Accumulated Evidence Behind Herbal Medicine - Recent Developments Kerry Bone Adjunct Associate Professor, University of New England Co-Founder and Director.

Accumulated Evidence Behind Herbal Medicine -

Recent Developments

Kerry BoneAdjunct Associate Professor, University of New EnglandCo-Founder and Director R & D, MediHerb

30 Years of Growing theEvidence Base

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Topics for Today

• Pelargonium and respiratory tract infections• Ginkgo and glaucoma - any benefits?• Ginkgo and increased bleeding - is it a

problem?• Olive leaf - does it have any clinical evidence?• Horsechestnut and chronic venous insufficiency• Chaste tree - is it really effective for PMS?• Andrographis - good for winter infections?• Saffron and depression - more than just an

expensive spice?• Are herbal extracts intelligent mixtures? 3

Pelargonium: What is It?

• The root of Pelargonium sidoides is a traditional South African herb with a long history of use for respiratory health problems

• It has become Europe’s largest selling herb for respiratory conditions (much greater sales than Echinacea)

• The therapeutic use of the root of Pelargonium sidoides was originally introduced into Europe in the early 20th century by Charles Stevens as a cure for tuberculosis (TB)

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Pelargonium: What is It?

• It was on the European market as the mysterious “umckaloabo” for decades until in the 1970s scientists began to unravel its botanical origins, key phytochemicals and clinical efficacy

• The herb contains in the root a variety of phytochemicals, including an essential oil, simple phenols, flavonoids, polyphenols and highly oxygenated coumarins

• Its pharmacology is not fully understood, but it is thought to have antibacterial, antiviral, expectorant and immune modulating activities

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Pelargonium for Acute Bronchitis

• Systematic review – 6 randomised trials – included 1647 patients

• Two trials involved children, 6-12 yrs and 6-18 yrs

• Most trials were good quality: Pelargonium was beneficial in the

treatment of acute bronchitis in all trials Meta-analysis for the 4 adult trials

indicated bronchitis scores were significantly reduced by day 7

• Dosage: 3 trials used tincture equivalent to approximately 0.4g/day dried herbAgbabiaka TB, Guo R, Ernst E. Pelargonium sidoides for acute bronchitis: a systematic review and meta-analysis. Phytomedicine 2008; 15: 378 6

Pelargonium for Acute RTIs• Cochrane review in 2008• Included 8 trials and excluded 4 because of

excessive risk of bias• “…may be effective in relieving symptoms in

acute bronchitis in adults andchildren, and sinusitis inadults.”

Timmer A, Günther J, Rücker G et al. Pelargonium sidoides extract for acute respiratory tract infections. Cochrane Database Syst Rev 2008; (3): CD006323 7

Ginkgo and Glaucoma• A US research team first speculated that Ginkgo

extract that might benefit glaucoma patients through improvement in ocular blood flow1

• A phase I crossover trial of Ginkgo with placebo control in 11 healthy volunteers found a significantly increased end diastolic velocity in the ophthalmic artery (baseline versus Ginkgo treatment; 6.5±0.5 versus 7.7±0.5 cm/sec, p=0.023), with no change seen in placebo

• Ginkgo did not alter arterial blood pressure, heart rate or intraocular pressure

1 Chung HS, Harris A, Kristinsson JK et al. Ginkgo biloba extract increases ocular blood flow velocity. J Ocul Pharmacol Ther 1999; 15(3): 233-240

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Ginkgo and Glaucoma• Significant improvements in visual field indices

but not intraocular pressures were recorded in a randomised, double blind, placebo-controlled trial involving patients with normal tension glaucoma (NTG). Patients received standardised Ginkgo extract (120 mg/day) for 4 weeks1

• Ginkgo extract (160 mg/day) for an average of 12.3 years slowed the progression of visual field damage (p<0.005 compared to baseline data) in patients with NTG in an observational study2

1 Quaranta L, Bettelli S, Uva MG et al. Effect of Ginkgo biloba extract on pre-existing visual field damage in normal tension glaucoma. Ophthalmology 2003; 110(2): 359-362

2 Lee J, Sohn SW, Kee C. Effect of Ginkgo biloba Extract on Visual Field Progression in Normal Tension Glaucoma. J Glaucoma 2012 [Epub ahead of print] 9

Ginkgo and Bleeding• A 2005 systematic review of case reports

concluded that the causality between Ginkgo intake and bleeding is unlikely1

• A systematic review of 8 randomised controlled trials, also published in 2005, concluded that the available evidence does not demonstrate that Ginkgo extract causes significant changes in blood coagulation parameters2

