A 22
Log P 2.5 – 4.0 HBD/HBA = 1/6
cLogP = 2.6, PSA = 120 Å2
MW >500
HBD/HBA = 2/4 40% reduction Rhesus CSF A 40
after IV infusion
high metabolism, low %F
Persistence and serendipity!
Zhu, Z. et al. J.Med.Chem. 2010, 951.
Stanton, M. et al. J. Med. Chem. 2007, 3431. US20080103351
Sankaranarayanan, S. et al. J.Pharm. Exp. Barrow, J. et al. J.Med.Chem. 2008, US20080200445
Ther. 2009, 131-140. 6259. US20070287692
17. G protein-coupled receptors
orthosteric NH2 allosteric
binding site binding site(s)
transmembrane
heptahelical domain
(7TM domain)
COOH
• Classical GPCR ligands modulate signaling through the orthosteric site by:
– Blocking the native agonist (competitive antagonist)
– Directly stimulating a receptor response (agonist)
– Blocking constitutive activity (inverse agonist)
• Functional assays identify: Allosteric Modulators Offer Advantages
• Selectivity
– Negative allosteric modulators • Mimic physiological conditions
• No desensitization, down regulation or
– Positive allosteric modulators internalization
• Less side effects
– Allosteric agonists
Challenges: Steep/Flat SAR, ‘mode switching’
– Neutral cooperativity
18. Druggability Challenges for Allosteric Ligands of GPCRs
Allosteric modulators can act at multiple distinct, often overlapping, but
also non-overlapping sites on the same receptor. SAR fails to translate.
Shallow (steep or flat) SAR and difficult to add polar and/or solublizing
groups to generally small, lipophilic chemotypes
Allosteric modulators can differentially regulate coupling of mGlus to
different signaling pathways
Members of a single structural class can have a range of activities
from PAM to NAM and can include neutral ligands, ago-PAMs, allosteric
agonist to partial antagonist
‘Molecular Switch’ – unexpected alteration of pharmacology within an
established series due to subtle, single heavy atom modifications.
Wood, et al., Biochemistry 2011, 50, 2403-2410.
19. Receptor Reserve: Excess Receptors Beyond Those
Necessary for a Maximal Response
• High Receptor Reserve:
Potency < Affinity
• Low Receptor Reserve:
Potency ≈ Affinity
• In vivo there is a large range
of mAChR receptor reserve
levels
• In a given cell, mAChR
coupling to distinct pathways
can have different receptor
reserves
VU0364572 allosteric agonist/PAM
High reserve M1 EC50 = 110 nM (96% AcH max)
Low reserve M1 EC50 = 1300 nM
Highly selective (M2-M5, Ricerca)
Rat CLp = 14.7 mL/min/kg, %F 37
Brain AUC/Plasma AUC = 1.4
Potentiate NMDA currents in hippocampal CA1
Lebois, E.P. et al. Bioorg. Med. Chem. Lett. 2011, 6451.
20. Receptor Reserve – Weak Partial Agonist Considerations
• Weak partial agonists
can have increased
efficacy and potency in
high receptor reserve
• Weak partial agonists
can look like antagonists
in low receptor reserve
• High receptor reserve
systems set the highest
bar for identifying
antagonists
• This is critical for an
antagonist program as it
is the safest way to
identify true antagonists
21. Probe Dependence
• Allosteric ligands induce
distinct GPCR
M4 Allosteric Modulator LY2033298
conformations which
impact interactions with
orthosteric ligands and
Probes: intracellular signalling
partners
orthosteric agonist • Surrogate probes may
LY2033298 > M4 Potentiator be preferred however
[3H]-QNB antagonist
Selective PAM undesired pharmacology
LY2033298 > M4 „Neutral‟
may occur
• Utilize more native
systems during LO
transition
M1/M4 preferring agonist (Xanomeline)
LY2033298 > M4 Potentiator
non-selective (M2 modulator)
Melancon, B. J. J. et. al. J. Med. Chem. 2012 in press
22. Metabotropic Glutamate Receptor 5 and Schizophrenia
Schizophrenia
- Afflicts 1% of the worldwide population
- Three symptom clusters: positive, negative and cognitive
NMDA receptor hypofunction hypothesis
- PCP and ketamine (NMDA receptor antagonists) induce schizophrenia-like
symptoms in humans and rats (Krystal JH et al., 1994; Gaspar PA et al., 2009)
Metabotropic Glutamate Receptor 5
- Close signalling partner with NMDA receptors; regulating NMDA receptor
function, cognition enhancement
- non-dopminergic approach required to develop more effective antipsychotics
that will target negative and cognitive symptoms.
