R plus Copper evaluation of the data in oncology

Neutraceuticals in Cancer

1. https://pib.gov.in/PressReleaseIframePage.aspx?PRID=2009169

2. https://www.youtube.com/watch?v=LsM-9XSy2DA

3. https://www.youtube.com/watch?v=LsM-9XSy2DA

4. Three paragraphs on Dr Mittra , citing 24 references Resveratrol plus copper is not a substitute for established cancer treatments like surgery, radiotherapy, chemotherapy and hormone therapy Effectiveness of copper plus resveratrol remains to be established and is currently under investigation

5. Published: 6 January 2024 Int. J. Mol. Sci. 2024, 25, 747. https://doi.org/10.3390/ijms25020747 Leicester Cancer Research Centre, University of Leicester and Leicester Royal Infirmary, Leicester LE2 7LX, UK;

6. Resveratrol – proposed beneficial to human health across multiple morbidities No conclusive clear evidence - in ANY healthcare setting Large studies / high quality data / clear endpoints - required 20 years / 200 studies / 24 indications Dose / purified form - knowledge gaps No consensus treatment regimen Generally well tolerated upto 1 gm/day Consistently reduces human inflammatory biomarkers Can benefit human health

7. Resveratrol 1992 – French paradox Diet rich in saturated fats Low incidence of coronary artery disease Why? Moderate intake of wine in France Interest in resveratrol gained momentum

8. Resveratrol 13,000 publications Majority of research only preclinical Potential Cardio-protective Neuro-protectice Anti- tumor Anti-diabetic Anti-bacterial Anti-ageing No systematic development Lack of patentability Manufacturing difficulty Differences in regulatory requirements

9. 8836 studies screened 6736 studies evaluated 518 full text eligible studies 194 studies included 2100 duplicates 6281 not meeting inclusion criteria 324 excluded 132 – trial registration/ protocol 079 – conference abstracts 042 – mixture/ combination 023 – review 020 – duplicate entries 014 – not in English 008 – no / wrong outcome 002 – ex vivo exposure 002 – cosmetic use 001 – corrigendum 001 – paper retraction PRISM diagram showing study selection flow and reasons for exclusion Full text articles in English from: Medline Embase Cochrane Database Cochrane Centra register of controlled trials Upto 24/2/2023

10. Exclusion Criteria Resveratrol dose not specified Resveratrol containing extracts or mixtures Red wine enriched with resveratrol In combination with other agents Non human studies Using resveratrol metabolites 2004 onwards 6126 individuals received resveratrol under trial conditions Peak in 2018 with 22 studies Across 31 countries in 5 continents

11. Peak

12. Trials conducted in 31 countries Iran 20 USA 16 China 15 Brazil 12 UK 10 Australia 10

13. Risk of Bias

14. 1

15. One more trial in cancer patients BUT .... Using SRT501 – a formulation that significantly increases bioavailability

16. Geriatric Max studies

17. 10/194 (5%) studies Median number of patients per study = 22

18. Median duration of administration = 8 weeks 1 year 2 yrs 1 6 No. of trials

19. Frequency of total daily dose vs no of trials Max 5 gm/day

20. Clinical Efficacy in 42/194 (21.6%) studies

21. 31% 1% 69%

22. Resveratrol RESHAW study 2 year crossover study Preventive therapy in healthy individuals To study effect on brain health in post menopausal women N = 146 86% completed study 88% would continue resveratrol after end of study

23. Resveratrol Toxicity – 104 RCTs 27 trials listed adverse events 42 stated no adverse events 35 no mention about adverse events Commonly reported AEs Diarrhoea Constipation Bloating Nausea Abdominal cramps Vomiting Steatorrhoea Heartburn Reflux

24. Challenges Effect on cytochrome p450 (CYP3A4 and 2E1) Drug interactions effect unknown Two types of resveratrol – cis vs trans UV light converts it to cis isomer, which has limited/no bioactivity Rapid metabolism Low systemic bioavailability Two metabotypes – lunularin producers vs non producers Effect of gut microbiome unknown

25. Promising areas Consistent decrease in plasma glucose and insulin Regulation of lipid metabolism Improvement in insulin sensitivity Potential to benefit Type2 DM

26. The future of Resveratrol 17 trials ongoing in 2023 Recurrent respiratory tract infections in children Primary ovarian insufficiency Colorectal polyp prevention Forward thinking continues .....

27. FSSAI, Food Safety and Standards (Advertising and Claims) Regulations, 2018

28. Discussion Moderated by Dr Amish Vora

29. 240 Are you aware of the TMH ACTREC Rs 100 copper resveratrol tablet claim of preventing metastasis and/or substituting adjuvant therapy for cancer? Yes = 237 No = 3

30. Table 1: What is your opinion regarding the press release and press conference done by TMC ACTREC Description No. Percentage It was appropriate 01 0.4 % It must be appropriate because it was done by a reputed center of national importance like TMH ACTREC 02 0.8 % No opinion 04 1.7 % It was premature 06 2.5 % It was premature and has resulted in misinterpretation by the media 14 5.9 % It was premature and has resulted in misinterpretation by the media and the lay persons 210 88.6 %

31. Table 2: There is a clarification statement issued by TMC ACTREC, which has also been published in some newspapers. This states that " Resveratrol plus copper …. is not a substitute for established cancer treatments". What is your opinion regarding this clarification? (N = 237) Description No. Percentage It is appropriate and will dispel the misconception that has resulted from the original press meeting and release 30 12.7 % Not sure 30 12.7 % It is too little too late. The damage is already done 177 74.7 %

32. Figure 2: Responses that the oncologists would give when cancer patients or their relatives ask about the Rs 100 tablet. (more than one answer was permitted and hence the total exceeds 237) (23.6%) (42.2%) (1.3%) (43.5%) (70.5%) (39.2%)

33. Figure 1: Thoughts in the minds of responding oncologists – How to reply if and when cancer patients ask about the Rs 100 tablet (more than one answer was permitted and hence the total exceeds 237) (45.2%) (51.9%) (51.9%) (51.5%) (33.8%) (27.9%)

34. Expert Interviewed by Dr Purvish Parikh

35. Thank you everyone Next OBTO on Tuesday 9 th April 2024 at 700 pm on zoom

36. Purvish questions for Raktim : 1. What is the global nutraceutical market and what is it in India?  2. At what rate is this market growing?  3. As the CEO of nutraceutical company what made you focus on specific diseases like cancer.  4. As member of the govt committee on nutraceuticals , how did you shape policy and regulations.  5. How did you decide about research, trials and indications for your cancer nutraceutical products.  6. You have the experience of marketing in regulated market also, like EU and Gulf regions. How are regulations different there?  7. Govt is concerned about some products being licensed under FASSI whereas their efficacy claims suggests they should come under CDSCO. What is your opinion regarding the same

37. Board Room, TMH, Parel , Mumbai 400013

38. Amish Vora questions to Purvish Parikh: What is the difference between health supplements, nutraceuticals and drugs? Are functional foods, dietary supplements and nutraceuticals the same? Who is responsible for giving them marketing approval? Does FSSAI permit use of tablets, capsules or syrups? When can FSSAI approve capsules, tablets or syrups containing minerals or vitamins or both? What are the general quality requirements for such cpsules , tablets or syrups? What are the mandatory label requirements regarding precautions, precautions and product-drug interactions? What about claims where evidence is insufficient or novel combinations are to be introduced? What is considered as advertisement under FSSAI Food Safety and Standards Regulations? Can any product claims to prevent, treat or cure any disease – under FSSAI regulations?