Executive summaery Heptavite AF

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Heptavite AF® Effective anti-fibrotic therapy for Arresting and reversing hepatic Fibrosis Hepatic Fibrosis : Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is either overproduced, degraded deficiently, or both. The trigger is chronic injury, especially if there is an inflammatory component. Fibrosis itself causes no symptoms but can lead to portal hypertension (the scarring distorts blood flow through the liver) or cirrhosis (the failure to properly replace destroyed liver cells results in liver dysfunction). Diagnosis is based on liver biopsy. Treatment involves correcting the underlying condition when possible. Various types of chronic liver injury can cause fibrosis . Self-limited, acute liver injury (eg, acute viral hepatitis A), even when fulminant, does not necessarily distort the scaffolding architecture and hence does not cause fibrosis, despite loss of hepatocytes. In its initial stages, hepatic fibrosis can regress if the cause is reversible (eg, with viral clearance). After months or years of chronic or repeated injury, fibrosis becomes permanent. Fibrosis develops even more rapidly in mechanical biliary obstruction.

Fig 1:Hepatic Stellate cell activation & subsequent events


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The hallmark of liver fibrosis is an increased extracellular matrix deposition, caused by an activation of hepatic stellate cells (HSC). Therefore, this cell type is an important target for pharmacotherapeutic intervention. Antifibrotic drugs are not efficiently taken up by HSC or may produce unwanted side-effects outside the liver. Pathophysiology of Hepatic Fibrosis : Activation of the hepatic perivascular stellate cells HSC (Ito cells, which store fat) initiates fibrosis. These and adjacent cells proliferate, becoming contractile cells termed myofibroblasts. These cells produce excessive amounts of abnormal matrix (consisting of collagen, other glycoproteins, and glycans) and matricellular proteins. Kupffer cells (resident macrophages), injured hepatocytes, platelets, and leukocytes aggregate. This releases reactive O2 species and inflammatory mediators (eg, platelet-derived growth factor, transforming growth factors, and connective tissue growth factor). Thus, stellate cell activation results in abnormal extracellular matrix, both in quantity and composition.

In acute liver diseases, such as self-limited viral hepatitis, fibrogenesis is balanced by fibrolysis, i.e., the removal of excess ECM by proteolytic enzymes, the most important of which are the matrix metalloproteinases (MMPs). With repeated injury of sufficient severity, as occurs in many chronic liver diseases, fibrogenesis prevails, finally resulting in morphologically apparent fibrosis or cirrhosis

Fibrogenesis is accompanied by an upregulation of collagen synthesis, a downregulation MMP secretion and activity, and by an increase of the physiological inhibitors of the MMPs, the tissue inhibitors of MMPs (TIMPs), of which the universal MMP-inhibitor TIMP-1 is the most important (1,2). Collagens, MMPs and TIMPs are mainly produced by activated hepatic stellate cells (HSC, synonymous with Ito cells) and by activated portal fibroblast (PF) (1-4).


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Hepatic Fibrosis -- Role of Hepatic Stellate Cell Activation

Fig 3 : Matrix and cellular alterations in hepatic fibrosis. Changes in the subendothelial space of Disse and sinusoid as fibrosis develops in response to liver injury include alterations in both cellular responses and extracellular matrix composition. Stellate cell activation leads to accumulation of scar (fibril-forming) matrix. This in turn contributes to the loss of hepatocyte microvilli and sinusoidal endothelial fenestrae, which result in deterioration of hepatic function. Kupffer cell (macrophage) activation accompanies liver injury and contributes to paracrine activation of stellate cells. (Reprinted with permission from Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000;275:2247-2250).


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Fig 4 Phenotypic features of hepatic stellate cell activation during liver injury and resolution.


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Fig 5 :Formal pathogenesis of liver fibrosis (fibrogenesis).


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Fig 6 :Compilation of the most important components of extracellular matrix and of mediators synthesized by activated hepatic stellate cells (HSC). Abbreviations: CF – colony-stimulating factor; ET – endothelin; HGF – hepatocyte growth

factor; IGF – insulin-like growth factor; KGF – keratinocyte growth factor; LTBP – latent TGF-β binding protein; MCP – monocyte chemotactic peptide; MIP – macrophage inflammatory protein; PAF – platelet activating factor; PDGF – platelet-

derived growth factor; PGF – prostaglandin F; SF – scatter factor; TGF – transforming growth factor.


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Fig 6 :Cellular interactions. Synopsis of cellular interactions of resident liver cells (red) and immigrated inflammatory cells (green) with hepatic stellate cells in the process of activation and transdifferentiation to myofibroblasts. The most important paracrine mediators are given.


