PHOSPHATIDYLCHOLINE

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 1 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

What is Phosphatidylcholine?

Phosphatidylcholine is a class of phospholipids called "essential phospholipids." Although the structure is somewhat similar to other phospholipids, there are some differences that have profound affects on the health and well-being of your body.

The most distinguishing physical characteristics between simple phospholipids and phosphatidylcholine are the choline head and the polyunsaturated essential fatty acid chains that make up the tail.

Representation of the phosphatidylcholine molecule showing the choline head attached to the phosphate group which is attached to the triglyceride shoulder. Two polyunsaturated fatty acid chains are also connected to the triglyceride shoulder. (Not shown to scale).

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 2 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

What does phosphatidyl choline do?

PC acts as a supplier of choline, which is needed for cell membrane integrity and to facilitate the movement of fats in and out of cells. It is also a component of the neurotransmitter the human body can synthesize choline, additional amounts from the diet are considered preliminary studies for a wide variety of neurological and psychiatric disorders, though not participates in many functions involving cellular components called phospholipids. acetylcholine and is needed for normal brain functioning, particularly in infants. Although essential under certain circumstances. For this reason, PC has been used in a number of every study suggests that supplemental choline is capable of reaching the brain.1 Choline

Phosphatidylcholine Biosynthesis and Biological Function

(http://www.lipidlibrary.co.uk/Lipids/pc/index.htm) There are three mechanisms for the biosynthesis of phosphatidylcholine. Choline itself is not synthesized as such by animal cells and is an essential nutrient. It must be obtained from dietary sources or by degradation of existing choline-containing lipids, for example those immediately phosphorylated by a choline kinase in the cytoplasm of the cell to diphosphocholine. The membrane-bound enzyme CDP-choline: 1,2-diacylglycerol

produced by the second pathway described below. Once taken up into cells, choline is phosphocholine, which is reacted with cytidine triphosphate (CTP) to form cytidine cholinephosphotransferase in the endoplasmic reticulum catalyses the reaction of the last

compound with sn-1,2-diacylglycerols to form phosphatidylcholine. This is the main to the biosynthesis of phosphatidylethanolamine.

pathway for the synthesis of phosphatidylcholine in animals and plants, and it is analogous

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 3 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

The discovery of the importance of this pathway depended a little on serendipity in that in experiments in the lab of Professor Eugene Kennedy, samples of adenosine triphosphate (ATP) contained some cytidine triphosphate (CTP) as an impurity. However, luck is of little

value without receptive minds, and Kennedy and co-workers demonstrated that the phosphatidylcholine. The above

impurity was an important metabolite that was essential for the formation of

phosphatidylethanolamine, is significantly different from that for phosphatidylglycerol, phosphatidylinositol and cardiolipin. Both make use of nucleotides, but with the latter, the diacylglycerol. nucleotide is covalently linked directly to the lipid intermediate, i.e. cytidine diphosphate

reaction,

together

with

the

biosynthetic

mechanism

for

The source of the sn-1,2-diacylglycerol precursor, which is also a key intermediate in the formation of phosphatidylethanolamine and phosphatidylserine, and of triacylglycerols, is which is present mainly in the endoplasmic reticulum of the cell. phosphatidic acid. In this instance, the important enzyme is phosphatidic acid phosphatase,

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 4 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

The second pathway for biosynthesis of phosphatidylcholine involves sequential methylation of phosphatidylethanolamine, with S-adenosylmethionine as the source of methyl groups, with mono- and dimethyl-phosphatidylethanolamine as intermediates and catalysed by the enzyme phosphatidylethanolamine N-methyltransferase. A single enzyme (~20 Kda) catalyses all three reactions and is located mainly in the endoplasmic reticulum

where it spans the membrane. This is a major pathway in the liver, but not in other animal those bacterial species that produce this lipid and in yeasts.

tissues or in general in higher organisms. It may be the main route to phosphatidylcholine in

This liver enzyme is especially important when choline is deficient in the diet. A by-product of S-adenosylmethionine to S-adenosylhomocysteine, which is hydrolysed in the liver to factor for cardiovascular disease and myocardial infarction.

of the biosynthesis of phosphatidylcholine from phosphatidylethanolamine is the conversion adenosine and homocysteine. It is noteworthy that elevated plasma homocysteine is a risk

Phosphatidylcholine biosynthesis by both pathways in the liver is necessary for normal human physiological conditions.

secretion of the plasma lipoproteins (VLDL and HDL), and it is relevant to a number of