1 Ernst E, Canter PH, Coon JT. Does Ginkgo biloba increase the risk of bleeding? A systematic review of case reports. Perfusion 2005; 18(2): 52-56

2 Savovic J, Wider B, Ernst E. Effects of Ginkgo biloba on Blood Coagulation Parameters: A Systematic Review of Randomised Clinical Trials. Evid Based Integrative Med 2005; 2(3): 167-176

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Ginkgo and Bleeding• A 2008 review also sought to understand the

evidence for the impact of Ginkgo on haemostasis and the case reports of increased bleeding1

• None of the trials reviewed investigating Ginkgo’s impact on haemostasis demonstrated any convincing evidence for an effect

• The 21 case reports identified were of low quality. Not only was there variability in Ginkgo products, but also the documentation of key factors such as product name, standardisation and other potentially active ingredients were generally absent

1 Bone KM. Potential Interaction of Ginkgo biloba Leaf with Antiplatelet or AnticoagulantDrugs: What Does the Evidence Imply? Mol Nutr Food Res 2008; 52(7): 764-771 11

Ginkgo and Bleeding• The review concluded that, similar to most

medicinal herbs, the possibility of a rare idiosyncratic bleeding event due to Ginkgo use is very unlikely, but cannot be totally excluded1

• A 2011 systematic review and meta-analysis concluded that Ginkgoappeared to have littleimpact on haemostasis2

1 Bone KM. Potential Interaction of Ginkgo biloba Leaf with Antiplatelet or AnticoagulantDrugs: What Does the Evidence Imply? Mol Nutr Food Res 2008; 52(7): 764-771

2 Kellermann AJ, Kloft C. Is there a risk of bleeding associated with standardized Ginkgo biloba extract therapy? A systematic review and meta-analysis. Pharmacotherapy 2011; 31(5): 490-502

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Olive Leaf and Infections• Traditionally used to lower blood pressure

and to treat angina• Now has gained widespread popularity as a

herbal antibiotic and antiviral, even possibly with immune enhancing attributes

• Companies with olive-growing schemes have been quick to exploit this fad

• Where did this thinkingcome from and doesit have any clinicalevidence?

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Olive Leaf

• Olive leaf contains around 6% oleuropein and flavonoids as key constituents

• Oleuropein can be hydrolysed to produce elenolic acid and hydroxytyrosol. This will occur in liquid extracts on standing and will probably happen in the stomach.

• In research now more than 30 years old, hydroxytyrosol demonstrated broad antimicrobial activity and elenolic acid had antiviral activity, both in vitro

Bone K. Clinical Guide to Blending Liquid Herbs. Herbal Formulations for the Individual Patient. Churchill Livingstone, USA, 2003, pp. 352-356. 14

Olive Leaf:Unanswered Questions

• The bioavailability of elenolic acid and hydroxytyrosol is unknown

• Assuming 100% bioavailability, the concentrations of elenolic acid used in the in vitro antiviral studies translate to 60 to 100 g of olive leaf per day

• The same issue applies for hydroxytyrosol (in vitro to humans)

• There is no robust animal oral dose data nor clinical data to support the value of olive leaf during infections

Bone K. Clinical Guide to Blending Liquid Herbs. Herbal Formulations for the Individual Patient. Churchill Livingstone, USA, 2003, pp. TBA

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Olive Leaf and Hypertension• A recent double blind, randomised study compared

olive leaf extract (1000 mg/day and captopril (25 to 50 mg/day) over 8 weeks in 179 patients with hypertension

• Both treatments were effective• Means of systolic BP reduction from baseline were

-11.5±8.5 and -13.7±7.6 mm Hg for the olive leaf and captopril groups respectively

• The corresponding numbers for diastolic blood pressure were -4.8±5.5 and -6.4±5.2 mm Hg

• A significant reduction in plasma triglyceride levels was only seen in the olive leaf groupSusalit E, Agus N, Effendi I et al. Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: comparison with Captopril. Phytomedicine 2011; 18(4):251-258

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Horsechestnut and CVI• Chronic venous insufficiency (CVI) is impairment

of venous return, usually from the legs, often with oedema and perhaps stasis ulcers at the ankle1

• A 2006 Cochrane review was updated in 2010. Randomised, controlled clinical trials were included comparing oral horsechestnut standardised extract (HCSE) mono-preparations with placebo or reference therapy in CVI

• 17 trials met the inclusion criteria: 10 were placebo-controlled, 2 against treatment with compression stockings and placebo, 5 were controlled against other treatments

