Complementary Medicines 2 2021 PDF

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Complementary Medicines 2 PCOL2605/NURS2005 Dr Brooke Storey-Lewis School of Pharmacy Adapted from lectures written and presented by Prof. Peter Carroll (2017) COMMONWEALTH OF AUSTRALIA Copyright Regulation WARNING This material has been reproduced and communicated to you by or on behalf of the University of Sydney pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice

Learning Objectives 1. Describe the efficacy and possible mechanism of action of St John’s wort in depression 2. Describe how St John’s wort may produce drug-interactions 3. Understand the physiological role of co-enzyme Q10 4. Describe the effects of statins on co-enzyme Q10 5. Discuss the evidence for using co-enzyme Q10 in patients taking statins 6. Discuss the efficacy of Ginkgo biloba in the treatment and prevention of dementia 7. Describe how Ginkgo biloba may interact with NSAIDs and warfarin The University of Sydney

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St John’s Wort (Hypericum perforatum)

The University of Sydney

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St John’s Wort (SJW) Ancient Greece – Diuretic – Wound-healing – Menstrual disorders – Intestinal worms and snakebites – Mystical qualities, protection from demons The University of Sydney

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St John’s Wort (SJW) Ancient Greece – “Hypericum” thought to originate from Greek name Hyperikon – Hyper = over, eikon = image/apparition – Ward off evil spirits?

Early Christians – Greatest effect when harvested on Saint John’s Day (June 24) – Released blood red oil on the day of St. John’s beheading The University of Sydney

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St John’s Wort (SJW) Middle Ages – Herbalists recommend SJW to treat wounds and alleviate pain – 1525 Paracelsus (remember him?) recommends for treatment of depression, melancholy, over-excitation – Use spread from Europe to other continents in 18th-19th C – Teas, tinctures, oil preparations The University of Sydney

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St John’s Wort (SJW) Today – “relieve nervousness, mild anxiety and irritability” – “benefit during times of sadness” – “promote healthy mood balance” – “support healthy mood balance” – “relieves stress and mild anxiety” – “relief of sleeplessness” – “mood support” The University of Sydney

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St John’s Wort (SJW) – Efficacy in Depression? Cochrane review Linde et al., Cochrane Database of Systematic Reviews, 2008 (4) Method: –

Database search and analysis of randomised and double-blind trials which compared St John’s wort with placebo or standard antidepressants in patients with mild to severe depression

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USA, Canada, UK, Europe

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29 trials (5489 patients)

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SSRIs: Fluoxetine, sertraline, citalopram, paroxetine; TCAs: maprotiline, amitriptyline, imipramine

The University of Sydney

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St John’s Wort (SJW) – Efficacy in Depression? Cochrane review Linde et al., Cochrane Database of Systematic Reviews, 2008 (4) Results/Conclusions: –

Hypericum extract* is superior to placebo in patients with major depression

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Hypericum extract is similarly effective as standard antidepressants

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Hypericum extract has less side effects than standard antidepressants

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But.. bias?

*Hypericum extract just refers to a SJW extract; Hypericum is the genus name The University of Sydney

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What’s in it?

https://www.mountainherbalism.com/index.php/20 17/11/09/making-hypericum-tincture-2/ The University of Sydney

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St John’s Wort (SJW) How does it work? (Basic & Clinical Pharmacology, Ch. 64) – Hypericin initially reported to have MAO-A and –B inhibitor properties – not at recommended doses

– In-vitro studies using commercial extracts have shown: – Na uptake inhibition – 5-HT uptake inhibition – DA uptake inhibition

– Separate it out  Uptake inhibition shown with hyperforin isolates

The University of Sydney

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St John’s Wort (SJW) Are two preparations of St John’s wort the same? – Products are standardised according to the amount of hypericin derivatives – .. But now we think it’s the hyperforin that has anti-depressant effects

– If someone is taking SJW and finds it effective, recommend that they keep taking the same brand The University of Sydney

