Science and Technology

• Mende Biotech Ltd started producing Totarol™ in March 1999 and it has since then been sold all over the world, mainly to the cosmetic industry. The biggest client companies are L’Oreal (France and USA) and Jurlique in Australia.

Two shareholders - Doug Mende and Reinhard Hueber.

We have excelled in innovation and science to produce multi functional technology which has immense market potential in

human and animal health products!

Company Overview

• Totarol ™• A potent antibacterial, antimicrobial, antioxidant and anti-inflammatory compound

extracted from recycled totara wood. • Totarol™ has international organic certification• A natural Bio antiseptic system which is safe, odourless, tasteless and does not

degenerate over time. • Registered in the ingredient portfolios of over 30 companies, with current customers

including L’Oreal International. It took several years to pass REACH and L’Oreal registration processes and we are the only New Zealand company to complete this process so far.

• Citrus Bioflavonoid Liposome Solution – CBLS• Stimulates blood vessel formation (angiogenesis) and acts as an anti-inflammatory and

analgesic inhibitor.• 20 – 30% increase in cell migration and type 1 collagen replacement. • Promotes faster wound closure. • Completely new and patentable science

• T2G – Liquid K7 Totarol• Broad spectrum preservative base. Potential applications in cosmetics, wound/skin care

and animal health markets, antibiotic replacement• The base for all the Dairy Industry Products– extremely effective Mastitis treatment

The primary productTotarol™ is extracted from recycled Podocarpus Totara heartwood.

Totara trees were highly prized and originally harvested for their durability and used as canoes, fence posts and house foundations.

400 year old tree Trees harvested at turn of century Posts still used today on farms

Super Critical ExtractionWe have developed a novel, patented, supercritical extraction process to give us our unique product, Totarol™.

We mainly use recycled Totara fence posts and stumps as our timber resource, and are able to produce over 10 tonnes of Totarol™ per annum sustainably.

Recycled Fence Posts Supercritical extraction facilities

Totarol™ Organic ActiveTotarol™ is a naturally occurring plant extract with potent Bio-antiseptic activity that can replace antibiotics.

Totarol™ is one of the rare phytochemical actives against penicillin and methicillin resistant strains of Staphylococcus aureus

Totarol™ strongly inhibits lipid peroxidation and scavenges ROS (reactive oxygen species)

Totara heart wood Finished pure Totarol™ extract

• Our advanced wound dressing created for severe burns, using our new science and technology. T2G contains natural bio-actives in solutions that apply to all types of wounds and healing applications.

• We have brought together our own patented technologies

• Liquid K7 Totarol™ , CBLS synergize to give a broad spectrum antimicrobial compound, which also has activity against MRSA resistant organisms. It is an anti inflammatory, strong ROS antioxidant, non toxic and 100% natural.

• CBLS (citrus bioflavonoid liposome solution), stimulates blood vessel formation (angiogenesis)anti-inflammatory and analgesic properties in a new Liposome delivery system

Each of these compounds is readily available, registered as safe, meet regulation requirements and are easily manufactured and cost effective.

• Key research partners are Massey University, Estendart – clinical trials research provider and Callaghan Innovations.

T2G technology

Keeping the requirements for optimal wound healing in mind, BioActive T2G is designed to have the following properties:

– Is anti bacterial

– Is anti inflammatory

– Is analgesic (pain free application)

– Promotes blood flow

– Stimulates collagen Type I synthesis

– Reduces swelling

THE SCIENCE: Promotes 20% faster wound closure

© Doug Mende 8

T2G

Case Studies • Charles Bone had a car accident in 2005, in which he suffered major injuries to the leg. The wound

failed to heal with a wide range of current treatments.

• The first photo’s was taken at Royston Hospital after a second skin graft on the 25th June 2008.

• On the 2nd of July 2008 he started using the BioActive T2G wound dressing on a sterile dressing, bandaged and changed every second day; within a few days the wound showed improvement.

• Photo 2 was taken on 25th July 2008 which shows the wound practically healed.

• “ After three years, trying everything and a lot of pain this dressing worked and even more than that did not cause pain when applied:” Charles Bone  

After 10 days

Case Study – Severe Eczema

• Ryan Becket – 7 years old had been on anti-biotic treatment most of his life.