In one bacterial species, a third pathway for phosphatidylcholine biosynthesis that is cholinecholine directly with CDP-diacylglycerol.

dependent has been found in which the lipid is formed in one step via condensation of

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 5 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

While phosphatidylcholine is a major lipid in yeasts, recent work suggests that it is not

essential if suitable alternative growth substrates are available, unlike higher organisms even cell death. Enhanced synthesis of phosphatidylcholine appears to occur in cancer cells and solid tumours, and this may prove to be a target for therapeutic agents.

where perturbation of phosphatidylcholine synthesis can lead to inhibition of growth or

Whatever the mechanism of biosynthesis in tissues, it is apparent that the fatty acid compositions and positional distributions on the glycerol moiety are determined post synthesis by extensive re-modelling involving hydrolysis (phospholipases A1, A2 or B) and re-acylation, a process that is sometimes termed the 'Lands cycle'. The re-acylation step is catalysed by a specific lysophosphatidylcholine acyltransferase, which has been located

within the endoplasmic reticulum in organs such as the liver, adipose tissue and pancreas.

For example, the highly saturated molecular species of phosphatidylcholine found in the nucleus are formed from species with a more conventional composition by remodelling. In plants, fatty acids esterified to phosphatidylcholine can serve as substrates for desaturases, The process is further complicated in plants in that biosynthesis or partial synthesis (via plastids and mitochondria, from different fatty acid pools or with differing specificities. and this means that the fatty acid composition changes also after the initial synthetic process. lysophosphatidylcholine) occurs in different organelles, such as the endoplasmic reticulum,

Because of the generally cylindrical shape of the molecule, phosphatidylcholine spontaneously organizes into bilayers, so it is ideally suited to serve as the bulk structural element of biological membranes. Such properties are essential to act as a balance to those lipids that do not form bilayers or that form specific micro-domains such as rafts.

In addition to its function as a membrane constituent, phosphatidylcholine may have a role in signalling via the generation of diacylglycerols, especially in the nucleus. Although the pool of the precursor is so great in many tissues that turnover is not easily measured, the a number of agonists, suggests such a function especially in the cell nucleus. Diacylglycerols phosphatidylinositol, and would not be expected to be as active.

presence of phospholipases C and D specific for phosphatidylcholine, which are activated by formed in this way would be much more saturated than those derived from

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 6 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

thrombin treatment of endothelial cells activates a selective hydrolysis (phospholipase A2) of

The plasmalogen form of phosphatidylcholine may also have a signalling function, as

molecular species containing arachidonic acid in the sn-2 position, releasing this fatty acid

for eicosanoid production. The diacyl form of phosphatidylcholine may have a related function in signal transduction in other tissues. In addition, it is known that the enzyme 3hydroxybutyrate dehydrogenase requires to be bound to phosphatidylcholine before it can function optimally.

Phosphatidylcholine is the biosynthetic precursor of sphingomyelin and as such must have

some influence on the many metabolic pathways that constitute the sphingomyelin cycle. It is also a precursor for phosphatidic acid, lysophosphatidylcholine and platelet-activating factor, each with important signalling functions, and of phosphatidylserine.

On catabolism of choline-containing lipids, much of the choline is re-used for phosphatidylcholine biosynthesis, often after being returned to the liver. Some is oxidized in the kidney and liver to betaine, which serves as a donor of methyl groups for Sadenosylmethionine production. A proportion is used in nervous tissues for production of acetylcholine, which is a neurotransmitter of importance to learning, memory and sleep. Some choline is lost through excretion of phosphatidylcholine in the bile.

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 7 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

EFFICACY
I. LIVER
Experimental and clinical results support the assumption that the therapeutic application of on the biological membranes of sinus endothelial cells and hepatocytes. PHOSPHOTIDYLCHOLINE (PPC) has protective and even curative and regenerative effects

The cytoprotective effect of PPC has been corroborated in 13 in vitro and in 117 in vivo

experiments, in which 31 different models with 8 different animal species were used. Types of intoxication which are known to play a role in the etiology of liver disease have mostly been applied: chemical substances, medicaments, alcohol, cholestasis, immunological phenomena, exposure to radiation, etc.