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St John’s Wort (SJW) – Blackmores St John's Wort (tab) - Hypericum perforatum (St John's wort) extract equiv. dry flowering herb top 1.8 g (standardised hypericin derivatives 990 mcg) – Ethical Nutrients Clinical Strength St John's Wort (cap) Hypericum perforatum herb dry 1.35 g (equiv. hypericin 900 mcg)

The University of Sydney

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St John’s Wort (SJW) What are the risks? – Induces CYP3A4 – and to a lesser extent, CYP1A2 and CYP2C9

– Induces p-glycoprotein

Alter plasma concentrations of other drugs, affect absorption/elimination

– Serotonin syndrome/toxicity – https://amhonline.amh.net.au/interactions/tables The University of Sydney

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SJW Take home messages – Shown to be efficacious in treating depression – Potential to cause drug-interactions – Pharmacokinetic (CYP induction/p-glycoprotein induction) – Pharmacodynamic (serotonin syndrome)

– Patients should be counseled on this risk The University of Sydney

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https://www.tga.gov.au/alert/stjohns-wort-information-sheethealth-care-professionals

The University of Sydney

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Co-enzyme Q10 (CoQ10) aka ubiquinone, ubiquinol, ubidecarenone

10 The University of Sydney

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CoQ10 – Vital component for energy production within the cell – Ubiquitous (‘ubiquinone’) – Supports ATP production in the mitochondria

– Synthesised from tyrosine – Fat soluble anti-oxidant – Structure similar to vitamin K The University of Sydney

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CoQ10 – Heart failure

– Cardiac surgery

– Use with statins

– Parkinson’s disease

– Hypertension

– Stamina/muscle strength

– Angina

– Anti-oxidant

– Migraine

– Anti-cancer

– Improved circulation

– General wellbeing

The University of Sydney

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CoQ10 and statins – Statin therapy can lower serum levels of CoQ10 – Side chain of CoQ10 is synthesised from acetoacetyl CoA through the mevalonate pathway, and involves the enzyme HMG-CoA reductase – Majority of serum CoQ10 is carried on LDL cholesterol

The University of Sydney

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CoQ10 and statins

The University of Sydney

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Benzoquinone group synthesised from tyrosine 1

2

3…

10

The University of Sydney

Isoprenoid subunits in side chain synthesised from acetoacetyl co-enzyme A via HMG-CoA reductase

Inhibited by statins Page 64

CoQ10 and statins – Statins may produce muscle symptoms e.g. pain, weakness, tenderness etc – Important that any muscle symptoms are investigated –  muscle damage and rhabdomyolysis

– Measure creatine kinase (CK) levels The University of Sydney

Abd TT & Jacobson TA (2011). Expert Opin. Drug Saf. 10, 373-387

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CoQ10 and statins – Mechanisms by which statins produce muscle symptoms unclear – Suggestion that muscle symptoms may be due to reduced CoQ10 – Conflicting results in trials investigating CoQ10 in treating muscle symptoms – 2015 meta-analysis concluded no significant benefit 100 mg - 400 mg/day – Later study with 600 mg/day  no benefit – 2018 meta-analysis amelioration of statin-associated muscle symptoms The University of Sydney https://www.nps.org.au/news/can-co-enzyme-q10-supplementation-prevent-or-treat-statin-associated-muscle-symptoms Page 66

Qu et al 2018 J Am Heart Assoc. 7(19): e009835

CoQ10 and statins Benign statin-induced myalgia – Reduce the statin dose – Switch to another statin – Switch to alternative therapy – Trial of CoQ10 ($$$, exercise caution with co-admin of anticoagulants)

The University of Sydney

https://www.nps.org.au/news/can-co-enzyme-q10-supplementation-prevent-or-treatstatin-associated-muscle-symptoms

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CoQ10 and warfarin – Reports of decrease in INR following co-admin warfarin & CoQ10 – Structure similar to vitamin K, pro-coagulant effect – Can use warfarin and CoQ10 together, monitor INR

CoQ10 The University of Sydney

10

K2

https://www.nps.org.au/news/can-co-enzyme-q10-supplementation-prevent-or-treatstatin-associated-muscle-symptoms Am. J. Health-Syst Pharm 2000, 57, 1223

