Ayurveda Biology Transcending the science of Life Pharmacological
Ayurveda Biology Transcending the science of Life
Pharmacological Networking
Molecules are the building blocks of life Reductionism Few are dominant in biological system These enormous molecules, almost always synthesized by living things, are called macromolecules. Holism Brief introduction to building blocks of life
Biochemical pathways
Impairments in biochemical pathways lead to disease Drug - restores the balance How……. ? That is the mode of action.
Lock and Key analogy of drug action A drug acting as a selective ‘key’ that fits into the ‘lock’ of a specific drug target. Classical hypothesis of mode of action of drugs
Drug discovery process Classical approach 10 -15 years…………. 500 -700 m US$ cost………. . .
Alternate Approach Reverse Pharmacology
c us hi yt r e Ev o. A M ng fo on
Fever - Example of disease/symptom A rise in temperature Alters the body’s temperature set-points Action on thermoregulatory centre of hypothalamus. Prostaglandin E 2 - primary mediator of heat
Antipyretic drugs NSAIDs such as ibuprofen, naproxen, ketoprofen, and nimesulide. Aspirin, and related salicylates such as choline salicylate, magnesium salicylate, and sodium salicylate (ASA Acetylsalisilic acid). Paracetamol (USAN acetaminophen) and JAN: Inhibition of Cyclooxygenase (COX) enzyme
Whether TM, like Ayurveda, knew about this? ? ?
Common cold There is no cure for the common cold……. Why? ? Rhinovirus - most common virus Nasal Congestion mucosal inflammation, often involving increased venous engorgement, increased nasal secretions, and tissue swelling/edema (Intercellular Adhesion Molecule 1 Nasal Congestion mucosal inflammation, often involving increased venous engorgement, increased nasal secretions, and tissue swelling/edema
Potentially target alpha-adrenergic receptor Induces vasoconstriction of the blood vessels in the nose, throat, and paranasal sinuses, which results in reduced inflammation (swelling) and mucus formation in these areas. A common practice - works well No much of scientific back-up Hot vapor reduces the nasal block
Diseaseome
Let us read this para…. Over the past decade, there has been a significant decrease in the rate that new drug candidates are being translated into effective therapies in the clinic. In particular, there has been a worrying rise in late-stage attrition in phase 2 and phase 3. Currently, the two single most important reasons for attrition in clinical development are (i) lack of efficacy and (ii) clinical safety or toxicology, which each account for 30% of failures. Many reasons have been proposed for this decline in pharmaceutical research and development productivity. However, the fundamental problem may not be technological, environmental or even scientific but philosophical —there may be issues with the core assumptions that frame our approach to drug discovery. The increase in the rate of drugs failing in late-stage clinical development over the past decade has been concurrent with the dominance of the assumption that the goal of drug discovery is to design exquisitely selective ligands that act on a single disease target. VOLUME 4 NUMBER 11 NOVEMBER 2008 NATURE CHEMICAL BIOLOGY
The philosophy of rational drug design, or more specifically, the ‘one gene, one drug, one disease’ paradigm, arose from a congruence between genetic reductionism and new molecular biology technologies that enabled the isolation and characterization of individual ‘disease-causing’ genes, thereby enabling the full realization of Ehrlich’s philosophy of ‘magic bullets’ targeting individual chemoreceptors. Network biology analysis predicts that if, in most cases, deletion of individual nodes has little effect on disease networks, modulating multiple proteins may be required to perturb robust phenotypes. As increased understanding of the role of networks in the robustness and redundancy of biological systems challenges the dominant assumption of single target drug discovery Polypharmacology, not any promiscuous aggregation of small molecules, is the specific binding of a compound to two or more molecular targets
The protein network of curcumin A PIN of curcumin with 482 nodes and 1688 interactions was constructed. study provides an efficient way to elucidate possible mechanisms of curcumin, and provides reference for its clinical application and further drug development. Acta Pharm Sin B. 2015 Nov; 5(6): 590– 595
Uma et al Proc Indian Natn Sci Acad 81 No. 3 June 2015 pp.
Network pharmacology can be a very useful tool to understand non-linear, complex relations between bioactives and underlying pathophysiological processes. It also provides a scientific platform for research on Ayurveda and other traditional medicines. Systematic analysis of pharmacological networks can give newer insights into rationale, indications and possible mechanisms of traditional medicines. Uma et al Proc Indian Natn Sci Acad 81 No. 3 June 2015
Drug repurposing: repositioning, re-profiling, re-tasking, therapeutic switching A significant advantage is that its safety is known and the risk of failure for reasons of adverse toxicology are reduced. For metformin, the most important mechanism may involve the inhibition of m. TOR signaling via AMPactivated protein kinase (AMPK)-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of COX-1/COX-2 and modulation of the NFκB or STAT 3 pathway. In addition, aspirin may activate AMPK, and both agents may affect Notch, Wnt/β-catenin, and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer. (Cancer Prev Res (Phila). 2014 Apr; 7(4): 388 -97)
Drugs…… Very important Made dramatic changes in therapeutic field Basically a product of reductionist approach Be(a)ware of acute and chronic effects Potentially multi-targeted Think how to reduce Be healthy
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