The hepatoprotective effects of PPC have been confirmed as compared to the controls and were the more pronounced the earlier PPC was administered:

1. Structures of membranes were normal or largely normalized; 2. Fatty infiltrations and hepatocyte necrosis could be diminished or even eliminated; 3. Corresponding data were found for lipid peroxidation, transaminase and

cholinesterase activity, and for serum lipids; liver cell metabolism increased;

4. The increase of RNA and protein synthesis and of the liver cell glycogen content indicated a stimulation of the liver cells;

5. Reduced collagen production, collagen/DNA ratio and liver hydroxyproline indicated a reduced formation of connective tissue.

Through May 2004, 127 open, 46 single-blind and 19 double-blind clinical trials with a total on 4 groups and 5 on 5 groups of criteria (including electron microscopy). 48 studies children.

of 12,197 patients were carried out. 137 of these studies were based on 3 groups of criteria, 43 including histological controls were performed. 17 studies were even done on newborns and

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 8 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

The dosage of PPC ranged from 525 mg to 2700 mg/day when administered orally. The

duration of treatment lasted from some weeks to up to 30 months. The main liver indications were: acute hepatitis, chronic hepatitis, fatty liver, toxic liver damage, and cirrhosis of the liver.

The clinical findings, showing the efficacy of PPC, can be summarized generally as follows: 1. Accelerated improvement or normalization of subjective complaints, clinical findings and several biochemical values.

2. Improved histological result as compared to the control groups. 3. Shortened hospitalization duration. Two pharmacological, 11 open and 1 double-blind trials have shown the effectiveness of PPC

in hepatotoxicity of anti-TB agents, which is the only representative clinical model of liver damage to assess effectiveness of a liver therapeutic in intoxication.

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 9 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

ABSTRACT

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 10 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 11 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 12 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 13 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 14 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 15 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 16 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 17 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

II. FIBROSIS AND CIRRHOSIS IN THE BABOON

55%-60% phosphatidylcholine [PC] protects against fibrosis in alcohol-fed baboons. The

present study was undertaken to determine whether PC is the active agent. Virtually pure without alcohol, and the results were compared with those of unsupplemented groups.

PC (equivalent to that contained in the lecithin) was administered for up to 6.5 years with or

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 18 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

ABSTRACT

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 19 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 20 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 21 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 22 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 23 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 24 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 25 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 26 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 27 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 28 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 29 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 30 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 31 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 32 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 33 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 34 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 35 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 36 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 37 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 38 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 39 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 40 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 41 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 42 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 43 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 44 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 45 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 46 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 47 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 48 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 49 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 50 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 51 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 52 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 53 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 54 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 55 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 56 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 57 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 58 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 59 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 60 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 61 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 62 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 63 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 64 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 65 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 66 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 67 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 68 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 69 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 70 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 71 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 72 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 73 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 74 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 75 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

II) BRAIN DISEASE

Choline is a precursor to the neurotransmitter acetylcholine, essential for memory and cognition. Also, it is a phospholipid that helps promote neuronal membrane fluidity, which is important for communication between brain cells. One form of this fat, phosphatidyl choline, is the active ingredient in lecithin--an emulsifier commonly found in processed plays a role in repairing and maintaining neurons.

foods, and derived from either soy or animal sources. In the brain, phosphatidyl choline also

Many studies have been conducted on choline.

in people with mild memory impairment, but in normal healthy people as well.

Choline, in its various forms, is widely reputed to enhance cognition and memory not only

The importance of the nutrient choline was emphasized a few years ago when the National

that volunteers on a choline-deficient diet were not able to produce enough of this nutrient to maintain health. This demonstrated that choline must be obtained from the diet. Choline is used in the synthesis of structural components of all human cell membranes and is a memory, and many other functions. precursor of acetylcholine, an important neurotransmitter involved in muscle control,

from the Department of Nutrition of the University of North Carolina at Chapel Hill demonstrated

Academy of Sciences classified it as an essential nutrient. A study by Dr. Steven Zeisel (1991)

been shown to yield benefits to brain function. Its a testament to the investigative powers of science, and a boon to our bodies, that the precise nutritional compounds needed to maintain healthy memory and thinking have been illuminated.