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CoQ10 statins and heart failure – Statins lower serum CoQ10 – Heart contains high concentrations of CoQ10 (energy production etc) – Claims that statin therapy may precipitate heart failure – Statins do not change cardiac parameters – Large trials show no increase in heart failure (some decrease) – CoQ10 supplementation in HF patients not necessary The University of Sydney

JAMA 2006, 296, 2105-2111

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CoQ10 – Doses generally in the range 100-300 mg/day, though trials have used higher doses – Better absorbed orally when: – Taken with a fatty meal – Mixed with oil in capsules

Bioequivalence? Some on the market in oil, some not

– Generally well tolerated The University of Sydney

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Ginkgo biloba

The University of Sydney

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Ginkgo biloba – Extract prepared from leaves of the Ginkgo tree – One of the oldest living tree species – 200 mya – Trees have life expectancy of 1000 years – Contains many different compounds – Flavone glycosides – Terpenes The University of Sydney

Ginkgo biloba Claimed actions – Inhibition of platelet aggregation – Vasodilation and improvement in cerebral and peripheral blood flow – Anti-oxidant, free radical scavenger – Anti-inflammatory – Enhance cognitive function The University of Sydney

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Ginkgo biloba Products containing Ginkgo biloba often claimed to: – Improve and enhance memory – Aid mental alertness and reduce mental fatigue – Enhance cognitive function and improve learning

The University of Sydney

https://www.naturesway.com.au/nature-s-way-high-strength-gingko-biloba-100s

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Ginkgo biloba in dementia – Some trials have claimed it is efficacious in improving cognitive function and treating dementia – Placebo-controlled trial in 309 patients taking 120 mg of EGb 761 daily for a year showed small benefit on cognitive function – Another reported that Ginkgo appears more effective than placebo in the treatment of dementia

The University of Sydney

LeBars PL et al, (1997) JAMA, 278(16), 1327-1332 Weinmann et al. BMC Geriatrics 2010, 10:14 http://www.biomedcentral.com/1471-2318/10/14

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Ginkgo biloba in dementia Randomised, double blind, placebo controlled trials, published in peer reviewed international journals, plus a Cochrane review in 2009, do not support the efficacy of Ginkgo biloba in the treatment or prevention of dementia. Birks J & Grimley EJ, Cochrane Data Base of Systemic Reviews, 2009(1), CD003120 DeKosky ST et al, (2008) JAMA 300(19), 2253-2262 Dodge HH et al, (2008) Neurology 70, 1809-1817 Snitz BE et al, (2009) JAMA 302(24), 2663-2670 Solomon PR et al, (2002) JAMA 288(7), 835-840 The University of Sydney

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Meta-analysis of 9 placebocontrolled trials 2561 patients 22-26 weeks duration Stricter inclusion criteria vs. Cochrane “overall benefits for EGb761 or stabillising or slowing decline in cognition, function, behaviour and clinical global change of patients with dementia and cognitive impairment” Critically analyse available evidence The University of Sydney

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Ginkgo biloba – Generally well-tolerated – GI disturbance, headache, dizziness, allergic reactions – Inhibition of platelet aggregation may increase bleeding potential – Stop one week prior to surgery – Potential interactions – antiplatelets/anticoagulants – e.g. aspirin and warfarin, can cause haemorrhage – OTC NSAIDs The University of Sydney

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Ginkgo biloba Bioequivalence? – Natural Health Products Tebonin - Ginko biloba (ginko) equiv. dry leaf 6 g, standardised to bilobalide 3.5 mg and ginkgolides 3.7 mg – Blackmores Ginkgoforte - Ginkgo biloba extract equiv. dry leaf 2 g (standardised ginkgo flavonglycosides 10.7 mg, ginkgolides and bilobalide 2.7 mg) – Herbal Ginkgo Biloba - Ginkgo biloba extract equiv. dry leaf 2 g (equiv. 9.6 mg ginkgo flavonglycosides, 1.6 mg ginkgolides and bilobalide)

If its working, continue taking the same brand The University of Sydney

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