• Because of scratching the eczema progressed into wounds covering 70% of his body.

First treatment started 16th February 2010

Comments from Ryan’s parents • We decided to try something new and natural for Ryan’s Eczema and did not want Ryan to be

continually on anti biotic treatment.

• By using the wound gel 3-4 times a day, Ryan's eczema has mostly cleared up, especially around his chest and arms, elbows and behind the knees in a period of one week.

• We are still using the gel on the inside of his legs and will keep using the gel for Ryan's skin.

• Andrea Beckett - 2nd March 2010

• MetriKlenz is a product developed for Dairy Cow Internationals by Mende Biotech and Black Rock Commercial for the treatment of infusing the uterus of infected dairy cows to improve their ability to have a fertile cycle earlier. Totarol was chosen as the product of choice because of its many natural healing qualities including specifically, anti-bacterial, anti-inflammatory, gram positive and gram negative activity.

• The concept was to promote the healing process of intrauterine infections – Metritis. Infusing Totarol directly into the infected uterus, diagnosed using a metricheck tool, increases the healing and cleansing of the infected endometrium therefore increasing the chance of a fertile cycle and conception to artificial breeding. Improving the healing time by one full cycle, 21 days, the cow has the chance to conceive earlier which gives the client more production – Ave 1.7kg MS/day x $7.50 x 21 days = $267.75 per cow. Animal welfare is foremost in the concept of MetriKlenz.

• A pre trial was organised over 5 farms, 2100 cows checked and 380 treated, a total of 18% infected. • Treatment was of the ‘at risk’ cows, cows that were late calving and infected ‘dirty’. These are the hardest to get in calf,

generally remain the late calving cows, and produce less than their peers due to massive infection, late calving and require >3 cycle to conceive.

• The table below shows amazing results:• Late calving and dirty cows are the hardest to get back in calf especially to AB mating. An average of 76.4% of the

treated cows managed to get in calf during the first 2 cycles of AB, well above the NZ herd average of 68%.• This product is now on the market.

Proof of Concept – Dairy industry

Products developed and market ready

– Broad spectrum Preservative Liquid K7 Totarol has completed development, patented and registered INCI name

– New T2G Mastitis, Metritis treatments are still under development and require extra funding. – Our new T2G-Active teat spray application is awaiting registration.– Pyoderma Natural Dog Shampoo and sprays are waiting registration– Wound balms , teat balms, awaiting trials

All products are 100% natural in make-up where possible!

Commercial partnerships are being established to get market registration and distribution on:•Bovine, Equine and pet care products•Mastitis and Metritis in Dairy herds; products such as Teat sprays and balms•Mud fever products for horses •Skin and wound care in the pet industry and human application

Current projects

• We have combined Totarol, Liquid K7 Totarol and CBLS in organic cosmetic products that have both acted as a broad spectrum preserving agents in a challenge test; stopping organism activity but in another test using Totarol and CBLS at the same rates but with different carriers acted as a stimulator to the repair of wounds.  After 24 hours the wound size was 86.9% of the control untreated wound (that is, it appeared to be healing at a 15% faster rate).  This slightly faster rate was still maintained at 48 hours (17.7% faster).  However after 68 hours this healing rate had increased considerably and the wound healing rate was now 36.6% faster than that for the control cultures.

• This sample had no effect on the production of Type I collagen.  However there was some elevation of Type III collagen synthesis and secretion.  It was approximately 6.7 times greater. 

The Science

Table 1: MIC of Totarol-containing extract against Gram-positive bacteriaBacterial strain Antibiotic resistance MIC (μg/mL)

Staphylococcus aureus Acc2243 Not resistant 8

Enterococcus faecalis Acc2244 Not resistant 8

Staphylococcus aureus MRS02/2215 Epidemic MRSA 4

Staphylococcus aureus MRS02/2214 Multiresistant MRSA 4

Staphylococcus aureus MRS/02/2249 Community MRSA 8

Enterococcus faecalis Acc2244 High-level gentamicin 8

Enterococcus faecalis Acc2244 Vancomycin 4

Streptococcus pyogenes ARL02/752 Erythromycin 4

The Science • Excellence in science and innovation has produced multi-functional technology with immense market

potential in areas such as animal and human health, cosmetics, food and nutrition. T2G Biotechnology’s current focus is producing animal health treatments, specifically products for mastitis-related treatment and prevention in the dairy industry. Products for cosmetics and companion animals have already been developed. We can replace antibiotics and Iodine from the Dairy industry!

