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Leeches and Maggots and Bees ?
Ronald A. Sherman, MD, MScBioTherapeutics, Education & Research Foundation
Oh, my !
Biotherapy is here. Are you ready?
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Qualifications Statement
University of California, Irvine, CA
Board of Directors - BioTherapeutics, Education & Research (BTER) Foundation
Co-Founder & Laboratory Director - Monarch Labs
Physician - multi-cultural patients of limited means
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What are Your Qualifications?
Insert image of diverse crowd or Village people or the large group of para-hospital personnel. Make sure it is licensed or public domain.
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Your Patients’ Qualifications and Receptivity
Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of
complementary health approaches among adults: United States, 2002-2012. Natl
Health Stat Report. 2015;(79):1-16.
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Leechesand Maggots
and Bees ? . . . Oh my!
Ronald A. Sherman, MD, MScBioTherapeutics, Education & Research Foundation
Integrative Healthcare Symposium, February 20 - 22, 2020
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Some of the images in this lecture were obtained from other published sources. For all copyrighted images and text, permission was sought and granted whenever possible. In all cases of material for which copyrights are held by a person or entity other than the presenter or the BTER Foundation, Fair Use (Section 107 of the Copyright Act) is claimed on the basis of the following factors:
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Fair Use Disclosure
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What is Biotherapy?
The use of live organisms (animals and microbes) to diagnose
or treat illness.
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How many Biotherapeuticmodalities can you think
of?
(Give examples of medicinal animals)
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Viruses
Nematodes
Annelids
Mammals
Bacteria
Fungi
Insects
Fish
Archaea
Platyhelminth
Sherman & Cooper 2018. Biotherapy: Medicinal Maggots and Invertebrate Immunology . In Cooper (Ed.), Advances in Comparative Immunology https://doi.org/10.1007/978-3-319-76768-0_30
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Objectives –
1. Define Biotherapy and list at least 5 living organisms
used therapeutically.
2. List at least 2 organisms used to treat GI disease
3. List at least 2 indications for bee venom Rx
4. Describe the mechanism of action for phage Rx
5. Describe the differences between the way leech
therapy works and the way maggot therapy works
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Outline –✓ BioTherapy - Definitions & Examples
✓ Diversity of Therapeutic Animal Kingdom
❑ Selected Modalities –
• Hirudotherapy
• Bee Venom Therapy
• Maggot Debridement Therapy
• Microbes – FMT & Phage
• Service animals
• Hippotherapy
• Ichthyotherapy
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Outline –
o History
o Biology / Mechanism of Action
o Review of Scientific Literature
o Indications / Contraindications
o Warnings / AE
o Regulatory Issues / Future
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Jason Headley (with Monica Barbaro): It’s Not About The Nail.https://www.youtube.com/watch?v=-4EDhdAHrOg
When all you have is a hammer . . .
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Your Patients’ Qualifications and Receptivity
Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of
complementary health approaches among adults: United States, 2002-2012. Natl
Health Stat Report. 2015;(79):1-16.
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Hirudotherapy• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Asclepius_statue exhibited in the Museum of Epidaurus Theatre Photo by by Michael F. Mehnert
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Hirudotherapy
KQED Productions: Take Two Leeches and Call Me in the Morninghttps://www.youtube.com/watch?time_continue=121&v=O-0SFWPLaII
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
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Hirudotherapy
physiologically active salivary products
Mechanism Saliva Components
Inhibition of coagulation cascade Hirudin
Inhibition of platelet aggregation Calin, Apyrase, Saratin
Vasodilatation Histamine
Permeability factors Hyaluronidase, Collagenase
Proteinase inhibitors Bdellin, Eglin
Analgesics Not yet defined
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HirudotherapyMichalsen, A et al (2001). Effect of leech therapy (Hirudo medicinalis) in painful
osteoarthritis of the knee: a pilot study. Ann. Rheum. Dis. 60: 986.
Michalsen, A et al (2003). Effectiveness of leech therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann.Intern.Med. 139: 724–730.
Michalsen A (2008). Effectiveness of leech therapy in women with symptomatic arthrosis of the first carpometacarpal joint: a randomized controlled trial. Pain.
137: 452–459.
Andereya S et al (2008). Assessment of leech therapy for knee osteoarthritis: a randomized study. Acta Orthop. 79: 235–243.