Choline and amino acids such as L-glutamine, acetyl-L-carnitine, and phenylalanine have

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 76 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

ABSTRACT
Choline, an essential nutrient for humans SH Zeisel, KA Da Costa, PD Franklin, EA Alexander, JT Lamont, NF Sheard and A Beiser Department of Nutrition, University of North Carolina, Chapel Hill 27599-7400. biosynthesis of the neurotransmitter acetylcholine and also is an important source of labile choline is not considered an essential nutrient in humans. Healthy male volunteers were methyl groups. Mammals fed a choline-deficient diet develop liver dysfunction; however, Choline is required to make essential membrane phospholipids. It is a precursor for the

hospitalized and fed a semisynthetic diet devoid of choline supplemented with 500 mg/day receive choline (control), and the other that received no choline (deficient) for three choline for 1 wk. Subjects were randomly divided into two groups, one that continued to

semisynthetic diet contained adequate, but no excess, methionine. In the choline-deficient

additional wk. During the 5th wk of the study all subjects received choline. The

during the 3-wk period when a choline-deficient diet was ingested; plasma and erthrocyte

group, plasma choline and phosphatidylcholine concentrations decreased an average of 30% phosphatidylcholine decreased 15%; no such changes occurred in the control group. In the

choline-deficient group, serum alanine aminotransferase activity increased steadily from a mean of 0.42 mukat/liter to a mean of 0.62 mukat/liter during the 3-wk period when a

of liver and renal function were unchanged in both groups during the study. Serum

choline-deficient diet was ingested; no such change occurred in the control group. Other tests

cholesterol decreased an average of 15% in the deficient group and did not change in the

stores of choline in tissues and developed signs of incipient liver dysfunction. Our excess methionine and folate are not available in the diet.

control group. Healthy humans consuming a choline-deficient diet for 3 wk had depleted

observations support the conclusion and choline is an essential nutrient for humans when

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 77 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 78 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 79 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 80 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 81 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 82 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 83 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 84 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 85 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 86 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 87 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

III) FAT DEPOSITS

Although tumescent liposuction with microcanulas[1] has been proven as a highly efficient method in correcting unwanted localised fat deposits with few side effects, some patients object to surgery. Anecdotal evidence from both South-America and Europe states that deposits. injecting phosphatidylcholine might be a safe and efficacious way to correct localised fat

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 88 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

ABSTRACT

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 89 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 90 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 91 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 92 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

IV) GASTRIC MUCOSA

In the upper part of the gastrointestinal tract (GI) endogenous PC is part of the lining of the mucosa. In the lower part PC and bile salts emulsify fat by forming chylomicrons and enable absorption. The importance of the intact lining was demonstrated by experiments, where the bile acid caused dissolution of the PC in the lining, causing mucosal bleeding in the rats [1]. After the oral application of radioactive labeled PC to the rats, audio graphic graphs the gastro protective effect of PC in vivo. demonstrated the coverage of GI by exogenous PC. These results justified the evaluation of

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 93 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

ABSTRACT

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 94 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 95 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 96 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 97 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 98 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

V) REDUCTION OF ORGAN INJURY & DYSFUNCTION IN RODENT MODELS OF GRAM- NEGATIVE AND GRAM POSITIVE SHOCK
Lysophosphatidylcholine (LPC) modulates the inflammatory response and reduces mortality in animal models of sepsis. It was investigated that the effects of LPC from synthetic (sLPC) and natural, soy bean derived LPC, (nLPC) sources on the organ injury/dysfunction caused lipoteichoic acid (LTA).Rats were subjected to (i) endotoxaemia (LPS 6 mg kg(-1) i.v.) and treated with sLPC (1-100 mg kg(-1)), (ii) endotoxaemia and treated with nLPC (10 mg kg(-1)) sLPC (10 mg kg(-1)). Endotoxaemia or Gram-positive shock for 6 h resulted in increases in or (iii) Gram-positive shock (PepG 10 mg kg(-1) and LTA 3 mg kg(-1) i.v.) and treated with serum makers of renal dysfunction and liver, pancreatic and neuromuscular injury. Administration of sLPC, at 1 or 2 h after LPS, dose dependently (1-10 mg kg(-1)) reduced the detrimental in endotoxaemia. sLPC also afforded protection against the organ injury/dysfunction. High doses of sLPC (30 and 100 mg kg(-1)) were shown to be injury/dysfunction caused by Gram-positive shock. nLPC was found to be protective in endotoxaemic animals. The beneficial effects of sLPC were associated with attenuation in circulating levels of interleukin-1beta (IL-1beta).In conclusion, LPC dose and time dependently reduces the organ injury and circulating IL-1beta levels caused by Gramnegative or Gram-positive shock in the rat. Thus, we speculate that appropriate doses of LPC of various etiologies. organ

by systemic administration of lipopolysaccharide (LPS) or peptidoglycan (PepG) and

may be useful in reducing the degree of organ injury and dysfunction associated with shock

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 99 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

ABSTRACT

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 100 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 101 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 102 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 103 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 104 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 105 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 106 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 107 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 108 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

