Treatibles Takakura CBD Meeting

Date: May 27, 2022

Presenter: Chie MOGI, D.V.M., Ph.D.

1. Clinical Parameters After CBD Use

• Subjects: Five dogs, age average $11.4 \pm 3.8$ years (range 5–15 years).

• CBD Products: [Treatibles] Organic hemp oil 250 mg.

• Evaluated Parameters:

  • Blood biochemical tests

  • Inflammatory response: CRP

  • Haemostasis: SDMA

  • Blood oxidation indices: d-ROMs and measurement with BAP reagents (Wismerll Reagents).

Key Findings

• Indicators of renal, hepatic, and immune function: Pre- and post-treatment comparisons of SDMA, ALT, and CRP showed no significant changes.

2. Case Report: Maltese with Constant Licking Disorder

• Patient: Neutered male, 4 years 0 months old, 2.5 kg.

• Symptoms: Continuous licking of the penis, abdomen, and hind legs when eating, dysphoria (picking up food while walking), and defensive aggressive behavior.

• Treatment:

  • Sweet Potato Soft Chewables – 3 mg CBD for Dogs (Treatibles / AD Remedies, Inc., TN, U.S.A.), three times a day ($3.2 \text{ mg/kg/day}$).

  • From Day 91 onwards, adjusted to one piece at 8:00 AM and one at 5:00 PM ($2.1 \text{ mg/kg/day}$).

  • Concomitant use with Prednisolone ($1.25 \text{ mg}$ once every 3 days) and Oclacitinib ($0.9 \text{ mg}$ SID; given for 2 days, skipped the next day).

• Published Study Reference:

  HSOA Journal of Alternative, Complementary & Integrative Medicine

  Use of Prednisolone, CBD and Behavior Modification as a Treatment for Atopic Dermatitis in a Canine: A Case Report

  Chie Mogi, Koji Kawano, Norihito Mizuno, Takaaki Fukuyama

   

3. Case Report: Avulsion Fracture of Patella

• Patient: Mixed breed, 11-year-old neutered male.

• History: Sustained a knee injury during a walk and became almost immobile; diagnosed with an avulsion fracture on X-ray and placed on conservative treatment.

• Intervention: Application of Treatibles Organic Hemp Cream to the knee.

• Outcome: Two hours after application, the patient was able to climb stairs and urinate independently.

4. Case Report: Separation Anxiety

• Patient: Labrador, 1-year-old, shelter dog.

• Symptoms: Strong attachment to the owner and excessive barking due to demands.

• Outcome: 20 minutes after eating a Treatibles Soft Chew Calm (sweet potato flavor), the dog lay down and fell asleep.

5. Case Studies of CBD Interventions in Advanced Senior Years

Four Toy Poodles evaluated at Dog Salon Taroimo:

• Knight: 16y, Male | Treatibles Hard Chew Ease ($1.2 \text{ mg/kg/day}$)

• Tom: 15y, Male | Treatibles Hard Chew Ease ($1.2 \text{ mg/kg/day}$)

• Greece: 16y, Female | Mary’s Tales – 300mg CBD Hemp oil ($1.2 \text{ mg/kg/day}$)

• Takeo: 15y, Male | Mary’s Tales – 300mg CBD Hemp oil ($1.36 \text{ mg/kg/day}$)

Summary of Physical Examinations and Blood Findings (Tougasaka Veterinary Hospital)

• Weight slightly decreased in all three animals while a high appetite was maintained.

• Blood tests showed no significant changes across all three dogs.

• Knight: Renal and hepatic functions unchanged; mild anemia progressed, potentially associated with chronic disease.

• Greece: Renal function and anemia levels unchanged; liver enzymes (ALP) elevated, SDMA lowered, BUN unchanged, CRP slightly elevated.

• Takeo: Renal function and anemia levels unchanged; liver enzymes (ALP) elevated, BUN elevated, SDMA decreased, ALT rising slightly, CRP slightly decreased.

6. Epilepsy Case Study

• Patient: Lakeland Terrier, 4 years old, male, with concomitant use of the antiepileptic drug zonisamide.

• Transition: Switched from Mary’s 300 to Treatibles 250.