 • Recent decades have seen a substantial increase in resistance to antibiotics in both humans and animals.

There is now a global push to reduce antibiotic use in animals in an effort to slow rates of resistance in humans. The key issue is that if levels of resistance reach a critical mass, few alternatives to antibiotics currently exist to take their place. TotarolTM provides an alternative.

• TotarolTM extract has activity against bacteria that cause acne (Propionibacterium acnes) and tooth decay (Streptococcus mutans); it is active against Staphylococcus aureus (leading cause of skin infections in humans and mastitis in dairy cows). It is one of the rare phytochemicals active against so-called ‘superbug’ methicillin-resistant Staphylococcus aureus (MRSA).

 • Laboratory testing on a recently developed TotarolTM-containing formulation demonstrated antibacterial

activity that was several orders of magnitude greater than selected antibiotics against Staphylococcus aureus and Streptococcus uberis, even at low concentrations of TotarolTM.

 • Independent analysis by Trinity Bioactives compared the activity of T2G’s teat spray formulation on S. aureus

and S. uberis against the activity of penicillin and tetracycline and the spray formulation was several orders of magnitude more effective than the antibiotics. The same testing demonstrated 100% inhibition rates after 16hrs, 24hrs and 41hrs at TotarolTM concentration levels as low as 0.005%. Test results are available for review.

•Bio-actives are the next generation components in wound management technologies with their market share expected to double over the next 3 years. A key element is going to be getting cost effective bio-actives, which are just as effective or better than normal applications and are also environmentally friendly. •The natural products identified in addition to the anti-bacterial activities of Totarol™ are all easily sourced. This ensures that products developed from this technology will be able to enter the market place in volume and at a low cost to the producer.•T2G technology provides cell migration which is vital for wound healing. CBLS and Totarol™ combine to stimulate a cell’s ability to migrate by initially targeting endogenous estradiol receptors due to the compounds ability to act as a phytoestrogen. This leads to the production of VEGF (vascular endothelial growth factor) in endothelial cells that line blood vessels. VEGF binds to its receptors and triggers a cellular response based on the concentration of VEGF produced.

•Aortic ring assay used to demonstrate angiogenesis Stages of Blood Vessel Formation

Summary of the Science

Markets

• It is essential for growth and return that we produce and manufacture our own finished products and do not stay a raw material supplier and retain our science and technologies.

• Key markets we have indentified are in the health and healing markets particularly in the Bovine industry.

Mastitis• 1993 Holdaway study put the cost of Mastitis at $85 /cow/year or NZ$380m in total

treatment costs. The study was revisited in 2005/6. All current treatments are penicillin based and the disease is showing evidence of resistance. The incidence of Mastitis has risen and highlights the need to look for alternatives, given that milk loss and retention costs could double the ‘real’ cost to the dairy sector. Estimates suggest preventative treatment of 4.5m cows with Totarol™ at $30 per cow per season or $135m in total treatment costs, thus saving the sector $55 per cow ($240m).

Metritis• Delayed conception as a result of this condition results in increased costs and

reduced production. Pre Artificial Breeding conditioning of the Uterus dramatically improves conception rates for the first cycle. A 2010 study with 3500 cows showed this procedure led to an increase in production that equated to $267.75 per cow.

Markets

Markets

Mende Biotech Ltd and T2G Biotechnology Ltd have the following competitive advantages:

• natural and organic products which are safe for the environment

• multi application products with non-resistant strains of antibiotic activity

• synergistic ingredients with a wide range of additional applications and potential markets

• because Totarol does not move into the blood stream, no milk withholding for mastitis

• 200+ years of supply

• Mende Biotech Ltd is the only commercial supplier of Totarol

• Patents have been established on several products with more to come with new technologies especially regarding delivery systems, which will be stable and cost effective.