Backer M et al (2011). Effectiveness of leech therapy in chronic lateral epicondylitis: a randomized controlled trial. Clin.J.Pain. 27: 442–447.
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Hirudotherapy• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
PhotoDisc
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Photo by Aletha Tippett, MD, MChem
FDA-cleared:Venous congestion in soft tissue wounds (reconstructive surgery)
Not FDA-cleared:Venous stasis; congestive heart failure; PVDz; ischemia; dentistry; arthritic pain and more
HirudotherapyHirudotherapy
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• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Hirudotherapy
PhotoDisc
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Hirudotherapy
PhotoDisc
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Hirudotherapy
PhotoDisc
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Hirudotherapy
PhotoDisc
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Elliott, Pritchard, Weinstock (2013) Helminth Therapy. In Grassberger, Sherman, Gileva, Kim, & Mumcuoglu (Eds.), Biotherapy - History, Principles and Practice.
“The best solutions address root cases of a problem. The therapeutic use of helminths (parasitic worms) proposes to treat a root cause of autoimmune disease, loss of exposure to these organisms due to modern hygienic lifestyle.”
Helminthic Therapy
Trichuris suis egg Photo by Joel Weinstock
Necator americanusPhoto by Jasper Lawrence
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Helminthic TherapyCD4 Cell Subtype
Cytokine produced (and its activity)Effect of
Helminths
Th 1IFN-gamma (Macrophage killing of intracellular bacteria & viruses)
i
Th 2 IL-4 (B cell proliferation) h
Th 17 IL-17 (Neutrophil proliferation) i
Th 3 TGF beta (suppresses activity of Th1 & Th2 cells) h
Tr 1 IL-10 (suppresses activity of Th1, Th2, Th17) h
Treg Suppresses growth of Th1, Th2, Th17 h
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Elliott, Pritchard, Weinstock (2013) Helminth Therapy. In Grassberger, Sherman, Gileva, Kim, & Mumcuoglu (Eds.), Biotherapy - History, Principles and Practice.
Animals given helminths were protected from developing:
Inflammatory bowel disease
Multiple sclerosis
Rheumatoid arthritis
Asthma
Diabetes
Helminthic Therapy
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Elliott, Weinstock. (2012). Helminth-host immunological interactions: prevention and control of immune-mediated diseases. Ann N Y Acad Sci. 1247:83-96
Elliott, Mawa, et al. (2003). Associations between helminth infection and CD4+ T cell count, viral load and cytokine responses in HIV-1-infected Ugandan adults. Trans R Soc Trop Med Hyg. 97:103-8
Borkow, Leng, et al. (2000). Chronic immune activation associated with intestinal helminth infections results in impaired signal transduction and anergy. J ClinInvest. 106:1053-60.
Sabin, Araujo, et al. (1996). Impairment of tetanus toxoid-specific Th1-like immune responses in humans infected with Schistosoma mansoni. J Infect Dis. 173:269-72.
Bentwich, Weisman, et al. (1996). Immune dysregulation in Ethiopian immigrants in Israel: relevance to helminth infections? Clin Exp Immunol. 103:239-43.
Helminthic Therapy
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Summers, Elliott, et al. (2005). Trichuris suis therapy in Crohn’s disease. Gut, 54, 87–90.
Summers, Qadir, et al. (2003). Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am J Gastroenter, 98, 2034–41
Schölmerich, Fellermann, et al. (2017) International TRUST-2 Study Group. A Randomised, Double-blind, Placebo-controlled Trial of Trichuris suis ova in Active Crohn's Disease. J Crohns Colitis. 11:390-9.
Fleming, Hernandez, et al. (2019). Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: Results of the HINT 2 clinical trial. Mult Scler, 25, 81–91.
Fleming, Isaak, et al. (2011). Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study. Mult Scler. 17:743-54
Benzel, Erdur, et al. (2012). Imune monitoring of Trichuris suis egg therapy in multiple sclerosis patients. J Helminthol. 86:339-47.
Voldsgaard, Bager, et al. (2015). Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect. Mult Scler. 21:1723-9.
Bager, Arnved, et al. (2010). Trichuris suis ova therapy for allergic rhinitis: a randomized, double-blind, placebo-controlled clinical trial. J Allerg Clinl Immunol, 125:123-30.