Ulcerative Colitis
http://www.klinikum.uni-heidelberg.de/Lecithin-zur-Behandlung-chronisch-entzuendlicherDarmerkrankungen.102390.0.html
Die chronisch entzndlichen Darmerkrankungen (Colitis ulcerosa und Morbus Crohn) betreffen in hohem Mae Menschen im jugendlichen und mittleren Lebensalter. Immer mehr Menschen leiden unter diesen beiden Krankheiten, nmlich bis zu 2% der Bevlkerung. Der chronische Verlauf mit akuten entzndlichen Schben sowie zahlreichen Komplikationen (Fistel- und Abszessbildung, Stenosen, Blutungen, Funktionsverlust des Dickdarms, extraintestinalen Manifestationen wie Gelenkbeschwerden oder Augenentzndungen) kennzeichnen den typischen Verlauf dieser Erkrankungen.
Phosphatidylcholine - mucosal protection as a prophylactic and therapeutic principle The chronic inflammatory bowel disease (ulcerative colitis and Crohn's disease affect) were largely people in youth and middle age. More and more people suffer from these two diseases, namely, up to 2% of the population. The chronic course of acute inflammatory episodes, and numerous complications (fistula and abscess formation, stenosis, bleeding, loss of function of the colon, extraintestinal manifestations such as joint pain or inflammation of the eyes) characterize the typical course of these diseases.

Beide Krankheitsbilder sind insofern problematisch, als oft trotz zahlreicher Manahmen keine Ruhe (Remission) in das Krankheitsbild kommt. Zwar sind in den letzten Jahren merkliche Fortschritte durch den Einsatz von Immunsuppressiva festzustellen, dennoch leiden immer noch zahlreiche Patienten an chronischaktiven (Dauerschub) oder chronisch-rezidivierenden (immer wiederkehrende Schbe) Verlufen. Andere Patienten sind auf die dauerhafte Einnahme von Cortison angewiesen, obwohl von den entsprechenden Fachgesellschaften nur mehr die kurz- und mittelfristige Therapie empfohlen wird
Both diseases are problematic inasmuch as often occurs in spite of numerous measures, no rest (remission) in the clinical picture. Although in recent years, significant progress by the use of immunosuppressive agents to determine yet still suffer many patients with chronic-active (continuous thrust) or chronic recurrent (recurrent episodes) gradients. Other patients are on the permanent taking cortisone dependent, although by the appropriate professional societies only the short-and medium-term therapy is recommended.

Die Colitis ulcerosa zeigt eine kontinuierliche Ausbreitung, die immer im Rektum beginnt und gegebenenfalls das ganze Colon betreffen kann (Pancolitis ulcerosa). Es kommt zur oberflchlichen Entzndung der Darmschleimhaut (Mukosa), die zu Erosionen und Ulzerationen (Geschwren) fhren kann und hufig mit Blutungen einhergeht. Die Oberflche der Schleimhaut wird reduziert und schlielich kann der Dickdarm durch Vernarbungsprozesse ein fahrradschlauchartiges Aussehen annehmen. Dann ist die Funktion des Dickdarms meist soweit reduziert, dass dieser seiner Aufgabe den Stuhl einzudicken, um wertvolles Wasser wieder zurck zu gewinnen nicht mehr nachkommen kann. In diesem Fall ist meist kein Blut mehr im Stuhl, man spricht von einer ausgebrannten Colitis.
Ulcerative colitis shows a continuous spread, the always begins in the rectum and may possibly affect the entire colon (pancolitis colitis). This leads to superficial inflammation of the mucous membrane (mucosa) can lead to erosions and ulcerations (sores), and often accompanied by bleeding. The surface of the mucosa is reduced and eventually may accept a scarring of the colon by fahrradschlauchartiges appearance. Then the function of the colon usually reduced to the extent that this thicken his task - the chair in order to win back the precious water back to meet no more - can. In this case, is usually no more blood in the stool, one speaks of a "burned-colitis".