23. Evidence for Therapeutic Potential for Schizophrenia via
Facilitation of mGluR5 Function
• Modulating dopamine release → positive symptoms
Renoldi et al., 2007; Liu et al., 2008
• Affecting dopamine-mediated behaviour
Liu et al., 2008; Spear et al., 2011
• Enhancing cognitive function → cognitive symptoms
Balschun et al., 2006; Liu et al., 2008;
Uslaner et al., 2009; Ayala et al., 2009
• Enhancing synaptic plasticity
Le Vasseur et al., 2008; Kwon and Castillo,
2008; Rebola et al., 2008
• Hedonic processes → negative symptoms
Vardigan et al., 2010
24. mGlu5 PAMs – in the beginning….
O‟Brien et al., Mol. Pharm. 2003, 64, 731-740; O‟Brien et al. J. Pharm. Exp. Ther. 2004, 309, 568-579;
Lindsley et al. J. Med. Chem. 2004, 47, 5825-5829; Kinney et al. J. Pharm. Exp. Ther. 2005, 313, 199-212;
Hemstapat, et al. Mol. Pharm. 2006, 70, 616-626.
25. mGlu5 PAMs – A New Series, A new ‘Switch’
Nature of HBA and amide steric bulk can promote „switches‟
Western basic pyridine routinely instills NAM character- „Molecular lock‟
Rodriguez et al. Mol. Pharmacol. 2010, 78, 1105-1123.
Williams et al. Bioorg. Med. Chem. Lett. 2011, 21, 1350-1353.
Sams et al. Bioorg. Med. Chem. Lett. 2011, 21, 3407-3410.
26. mGlu5 NAMs – A New Series, A new ‘Switch’
VU0364289 Reversal of Amphetamine Induced Hyperlocomotor Activity
20%BCD vehicle i.p./Amphetamine 1.0 mg/kg; n=14
1600 10e 56.6 mg/kg i.p./Amphetamine 1.0 mg/kg; n=12
(Total Beam Breaks/5 min interval) 1400
1200
Ambulations
1000
800 # # # # #
# # # #
600
# #
400
200
0
0 20 40 60 80 100 120
Time (min)
Rodriguez et al.,Bioorg. Med. Chem. Lett., 2009, 19, 3209-3213
Zhou et al. ACS Med. Chem. Lett. 2010, 1, 433-438.
Xionget al.,Bioorg. Med. Chem. Lett., 2010, 20, 7381-7384
28. Ago-PAMs vs PAMs: PAMs could maintain spatial and
temporal aspects of mGluR5 signaling
LTD – Cognition
impairment?
Epileptiform
activity?
Theoretically, pure positive allosteric modulators should maintain
activity-dependence of mGluR5 activation and reduce adverse
effect liability relative to mGluR5 agonists.
29. Allosteric agonist activity is dependent on mGluR5 expression levels
and may have no impact in native systems
• No agonist activity in
cultured astrocytes
• No agonist activity in
neuronal populations
assessed using
electrophysiology
• Representative pure
VU0360172 VU0361747
PAMs and ago-PAMs
have identical activity
in animal models of
antipsychotic-like
efficacy..
Noetzel, M. Mol. Pharmacol. 2011, in press (doi:10.1124/mol.111.075184)
30. Finding true Ago-PAMs: VU0424465 is a robust agonist in low
expressing cell lines and native systems
EC50 = 7 nM (69%) cLogP = 3.6
rmGlu5: Ago-PAM PPB (h, r) 97.8, 97.2%
Astrocytes: Ago-PAM AHL- beh. disturbances
VU0424465
VU0424465
31. mGluR5 orthosteric and allosteric agonists induce
epileptiform activity in hippocampal area CA3
VU0360172 VU0424465
(Pure PAM) (Ago-PAM)
33. Is There a Big Enough Safety Window?
• Group I agonist DHPG is epileptogenic (Merlin and Lisa, 2002)
Relative Incidence of Behavioural Effects (%)
Observation Compound A Compound B PTZ threshold cpd B
Excitation 77 0
Forepaw trampling 60 0
Salivation 50 0
Chewing movements 40 0
Flat body posture 33 0
Tremor 23 0
Piloerection 10 0
Sniffing 7 3
Body twitches 3 0
Spasms 3 0
Clonic convulsions 3 0
Wet urogenital region 3 0
Monitor Ago-PAM activity to identify compounds free from potential pro-convulsive activity
34. Summary and Druggability Principles for Allosteric
GPCR Modulation
Receptor reserve: consider multiple recombinant systems with different
expression levels, primary neurons or other native systems
Selectivity screening/Probe Dependence: Profile key compounds in
functional GPCR assays with full agonists CRCs (select Millipore panel),
utilize multiple probes and/or native orthosteric ligand
Mode Switching: Avoid scaffolds that show a strong tendency for
dramatic changes in activity with subtle structural changes. Metabolite
ID and in vivo testing of metabolites is critical for key compounds and
final candidates.
Ago-PAM activity: Drive chemistry effort using cell lines with relatively
low receptor expression. Cross check in native systems.
