LOLA (HEPA-MERZ®):

L-Ornithine L-aspartate (LOLA) is a stable salt of two naturally occurring nonessential L-amino acids: ornithine and aspartic acid. Both of these amino acids are orally active. L-Ornithine L-aspartate (LOLA) plays an efficient role in lowering the blood ammonia level. They have also shown to alleviate the symptoms of hepatic encephalopathy associated with liver cirrhosis. L-Ornithine L-aspartate (LOLA) has demonstrated significant improvement in the mitochondrial functions.

Highlights of Mechanism of Action of LOLA:

LOLA supports ammonia detoxification through two complementary mechanisms:

Pathway 1: Urea synthesis (Mainly in liver)

LOLA helps the liver convert ammonia into urea, which can then be eliminated through the kidneys.

How ornithine and aspartate work in the urea cycle

Think of the urea cycle as a waste-treatment system with two important contributors i.e. ornithine and aspartate. The role of ornithine and aspartate in urea cycle is explained below: 

1. Protein metabolism produces ammonia. Ammonia contains nitrogen that the body needs to detoxify.

2. Ornithine helps the cycle continue. It combines with carbamoyl phosphate to form citrulline. Ornithine is regenerated later in the cycle, allowing it to participate again.

3. Aspartate supplies the second nitrogen atom of urea. In the cycle, citrulline combines with aspartate to form arginosuccinate. Through subsequent reactions, this contributes to the formation of arginine, which is then broken down to produce urea and regenerate ornithine.

4. Urea is eliminated. It enters the bloodstream, travels to the kidneys, and is excreted in urine.

Pathway 2: Glutamine synthesis (in Liver, muscle and other tissues)

What is glutamine?

Glutamine is an amino acid that can safely carry nitrogen between tissues. The body produces it by combining glutamate with ammonia.

In simplified form:

Glutamate +
Ammonia = Glutamine

This reaction is catalysed by an enzyme called glutamine synthetase. when ammonia combines with glutamate, the nitrogen of ammonia becomes part of the glutamine molecule.

 One important detail: glutamine can carry two nitrogen atoms—one in its amino group and another in its amide group. The nitrogen captured directly from ammonia is the amide nitrogen in this reaction.

Transport of Glutamine through blood: Glutamine enters the bloodstream and carries its nitrogen from the tissues such as muscle, that may have come from ammonia produced in the tissues, to the organs including the liver and kidneys.

 How does glutamine release and utilize at various destination:

• Liver: Glutamine can release ammonia, which the urea cycle converts into urea for excretion in the urine.
• Kidneys: Glutamine breakdown produces ammonium ion, which is excreted in the urine, helping regulate acid–base balance.
• Other tissues: Glutamine can also be used to make proteins and other
  molecules, or broken down for energy; its nitrogen may be reused in metabolism.

The most important point to be noted here is that glutamine is not the final elimination product like urea, it has different fates depending upon the site where it goes.

What is the Role of LOLA in Glutamine synthesis:

LOLA (L-ornithine-L-aspartate) supports the removal of excess ammonia throughout the body by promoting its incorporation into glutamine, particularly in muscle and other tissues

• ·      Ornithine-derived glutamate: Ornithine can be converted through metabolic reactions into glutamate, which serves as a substrate for glutamine synthesis.
• Aspartate-derived glutamate: Aspartate can contribute to metabolic pathways that produce glutamate, which can then be used to synthesise glutamine.

🩺This path is particularly important when the liver’s normal ammonia processing capacity is impaired.

🩺The key difference is that the urea cycle converts ammonia into a waste product for excretion, whereas glutamine synthesis captures ammonia by incorporating it into an amino acid.

🩺The important point: LOLA supports the body’s existing ammonia-removal machinery; it does not simply bind ammonia directly and carry it out of the body.

What are the Therapeutic Indications of LOLA (HEPA-MERZ®):

Through the mechanism that is described above, it is evident that LOLA is effective in the treatment of hyperammonaemia (increased level of ammonia) and the neurological disturbances (hepatic encephalopathy) related to the liver diseases such as Cirrhosis, Hepatitis, & fatty liver etc.

Betaine Glucuronate + Diethanolamine Glucuronate+ nicotinamide ascorbate (JETEPAR®):

JETEPAR® is a drug with specific detoxifying activity, attributed to its ingredients: betaine glucuronate, diethanolamine glucuronate (glucodiamine), and nicotinamide ascorbate.

What is Betaine Glucuronate?

Before moving toward betaine glucuronate, let’s first unlock the mystery of Betaine

What is Betaine?

·       Betaine is a stable and nontoxic natural substance. Because it looks like a glycine with three extra methyl groups, betaine is also called trimethyl glycine

·       First identified in Beta vulgaris, later found in significant concentrations in wheat bran, wheat germ, spinach, beets (beetroot), microorganisms, and aquatic invertebrates.

·       Betaine is safe at a daily intake of 9–15 g for human and distributes primarily to the kidneys, liver, and brain. Besides, dietary intake, betaine can be synthesized from choline in the body

 What is the biological role of betaine?

Betaine primarily act as methyl donor and Osmoprotectant, having significant anti-inflammatory properties as well.

1. Major Role: As Methyl Donor in liver Metabolism

·       Betaine is a vital methyl group donor in the transmethylation reaction occurring primarily in liver and kidney, a process catalysed by the BHMT (betaine-homocysteine methyltransferase). This reaction involves the conversion of homocysteine to methionine which is then transformed into S-adenosine methionine (also known as SAM or AdoMet or SAMe)

🩺SAM a.k.a AdoMet is the second most widely used enzyme substrate after ATP. AdoMet donates its methyl group to a large variety of acceptors including nucleic acids (DNA), proteins and lipids. Too little and too much of the molecule SAMe (S-adenosylmethionine) can cause fatty liver disease (steatosis), but they do it through completely opposite chain reactions.

In addition, Researches on betaine have shown that it reverses the dysregulated expression of genes involved in triglyceride metabolism and alleviates hepatic steatosis by altering the DNA methylation level in the genome and specific gene promoter in high-fat fed mice.

·       Due to the ability of betaine to reduce homocysteine, it is often considered for the treatment of homocystinuria to decrease elevated homocysteine blood levels.