Die Gefahr, einen bsartigen Krebs zu entwickeln, ist weitaus geringer als bislang vermutet. Dennoch ist das Risiko eines Karzinoms bei Patienten mit Colitis ulcerosa, besonders wenn der gesamte Dickdarm entzndet ist, erhht.
The risk of developing a malignant cancer is much lower than previously suspected. Nevertheless, the risk of cancer in patients with ulcerative colitis, especially if the entire colon is inflamed, increased

Zum Schutz vor Entzndungen durch die ortsstndige, bakterielle Flora haftet der Schleimhaut des Dickdarms eine fest anliegende Schleimschicht an, die den direkten Kontakt der Darmzellen mit Giftstoffen und Bakterien wirkungsvoll verhindert. Ein Hauptbestandteil dieses Schleims ist Phosphatidylcholin (wie es im Lecithin vorkommt), welches den Schleim an die Schleimhaut bindet und somit zur Entstehung dieser Schleimbarriere beitrgt. Dieses Phosphatidylcholin (PC) ist ein Fett und kann die wssrige Lsung, in welcher der Darm permanent liegt, fernhalten und so die Schleimhaut vor dem Aufweichen schtzen. Dadurch werden Fremdstoffe, Gifte und Bakterien auf Distanz gehalten, die sich in der wssrigen Lsung befinden und die bei zu engem Kontakt mit der Schleimhaut zu Entzndungen fhren.

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 109 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

To protect against infection by the ortsstndige, bacterial flora of the mucous membrane of the colon is liable to a tightly fitting layer of mucus, which prevents direct contact of the intestinal cells with toxins and bacteria effectively. A major component of this mucus phosphatidylcholine (as it appears in the lecithin), which binds to the mucus membrane and thus to the emergence of this mucus barrier helps. This phosphatidylcholine (PC) is a fat, the aqueous solution in which the bowel is permanently keep and protect the mucosa from the soaking. This foreign matter, toxins and bacteria are kept apart, are located in the aqueous solution and in the lead to close contact with the mucosa to inflammation.

In eigenen Untersuchungen konnten wir zeigen, dass Phosphatidylcholin aktiv in den Schleim der Darmschleimhaut ausgeschieden wird. Erstaunlicherweise findet dies vor allem im letzten Teil des Dnndarms und viel weniger im Dickdarm selbst statt, obwohl wir PC im Mucus (Schleim) des Dickdarms nachweisen knnen. Der zunchst locker aufsitzende, PC enthaltende Schleim wird also zusammen mit der Aufnahme der Gallensuren im Dnndarm fest an die Oberflche des Darms gebunden und wandert so langsam und kontinuierlich als Schutzfilm im Dickdarm abwrts bis hin zum Enddarm.
In our own studies we have shown that phosphatidylcholine is actively secreted in the mucus of the intestinal mucosa. Amazingly, this takes place mainly in the last part of the small intestine and a lot less in the colon itself, although we can demonstrate PC in mucus (phlegm) in the colon. The first loose sessile, PC-containing mucus is so tightly together with the inclusion of bile acids in the small intestine to the surface of the intestine bound and moves so slowly and steadily as a protective film in the colon down to the rectum.

Wir machten die hochinteressante Feststellung, dass die PC-Konzentration im Schleim des Dickdarms bei Patienten mit Colitis ulcerosa deutlich vermindert ist. Wir glauben daher, dass der Mangel an PC urschlich an der Entstehung der Colitis ulcerosa beteiligt ist. Durch den Mangel an Phosphatidylcholin kommt es zu einer verminderten Fettschutzschicht, daher knnen die wssrigen Bestandteile aus dem Darminhalt in direkten Kontakt zur Darmwand treten. Darin enthaltene Bakterien, Fremdkrper und Giftstoffe fhren jedoch bei Kontakt zum Darm zu Gegenreaktionen des Immunsystems; es kommt zur Entzndung. Nachdem die Entzndung letztlich schdlicher ist als die eigentlichen Fremdstoffe, hilft es auch, wenn durch Cortison, Immunsuppressiva (Azathioprin, 6-Mercaptopurin) oder die sogenannten Biologika (Infliximab) die Entzndung unterdrckt wird.
We made the interesting observation that the PC concentration is decreased in the mucus of the colon in patients with ulcerative colitis significantly. We therefore believe that the lack of PC causally in the development of ulcerative colitis is involved. The lack of phosphatidylcholine leads to a decrease in "protective fat", so the aqueous components from the intestinal contents to enter into direct contact with intestinal wall. Contained bacteria, foreign bodies and toxins on contact, however, lead to a backlash of the intestinal immune system, is inflammation. Once the inflammation is ultimately harmful than the actual foreign substances, it also helps if by cortisone, immunosuppressants (azathioprine, 6mercaptopurine), or the so-called biologics (infliximab), the inflammation is suppressed.

