Transcript ncn-talks-clinical-tanya-kwiez-N-Acetyl-Cysteine-in

BioMedica Nutraceuticals UK Ltd, March 2015.
Presented by Tanya Kwiez (MSc- Human Nutrition,
MICD, BHSc, Adv Dip ND.)
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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.
2
OH
C
CH2
CH
SH
O
NH
C
CH3
O
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Oral glutathione undergoes digestion.
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Cysteine rapidly oxidised.
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Disulphide bonds- NACs sulfhydryl group reacts to
split disulphide bridges in proteins.
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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 precursor to cysteine it chelates toxic elements and
stimulates GSH, especially when Vitamins C and E
present.
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Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for
conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014 Feb;141(2):150-9.
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Oral NAC
administration (rapid
absorption)
Extensive first-pass metabolism
in
liver and intestine
deacetylation
LIVER
cysteine
NAC
INTESTINE
+
glutamate
glutamate-cysteine ligase
GSH
3% of NAC
excreted in
feces
GSH
synthase
glycine
+
Glutamylcystein
ee
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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.)
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Glutathione- capacity to regenerate itself.
Glutathione- involved in the regeneration of Vitamin
C as well.
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•Antioxidant
•Enzyme cofactor
•Immune modulation
•Mucolytic
•Reduced
ligand &
receptor
affinities e.g.
cytokines,
angiotensin
II*
•Biofilm
disruption
•NMDA modulation
•Detoxification •Anti-clotting
•Chelation
•Antioxidant
•Anti-mutagenic
& anti-neoplastic
•Antiox.
•Antimutagenic
& antineoplastic
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Cysteine precursor for GSH synthesis.
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Enzyme co-factor, antioxidant and immune
modulation.
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Anticlotting, anti mutagenic and anti
neoplastic.
Mucolytic, biofilm disruption and reduced
ligand and receptor affinities; eg- cytokines,
angiotensin II.
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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)
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Anti-apoptic (in vitro)
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Relatively low bioavailability from oral dosing -safety
significance. 4-10-%: 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!)
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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.
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NAC the mucolytic. NAC is also referred as “the slime
loosener”. NAC breaks down mucous into smaller,
less viscous units.
Mucolytic actions:
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Disruption to the biofilms of persistent infections.
2.
Reduction of mucous and viscosity (sulfhydryl
group of NAC reacts to split disulfide bonds within
bronchial mucous secretions.
3.
Improved endoscopy/bronchoscopy visibility.
4.
Fertility- improved ovulation in PCOS, reduced
semen viscosity.
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“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.)
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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.)
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Chronic Bronchitis: Positive systematic review found
400- 600mg/day for 3-6 months significantly
reduced exacerbations and decreased symptoms.
Cystic Fibrosis:
1.
At lower doses (700mg/day) NAC acts as a
mucolytic and general anti-inflammatory.
2.
At higher doses (600- 1000mg 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.)
3.
Inhibited MPO- significantly decreased lower
respiratory airway oxidative stress. (Vasu et al 2011,
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Rushworth & Megson 2014.)
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“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.)
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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
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Use of either 600mg bid or 400mg bid tds
improves eradication rates from antibiotic
treatments for H.pylori.
Eradication rates were up to doubled in small
samples (Zala 1994, Gurbuz 2005.)
2010 study- 2 parts: 1. In vitro- Investigated
NACs effects on cultured H.pylori from patients
who had 4 failed eradication treatments. 2. Open
label clinical trial- 40 patients randomised to
receive antibiotics/PPI with or without NAC
600mg/day for 1 week prior to treatment
(Cammarota et al, 2010.)
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Antioxidant role is numerous- Neuropsych,
thyroid, IBD, mitochondria, CVD, fertility,
athletes.
Brain Antioxidants: NAC and vitamin C.
Thyroiditis: NAC and Se.
Hyperthyroidism: NAC, Se and vitamin E.
Mercury chelation: NAC, Se +/- Zn.
Superoxide elevation, long term oxidative
stress patients: NAC, SOD and vitamin C.
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2 RCTs confirm increased rates of ovulation
with 1-2g/day days 3-7 of menstrual cycle.
PCOS: Several trials have suggested reduced
IR and androgen levels in PCOS patients
treated for 5-6 weeks with 1.8- 3 g/day.
Increased rates of ovulation, endometrial
layer thickness and pregnancy when given
with Clomid (Clomiphene) in PCOS (Fulghesu et al,
2002, Badaway, Baker, El Nasher & El Totongy 2006, Millea 2009,
Rizk, Bedaiwy & Al-Inany 2005.)
