Antimicrobial PDT (photodynamic therapy) Now Available

Antimicrobial PDT (photodynamic therapy) Now Available

Bacterial contamination and emerging infections such as resistant organisms, and viruses, combined with increased international travel pose a great risk. Pathogens like viruses and resistant bacteria, malaria, and chroni viral infections such as HIV and Hepatitis C for example need a reduction of blood components of the micro-organisms. The expectation of a pathogen reduction system is that it achieves high enough levels of pathogen reduction to reduce or prevent the likelihood of disease transmission while preserving adequate cell and protein quality.

In addition the system needs to be non-toxic, non-mutagenic and should be simple to use.

The micororganim / virus reduction Technology that we use, uses riboflavin (vitamin B2) plus UV (ultraviolet light) light to induce damage in nucleic acid-containing agents of the micro-organism. The system has been shown to be effective against clinically relevant pathogens and inactivates leucocytes without significantly compromising the efficacy of the product or resulting in product loss. Riboflavin is a naturally occurring vitamin with a well-known and well-characterized safety profile.

This therapy is offered at Dr Craige Golding Medical practice using low level laser light therapy intravenously with photosensitizers. The device used is the Weber Medical low-level light laser equipment with fibreoptic cables providing IV access.

Photodynamic inactivation (PDI) has been used to inactivate microorganisms through the use of photosensitizers. The inactivation of mammalian viruses and bacteriophages by photosensitization has been applied with success since the first decades of the last century. Due to the fact that mammalian viruses are known to pose a threat to public health and that bacteriophages are frequently used as models of mammalian viruses, it is important to know and understand the mechanisms and photodynamic procedures involved in their photoinactivation.

Please check the following publication from August 2019 for more details:
https://pubs.rsc.org/en/content/articlehtml/2019/pp/c9pp00211a?page=search

One of the best photosensitizers for the treatment of viral diseases is Riboflavin (Vitamin B2) which is available for intravenous infusion.

We already have good clinical data available with this protocol showing there are no side-effects for patients, and very good results in treatment of Malaria and Hepatitis B and C virus.  Riboflavin can be stimulated with UV light (370 nm) and blue laser (447 nm) for production of reactive oxygen species.

Riboflavin + UV Light (UVA and UVB):

  • Riboflavin modifies nucleic acids upon exposure to light
  • When applied to blood, this mechanism renders pathogens and leukocytes unable to replicate
  • Chemistry is not based on covalent modification
  • Riboflavin and its photo-products are non toxic and non-mutagenic and are naturally present in normal blood

By using the Weber medical technology, Riboflavin can be stimulated systemically in the blood by insertion of a sterile catheter in a 22 G cannula for targeting the virus in the blood and additionally this will lead to a resistance to the virus by having an effect on the destroyed damaged virus material.
Since the Corona virus mainly binds to cells in the respiratory tract the inner mouth can be treated locally by using a special mouth applicator with UV and blue laser as mentioned above.

In case of deeper infection a circular irradiating fiberoptic cable can be inserted in a suction catheter and can be used for treatment in the hypopharynx area.

In case of severe lung infection the special fiberoptic cable (1,5 mm soft plastic fiber) can also be inserted in a tube for intrabronchial application.

Riboflavin is already used successfully for disinfection of blood products to keep them virus free (see studies below and attached).

In the attached study of Keil et al. the efficacy of Riboflavin PDT with UV on Mers-Cov corona virus could already be demonstrated.

Background :

• Discovered at beginning of 20th century
• Neglected due to the discovery of antibiotics and lacking technology for clinical application
• Today: Continuous onset of multi-drug-resistant pathogens, stealth pathogens, viral pandemics
• 2005: Approval of first laser machine for systemic intravenous (IV) light application

Antimicrobial PDT is a new treatment option for infectious diseases with many favourable features:
– Efficiency against multi-drug-resistant pathogens
– No new resistances emerges
– Little side-effects
– Cost-efficiency.

Mechanisms of action :

  • Photosensitizer binds to microbes
  • “Light Activation“: Photosensitizer absorbs photons
  • Excitation of Photosensitizer to highly reactive states
  • Reaction with ambient oxygen: – Type I Photochemical Pathway: Generation of  reactive oxygen species – Type II Photochemical Pathway: Generation of singlet oxygen
  • Both species induce irreparable oxidative damages to microbes as they interact with numerous enzymes leading for example to the inhibition of protein synthesis and molecular alteration of DNA strands
  • Microbial death

Photosensitizers :
Riboflavin: • Vitamin B2 • Activated by Blue Light with a peak at 447nm
Curcumin: • Derived from Curcuma Longa • Excitation peak at 447nm (blue)

Hypericin: • Extract from St. John´s Wort • Excitation peak at 589nm (yellow)

Mirasol Pathogen Reduction Technology (PRT): Combination of Riboflavin and ultraviolet light as well as blue light for the reduction of pathogen loads in blood products (anti viral, anti bacterial and anti paracytic) is offered at Dr Craige Golding Medical practice

In vitro research :

In HIV research, several studies show a positive effect of PDT on HIV (Degar 1992, Hudson 1993, Lenard 1993, North 1993, Lavie 1995, Ben Hur 1997, Li 2011 etc.). In Germany, Hypericin was even tested by the famous Robert-KochInstitut: The researchers found an anti-HIV effect in-vitro, BUT only in combination with light.

