NHP Update: What Works and What Doesnt

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NHP Update What Works and What Doesnt

• Heather Boon, BScPhm, PhD
• University of Toronto
• (heather.boon_at_utoronto.ca)

No Conflicts of Interest to Declare
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Lecture Map

• Whats new in NHPs
• hot topics - colds/flus- weight loss

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NHPs for Colds/Flus
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Case 1

• It is a slow Saturday morning at the pharmacy
  when you notice Tim Brown in the cough and cold
  section looking perplexed.
• As usual, Tim is wearing his biking gear and has
  brought his fancy racing bike into the store with
  him
• As you approach, you notice he is juggling a
  number of NHPs.

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Tims question

• Im competing in the World Masters cycling
  competition next month in Edmonton and I cant
  get sick. What should I be taking?
• Note he is holding a bottle of echinacea, one of
  Cold-FX and a bottle of Vitamin C that contains a
  free sample of zinc lozenges

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Review of NHPs

• Echinacea
• Ginseng
• Vitamin C
• Zinc

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http//www.cobleskill.edu/courses/orht321/Echinace
a20purpurea200104.jpg
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Echinacea (Echinacea purpurea Echinacea
angustifolia Echinacea pallida)

• Pharmacology
• Exact mechanism of action unclear
• 4 groups of compounds appear to contribute to
  immunomodulatory activity alkamides,
  glycoproteins, polysacchardies and caffeic acid
  derivatives (CADs)
• Alkamides have anti-inflammatory properties and
  are found in roots of E. angustifolia and the
  roots ariel parts of E. purpurea - may also
  have some immunomodulatory potential
• glycoproteins, polysacchardies and CADs have been
  shown in mice to activate macrophages and NK
  cells anti-viral activity

Linde et al. Cochrane Echinacea review 2005
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Linde et al. Cochrane Review Treatment (2006)

• Of the placebo controlled studies reviewed- 9
  reported significant effects over placebo- 1
  reported a trend in favour of echinacea- 6
  reported no difference over placebo
• Heterogeneity of extracts makes findings
  difficult to interpret
• Likely that unpublished negative trials exist

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Cochrane 2006 Tx Conclusion

• There is some evidence that preparations based
  on the aerial parts of Echinacea purpurea might
  be effective for the early treatment of colds in
  adults but results are not fully consistent.
  Beneficial effects of other Echinacea
  preparations, and for preventative purposes might
  exist, but have not been shown in independently
  replicated, rigorous randomized trials.

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Barrett et al. Annals of Internal Medicine
2002137939-946

• Randomized, double-blind, placebo-controlled
  community-based trial (n148 students)
• Intervention encapsulated mixture of unrefined
  E. purpurea herb (25) and root (25) and E.
  angustifolia root (50) from Shaklee Tecnica 1g
  doses 6x/day on 1st day and 3x/day for up to 9
  more days)
• No sig difference on any outcome measure
  including cold duration and symptom severity
  measures

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Goel et al. J of Clinical Pharmacy and
Therapeutics. 20042975-83

• Randomized, double-blind, placebo-controlled
  trial (n282 enrolled but only 128 experienced a
  cold)
• Intervention Echinilin (Natural Factors) E.
  Purpurea standardized to alkamide (0.25 mg/mL),
  cichoric acid (2.5mg/mL) and polysaccharide (25
  mg/mL) content
• Total daily symptom scores lower (plt0.01) in
  echinacea group
• decreased symptom severity and duration

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Taylor et al. JAMA 2003 290(21)2824-2830

• Randomized, double-blind, placebo controlled
  trial (n407 children aged 2-11 yrs)
• Assessed 707 URIs over 4 months
• Intervention dried pressed E. purpurea juice of
  above ground flowering herb (Madaus AG) 2-5 yrs
  3.75 mL BID 6-11 yrs 5 mL BID for maximum of
  10 days
• No difference in duration or severity between
  treatment groups
• sig. lower incidence in subsequent URIs after
  echinacea (64 had had more than 1 URI vs 52
  taking echinacea)
• Increased incidence of rash with echinacea7.1vs
  2.7

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Prevention of Colds/Flus - Cochrane Review (2006)