Market Advantage

•Complete R&D and market registrations•Confirm multi national partnerships•Secure business funding to go forward

Ongoing• Totarol can be made cheaply but an infrastructure investment will be required so products are competitive to market prices at the moment.•Increase our global market of Totarol sales especially with L’Oreal and other international players

Present needs

Present Business Structure:

Doug Mende: overall management, science and manufacture.Doug has extensive experience in native land management and commercialization research in New Zealand Native plants, which lead to setting up Mende Biotech. The past 16 years developing Totarol™ and other bio-actives; developing Super Critical extraction technology for solids like Totarol™ , Manool, Taramea and a number of other compounds, development to finished product market development. Doug won the New Zealand 2008 Natural Product Science and Technology award.

Lorraine Moloney: Administration, accounts

Kieran Nolan: Business management

Reinhard Hueber: International Marketing of Totarol

Present business Structure

• Arcelin, G. Totarol: Acute Toxicity Study in Rats. RCC Study Report Number 847905, 2003• Tognucci, A. Determination of the flammability of Totarol. RCC Study Report Number 847904, 2003 • Bendall, J. G.; Cambie, R. C. Totarol: A non-conventional diterpenoid. Aust. J. Chem., 48, 1995, 883-917• Haraguchi, H.; Ishikawa, H.; Sakai, S.; Ying, B.-P.; Kubo, I. Inhibition of lipid peroxidation by diterpenoid from Podocarpus nagi.

Experientia, 62, 1996, 573-576• Mende Biotech Ltd. Totarol information pack. Sourced from: http://www.docs.totarol.com• Kubo I, Muroi H, Himejima M. Antibacterial activity of Totarol and its potentiation. Journal of natural products 1992; 55(10): 1436-40. • Muroi H, Kubo I. Antibacterial activity of anacardic acid and Totarol, alone and in combination with methicillin, against methicillin-

resistant Staphylococcus aureus. Journal of Applied Bacteriology 1996; 80(4): 387-94. Full text not available.• Moorhead SM, Bigwood T, AgResearch. Report on the efficacy of Totarol and Totarol in combination with tea tree oil as an

antimicrobial against gram-negative bacteria. Client report for Mende-DEK Ltd Nov 2003. • Evans GB, Furneaux RH, Gainsford GJ, Murphy MP. The synthesis and antibacterial activity of Totarol derivatives, part 3: modification

of ring-B. Bioorganic and medicinal chemistry 2000; 8(7): 1663-75.• Clarkson C, Musonda CC, Chibale K, Campbell WE, Smith P. Synthesis of Totarol amino alcohol derivatives and their antiplasmodial

activity and cytotoxicity. Bioorganic and medicinal chemistry 2003; 11(20): 4417-22. Full text not available.• Wikipedia – the free encyclopedia. Available at: http://en.wikipedia.org/wiki• Constantine GH, Karchesy JJ, Franzblau SG, LaFleur LE. Totarol from Chamaecyparis nootkatensis and activity against Mycobacterium

tuberculosis. Full text not available.• Micol V, Mateo CR, Shapiro S, Aranda FJ, Villalain J. Effects of Totarol, a diterpenoid antibacterial agent, on phospholipid model

membranes. Biochimica et Biophysica Acta 2001; 1511(2): 281-90. Full text not available.• Haraguchi H, Oike S, Muroi H, Kubo I. Mode of antibacterial action of Totarol, a diterpene from Podocarpus nagi. Plata Medica 1996;

62(2): 122-5. Full text not available.• AMA Laboratories Inc. 50 human subject repeat insult patch test skin irritation / sensitisation evaluation (occlusive patch) Jan 2000.• Webster GF. The pathophysiology of acne. Cutis 2005; 76(2 suppl): 4-7. Full text not available.• [1] Dreno B, Foulc P, Reynaud A, Mose D, Habert H, Richet H. Effect of zinc gluconate on propionibacterium acnes resistance to

erythromycin in patients with inflammatory acne: in vitro and in vivo study. European journal of dermatology 2005; 15(3): 152-5. Full text not available.

References to support presentation

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Links to companies using Totarol

http://www.totarol.comDocuments site: www.docs.totarol.com Logon:doug Password: farmer