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N- acetylcysteine in Clinical Practice.

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Presentation on theme: "N- acetylcysteine in Clinical Practice."— Presentation transcript:

1 N- acetylcysteine in Clinical Practice.
BioMedica Nutraceuticals UK Ltd, March 2015. Presented by Tanya Kwiez (MSc- Human Nutrition, MICD, BHSc, Adv Dip ND.)

2 Discussion overview The clinical significance of the acetylated form of cysteine and major biological pathways of NAC activity. BioFilms and the significance of biofilm forming organisms in persistent infections. The primary therapeutic actions of NAC and the vast amount of patient cases we can apply it in. Chronic respiratory conditions, H-pylori, fertility, CVD, neuropsychiatry, mental health impact.

3 The N-acetylcysteine molecule (C5H9NO3S)

4 NAC significance in so many varying conditions
Oral glutathione undergoes digestion. Cysteine rapidly oxidised. Disulphide bonds- NACs sulfhydryl group reacts to split disulphide bridges in proteins. Metal ion complexes (a complex ion has a metal ion centre with molecules/ions surrounding it – ligands.) GSH has a high metal ion binding affinity. Toxic metals- arsenic, cadmium, lead and mercury contribute to chronic diseases. Enhancing natural chelation through NAC: As an orally available pre- cursor to cysteine it chelates toxic elements and stimulates GSH, especially when Vitamins C and E present.

5 NAC cellular potential
Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther Feb;141(2):150-9.

6 Metabolism of NAC (Ercal & Gurer-Orhan, 2002.)
Oral NAC administration (rapid absorption) Extensive first-pass metabolism in liver and intestine LIVER INTESTINE 3% of NAC excreted in feces

7 NAC the antioxidant Most famous clinical use of NAC is for acetaminophen poisoning (Tylenol.) Acetaminophen liver metabolism after digestion- metabolite N-acetyl benzoquinoneimine (hepatic glutathione pool depleted.) NAC administration actions replenish GSH levels (Moldeus & Cotgreave, 1994.) Many antioxidants in the body. What distinguishes Glutathione (GSH) from others? Regeneration. Extracellular action to reduce cystine to cysteine which allows transportation into the cell at 10 times faster rate than cystine. Also further use into GSH (Moldeus & Cotgreave, 1994.) Glutathione- capacity to regenerate itself. Glutathione- involved in the regeneration of Vitamin C as well.

8 Reduced ligand & receptor affinities e.g. cytokines, angiotensin II*
NMDA modulation Detoxification Antioxidant Enzyme cofactor Immune modulation Anti-clotting Antioxidant Anti-mutagenic & anti-neoplastic Mucolytic Reduced ligand & receptor affinities e.g. cytokines, angiotensin II* Biofilm disruption Antiox. Anti-mutagenic & anti-neoplastic Chelation Samuni Y, Goldstein S, Dean OM, Berk M.The chemistry and biological activities of N-acetylcysteine.Biochim Biophys Acta Aug;1830(8):

9 NAC in action Cysteine precursor for GSH synthesis.
Enzyme co-factor, antioxidant and immune modulation. Anticlotting, anti mutagenic and anti neoplastic. Mucolytic, biofilm disruption and reduced ligand and receptor affinities; eg- cytokines, angiotensin II.

10 NAC in action Anti-inflammatory- ↓ TNFα, IL-1β, IL-6, IL-10 & suppressed microglial activation (Sumani et al 2013) Glutaminergic modulation (Sumani et al 2013) Insulin sensitising in PCOS (Riskz et al 2005) Anti-androgenic in PCOS (Fulghesu et al 2002, Riskz et al 2005) Anti-apoptic (in vitro)

11 NAC bioavailability Relatively low bioavailability from oral dosing -safety significance %: Rapid deacetylation in the intestinal mucosa and first pass liver metabolism. Powerful, safe and effective nutrient (High bioavailability isnt necessary for effective, potent clinical effect. 4-10%- shows how powerful what is absorbed actually is!) Pharmaceutically availability via oral, IV or inhalation (some trials have shown associated risks with IV/ inhalation methods.) Peak plasma levels at 5- 6 hours orally. Take home message- High bioavailability , large doses not usually needed and very safe tolerated oral use.

12 Clinical Insights- Chronic Respiratory Conditions
NAC the mucolytic. NAC is also referred as “the slime loosener”. NAC breaks down mucous into smaller, less viscous units. Mucolytic actions: Disruption to the biofilms of persistent infections. Reduction of mucous and viscosity (sulfhydryl group of NAC reacts to split disulfide bonds within bronchial mucous secretions. Improved endoscopy/bronchoscopy visibility. Fertility- improved ovulation in PCOS, reduced semen viscosity.

13 Chronic Respiratory Conditions
“Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory lung diseases that are characterised by systemic and chronic localized inflammation and oxidative stress.” (Kirkham and Rahman, 2006.) COPD: Numerous clinical trials with NAC. Asthma- Small, single blinded study using 600mg bid NAC with corticosteroids in patients discharged from hospital following asthmatic exacerbation- failed to demonstrate a superior effect (Alivali et al, 2010.) General consensus- COPD patients benefit: particularly patients with moderate- severe forms taking 600mg bid (2x daily) for up to 12 months to prevent exacerbation. (De Backer et al 2013, Rushworth & Megson 2014, Zheng et al 2014.)

14 Chronic Respiratory Conditions
Chronic Bronchitis: Positive systematic review found mg/day for 3-6 months significantly reduced exacerbations and decreased symptoms. Cystic Fibrosis: At lower doses (700mg/day) NAC acts as a mucolytic and general anti-inflammatory. At higher doses ( mg TID for 1-3 months) increased neutrophil GSH content, reduction in neutrophil influx in CF airways, sputum elastase activity and sputum IL-8 levels (attributed to decreased airway inflammation.) Inhibited MPO- significantly decreased lower respiratory airway oxidative stress. (Vasu et al 2011, Rushworth & Megson 2014.)

15 BioFilms “Formation of biofilm is a survival strategy for bacteria and fungi to adapt to their living environment, especially in the hostile environment. Under the protection of biofilm, microbial cells in biofilm become tolerant and resistant to antibiotics and the immune responses, which increases the difficulties for the clinical treatment of biofilm infections.” (Wu et al, 2014.) “Lung infection is the main cause of morbidity and mortality in patients with cystic fibrosis and is mainly dominated by Pseudomonas aeruginosa. The biofilm mode of growth makes eradication of the infection impossible, and it causes a chronic inflammation in the airways.” (Ciofu et al, 2014.)

16 Biofilms A self-produced matrix composed of extracellular polymeric substances including polysaccharides, DNA, proteins and lipids that alter the surface properties of the bacteria themselves to both promote and prevent initial attachment to a surface or cell aggregation Biofilms usually house multiple strains of single species as well as being often polymicrobial Both the matrix & the diverse strains enhance antimicrobial resistance

17 Biofilm for