• 3 echinacea-placebo comparisons in 2 studies
• no significant differences in
• of people with 1 or more cold
• duration of colds
• severity of colds
• no significant AEs reported
• Cochrane conclusion no effect for prevention

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Echinacea Cautions

• Theoretical caution in cases of chronic immune
  dysfunction and autoimmune conditions
• adverse reactions uncommon, but include allergic
  reactions which vary from mild to anaphylatic
• Safety has not been established in pregnancy and
  lactation
• Drug Interactions theoretically may interfere
  with immunosuppressant therapy (e.g.,
  cyclosporin, prednisone)

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Back to the case

• One of Tims friends recommended Echinacea
• What do you think about echinacea as prevention
  for colds?
• What about if he had a cold right now?

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What about for a child?

• Tim has 4 children aged 4 years to 12 years of
  age.
• He is worried that he is most likely going to
  catch a cold from them
• Can they take echinacea?

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http//www.pharmacy.utas.edu.au/cmed/images/ginsen
g.jpg
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Ginseng (Cold-FX and others)

• Tims best friend Steve is a professional hockey
  player and their trainer insists they all take
  Cold-FX during the hockey season to prevent colds
• Steve says it really helps the team
• Should Tim and/or his kids take Cold-FX
• To treat current symptoms?
• Prevent future colds?

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Ginseng

• Three main types widely available in Canada
• Panax ginseng (Asian ginseng)
• Panax quinquefolius (Canadian/American ginseng)
• Note Siberian ginseng (Eleutherococcus
  senticosus) is a different plant!

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Ginseng Immune Effects

• Documented Immune effects for Panax spp. include
• Enhanced fcn of peripheral blood mononuclear
  cells in immune compromised pts
• Increase in T-helper cells (Rg-1 induced)
• T-cell and macrophage cytokine induction
• Reduction of leukotriene release (Rb1 induced)
• Immunostimmulatory activity in the aged

Kitts and Hu. Public Health Nutrition 2000
3(4A), 473-485
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Ginseng for colds?
VS
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Tx or prevention of Colds

• Lots of hype
• extracts from roots of North American ginseng
• RCT (cold-FX) n328 aged 18-65
• Dose twice daily or placebo x 4 months
• Reduced all of the following- mean number of
  colds per person- proportion of people that had
  2 colds(but not number of people that only got
  1 cold!)- severity of symptoms- number of days
  cold symptoms were reported

CMAJ 2005 173(9)1043-1048
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Ginseng Adverse Effects

• Ginseng has been well tolerated by most people
  when used at recommended doses
• may lower blood sugar levels
• may have estrogen-like effects, and has been
  associated with reports of breast tenderness,
  loss of menstrual periods, vaginal bleeding after
  menopause, breast enlargement (reported in men),
  difficulty developing or maintaining an erection,
  or increased "sexual responsiveness."
• Avoid use of ginseng in patients with hormone
  sensitive conditions, such as breast cancer,
  uterine cancer, or endometriosis.
• Applicability to extracts for colds not clear

www.naturalstandard,com
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Ginseng and Anti-coagulants

• Study 1 double-blind RCT 20 healthy pts 3
  days of warfarin in weeks 1 and 4 American
  ginseng (500 mg of 5 ginsenosides)/placebo from
  week 2-4
• INR and peak warfarin plasma levels significantly
  decreased (Yuan et al. Annals of Internal
  Medicine 2004 14123-27)
• Study 2 Open-label crossover randomized study
  in 12 healthy male participants Single 25 mg
  dose of warfarin alone vs. after 7 days
  pre-treatment with Panax ginseng (continued 7
  days after warfarin dose)
• INR and platelet aggregation were not affected by
  treatment with ginseng No effect on the
  pharmacokinetics or pharmacodynamics of either
  S-warfarin or R-warfarin (Jiang et al. Br J Clin
  Pharmacol 2004 57(5)592-599)

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Ginseng (Cold-FX and others)

• Tims best friend Steve is a professional hockey
  player and their trainer insists they all take
  Cold-FX during the hockey season to prevent colds
• Steve says it really helps the team
• Should Tim and his children take Cold-FX
• To treat current symptoms?
• Prevent future colds?
• Is ginseng better than echinacea?
• Can he take BOTH?