1 Raffetto JD, Khalil RA. Mechanisms of varicose vein formation: valve dysfunction andwall dilation. Phlebology 2008; 23(2): 85-98

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Horsechestnut and CVI• Most studies assessed clinical outcomes in

terms of leg pain, oedema and pruritis. Other endpoints assessed included leg volume and circumference

• Meta-analysis of 6 trials (502 patients) suggested a significant reduction in leg volume from HCSE versus placebo

• One trial indicated that HCSEmay be as effective astreatment with compressionstockings

Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufficiency.Cochrane Database Syst Rev 2006; (1): CD003230

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Why Should a Herb Help CVI?• Varicose veins and CVI have long been regarded

as disorders of valvular incompetence• However, recent evidence suggests that

changes in the vein wall could well precede incompetence

• For example varicosities are often observed below competent valves and often can occur before valvular incompetence

• Defects in extracellular matrix and collagen composition in the vein wall are thought to be part of this processLim CS, Davies AH. Pathogenesis of primary varicose veins. Br J Surg 2009; 96(11):1231-1242Naoum JJ, Hunter GC. Pathogenesis of varicose veins and implications for clinical management. Vascular 2007; 15(5): 242-249

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Chaste Tree (Vitex) and Female Reproductive

Disorders• An in press systematic review included 12 randomised controlled trials

• Eight investigated premenstrual syndrome, two premenstrual dysphoric disorder and two latent hyperprolactinaemia

• For premenstrual syndrome, seven of eight trials found Vitex extracts to be superior to placebo (6 studies), pyridoxine (1) and magnesium oxide (1)

• In premenstrual dysphoric disorder, one study reported Vitex to be equivalent to fluoxetine, while in the other, fluoxetine outperformed Vitexvan Die MD, Burger HG, Teede HJ et al. Vitex agnus-castus extracts for female reproductive disorders: A systematic review of clinical trials. Planta Medica 2012, In Press 20

AndrographisCondition Daily

Andrographolide Dosage

Results

Common cold

60 mg Significant symptom improvement at day 5, overall efficacy 2.1 times higher than placebo

Common cold

60 mg Significant symptom improvement at day 2

Common cold

48 mg Significant symptom improvement, reduction of intensity of rhinitis, sinus pain and headache at day 4

Prevention of common cold

11.2 mg/day Significant decrease in incidence in children

Tonsillitis 6 g/day dried herb As effective as acetaminophen in relieving fever and sore throat at day 3

Bone KM, Mills SY. Principles and Practice of Phytotherapy: Modern Herbal Medicine. Elsevier, UK. 2nd Edition, In Press 21

Andrographis and Winter Infections

• Two systematic reviews have been published• In one review, 7 double blind, controlled trials

(n=896) that met inclusion criteria for evaluation of efficacy were considered

• All trials scored at least 3 (out of a maximum of 5) for methodological quality on the Jadad scale

• Collectively, the data suggested that Andrographis was superior to placebo in alleviating the subjective symptoms of uncomplicated upper respiratory tract infection. There was also preliminary evidence of a preventative effect1

1 Coon JT, Ernst E. Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Medica 2004; 70(4): 293-298

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Andrographis and Winter Infections

• In the second review, 433 patients from 3 trials were included in a meta-analysis

• Andrographis either alone or in combination with Eleutherococcus was more effective than placebo in the treatment of uncomplicated acute upper respiratory tract infection1

• Doses used were typically up to 1000 mg/day of extract (about 6 g of herb) delivering 50 to60 mg/day andrographolides

1 Poolsup N, Suthisisang C, Prathanturarug S et al. Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract

infection: systematic review of randomized controlled trials. J Clin Pharm Ther 2004; 29(1): 37-45

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Saffron and Depression• Saffron has shown promising results for

depression in several small trials, involving around 40 patients

• Tested against a placebo andconventional antidepressants,both a tricyclic (imipramine)and an SSRI (fluoxetine)

• The daily dose used was typically 30 mg of extract corresponding toabout 150 to 180 mg of driedstigma

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Saffron and Depression• The two double blind, placebo-controlled trials

found that saffron was significantly better (p<0.001) than placebo in improving the mood of patients with mild to moderate depression1,2

• There were no more sideeffects in the saffron groupthan for placebo

• A drop in the Hamilton scale for the patients taking thesaffron began at 2 weeks and it continued to fall until the end of the trial

1 Akhondzadeh S et al. Crocus sativus L. in the treatment of mild to moderate depression: a double-blind, randomized and placebo-controlled trial Phytother Res 2005; 19(2): 148-151