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Fig 7 :Up-to-date mechanisms of fibrogenesis. HSC activation, EMT, influx of fibrocytes, and differentiation of peripheral monocytes to fibroblasts at sites of injury.


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Fig 8:Matrix elements and fibrotic changes. Major components of the extracellular matrix (connective tissue) of the liver and the four most important changes in the fibrotic matrix.


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Clinical pharmacology : Heptavite AF® is a combinatorial formulation of nutraceuticals, having well defined Antifibrotic ,antioxidant , Anti inflammatory , immunomodulating and cytoprotective Activities. The key synergistic effect of Heptavite AF® is increased antioxidant profile of of hepatocytes and hepatic Extracellular Matrix ECM resulting in down regulation of activated Hepatic Stellate cells. The Key target of Hepatavite AF is Deactivation and down regulation of Hepatic Stellate cells which is the hallmark of hepatic fibrosis and subsequent cirrhosis. Further more it also has a direct effect on hepatic fibrosis through various mechanisms discussed below. 1 Heptavite AF® AF role in down regulating Activated HSC (Direct effect on Hepatic fibrosis). 2 Alleviation chronic inflammation as a result of oxidative stress a leading cause of HSC Activation . 3 As a potent Hepatic antioxidant.

Fig 9: MOA Heptavite AF®


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Heptavite AF® role in down regulating Activated HSC : The main key target of Heptavite AF® is deactivation & down regulation of Activated HSC which are the main causative factors of hepatic fibrosis due to various etiologies. Curcumin as potent Antifibrotic:

The beneficial antioxidative, anti-inflammatory and antitumorigenic effects of curcumin have been well documented in relation to cancer and other chronic diseases. Recent evidence suggests that it is of therapeutic interest in chronic liver disease. Hepatic fibrosis (scarring) occurs in advanced liver disease, where normal hepatic tissue is replaced with collagen-rich extracellular matrix and, if left untreated, results in cirrhosis. Curcumin inhibits liver cirrhosis in a rodent model and exerts multiple biological effects in hepatic stellate cells (HSCs), which play a central role in the pathogenesis of hepatic fibrosis. In response to liver injury, these cells proliferate producing pro-inflammatory mediators and extracellular matrix. Curcumin induces apoptosis and suppresses proliferation in HSCs. In addition, it inhibits extracellular matrix formation by enhancing HSC matrix metalloproteinase expression via PPARgamma and suppressing connective tissue growth factor (CTGF) expression. In this issue, Chen and co-workers propose that curcumin suppresses CTGF expression in HSC by inhibiting ERK and NF-kappaB activation. These studies suggest that curcumin modulates several intracellular signalling pathways in HSC and may be of future interest in hepatic fibrosis therapy

Fig 10 :Curcumin Moleculare structure


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Fig 11 :Mechenism of Action of antifibrotic activity of Curcumin


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Catechins: Catechins are one of the most potent antoxidant found to prevent oxidative stress induces proteins & DNA damage .It is also capable of interrupting TGF-beta signaling in activated HSC by suppressing gene expression of type I and II TGF-beta receptors. EGCG inhibits CTGF gene expression, leading to the reduction in the abundance of ECM, including alphaI(I) procollagen. Exogenous CTGF dose dependently eliminates the antifibrogenic effect. EGCG attenuates oxidative stress in passaged HSC by scavenging reactive oxygen species and reducing lipid peroxidation. De novo synthesis of GSH is a prerequisite for EGCG to interrupt TGF-beta signaling and to reduce the abundance of alphaI(I) procollagen in activated HSC in vitro. In summary interruption of TGF-beta signaling by EGCG results in the suppression of gene expression of CTGF and ECM in activated HSC in vitro. Also antioxidant property of EGCG derived from de novo synthesis of intracellular GSH plays a critical role in its antifibrogenic effect.

Fig 12 :Molecular structure Catechin


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Isoflavones Isoflavones has been indicated to reverse hepatic fibrosis and exhibit therapeutic effects both in vitro and in vivo Administration of isoflavones improved CCl(4)-induced liver fibrosis. It is attributed to its effect of inhibiting the expression of TIMP-1 and promoting the apoptosis of hepatic stellate cells. GbE confers its anti-fibrosis effects through inhibiting HSC proliferation, reducing TGF-beta1 and CTGF expression and consequently suppressing the collagen production and ECM secretion. Inhibition of hepatic stellate cell (HSC) activation and nuclear factor kappaBP65 (NF-kappaBP65) expression was demonstrated in the livers of EGB-treated rats. The activation of NF-kappaB is found to be significantly suppressed in EGB-treated rats determined by electrophoretic mobility shift assay (EMSA). Furthermore, EGB reduced expressions of transforming growth factor-beta1 (TGF-beta1) and collagen I mRNA. In conclusion, isoflavones are able to ameliorate liver injury and prevent rats from CCl4-induced liver fibrosis by suppressing oxidative stress. This process may be related to inhibiting the induction of NF-kappaB on HSC activation and the expression of TGF-beta1. It also impart its anti fibrotic properties by enhancing the antioxidant enzymes systems of the liver ie The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were found notably elevated by GBE. while malondialdehyde (MDA) content was significantly decreased in the rats treated with CCl4 + EGB