Following effects on HIV have been observed:
– PDT inhibits HIV attachment and entry to human cells  early blockage of HIV replication – PDT can inactivate free viral particles – selective destruction of infected white cells. Two pathogen reduction technologies – methylene blue plus light and shortwave ultraviolet light – effectively inactivate hepatitis C virus in blood products Eike Steinmann, Ute Gravemann, Martina Friesland, Juliane Doerrbecker, Thomas H. Müller, Thomas Pietschmann and Axel Seltsam*

RESULTS: HCV was sensitive to inactivation by both pathogen reduction procedures. HCV in plasma was efficiently inactivated by MB plus light below the detection limit already by 1/12 of the full light dose. HCV in PCs was inactivated by UVC irradiation with a reduction factor of more than 5 log.

CONCLUSIONS: Pathogen reduction technologies such as MB plus light treatment and UVC irradiation have the potential to significantly reduce transfusion-transmitted HCV infections.

Multi-drug-resistant MRSA:

Maisch et al. examined penetration and antibacterial efficacy of XF73 (a cationic porphyrin PS) against MRSA using an ex vivo model.
Photoinactivation of pre-incubated S. aureus demonstrated >3 log10 reduction, while illumination after XF73 was delivered to the bacteria on the skin resulted in a approximately 1 log10 growth reduction independently of the antibiotic resistance pattern of used S. aureus strains.

Possible new treatment for malaria:

Abstract: Anti- microbial Photodynamic Therapy: A new treatment option for Malaria? Michael Weber, MD / Robert Weber, MSc / Martin Junggebauer, MSc / Habeeb Ali, MD Objectives: Evaluation of a treatment protocol consisting of anti- microbial photodynamic therapy (aPDT) and additional intravenous low-level-laser-therapy as a new treatment option for Malaria. Methods: 20 patients suffering from Plasmodium Falciparum were separated in one treatment group and one control group, both consisting of 10 patients. Patients in the treatment group received aPDT as well as intravenous low-level laser therapy. Patients in the control group received conventional therapy only.

Results: After 9 days, 88,9% of treatment group patients were completely parasite-free whereas the same holds true for only 50% of control group patients. Almost all symptoms could be alleviated more rapidly in the treatment group. Conclusion: The results indicate that the applied protocol can be an effective treatment option to treat Malaria caused by Plasmodium Falciparum. They strongly encourage further studies with bigger sample sizes.

Hepatitis C : First pilot data (Weber Medical Clinic, Germany):

  • 5 patients with HCV treated with Riboflavin and 447nm blue laser • Results: Noticeable decreases of viral loads in all treated patients • The effects became significant after 3-5 treatments
  • Even patients that had been treated with conventional methods for many years without noticeable effects reacted very positive to aPDT. After five treatments the viral load decreased by 70% in average

Lyme’s disease latest studies : Infectious disease caused by Borrelia bacteria which is spread by ticks • Early symptoms (stadium 1) may include fever, headache and tiredness

  • If untreated, chronic disease may develop with symptoms including chronic fatigue, facial paresis, joint pains, depression, severe headaches with neck stiffness, myocardial problems and co-infections due to weakened immune system (stadium 2 and 3)
  • It is estimated to affect 300,000 people a year in the United States and 65,000 people a year in Europe
    What do borrelia bacteria do?
  • They screw into collagen fibers in connecting tissue, leading to inflammation and acidity
  • Structure of connecting tissue is affected and immune cells are disabled
  • Vascular processes lead to circulatory disorders, nutrient deficiency in the affected tissue and loss of functions
  • Main problem: Resistance against antibiotics (especially intra-cellular bacteria* and cell wall-deficient (CWD) borrelia)
  • CWD borrelia: Antibiotics (i.e. Penicillin) lead to changes of form, properties and markers of the bacteria
  • Development of chronic lyme disease as antibiotics and the immune system cannot fight intra-cellular and CWD borrelia (bacteria can survive for several years)
  • Often connected to co-infections due to weakened immune system
    *Borrelia can hide in neuronal cells, fibroblasts, lymphocytes, macrophages etc
    Study Dr. I. Zuern, Germany (2016):
  • 3 groups with 10 chronic lyme patients each
    • Patients in all 3 groups received the following therapies:
    – Physical vascular therapy (Bemer) – Immunotherapy – Vitamins and additional natural supplements – Neural Therapy – Procain bases infusions – Oxygen therapy

Group B: Additional Yellow Laser 589nm + Hypericin (10-15 treatments, 2-3 times per week)

Group C: Additional 447 nm Blue Laser + Riboflavin (10-15 treatments, 2-3 times per week)

Diagnostics: Lymphocyte Transformation Test (LTT) : Detection of the activity of chronic, persistent infections based on pathogen-specific T cell response (Borrelia, Chlamydia, Yersinia, Giardia lamblia, Herpes viruses etc.)