Helminthic Therapy
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Helminthic TherapyIllness / Condition
Helminth Tested
References / Sponsor
Crohn's Disease T. suisSummers et al, 2003; Summers et al, 2005; Scolmerich et al, 2017
Ulcerative colitis T. suisSummers et al, 2003; Summers et al, 2005; Scolmerich et al, 2017
Multiple sclerosisT. suis; N. americana
Fleming et al, 2011, 2019; Benzel, 2011; Voldsgaard et al, 2015
Peanut food allergy T. suis ClinicalTrials NCT 01070498
Allergic rhinitis T. suis Bager et al, 2010
Autism T. Suis ClinicalTrials NCT01040221
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• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Helminthic Therapy
Whipworm egg Photo by Joel Weinstock
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• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Helminthic Therapy
Necator americanusPhoto by Jasper Lawrence
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Apitherapy
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Bee Venom Therapy
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future123RF
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Bee Venom Therapy
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
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Bee Venom Therapy
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Kim, C. M. H. 2013. Apitherapy – Bee Venom Therapy, pp. 77–112. In Grassberger, M., Sherman, R.A., Gileva, O.S., Kim, C.M.H., Mumcuoglu, K.Y. (eds.), Biotherapy - History, Principles and Practice. Springer Netherlands, Dordrecht.
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Bee Venom Therapy
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Kim, C. M. H. 2013. Apitherapy – Bee Venom Therapy, pp. 77–112. In Grassberger, M., Sherman, R.A., Gileva, O.S., Kim, C.M.H., Mumcuoglu, K.Y. (eds.), Biotherapy - History, Principles and Practice. Springer Netherlands, Dordrecht.
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Bee Venom Therapy
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Benadryl Advertisement
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EnzymesPhospholipase A2
HyaluronidaseAcid PhosphataseAlpha-d-glucosidaselysophospholipase
Major Constituents of Venom
Biologic AminesHistamineDopamineNorepinephrine
PeptidesMelittinApaminMast cell degraulating peptideSecapinTertiapinProtease inhibitorProcamine A, B
Piek, T. (1986). Venoms of the Hymenoptera: biochemical, pharmacological, and behaviouralaspects. London ; Orlando: Academic Press.
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Seo BK, Han K, et al. (2017). Efficacy of Bee Venom Acupuncture for Chronic Low Back Pain: A Randomized, Double-Blinded, Sham-Controlled Trial. Toxins (Basel). 9. pii: E361.
Significant reduction in pain, significant improvement in function for BVT group over sham group.
Shin B-C, Kong JC, et al. (2012). Bee venom acupuncture for chronic low back pain: A randomised, sham-controlled, triple-blind clinical trial.Eur. J. Integr. Med.2012,4,e271–e280.
No benefit of BVT over conventional therapy (NSAIDS).
Lee SH, Hong SJ, Kim SY. (2003). Randomized controlled double blind study of bee venom therapy on rheumatoid arthritisis. J Kor Acu Mox Soc 20:80–8.
Significant benefit of BVT over NSAIDS for pain, swollen joints, but not for morning stiffness.
Bee Venom Therapy
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Bee Venom Therapy
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Kim, C. M. H. 2013. Apitherapy – Bee Venom Therapy, pp. 77–112. In Grassberger, M., Sherman, R.A., Gileva, O.S., Kim, C.M.H., Mumcuoglu, K.Y. (eds.), Biotherapy - History, Principles and Practice. Springer Netherlands, Dordrecht.
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Maggot Therapy• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
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1934 – Used by over 1,000 doctors and surgeons in North America
1990 – First controlled clinical trials
2003 – FDA regulates medicinal maggots
2004 – FDA grants marketing to the first live medicinal animal: Medical Maggots™
Maggot Therapy
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67 year old man,
who’s ischial
pressure ulcer was
treated with 2
cycles of MDT.
Seen here before
MDT and 10 days
later.
Maggot Therapy for Pressure Ulcer
Photos by RA Sherman
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59 year old man with
DFU & osteomyelitis,
refused amputation.
Maggot therapy
debrided his wounds,
including the non-
viable big toe; the
remains of that toe
were removed
surgically. He left the
facility with his foot
fully healed.
Photos by RA Sherman
Maggot Therapy for Diabetic Foot Ulcer
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73 yo man with sclerodactyly and bilat.
foot ulcers for 3 yrs; seen here before
and after first maggot treatment, and
then 1 year later.
