STIMOL 1 G / 10 ML ORAL SOLUTION

Indications

• Maintenance treatment of hyperammonaemia due to urea cycle disorders
• Support for energy levels
• Stimulation of the immune system
• Detoxification of ammonia

Dosage

Children: For neonates and children, initial dosing is typically 12.5 mg/kg 4 times a day, adjusted according to response, with a maximum of up to 200 mg/kg daily. It is recommended

Adults: Refer to the BNF for specific dosing guidelines, as they may vary based on clinical scenarios and individual patient response.

Mechanism of action

L-citrulline is converted to L-arginine by argininosuccinate synthase. L-arginine is responsible for mediating the therapeutic effects of citrulline, particularly its role as a precursor to nitric oxide (NO). NO is produced by nitric oxide synthase (NOS) from L-arginine, which subsequently activates guanylate cyclase to form cyclic GMP, mediating various physiological effects.

Pharmacodynamics

Citrulline is a precursor of arginine, enhancing nitric oxide synthesis, which has cardiovascular benefits, including vasodilation and improved blood flow. It is not directly involved in protein synthesis but contributes to metabolic processes and detoxification of ammonia, a toxic by-product of amino acid metabolism. Citrulline may also promote energy levels and support immune response.

Pharmacokinetics

Citrulline is absorbed in the gastrointestinal tract and is converted to arginine in the kidneys and other tissues. The bioavailability of citrulline is higher than that of arginine when taken as a supplement. Following absorption, it enters systemic circulation where it can exert its effects or be converted to arginine. The half-life of citrulline is relatively short; hence, multiple doses may be necessary for sustained effects.

Adverse effects

• Hyperhidrosis
• Bradycardia
• Diarrhoea
• Fever
• Vomiting
• Hyperglycinaemia
• Rash

Precautions

• Caution in conditions involving sodium retention with oedema
• Caution in congestive heart failure
• Caution in neonates due to risk of kernicterus and increased side-effects

Pregnancy

Manufacturer advises to avoid unless essential, as no information available.

Breast-feeding

Manufacturer advises to avoid, as it is present in milk in animal studies.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Dispersible tablets
• Oral solution
• Powder
• Solution for infusion

Indications

• Support in energy metabolism
• Management of metabolic disorders
• Potential role in exercise performance enhancement

Dosage

Children: Refer to specific guidance in the BNF for Children.

Adults: Refer to specific guidance in the BNF.

Mechanism of action

Malate participates in the malate-aspartate shuttle, which is essential for transferring reducing equivalents across the mitochondrial membrane. This shuttle allows for the conversion of NADH produced during glycolysis to NADH within the mitochondria, thus facilitating ATP production. Additionally, malate is involved in gluconeogenesis, where it contributes to the synthesis of glucose from non-carbohydrate precursors.

Pharmacodynamics

Malate aids in energy metabolism, particularly in the conversion of nutrients to ATP. It supports the regeneration of NAD+, which is crucial for numerous metabolic reactions. By participating in the TCA cycle, malate enhances aerobic respiration and plays a role in maintaining the balance of metabolic intermediates necessary for cellular function.

Pharmacokinetics

Malate is readily absorbed in the gastrointestinal tract and is distributed throughout the body, where it enters various metabolic pathways. It is primarily metabolized in the liver and muscle tissues. The elimination of malate is through metabolic conversion, with its metabolites being further processed in the TCA cycle.

Pregnancy

There are no well-controlled studies of malate in pregnant women. Use only if clearly needed.

Breast-feeding

Malate is considered to be safe during breastfeeding, though limited data are available.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Malate salts
• Malic acid

Mechanism of action

L-citrulline is converted to L-arginine by argininosuccinate synthase. L-arginine is in turn responsible for citrulline's therapeutic affects. Many of L-arginine's activities, including its possible anti-atherogenic actions, may be accounted for by its role as the precursor to nitric oxide or NO. NO is produced by all tissues of the body and plays very important roles in the cardiovascular system, immune system and nervous system. NO is formed from L-arginine via the enzyme nitric oxide synthase or synthetase (NOS), and the effects of NO are mainly mediated by 3',5' -cyclic guanylate or cyclic GMP. NO activates the enzyme guanylate cyclase, which catalyzes the synthesis of cyclic GMP from guanosine triphosphate or GTP. Cyclic GMP is converted to guanylic acid via the enzyme cyclic GMP phosphodiesterase. NOS is a heme-containing enzyme with some sequences similar to cytochrome P-450 reductase. Several isoforms of NOS exist, two of which are constitutive and one of which is inducible by immunological stimuli. The constitutive NOS found in the vascular endothelium is designated eNOS and that present in the brain, spinal cord and peripheral nervous system is designated nNOS. The form of NOS induced by immunological or inflammatory stimuli is known as iNOS. iNOS may be expressed constitutively in select tissues such as lung epithelium. All the nitric oxide synthases use NADPH (reduced nicotinamide adenine dinucleotide phosphate) and oxygen (O₂) as cosubstrates, as well as the cofactors FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), tetrahydrobiopterin and heme. Interestingly, ascorbic acid appears to enhance NOS activity by increasing intracellular tetrahydrobiopterin. eNOS and nNOS synthesize NO in response to an increased concentration of calcium ions or in some cases in response to calcium-independent stimuli, such as shear stress. _In vitro_ studies of NOS indicate that the Km of the enzyme for L-arginine is in the micromolar range. The concentration of L-arginine in endothelial cells, as well as in other cells, and in plasma is in the millimolar range. What this means is that, under physiological conditions, NOS is saturated with its L-arginine substrate. In other words, L-arginine would not be expected to be rate-limiting for the enzyme, and it would not appear that supraphysiological levels of L-arginine which could occur with oral supplementation of the amino acid would make any difference with regard to NO production. The reaction would appear to have reached its maximum level. However, _in vivo_ studies have demonstrated that, under certain conditions, e.g. hypercholesterolemia, L-arginine could enhance endothelial-dependent vasodilation and NO production.

Pharmacodynamics

A non-essential amino acid and a precursor of arginine. Citrulline supplements have been claimed to promote energy levels, stimulate the immune system and help detoxify ammonia (a cell toxin). L-citrulline is made from L-ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from L-arginine as a by-product of the reaction catalyzed by the enzyme NO synthase. L-citrulline, while being an amino acid, is not involved in protein synthesis and is not one of the amino acids coded for by DNA. Although citrulline cannot be incorporated in proteins during protein synthesis, several proteins are known to contain citrulline as an amino acid. These citrulline residues are generated by a family of enzymes called peptidylarginine deiminases (PADs), which convert the amino acid arginine into citrulline. Proteins that contain citrulline residues include myelin basic protein (MBP), fillagrin and several histone proteins.