  • The in-vitro test is based on the principle of antigen/allergen-specific induction of cell division in lymphocytes following contact with their «fitting« antigen
  • A positive reaction in the LTT indicates the presence of antigen-specific lymphocytes (memory cells) in the patient’s blood ( immune response to different borrelia antigens)
  • Activity of infection can be measured

Tested antigens: -Borr. sensu stricto – Borr. afzelii – Borr. garinii -Borr. OspC

Measurement of antigen-specific t-cells in patient‘s blood:

Stimulation index (SI) >3,0 positive. Stimulation index (SI) 2,0-3.0 boarderline Stimulation index (SI) <2,0 negative

Very favourable outcomes in studies using Antimicrobial Photodynamic therapy!

Outlook and moving forward :

  • Very promising results from first in-vivo studies on aPDT
  • Seems to work against bacterial, parasitic and viral infections
  • Larger patient populations necessary
  • Development of ultraviolet diode should bring additional benefit
  • Promising future due to increasing drug resistances

Intravenous Ultraviolet Light Therapy

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References :

• J Appl Microbiol. 2018 Apr;124(4):1017-1022. doi: 10.1111/jam.13638. Epub 2018 Jan 31.
Evaluation of 405-nm monochromatic light for inactivation of Tulane virus on blueberry surfaces.
Kingsley DH1, Perez-Perez RE1, Boyd G2, Sites J2, Niemira BA2.
Link: https://www.ncbi.nlm.nih.gov/pubmed/29144595
• Avicenna J Med Biotechnol. 2015 Apr-Jun; 7(2): 57–63.
Published online 2015 Apr.
The Effects of Ultraviolet Light and Riboflavin on Inactivation of Viruses and the Quality of Platelet Concentrates at Laboratory Scale
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483315/
• Riboflavin and ultraviolet light: impact on dengue virus infectivityArticle in Vox Sanguinis 111(3) • June 2016 with 145 Reads
Link: https://www.researchgate.net/publication/303883589_Riboflavin_and_ultraviolet_light_impact_on_dengue_virus_infectivity
https://en.wikipedia.org/wiki/Pathogen_reduction_using_riboflavin_and_UV_light in Wikipedia
• Published: 30 March 2019
Different photodynamic effects of blue light with and without riboflavin on methicillin-resistant Staphylococcus aureus (MRSA) and human keratinocytes in vitro
Link: https://link.springer.com/article/10.1007/s10103-019-02774-9
• The effectiveness of riboflavin photochemical‐mediated virus inactivation and changes in protein retention in fresh‐frozen plasma treated using a flow‐based treatment device
First published: 29 July 2014
Link: https://onlinelibrary.wiley.com/doi/full/10.1111/trf.12775
• Original Article
Role of Riboflavin- and UV Light-Treated Plasma in Prevention of Transfusion-Related Acute Lung Injury
• Free Access
Link: https://www.karger.com/Article/FullText/363205
• Hamblin R, Viveiros J, Changming Y, Ahmadi A, Ganz R, Tolkoff J,. helicobacter pylori accumulates photoactive porphyrins and is killed by visible light. Antimicrobial Agents and Chemotherapy, 2005; 49, 7:2822-2827
• Heine H. Lehrbuch der biologischen Medizin. Stuttgart: Hippokrates, 3. Auflage 2007
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• Zuern, I. (2016): Pilot Study on Treatment of Chronic Lyme Disease with Yellow and Blue Laser
• Goodrich, Raymond et al, 2011: Pathogen Reduction Technology Treatment of Platelets,
• Plasma and Whole Blood Using Riboflavin and UV Light. Published in: Transfusion medicine and Hemotherapy: 2011;38:8–18
• Goodrich et al., 2005: Patent Application Publication, Pub. No.: US 2005/0282143 A1, United States. Pub. Date: Dec. 22, 2005
• Hamblin, MR; T Hasan (2004). “Photodynamic therapy: a new antimicrobial approach to infectious disease?”. Photochem Photobiol Sci 3 (5): 436–450. doi:10.1039/b311900a.PMC 3071049. PMID 15122361 • Miley, G.: The Knott Technique of ultraviolet blood irradiation in acute pyogenic infections. New York State Journal of Medicine. 1942: 38- 46.Pathogen Deactivation
• Ramabhadran TV, F. T. (1976). In vivo induction of 4-thiouridine-cytidine adducts in tRNA of E. coli B/r by near-ultraviolet radiation. Photochem Photobiol, 23(5), 315-21.
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• Weber et al. (2010): Intravenous Laser Blood Irradiation: Introduction of a New Therapy