PET Ligand development: Develop PET ligand in same series as
candidate. However within detailed molecular pharmacology studies
needed to validate utility of PET ligand.
35. Vanderbilt Center for Neuroscience Drug Discovery
Prof. P. Jeff Conn, Director
In vivo/Ephys Molecular Pharm Med Chem DMPK
Carrie Jones Colleen Niswender Craig Lindsley Scott Daniels
Jennifer Ayala Dave Weaver Satyawan Jadhav
Shaun Stauffer
Jana Shirey Evan LeBois Annie Blobaum
Corey Hopkins
Zixiu Xiang Alice Rodriguez Usha Menon
Kyle Emmitte
Alexis Hammond Paige Vinson Matt Mulder
Michael Wood
Paulianda Jones Greg Digby Katrina Brewer
Sameer Sharma
Alex Kane Tom Utley Ryan Morrison
Richard Williams
Analisa Thompson Daryl Venable Frank Byers
Phil Kennedy
Jerri Rook Kari Johnson Tom Bridges
Darren Engers
Jay Rosanelli Doug Sheffler Tammy Santomango
Rocco Gogliotti
Elizabeth J. Herman Joy Marlo James Salovich
Michael Bubser Ashley Brady Yiu-Yin Cheung
Merideth Noetzel Meredith Noetzel
Dan Foster Karen Gregory
Outside Collaborators: Robert Kessler
(Vanderbilt), Marc Caron (Duke), Tanya Daigle
(Duke)
Supported by NIMH, NIDA, NINDS, NARSAD.
37. GABA-A receptor PAMs provide precedent for different
in vivo effects of pure PAMs versus ago-PAMs
Pure PAMs: anxiolytic, Ago-PAMs: general
sedative - safe, large anesthetic; potentially
therapeutic window lethal adverse effects,
narrow therapeutic window
Other Potential Mechanisms for CNS Adverse Effect Liability
- Agonist activity at Ionotropic glutamate receptors (Kainate, AMPA, NMDA)?
- mGlu3 antagonist activity?
- Glutamate transporter inhibition?
- Excessive fold-shift of glutamate CRC on mGluR5?
Confidential-Janssen-Vanderbilt mGluR5 PAM Project
38. Xanomeline Induces Robust Improvement in
Behavioral Disturbances in AD Patients
Xanomeline (LY246708)
Bodick et al., Arch Neurology (1997) 54(4):465-73.
M1/M4 preferring agonist
AChE inhibitors have antipsychotic efficacy in AD patients (double blind, placebo-controlled
trials) (Cummings et al., 2001; Raskind et al., 1997; McKeith et al., 2000).
39. BIOLOGICS FOR
CHALLENGING TARGETS:
UNIQUE CHALLENGES
AND LESSONS LEARNED
GURIQ BASI, Ph.D.
VP, ELAN PHARMACEUTICALS
6TH DRUG DISCOVERY FOR NEURODEGENERATION CONFERENCE
40. Evolution of drug development for neurodegeneration:
Symptomatic to disease modifying
Neurodegenerative disease
L-DOPA Restrictions imposed by BBB = small molecules main-stay for
Rx
AChEI‟s No-go for neurotrophin biologics
Access of biologics to CNS
Neurotrophins
Historic
Immunotherap AD immunotherapy
y Targeted delivery
Alternative routes (nasal insulin)
Gene therapy Opportunity on case by case basis
RNAi Antibody Technology Platforms
CM&C, costs, and timelines to IND
41. Neurotrophins
Promises
Neuroprotection, Neuro-restoration
NGF, BDNF, Nerturin
Limitations
Poor bio-availability in target organ following systemic peripheral delivery
Undesirable side effects from non-targeted central delivery, e.g. generalized sprouting promoting
inappropriate connections, neuralgia
Solutions
Localized (chronic) central delivery to affected region(s)
Surgical implants for localized infusion (GDNF)
Targeted delivery
Gene therapy (Tuczyinski 2004) via implantation of genetically modified fibroblasts;
CERE-110 – viral delivery of NGF (recruiting P2, n=50 end May 2012)
CERE-120 (AAV2-Neurturin) - P2 (Dec 2008): Failed on 1o endpoint (efficacy in motor function at 12
mo), may have benefit at 18 mo. OLE in progress
Editor's Notes
For example, in hippocampal neurons, the receptor reserve for depolarization is high whereas the receptor reserve for NMDAR potentiation and for PI hydrolysis is much lowerThis becomes a particular consideration when one is trying to identify antagonists….
Historic: Nerenberg,S.T.,andPrasad,R.(1975). Radioimmunoassays for Ig classes G, A, M,D,and E in spinal fluids:normal values of different age groups. J. Lab.Clin.Med. 86, 887–898. Compromised BBB in neurodegenerative disease;