Der Schleim wird also hauptschlich im Dnndarm gebildet und anschlieend zum Enddarm bewegt. Auf dem Weg wird sich die Konzentration vermutlich durch Diffusion oder Spaltung bakterieller Enzyme vermindern. Damit ist der Enddarm die Stelle im Dickdarm, die die geringste Konzentration an Phosphatidylcholin enthlt und sich daher bei der Colitis ulcerosa als erstes entzndet. Das ist die erste sinnvolle Erklrung, warum die Colitis ulcerosa immer vom Enddarm her beginnt und sich von dort kontinuierlich ausbreitet.
The mucus will be formed mainly in the small intestine, and then moves to the rectum. On the way will lower the concentration, presumably by diffusion or division of bacterial enzymes. This is the place of the rectum in the colon that contains the lowest concentration of phosphatidylcholine and therefore in ulcerative colitis as first ignited. This is the first sensible explanation of why the ulcerative colitis always starts from her rectum and continuously spreads out from there.

Aufgrund dieser berlegungen erarbeiteten wir eine Behandlungsstrategie: Die Ergnzung des fehlenden Phosphatidylcholins msste zu einer Verstrkung des Schleimhautschutzes im Dickdarm fhren und sollte somit die Entzndung bei einer Colitis bessern.
Because of these considerations, we developed a treatment strategy: the extension of the missing phosphatidylcholine should lead to a strengthening of the mucosal protection in the large intestine and should therefore improve the inflammation in a colitis.

Da herkmmliches Lecithin durch die Verdauungssfte des Pankreas fast vollstndig verdaut wird, entwickelten wir ein Granulat, das sich erst am Ende des Dnndarms freisetzt und von dort den Dickdarm mit Phosphatidylcholin auskleiden kann.
Since conventional lecithin by the digestive juices of the pancreas is digested almost completely, we developed a granulate, which releases only at the end of the small intestine and the colon can undress from there with phosphatidylcholine

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 110 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

In einer ersten Studie konnten wir zeigen, dass dieses Granulat deutlich wirksamer ist als ein Scheinprparat. Es wurden ausschlielich Patienten im Dauerschub eingeschlossen; die Hlfte der Patienten erreichte innerhalb von 3 Monaten eine Remission (geringe Krankheitsaktivitt), wenn Sie das Granulat einnahmen. Demgegenber erreichten nur 10% der Patienten eine Remission, wenn sie das Scheinprparat (Placebo) einnahmen. Weder die Studienpatienten noch die Studienrzte wussten, wer PC und wer Placebo einnahm (doppelblinde Studie).
In a first study, we demonstrated that these granules is significantly more effective than a placebo. We included only patients in continuous thrust, half of the patients achieved remission within 3 months (low disease activity) if you are taking the granules. In contrast, only 10% of patients achieved a remission, when they took the sham preparation (placebo). Neither the study patients nor the investigators knew who who took PC and placebo (double blind study).

Bei allen analysierten Patienten ging die Stuhlfrequenz zurck, die meisten zeigten eine deutliche Zunahme der Stuhlkonsistenz bis hin zu festem Stuhlgang. Blutbeimengungen gingen zurck und verschwanden bei fast allen Patienten. Auch endoskopisch kam es zu einer deutlichen Besserung der entzndlichen Vernderungen im Colon. Dies ging einher mit einer bedeutenden Besserung des Allgemeinbefindens der Patienten.
In all analyzed patients decreased the frequency of stools, most showed a significant increase in stool consistency to solid stool. Blood in went back and disappeared in almost all patients. Also endoscopically, there was a significant improvement in inflammatory lesions in the colon. This coincided with a significant improvement of the general condition of patients.

Wir hatten also einen deutlichen Hinweis, dass bei Patienten mit chronisch aktiver Colitis das retardierte Phosphatidylcholin tatschlich wirksam ist. In beiden Gruppen sowohl in der Lecithin- als auch in der Placebogruppe kam es vermehrt zu Blhungen. Weitere nennenswerte Nebenwirkungen sind nicht aufgetreten.
So we had a clear indication that, in patients with chronic active colitis, the sustained release phosphatidylcholine effective. In both groups - both in lecithin than in the placebo group - there was more to flatulence. Other significant side effects have not occurred.