Maggot Debridement, post trauma
Photos by RA Sherman
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55 yo woman treated “conservatively” for months. She requests MDT due to persistent drainage, odor, pain. Seen here before application of dressing, and after removal 22 hrs later
Fungating Breast CA
Photos by RA Sherman
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• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Maggot Therapy
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Myiasis & Maggot Therapy
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1. Debridement✓ enzymatic
✓ mechanical
2. Disinfection ✓ kills bacteria
✓ dissolves and inhibits biofilm
3. Promotion of wound healing ✓ granulation tissue growth
✓ epithelial proliferation and migration
✓ tissue oxygenation
Maggot Therapy
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Sherman RA: Mechanisms
of maggot-induced wound
healing. Evid Based
Complement Alternat Med.
2014;2014:592419.
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2004 – FDA permits marketing of first live medicinal animal (Medical Maggots™) for:
“ . . . debriding non-healing necrotic skin and soft-tissue wounds, including pressure ulcers, venous stasis ulcers, neuropathic foot ulcers, and non-healing traumatic or post surgical wounds.”
Maggot Therapy
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Maggot Therapy
• Pain or DiscomfortPredicted by pre-existing wound painPublished studies: 5 - 30% of patients
• AnxietyNot common among patients; Problem for therapists and administrators
•Delayed deliveriesMaggots perishable; can not be stored. Courier industry delays: ideally < 2%
Warnings / Adverse Events
Sherman RA: Int J Lower Extrem Wounds. 2002;1:135-42
Sherman RA: Wound Repair Regen. 2002;10:208-14
Sherman RA: J Diabetes Sci Technol. 2009;3:336-44
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• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Maggot Therapy
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Microbes – FMT
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Poop Emoji PillowAmazon.com
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Bacteriophage
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Bacillus Anthracis lysed by Gamma-Phage Photo courtesy of CDC
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Bacteriophage
Frederick Twort10/22/1877 – 03/20/1950
(Photographer unknown)
Felix d'Herelle04/25/1873 – 02/22/1949(Photographer unknown)
Bacteriophage, TEM by Dr Graham Beards
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Bacteriophage
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
PhotoDisc
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Bacteriophage
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
PhotoDisc
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BacteriophageFebvre, Rao, et al. (2019). PHAGE Study: Effects of Supplemental Bacteriophage
Intake on Inflammation and Gut Microbiota in Healthy Adults. Nutrients, 11(3).
Leitner, Sybesma, et al. (2017). Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomized, placebo-controlled, double-blind clinical trial. BMC Urology, 17(1), 90.
Sarker, Sultana, et al. (2016). Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations: A Randomized Trial in Children From Bangladesh. EBioMedicine, 4, 124–137.
Roehnisch, Then, et al. (2014). Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma. J Transl Med, 12, 119.
Rhoads, Wolcott, et al. (2009). Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. J Wound Care, 18, 237–238, 240–243.
.
.
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Service Animals
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
123RF
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Canine Olfactory Detection
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Leahy, M. 2004. Olfactory detection of human bladder cancer by dogs: Cause or association? BMJ. 329: 1286.1.
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Hippotherapy
• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
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Ichthyotherapy• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / FuturePhoto by Dances
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Ichthyotherapy• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Photo by Dina Middin
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Ichthyotherapy• History
• Biology / Mechanism of Action
• Review of Scientific Literature
• Indications / Contraindications
• Warnings / AE
• Regulatory Issues / Future
Photo by Yamada Kazuyuki
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Concluding Thoughts
123RF
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Objectives –
1. Define Biotherapy
Therapeutic use of live animals & microorganisms
List at least 5 living animals used therapeutically.
Viruses, Bacteria, Leeches, Helminths, Fish, Honeybees,
Maggots, Dogs, Horses
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Objectives –
2. List at least 2 organisms used to treat GI disease
HelminthsBacteriaPhage
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Objectives –
3. List at least 2 indications for bee venom Rx
Pain syndromes
Autoimmune diseases
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Objectives –
4. Describe the mechanism of action for phage Rx
Bacteriophage are viruses that parasitize (and lyse)
host-specific bacteria
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Objectives –
5. Describe the differences between the way leech
therapy works and the way maggot therapy works
Leeches Suck.
Maggots d’RULE!
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Any Questions?
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Leeches
and Maggots
and Bees ?
Ronald A. Sherman, MD, MScBioTherapeutics, Education & Research Foundation
. . . Oh Yes!