Fig 13 :Molecular structure Isoflavone


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Silimarin Silymarin is a derivative from the milk thistle plant with few side effects that has been safely used for centuries to treat liver ailments. Research results of studies strongly suggest silymarin has hepatoprotective, antiinflammatory, and regenerative properties producing a beneficial effect for some types of Silymarin has a well studied role in hepatic billiary process mediated through downregulation of elevated procollagen alpha1(I), TIMP-1 and TGFbeta1 mRNA levels by 40-60% (P < 0.01). Silymarin suppresses expression of profibrogenic procollagen alpha1(I) and TIMP-1 most likely via downregulation of TGFbeta1 mRNA in rats with biliary fibrosis. The serum procollagen type III propeptide level mirrors profibrogenic mRNA expression in the liver. silibinin another active ingredient from S Marianum reduced the proliferation of freshly isolated rat hepatic stellate cells by about 75%, but had no detectable effect on their viability, morphology and their cytoskeletal architecture. It reduced the transformation towards myofibroblasts and down-regulated the gene expression of extracellular matrix components and the profibrogenic transforming growth beta. In short it inhibit hepatic stellate cell proliferation and transformation.

Fig 14 Molecular structure Silymarin

Fig 15Molecular structure silibinin


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Fig 16 :Summary of hepatoprotective effects by silymarin


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Heptavite AF® As a potent antioxidant: As discussed earlier Heptavite AF® is a combination of potent antioxidants having a well defined and proven role in preventing free radical induced damage. The Key antioxidant constituents of Heptavite AF® improve antiperoxidative profile of hepatic parenchyma and prevent further degradation by HSC Terminali arjuna Arjunic acid an active constituent is found to be a strong antioxidant and a free radical scavenger, more potent than ascorbic acid, in microsomes lipid peroxidation, DPPH, hydrogen peroxide induced RBCs hemolysis. It exhibit significant (P<0.05) reduction in lipid peroxidation (LPO). It also demonstrated a significant (P<0.05) increase in superoxide dismutase, catalase, glutathione peroxidase, glutathione-s-transferase glutathione reductase and glucose-6-phosphate dehydrogenase, reduced glutathione, vitamin A, vitamin C, vitamin E, total sulfhydryl groups (TSH) and non protein sulfhydryl groups (NPSH) in liver and kidney of alloxan induced diabetic rats.

Fig 17: Molecular structure Antioxidants from terminalia Arjua


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Alleviation chronic inflammation as a result of oxidative stress a leading cause of HSC activation: Chronic inflammation due to oxidative stress has been defined as a cause of HSC activation leading to hepatic fibrosis. Heptavite AF® by virtue of its potent antioxidative and anti inflammatory properties relieve the persistent inflammatory response ,which is a source of activation of HSC ,thus down regulating the activated HSC to prevent further role in hepatic fibrosis Almost all of the active ingredients have varying degree of antinflamatory activities with respect to hepatocllular parenchyma.However Curcuma longa, Picrorhiza kurroa , Silybum marianum are the most potent anti inflammatory ingredients of the composition


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Dosage & Administration: It is advised to use the product under doctors supervision. 1. Jaundice : 1 capsules twice daily for 2-3 weeks. 2. Viral Hepatitis: 1-2 capsules twice daily in combination with antiviral therapy { as alpha interferon + ribavirin } 3. Alcoholic Liver Disease: 1-2 capsules twice daily for 6 month 4. Cirrhosis: 1-2 capsules2-3 times daily in combination with antiviral therapy { as alpha interferon + ribavirin } Depending on the severity of disease daily 5. Chronic Active Hepatitis: 2 capsules twice daily for 3-4month Than 1 capsules twice daily for 5-6 month (until the symptoms are resolved) Dosage for children under 12 years : Half the dose prescribed for adult. Dosage for childrens b /w 2-6 : NA Adverse effects and precautions: None so far noted Contraindications (if any): in case of this formulation none. Additional Recommendations if any References on file “Product monograph Heptavite AF® ” Bionutrix Inc Final Note: This product Summary is continually updated to comprehend the latest scientific research regarding the active ingredients used in this product. References on File “Product Monograph Heptavite AF® Better Nutrition through Scientific Sense Copyright © Bionutrix Inc


Executive summaery Heptavite AF

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