2 Moshiri E et al. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: a double-blind, randomized and placebo-controlled trial. Phytomedicine 2006; 13(9-10):607-611

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Saffron and Depression• Saffron was compared against fluoxetine in two

published trials1,2

• The saffron was found to have similar remission rates for depression to the drug, of around 25%. There were no significant differences between the two patient groups in terms of side effects

• Both groups showed a significant improvement over the 6 weeks of treatment

• Similar improvements were demonstrated in the decrease in HAM-D scores from baseline: 12.2 for the herbal group, 15.0 for drug group1

1 Noorbala AA et al. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mildto moderate depression: a double-blind, randomized pilot trial. J Ethnopharmacol 2005; 97(2): 281-284

2 Akhondzadeh A et al. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients: a pilot double-blind randomized trial. Prog Neuropsychopharmacol BiolPsychiatry 2007; 31(2): 439-442 26

Why Treat with ComplexChemical Mixtures?

• The concept of multi-agent medicines is a developing theme in modern drug therapy. However, it represents nothing new for phytotherapy

• Due to their chemical complexity, even a single herbal extract is a nature-designed multi-agent medicine that can simultaneously target a range of desirable pharmacological effects

• This helps to explain why identifying the “active constituent” in many herbal extracts has proved to be so difficultBone KM, Mills SY. Principles and Practice of Phytotherapy: Modern Herbal Medicine.2nd Edition, Elsevier, UK. In press. 27

Why Treat with ComplexChemical Mixtures?

• For most if not all herbal extracts the “active constituent” is the whole extract itself, as illustrated by investigations into the antidepressant activity of St John’s wort

• The potential for chemical complexity to confer polyvalent activity or polypharmacology can also explain the apparent therapeutic versatility of herbal extracts

• As an example there is the rather large and novel range of clinical uses for Ginkgo, all somewhat supported by evidence from randomised, controlled trialsBone KM, Mills SY. Principles and Practice of Phytotherapy: Modern Herbal Medicine.2nd Edition, Elsevier, UK. In press.

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Polyvalent or Multifaceted Activity

• “Polyvalence can be defined as the range of biological activities that an extract may exhibit which contribute to the overall effect observed clinically or in vivo. It is often confused with synergism but the distinction lies in the fact that synergism is strictly concerned with only one pharmacological function, rather than a range of activities resulting in an overall effect.”1

1 Houghton P. Synergy and polyvalence: paradigms to explain the activity of herbal products. In: Houghton, P; Mukherjee PK. (eds). Evaluation of Herbal Medicinal Products. Perspectives on quality, safety and efficacy. ed 1. London, 2009, Pharmaceutical Press.

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Polyvalent or Multifaceted Activity

As outlined by Houghton, polyvalence can occur at three key levels:•Several types of phytochemicals are present that each exert a different biological effect•Phytochemicals of one particular chemical type are present that have more than one biological effect•Phytochemicals are present that modify the side-effects, absorption, distribution, metabolism or excretion of other active constituents

Houghton P. Synergy and polyvalence: paradigms to explain the activity of herbal products. In: Houghton, P; Mukherjee PK. (eds). Evaluation of Herbal Medicinal Products. Perspectives on quality, safety and efficacy. ed 1. London, 2009, Pharmaceutical Press.

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Herbal Extracts asIntelligent Mixtures

• In a recent review, Gertsch observed that herbal extracts might be “intelligent mixtures” of secondary plant metabolites that have been shaped by evolutionary pressures1

• He notes the concept of network pharmacology, as originally proposed by Hopkins2

• In the context of plant extracts, it is possible that different proteins within the same signalling network are only weakly targeted. However, this is sufficient to shut down or activate a given process by network pharmacology2

1 Gertsch J. Botanical Drugs, Synergy, and Network Pharmacology: Forth and Back to Intelligent Mixtures. Planta Med 2011, [Epub ahead of print].

2 Hopkins AL. Network pharmacology. Nature Biotechnol 2007; 25(10): 1110-111131

Herbal Extracts asIntelligent Mixtures

• In other words, network pharmacology can explain how a number of weakly active plant secondary metabolites in an extract may be sufficient to exert a potent pharmacological effect without thepresence of a highly bioactive compound1

1 Gertsch J. Botanical Drugs, Synergy, and NetworkPharmacology: Forth andBack to Intelligent Mixtures.Planta Med 2011;77(11): 1086-1098

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Acknowledgment

Thanks to Berris Burgoyne for assistingwith preparation of a some slides

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