• Results:

  • Mary’s 300 (Started June 18, 2019): 8 drops BID ($1.56 \text{ mg/kg/day}$), seizure interval of 49.5 days.

  • Day 454 (Treatibles 250mg): 8 drops start ($0.68 \text{ mg/kg/day}$), seizure interval extended to 82.5 days.

  • Day 571: Dose increased to 16 drops BID ($1.36 \text{ mg/kg/day}$) with an added $1.6 \text{ mg}$ PRN, seizure interval 54 days.

  • Additional Instructions: CBD gel pen instructed for use every night and after each seizure.

7. Pharmacokinetics: Route of Delivery Comparisons

• Delivery Methods: Oral, Transdermal, Inhalation (not for pets).

• Pharmacokinetic Data (from Bartner et al., 2018):

  • CBD oil has an average retention time of 217 minutes and a half-life of 200 minutes.

  • Transdermal cream has an average retention time of 298 minutes and a half-life of 128 minutes.

  • Bioavailability is 8.6 for transdermal cream compared to 100 for CBD oil.

  • Oral administration undergoes a first-pass effect in the liver where most of it is broken down.

Translated Diagram: Blood Concentration Profile of Transdermal Formulations vs. Oral Medications

• Y-axis: Drug blood concentration

• X-axis: Time

• Curves & Markers:

  • Oral medication 

  • Transdermal formulation 

• Therapeutic Zones:

  • Toxic range 

  • Therapeutic / Effective range 

  • Subtherapeutic / Ineffective range 

• Key Actions: Oral administration , Application / Patch , Removal / Peeling .

• Reference Translation: Modified from: Tetsuo Shiobara, Michiteru Otani (Supervisors), Q&A for Mastering Clinically Useful Transdermal Formulations, Aruta Shuppan, 2012 (from B).

Advantages of Transdermal Formulations

• Increased drug bioavailability.

• Maintenance of a stable, effective blood concentration range for a longer period.

• Less prone to fluctuations in efficacy and reduced side effects.

• Easier to use as it eliminates the time and effort required for forced administration.

8. Terpene Entourage Effects & CBD Pharmacology

• General Terpenoid Benefits:

  • Humulene: Antioxidant, antibacterial, analgesic, appetite suppressant.

  • Alpha and Beta Pinene: Anticancer and anti-inflammatory effects; crosses the blood-brain barrier, increases BDNF production, and has antidepressant effects.

  • Linalool: Calming effect, strong analgesic and bactericidal properties, activates immune cells, and has anti-inflammatory properties.

  • Beta-Caryophyllene: Chronic pain relief, anxiolytic, and antidepressant effects.

  • Myrcene: Sedative and analgesic action; facilitates CBD crossing the blood-brain barrier.

  • Limonene: Relieves anxiety symptoms; promotes transdermal absorption of CBD.

• Anxiolytic Effect of CBD without THC:

  • Exogenous cannabinoid administration involving CB1 agonists exhibits a biphasic, dose-dependent effect on anxiety: low doses are anxiolytic, while high doses are anxiogenic (evident in both rodents and humans).

9. Product Trial Impressions (Treatibles New Products)

• Leonberger (Sora, 6y, male, 132 lbs): Tested Treatibles Soft/Hard chew strong. Remained normal and relaxed during temperature shifts, showing normal or slightly more forward behavior during walks.

• Norwich Terrier (11y, male): Tested Treatibles Soft Chew for noise phobias (thunder, earthquakes, construction). Initially needed flavoring and higher dosing to calm down, which improved responsiveness when called.

• Norwich Terrier (12y, female, hind-limb lameness): Tested Treatibles CBD Unflavored Oil. Significant mobility improvements; regained the ability to stand up independently and play energetically.

10. Probiotics and Feline Applications

• Comparison of Probiotic Products: Introduction of Treatibles Happy Tummy Formula Soft Chewables.

• Cats with Mouth Ulcers:

  • Trial using Treatibles Soft Chews for cats without antibiotics.

  • Owners successfully administered by sprinkling liquid treats on top since cats wouldn’t eat them plain.

  • Palatability feedback from a leading Japanese breeder of American Shorthairs suggested chicken flavoring would be preferred.