KARE Biosciences

KAR101 (Ramatroban)

KARE Biosciences is developing KAR101 (ramatroban) as a disease modifying therapy for various indications including COVID-19.

KARE 101 is a novel dual receptor antagonist of the thromboxane A2/TP and prostaglandin D2/DP2 receptors. Ramatroban has been used for the treatment of allergic rhinitis for the past 20 years in Japan and has an excellent safety profile.

Recognizing Ramatroban's potential, KARE Biosciences has created the KAR series of dual thromboxane A2/TP and prostaglandin D2/DP2 receptor antagonists for the treatment of numerous diseases.

KidneyVite

Common Vitamin Deficiencies Resolved by KidneyVite

Vitamin K2: Vitamin K2 activates proteins that promote bone formation and retard calcification and hardening of blood vessels. Vitamin K has been shown to prevent vascular calcification or hardening of the blood vessels, a serious complication of kidney disease.

Zinc

Zinc deficiency leads to: (1) defects in immune system and infections; (2) loss of hair, taste, appetite; (3) Delayed wound healing. Note: Too much zinc can lead to copper deficiency. KidneyVite contains the right amount of zinc.

Copper

Copper deficiency leads to: (1) anemia decrease in white blood cell count

- osteoporosis

- decreased ability to break down fat in the body

Selenium

Selenium deficiency leads to:

- Heart disease (cardiomyopathy)

- Anemia

- Myopathy, myositis

Lycopene

Lycopene deficiency leads to:

- Oxidative stress

- Inflammation

Lutein

Lutein deficiency leads to

- Heart disease and stroke

- Cataract and age-related macular degeneration

- Cancer at various sites

What is KidneyVite?

Common Vitamin Deficiencies Resolved by KidneyVite

KidneyVite is the world's first complete multivitamin for kidney patients containing:

1. Active Folate (5-methy THF)

2. Vitamin K

3. Lycopene

4. Lutein

5. Other minerals (zinc, copper and selenium)

Why KidneyVite?

Common Vitamin Deficiencies Resolved by KidneyVite

Why KidneyVite?

Unlike many other vitamin supplements, KidneyVite contains 5-methyl tetrahydrofolate.

Why 5-methyl tetrahydrofolate should replace folic acid:

1. For it to be active, synthetic folic acid needs conversion to 5 methyl THF by liver enzyme MTHFR.

2. The conversion is impaired when ‘T’ genotype of MTHFR is present.

3. 2 copies of ‘T’ genotype severely impair MTHFR enzyme activity and ‘TT’ may be present in up to nearly one-third of any population, depending on its race/ethnicity.

4. Unmetabolised folic acid is associated with immune suppression (↓ NK cells) and cancer.

Thiazide diuretics+Mineralocorticoid receptor antagonist

Hypertension Combination Treatment Summary

Mineralocorticoid receptor antagonists (MRA) block the receptor for aldosterone. The MRA class of drugs including spironolactone, a steroid with side effect of gynecomastia, eplerenone as steroid without the side-effect of gynecomastia and recently approved finerenone, a nonsteroidal molecule.

Large clinical trials published in New England Journal of Medicine have demonstrated highly significant cardiovascular benefits of these drugs (1-3). All MRAs can lead to hyperkalemia by blocking the renal excretion of potassium. This can be fatal (4,5).

The LEGENDS hypertension study of 4.9 million patients with hypertension has conclusively demonstrated that diuretics are superior to ACE inhibitors and ARBS in conferring cardiovascular protection (6). Amongst the diuretics, indapamide is considered the preferred agent as per 2019 NICE guidelines because of its lack of metabolic side effects (7). Indapamide does not cause hyperglycemia and hyperlipidemia unlike other thiazide diuretics (8). Indapamide reduces cardiovascular risk including strokes (9).

Indapamide, like all other thiazide diuretics, causes hypokalemia. In order to avoid the hyperkalemia induced by MRAs and the hypokalemia induced by indapamide, these two agents are advantageously combined, further compounding the cardiovascular benefits as propounded in the Gupta 2010 patent (PCT), filed and issued in all major territories in the world including US, Canada, Europe, Australia, Japan, China, and India. In 2015, the recognized legendary guru of hypertension Prof. Norman Kaplan recommended(10):

“lf a choice is needed, the switch to indapamide seems most critical, at least until a generic formulation of indapamide combined with an MRA enters the therapeutic armamentarium, thereby most effectively controlling our most common and fastest growing cardiovascular risk factor.”

Conclusion

In India and worldwide, there is growing concern around cardiovascular disease with increasing obesity, diabetes, and hypertension. WHO recommends instead of single dose drugs, fixed-dose combinations as first line agents for hypertension (11). The combination of indapamide (0.5 and 1 mg) with spironolactone 25mg is ideally suited for women given the estrogenic effects on skin, hair and breasts. Men are optimally treated with eplerenone (50mg) + indapamide (0.5 or 1 mg).

Contact for Further Information

Ajay Gupta MBBS (AIIMS) MD-Medicine (AIIMS)

Clinical Professor of Medicine,

University of California Irvine,

Email: ajaygupta@karebio.com

Tel: +15624126259 (Whatsapp)

References

1. Pitt B, Zannad F, Remme WJ, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. New England Journal of Medicine. 1999;341(10):709-717.

2. Pitt B, Remme W, Zannad F, et al. Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction. New England Journal of Medicine. 2003;348(14):1309-1321.

3. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. New England Journal of Medicine. 2021;385(24):2252-2263.

4. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of Hyperkalemia after Publication of the Randomized Aldactone Evaluation Study. New England Journal of Medicine. 2004;351(6):543-551.

5. Dalli LL, Olaiya MT, Kim J, et al. Antihypertensive Medication Adherence and the Risk of Vascular Events and Falls After Stroke: A Real-World Effectiveness Study Using Linked Registry Data. Hypertension. 2023;80(1):182-191.

6. Suchard MA, Schuemie MJ, Krumholz HM, et al. Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis. The Lancet. 2019;394(10211):1816-1826.

7. NICE. Hypertension in adults:

diagnosis and management https://www.nice.org.uk/guidance/ng136/resources/hypertension-in-adults-diagnosis-and-management-pdf-66141722710213. Published 2019. Accessed March 4, 2023.

8. Sharabi Y, Grossman E, Nussinovitch N, Katz A, Rachima-Moaz C, Rosenthal T. [Indapamide--a substitute diuretic for hypertensives with hyperglycemia and/or dyslipidemia]. Harefuah. 1996;131(7-8):233-236, 295.

9. Beckett NS, Peters R, Fletcher AE, et al. Treatment of Hypertension in Patients 80 Years of Age or Older. New England Journal of Medicine. 2008;358(18):1887-1898.

10. Kaplan NM. Indapamide: is it the better diuretic for hypertension? Hypertension. 2015;65(5):983-984.

11. WHO. Guideline for the pharmacological treatment of hypertension in adults. https://apps.who.int/iris/bitstream/handle/10665/344424/9789240033986-eng.pdf. Published 2021. Accessed March 4, 2023.