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Guerrilla Warfare Guerrilla Marketing Guerrilla Innovation Guerrilla Tactics in Pharmaceutical Innovation and Testing Dr. V. Ravi Chandran R&D Practitioner Life Enhancing Technologies, LLC. Allen, TX USA Questions in my mind: Do I develop one Molecule at a time? Do I develop all the Drugs at one shot? Platform Technology? What area do I apply this Technology? Status in the early 2000 Efficacious Toxic I wanted to increase the efficacy and reduce the toxicity i.e. Increase the Therapeutic Index Drugs entering market Examples Leading Causes of Death 650,000 559,000 250,000 143,000 Heart Diseases Cancer Doctors* Stroke 131,000 Chronic Respiratory Diseases *JAMA Vol. 284, No.4, July 26, 2000 Guerrilla Tactic – 1 : Narrow area of attack with maximum impact Among Heart Diseases, Heart Attack is the leading cause of death in both men and women* *World Health Report 2004. Changing History, WHO 2004 pp 120-124 ISBN 92-4-156265-K CLASSICAL AGE OLD DRUG • What is Aspirin? • Chemically it is Acetyl Salicylic Acid Guerrilla Tactic – 2 : Solution is sometimes right before the eyes Guerrilla Tactic – 3 : New association among unrelated concepts Can we therefore develop a new anti-platelet drug that is effective, but has minimal or no side effects? A drug/chemical that thins blood is an effective cardioprotective agent. Important Conclusion Question Guerrilla Tactic – 4 : Specificity of Approach to New Drug Development Naturally Occurring We will attach a suitable chemical group to the existing drug to eliminate its toxicity and improve Therapeutic Index. Non Toxic Chemical Group Good Carrier to Site of Action Strategy Must have active group to form covalent permanent bond Must be detached & excreted or assimilated Group Selection Criteria Guerrilla Tactic – 5 : Look Inward Where do I Look for solution To this question? What is the most Advanced, compact Highly energy efficient, Lean, mean Fighting machine? Human Body Guerrilla Tactic – 6 : Versatile L - Threonine L - Tyrosine Which Amino Acids? Containing OH group L – Hydroxy Proline L – Serine Surprising Results in Animal Models All 3 Amino Acid Esters are equal effective L – Threonine ester is better than other two and Aspirin None of the 3 Amino Acids Esters showed any toxicity in rat models Guerrilla Tactic – 7 : Creativity turns Problems into Opportunities How to rapidly advance a NCE without an IND from Lab to Clinical Trials Guerrilla Tactic – 8 : Simple Techniques are sometimes most useful What can be an effective, simple and reliable technique to measure effectiveness of anti-platelet drugs in humans Human Clinical Trials % INCREASE PERCENTAGE INCREASE IN CLOTTING TIME 81mg 40 30 20 10 0 30.625 26.25 13.125 PLATROL PLATROL BAYER ASA Percentage increase in clotting time PLATROL vs.. Aspirin (Bayer) at 81mg dose based on 5-day average increase. The two PLATROL blocks shown above correspond to two separate volunteers who took the test drug over a period of 5 days. The third volunteer took Bayer Aspirin for 5 days. As per Figure 2, increase in clotting time for PLATROL occurred on the very first day of drug intake, and remained higher than Bayer ASA during the subsequent administrations. Surprise in Metabolism 10000 8000 Platrol 6000 Platrol 4000 Platrol 2000 ASA 0 TIME IN HOURS 16 12 9 7 5 3. 5 ASA 2. 5 0 0. 66 7 1. 