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Vitamin C

• Tims parents always take Vitamin C in the winter
  to prevent colds and flus
• There is 60 mg of Vitamin C in his multi-vitamin
  is that enough or should he take more?
• Will Vitamin C help if he currently has symptoms?
• Will it prevent him from getting colds in the
  future?

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Vitamin C Cold Prevention

• Placebo-controlled trials testing dose of 0.2
  g/day or more
• 30 studies (total n11,350)
• Overall RR of getting a cold while taking
  prophylatic vitamin C 0.96 (95 CI 0.92-1.00)
• Sub-group of marathon runners, skiers and
  soldiers on sub-arctic exercises (n642) RR
  0.50 (95 CI 0.38-0.66)
• Consistent benefit if developed a cold episode
  during prophylaxis 8 (95 CI 3-13) reduction
  of cold duration in adults 13.6 (95 CI 5-22)
  in children

Hemila H et al. Vitamin C for preventing and
treating the common cold Cochrane Database of
Systematic Reviews 2007 Issue 3. Article No.
CD000980.
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Vitamin C and Treatment of Colds

• Placebo-controlled trials testing dose of 0.2
  g/day or more
• Vitamin C therapy started after onset of symptoms
• No significant difference in cold duration
  compared to placebo based on 7 RCTs (total
  n3294)
• No significant difference in cold severity
  compared to placebo based on 7 RCTs (total
  n3294) based on 4 RCTs (n2753)

Hemila H et al. Vitamin C for preventing and
treating the common cold Cochrane Database of
Systematic Reviews 2007 Issue 3. Article No.
CD000980.
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Vitamin C AEs

• High doses
• Kidney stones, severe diarrhea, nausea, gastritis
• Tolerance/resistance
• Those taking chronic high doses should reduce use
  slowly
• Rare reports of scurvy in infants born to women
  taking high dose vitamin C throughout their
  pregnancy
• Vitamin C is present in breast milk

(source www.naturalstandard.com)
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Vitamin C

• Tims parents always take Vitamin C in the winter
  to prevent colds and flus
• There is 60 mg of Vitamin C in his multi-vitamin
  is that enough or should he take more?
• Will Vitamin C help if he currently has symptoms?
• Will Vitamin C help him prevent colds?

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Combinations

• Can he take Vitamin C with echinacea or with
  ginseng?
• Will this provide increased benefit?
• Are there any risks?

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Zinc
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Zinc Lozenges

• One brand of Vitamin C comes with a free trial
  pack of Zinc lozenges
• Tim saw an advertisement for those on TV last
  week and thinks they might be worth a try
• What do you think?

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Zinc Mechanism of Action

• Hypothesized to inhibit rhinovirus binding to the
  intercellular adhesion molecule-1 located in
  nasal mucosa (Novick SG et al. Med Hypotheses
  1996 46295-302)
• Might block facial and trigeminal nerve
  conduction (thus reduce nasal congestion and
  sneezing) (Novick SG et al. Med Hypotheses 1996
  46295-302)
• Does NOT appear to significantly inhibit
  replication of rhinovirus (Geist FC et al.
  Antimicrob Agents Chemother. 1987 31622-4)

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Zinc Absorption

• Assumption that ions from orally dissolved zinc
  dosage form will migrate into the nasal sinuses
• Likelihood that this occurs has been questioned
• Nasal sprays developed to overcome this potential
  problem BUT AEs (loss of smell) (see
  Alexander TH and Davidson TM. Laryngoscope 2006
  116217-20 Jafek BW et al. Am J Rhinol 2004
  18137-41)

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Clinical Effectiveness

• Questionable RCTs (many with design flaws) are
  almost equal split re outcome
• Most recent review (Caruso et al. Clinical
  Infectious Diseases 2007 45569-74)
• 14 RCTs identified only 4 met rigorous
  methodological inclusion criteria
• Overall 7 negative and 7 positive
• 4 high quality studies 3 negative (2 lozenges, 1
  nasal spray) 1 positive (nasal gel)
• Conclusion therapeutic effect has yet to be
  established

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Zinc AEs

• Lozenges
• Gastrointestinal (especially nausea) reduced by
  concomitant ingestion of food
• Irritation/sore mouth, aftertaste
• Nasal sprays/gels
• Nasal irritation, nose bleeds, changes in or loss
  of sense of smell

Source CAMline zinc review
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Summary Recommendations

• What (if anything) should Tim take and why?
• What counseling would you provide as part of this
  recommendation?
• Is any follow-up required? (If so, what?)