In einer weiteren Studie stellten wir erfreulicherweise fest, dass dieses Prparat in der Lage ist, Patienten mit einem steroidabhngigen Verlauf vom Cortison zu befreien. In dieser Studie konnten 80% der Patienten vom Cortison befreit werden, ohne dass sich die Colitis verschlechterte. 50% erreichten dabei eine Remission. Auch hier zeigten sich auer den bekannten Blhungen- keine Nebenwirkungen.
In another study, we happily noted that this drug is able to rescue patients with a history of steroid cortisone. In this study, 80% of patients are cleared of cortisone, without the colitis worsened. 50% achieved this remission. Here, too, showed themselves, except for the flatulence-known side effects.

In einer dritten Studie konnte nun die optimale Dosis des retardierten Phosphatidylcholins gefunden werden. Es wurden Patienten mit Pancolitis ulcerosa eingeschlossen, auch hier zeigte sich die gute Wirksamkeit des Prparates ohne weitere Nebenwirkungen. Die Ergebnisse dieser Studie werden in Krze verffentlicht.
In a third study it was now the optimal dose of sustained-release phosphatidylcholine are found. There were included patients with ulcerative pancolitis, also showed the good efficacy of the drug without side effects. The results of this study will be published shortly.

Ziel fr die Zukunft ist es, das retardierte Phosphatidylcholin mglichst bald als Medikament zulassen und somit allen Betroffenen zugnglich machen zu knnen. Dieses Zulassungsverfahren ist jedoch kompliziert und langwierig. Wirkung und Nebenwirkungsprofil mssen zur Sicherheit des Patienten in groen, europaweit durchgefhrten Studien dokumentiert werden. Diese Studien beginnen Mitte 2009 mit einem hochaufgereinigten PC-Prparat.
Goal for the future to allow the sustained release phosphatidylcholine as soon as a drug and thus make available to all interested parties being able to. This authorization is complicated and lengthy. Effect and side effect profile must be documented in the safety of patients in large European studies. These studies begin in mid 2009 with a highly purified PC preparation

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 111 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

bersicht ber abgeschlossene und geplante Studien: (Stand 03/2009) Abgeschlossen:

1. 2. 3.

Patienten mit chronisch aktiver Colitis ulcerosa, keine Steroide, keine Immunsuppressiva. Ziel: Verbesserung der klinischen Aktivitt durch Therapie mit Phosphatidylcholin. Patienten mit chronisch aktiver Colitis ulcerosa und steroidabhngigem Verlauf. Ziel: Reduktion bzw. Absetzen des Cortisons unter Therapie mit Phosphatidylcholin. Patienten mit Pancolitis ulcerosa, keine Steroide, keine Immunsuppressiva. Ziel: Findung der optimalen Dosis des Phosphatidylcholins.

Completed: 1 Patients with chronic active ulcerative colitis, no steroids, no immunosuppressive drugs. Objective: To improve the clinical activity by treatment with phosphatidylcholine. Patients with chronic active ulcerative colitis and steroid-dependent course. Objective: reduction or discontinuation of cortisone in therapy with phosphatidylcholine. Patients with pancolitis colitis, no steroids, no immunosuppressive drugs. Objective: Determination of the optimal dose of phosphatidylcholine.

In Planung: - Multizenter-Studie zur Dosisfindung mit neuem, hochaufgereinigtem PC-Prparat - Im Anschluss: Zulassungsstudie - Auerdem: Kinderstudie
In planning: - Multi-center dose-finding study with a new, highly purified PC preparation - Followed by: pivotal trial - Other: Study of Children

Kontakt
Lipid Therapeutics GmbH Alte Glockengieerei 9 69115 Heidelberg E-Mail: info@lipid-therapeutics.com Tel.: 06221-3350580 www.lipid-therapeutics.com

Studiensekretariat Prof. Stremmel: Medizinische Klinik IV Im Neuenheimer Feld 410 69120 Heidelberg E-Mail: anja.hanemann@med.uni-heidelberg.de Tel.: 06221-56-8701
Studienleiter
Prof. Dr. Wolfgang Stremmel Abteilung Gastroenterologie Medizinische Universittsklinik Universittsklinikum Heidelberg Im Neuenheimer Feld 410 69120 Heidelberg E-mail: wolfgang_stremmel@med.uni-heidelberg.de

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 112 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

Lecithin for Cholesterol Reduction

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 113 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 114 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 115 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 116 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 117 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 118 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 119 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 120 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD

51/B Mittal Court, 224, Nariman Point, Mumbai400021 India; Tel.: +91-22-22836802 * Fax: +91-22-22836809 E-mail: arun@vav.in* Internet: http//www.vav.in
Page 121 of 121 Prepared on : 22nd July 2008

VAV LIFE SCIENCES PVT LTD