5 SA IN PLASMA ng/ml SALICYLIC ACID CONCENTRATION IN PLASMA ng/ml Platrol Surprise in blood profile ASA Concentration in Blood ng/ml Time 800 Platrol 600 Platrol Platrol 400 ASA 200 ASA Platrol 15 13 11 9 7 5 3 0 1 ASA in blood ng/ml 1000 Hours after administration CONCLUSIONS L-Threonine ester of Aspirin is a good carrier of Acetyl Group Salicylic Acid is also a good carrier of Acetyl group Acetyl group is responsible for Anti-Platelet Activity of Aspirin Are we finally getting closer to finding a “super” Aspirin? Are there better carriers of Acetyl Group than Salicylic Acid? Guerrilla Tactic – 9 : Capitalize on what others totally missed Let us go back and take one more look at Aspirin and Salicylic Acid. Guerrilla Tactic – 10 : Nature has the Answer Is there a naturally occurring molecule (that is essential to the human body) comes very close to our requirements Yes! Make acetyl ester of all other naturally occurring OH containing Amino Acids. Acetylate LTyrosine and test it for antiplatelet activity. Anti-platelet Activity of Acetylated naturally occurring OH containing Amino Acids Rat Whole Blood Clotting Time (min) Doses: Vehicle, 10, 20, 50 and 100 mg/kg Clotting time (4 & 24 hours) Clotting time (min) 30.00 25.00 20.00 4 Hours AceTyro 15.00 24 Hours AceTyro 10.00 4 Hours AceSer 5.00 0.00 0 1 1.301 1.3979 Log Dose (mg/kg) 1.699 2 HUMAN TRIALS OAT and OAS Effect on Human Blood Clotting Time 9 Clotting Time (min) 8.5 8 Vol 1, 1000 mg (OAT) 7.5 Vol 2, 350 mg (OAT) 7 Vol 3, 1000 mg (OAT) 6.5 Vol 4, 750 mg (OAS) 6 5.5 5 0 10 20 30 Time (Hrs) 40 50 60 Dramatic results with Acetylated Amino Acids! Both at 81 and 325 mg dose, Bayer Aspirin increased clotting time only by 13% O Acetyl Serine increased clotting time by 23% O Acetyl Tyrosine increased clotting time by more than 50% and it was sustained after 24 hrs 1. 2. 3. 4. 5. 6. 7. 8. 9. Advantages of Acetylated Amino Acids Non-toxic All metabolites are natural to human body All 4 AA are good carriers of acetyl group Mechanism of action is identical to Aspirin No Toxicity whatsoever All AAA are nutritional supplements Require no FDA approval to test No NDA needed for marketing Ideally suited for long term therapy Guerrilla Tactic – 11 : Synergy Now, how about Acetylated Dipeptides Will they have any Anti – platelet activity? Synthesized O,O-Diacetyl Serine-Serine O,O-Diacetyl Serine-Tyrosine O,O-Diacetyl Serine-Threonine Human Trial Dose 600 mg of O,O-Diacetyl Seryl Serine H u man C lo ttin g T ime C lotting Time (min) 8 7 6 5 OOD iS erine 4 3 0 50 100 150 T im e (Hrs) 200 250 Salient Features of Di-Acetylated Dipeptide 1. 2. 3. 4. 5. 6. 7. Rapid increase in clotting time (up to 87.5%) Sustained increase in clotting time (37.5%) up to 8 days! Is it as good as dissolving clot like TPA? Or it can replace Aspirin in sudden heart attack? Likely so. Non Toxic No Side effects or adverse reactions Qualifies as nutritional supplement, hence requires no IND or NDA to test in human subjects Qualifies for matter of composition patent, as it is novel, and patentable. Life Enhancing Technologies Summary Largest Drug Pipeline in the World 9000 molecules in 3 years Creative processes and Guerrilla tactics Numerous Patents covering 80% of the market Better Alternatives for 6 out of top 10 – $ 41 Bill in sales Better Alternatives for 68 out of top 200 – $ 120 Bill in sales Be on the lookout for AAA – Once a day capsules, nontoxic, safe and effective cardioprotective agent S(-)Ketorolac- LThreonine Ester, a superior pain killer of narcotic strength, but with no addiction potential KeraKlear optic drops for dry eyes … Truly Life Enhancing! Thank You