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NAC studies often in combination with other
antioxidants to improve sperm parameters in men
Studies of NAC alone have administered 600mg/d
over 12-26wks which have increased sperm
motility, concentration & morphology
Other trials have found reduced viscosity which
may be a key treatment outcome
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Evidence of GSH depletion in blood vessels of
atherosclerotic animals and depleted platelet GSH
levels may contribute to over sensitivity to
thrombotic stimuli (Rushworth & Megson, 2014.)
Small RCT used combination of L-Arginine
(1.2g/day) and NAC (600 mg/day) for 6 months
reduced BP by ~5mmHg in T2DM patients with
HT (Martina et al, 2008.)
Homocysteine- Effects have been mixed however
Wiklund et al, 1996 reported up to a 45%
reduction with 2 grams/day over 2 weeks.
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Autism spectrum (Hardan et al, 2012,
Ghanizadeh & Moghimi-Sarani, 2013), small
pilot study found reduced symptoms
especially irritability.
ADHD (Garcia et al, 2013), Small study of
Lupus patients found patients with high
ADHD scores treated with either 2.4g/day or
4.8g/day for 3 months.
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Bipolar Disorder (Berk et al 2008, Magalhaes et al
2011, 2013.) 2g per day as an adjunct to stable
medication resulted in a dramatic effect sizes in
both manic episodes and depression.
Schizophrenia (Berk 2008, Lavoie et al 2008,
Farokina 2013.) 2 g per day as an adjunct to
stable medication: RCTs so far to date suggestive
of effect at reducing negative symptoms.
Significant QOL improvements. Sub-group
analyses revealed better results in late
presenters.
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Depression 2g per day.
New unpublished study cited by Professor
Berk suggests that greatest benefit seen at
the 6 month point of treatment.
Sub-group analyses suggest increased
efficacy in elderly patients rather than the
young.
Obsessive Compulsive Disorder (OCD).
Anxiety.
Addictions- Cannabis, cocaine, nicotine
studies.
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Remembering a little bit goes a long way.
Mucolytic: commonly 600mg- 1200mg/day
Antioxidant- commonly start on 600mg/day
plus accessory nutrients.
Mental Health- benefits observed with 2
g/day in most conditions.
Athletic performance studies have used
significantly higher doses.
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OCD, ADHD, Addictions and acute brain
injury- may benefit from higher dosage
4g/day. (Glutamate higher, higher oxidative
stress picture here.)
Generally extremely safe. Adverse effects
noted with IV and inhalation, not oral dosage.
“NAC has a long- established safety record in
adults and children, with FDA approval since
1963 (McClure et al, 2014.)
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“NAC is a safe, inexpensive, and well-tolerated
antioxidant with a well-defined mechanism of action.
Because of the highly favourable risk/benefit ratio and
the low rate of adverse events, physicians might
consider use of NAC in select patients to diminish
exacerbation of COPD symptoms; reduce the risk of
contrast-induced nephropathy; attenuate influenza
illness; decrease the rate of deterioration of pulmonary
function in idiopathic pulmonary fibrosis; and serve as
an adjunct to clomiphene in the treatment of infertility
in women with polycystic ovary syndrome.”
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Berk M, Malhi GS, Gray LJ, Dean OM, The promise of N-acetylcysteine in
neuropsychiatry. Trends Pharmacol Sci, 2013 Mar;34 (3): 167-177.
Rushworth CF, Megson IL, Existing and potential therapeutic uses for N-
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Ciofu O, Tolker- Nielson T, Ostrup Jensen P, Wang H & Hoiby N, 2014,
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acetylcysteine: the need for conversion to intracellular glutathione for
antioxidant benefits. Pharmacol Ther: 2014 Feb; 141 (2): 150-159.
Antimicrobial resistance, respiratory tract infections and role of biofilms
in lung infections in cystic fibrosis patients, Advanced Drug Delivery
Reviews, Elsevier.
Kirkham P & Rahman I, Oxidative stress in asthma and COPD:
Antioxidants as a therapeutic strategy, 2006, Pharmacology &
Therapeutics, Vol 111, Iss 2, pp. 476–494
Wu H, Moser C, Wang HZ, Hoiby N & Song ZJ, 2014, Strategies for
combating bacterial biofilm infections, International Journal of Oral
Science advance online publication 12 December 2014; doi:
10.1038/ijos.2014.65
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