Advantages of Orally Administered N-Acetylcysteine as an Effervescent Tablet

Abstract

PharmaNAC® is an effervescent formulation of N- acetylcysteine (NAC) manufactured according to the standards of the Pharmacopoeia of both the United States and Europe. The manufacturing process, packaging and mode of administration as a liquid make PharmaNAC® the source of NAC with the purity, stability, pharmacokinetics, bioavailability, palatability and gastrointestinal compatibility to provide for best patient compliance. Oral administration of NAC is superior to both inhalation using a nebulizer and intravenous administration. Treatment of glutathione deficiency with NAC is superior to treatment with methionine or direct treatment with glutathione.

Background: Use and advantages of N- acetylcysteine for oral administration

BioAdvantex Pharma's PharmaNAC® is an effervescent formulation of n-acetylcysteine (NAC) for oral administration. NAC is an acetylated form of the amino acid cysteine. NAC is used as mucolytic agent (1, 2), as a source of cysteine for synthesis of the antioxidant glutathione (3, 4) and as a source of cystine for the modulation of glutamate in glutamatergic signaling pathways (5-7) in the central nervous system. Clinically, NAC is used for mucus clearance in respiratory illness (1, 2) and control of oxidative stress in acetaminophen toxicity (3). NAC is also being studied for use in the control of oxidative stress in metabolic conditions including infertility (8-10), treatment of psychiatric disorders (5-7), management of addictions (11-14), control of obsessive- compulsive and self-injury behaviors (15- 17) and autism (18). High quality preparations of NAC used in clinical trials have a long history of safety with minimal side effects (1-21).

Availability of cysteine for glutathione synthesis; a role for orally administered NAC

The synthesis of glutathione requires the amino acid cysteine, an essential amino acid that humans cannot synthesize de novo. Cysteine is obtained from dietary protein. However, as a rare amino acid, dietary cysteine is available in limited amounts which may not be adequate in situations of oxidative stress. Cysteine can also be obtained by the conversion of the essential amino acid methionine in a biochemical process called sparing. However, like cysteine itself, methionine must also be obtained from the diet and it is also available in limited amounts. For sparing to function efficiently, sufficient reserves of methionine must be available for both the methionine requirement and the cysteine requirement, which is not the case in glutathione deficiency. Oral administration of NAC is an efficient and easy way to supplement cysteine levels to support glutathione synthesis.

Advantages of administration of oral NAC relative to glutathione

Oral administration of NAC is superior to the administration of glutathione for increasing levels of glutathione in the blood and tissues. In fact, NAC is absorbed in the gut and used by target tissues more efficiently than direct oral administration of glutathione (22, 23). Raising levels of glutathione by direct administration of glutathione is not effective due to its poor bioavailability (absorption and distribution to tissues) (24). It has been shown that administration of a daily dose of 3 grams of glutathione does not result in a clinically significant increase in systemic glutathione (24), whereas a daily dose of less than 2 grams of NAC provides a clinically effective increase of glutathione (3, 4).

With regard to therapy for the central nervous system (CNS), the limited amounts of orally administered glutathione that do become circulating are not able to cross the blood-brain barrier (6, 25) whereas NAC does. This property makes treatment with NAC effective for oxidative stress conditions associated with the CNS.

Advantages of oral NAC relative to intravenous or nebulized administration

Oral administration of NAC functions more efficiently as precursor to cysteine than the sparing process involving the administration of methionine (26).

Oral administration of NAC is as effective and is safer than intravenous administration of NAC. The risks and dosage problems associated with the intravenous administration of NAC which have been clearly documented in the medical literature (4, 5, 27) include anaphylactic reactions, hypotension and bronchospasms (28, 29) and, in case of intravenous overdose, seizures (30).

Analysis of published data shows that administration of NAC by inhalation using a nebulizer is not more effective than oral administration for clearing mucus in cystic fibrosis (31). Furthermore, NAC administered using nebulizer can result in an increase in oxidative stress as measured in the respiratory system (32), a result that is opposite the intended therapy and a cause of irritation of respiratory tissues (33). These clinical results make oral administration of NAC the method of choice when ease of use, expense and equipment needs are considered.