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Are there any herbs that will help me lose
weight?
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Herbs used for Weight loss include

• Ma Huang (Ephedra)
• Bitter orange
• Hoodia
• Garcinia
• Green tea
• Guarana

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Ma Huang(Ephedra sinica )

• contains ephedrine, which appears to cause
  weight loss when used in combination with
  caffeine
• The effect of ephedrine alone (without
  caffeine) is unclear.
• Although this herb has been shown to help reduce
  weight, it is unsafe for humans for this
  indication.
• Serious reactions, including heart attack,
  stroke, seizure, and death, have occurred with
  using ephedra.
• Not legally available in Canada for weight loss

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Bitter Orange (Citrus aurantium)

• common ingredient in weight loss
• aids and appetite suppressants
• 3 reviews all conclude that evidence for weight
  loss is questionable due to lack of data (i.e.,
  mostly combination products)
• Health Canada has received 16 reports in which
  products containing bitter orange (synephrine)
  were suspected of being associated with serious
  cardiovascular adverse reactions, including
  tachycardia, cardiac arrest, ventricular
  fibrillation, transient collapse, blackout and 2
  deaths

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Hoodia (Hoodia gordonii)

• Heavily marketed as an appetite suppressant and
  weight reduction aid.
• Folklore suggests that Bushmen of the Kalahari
  eat it to help ward off hunger and thirst during
  long trips in the desert.
• Phytopharm is currently attempting to isolate the
  appetite-suppressing molecule, P57, to create a
  patented diet drug in the future. (Pfizer
  discontinued studies of P57 in 2003)
• There are currently no available reliable human
  trials demonstrating efficacy and safety of
  hoodia for any indication.

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Garcinia (Garcinia cambogia )

• Evidence supporting hydroxycitric acid (HCA), the
  active ingredient in Garcinia cambogia, for
  weight loss is mixed.
• Additional study is warranted to clarify early
  findings.
• Key ingredient in Hydroxycut formulations
  (along with others such as green tea, caffeine)
  currently under investigation re case reports of
  liver toxicity
• HCA is not likely cause of liver toxicity
• Use cautiously in pts with a history of diabetes,
  rhabdomyolysis (breakdown of skeletal muscle), or
  with HMG-CoA reductase inhibitors ("statins").
• Avoid with Alzheimer's disease.
• Avoid if pregnant or breastfeeding.

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Green Tea (Camellia sinensis)

• several small human studies investigate the use
  of green tea extract capsules for weight loss
  or weight maintenance in overweight or average
  weight individuals.
• Study results are mixed but two recent
  meta-analyses report small positive effects on
  weight loss (may not be clinically significant)
• Better research is needed before a recommendation
  can be made in this area.

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Guarana(Paullinia cupana)

• Has the same stimulatory effect as caffeine and
  is often used for energy, weight loss, and as an
  additive to soft drinks (e.g. Dark Dog Lemon,
  Guts, and Josta).
• Guarana has been studied with other herbs, making
  it difficult to draw a conclusion based on the
  effects of guarana alone.
• Avoid with high blood pressure, psychological or
  psychiatric disorders, liver disorders, or
  irregular heartbeat. Avoid if taking other
  stimulatory agents, especially ephedra.
• Avoid if pregnant or breastfeeding.

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Final Tips

• NHPs are part of pharmacists scope of practice
• Specifically ASK about NHPs as part of every
  medication history
• Provide evidence-based advice look up what you
  dont know
• Report suspected adverse events associated with
  NHPs

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Recommended Books

• Barnes J, Anderson LA, Phillipson JD. Herbal
  Medicines. 3rd Edition. London The
  Pharmaceutical Press 2007.
• H Boon and M Smith. 55 Most Common Medicinal
  Herbs. 2nd Edition. Toronto Robert Rose Inc.,
  2009.

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Recommended Websites

• CAMline www.camline.ca
• National Centre for Complementary and Alternative
  Medicine. National Institutes of Health, USA
  http//nccam.nih.gov/
• Natural Standard www.naturalstandard.com
• Natural Medicines Comprehensive Database
  www.naturaldatabase.com