Birch triterpenes - An Overview

Drug Overview

Birch triterpenes, a topical gel comprising a dry extract from two species of birch bark, has obtained FDA approval for at-home application during dressing changes. This endorsement applies to patients aged six months and older, encompassing those with both junctional and dystrophic epidermolysis bullosa. The FDA (U.S. Food and Drug Administration) approved it as a topical gel in 2023.For Patients:

What Are the Clinical Indications for Birch Triterpenes?

Birch triterpenes are indicated for treating rare and severe forms of epidermolysis bullosa (EB), characterized by blister formation that may commence during infancy.

What Is the Dosage of Birch Triterpenes?

The recommended topical application involves applying it to the wound surface with an approximate thickness of one millimeter, and it should either be covered by a dressing or directly applied to the wound dressing.

What Are the Things to Inform the Doctor Before Taking the Drug?

The patient must inform the doctor if they are on other medications before starting this drug. They should also inform them about the below-mentioned conditions:

• Pregnancy.

• Heart disease.

• Liver disease.

• Migraines.

• Seizures.

• Kidney diseases.

• Stroke.

• Cancer.

• Depression.

• Breastfeeding.

• Diabetes.

How Are Birch Triterpenes Administered?

Birch triterpenes are typically administered topically. The recommended application involves applying the topical gel directly to the wound surface at a thickness of approximately 1 mm. It can either be covered by a dressing or applied to the wound dressing during the treatment.

What Are the Side Effects of Birch triterpenes?

• Headaches and dizziness.

• Redness.

• Itching.

• Itchy Bumps.

• Skin Rash.

Storage:

Keeping the drug in its original package and container is necessary. It must be safely secured and out of the children's reach. This action ensures their safety. Since bathrooms have substantial moisture levels, never keep or store drugs there. It should always be kept for storage at the optimal room temperature. Keep the temperature between 20 and 25 degrees Celsius.

For Doctors:

Indication:

A topical gel containing birch triterpenes has been approved for treating wounds associated with dystrophic and junctional epidermolysis bullosa in individuals six months and older. This approval extends to both adult and pediatric populations.

Dose:

Apply a one-millimeter-thick layer to the affected wound area.

Dosing Considerations:

• Wash hands before and after applying Birch triterpenes or use gloves during application.

• Apply a one mm layer of Birch triterpenes to the affected wound surface without rubbing it in.

• Cover the treated wound with a sterile, non-adhesive dressing, or apply Birch triterpenes to the dressing to establish direct contact with the wound.

• Administer Birch triterpenes to clean wounds during dressing changes until the wound achieves healing.

• If a Birch triterpene-treated wound becomes infected, discontinue treatment until the infection resolves.

• Each Birch triterpenes tube is for one-time use only; use the product immediately upon opening and discarding the tube.

• Do not touch eyes or mucous membranes; flush the area with water if accidental contact occurs.

• Birch triterpenes are for topical use only and should not be applied to mucous membranes or in the eyes.

What Are the Pharmacological Aspects of Birch Triterpenes?

Mechanism of Action:

The mechanism of action of Birch triterpenes in treating wounds associated with epidermolysis bullosa is currently not understood.

Pharmacodynamics:

• Anti-Inflammatory Effects: Birch triterpenes, particularly betulin and betulinic acid, have demonstrated anti-inflammatory effects in various studies. Inflammation is an intricate biological reaction that includes immune cells, blood vessels, and molecular mediators. Birch triterpenes have the potential to regulate inflammatory pathways by inhibiting pro-inflammatory cytokines and enzymes like cyclooxygenase-2 (COX-2) and lipoxygenase (LOX). By interfering with these pathways, Birch triterpenes can mitigate inflammatory responses.

• Antioxidant Activity: Oxidative stress ensues when there is a disparity between the generation of reactive oxygen species (ROS) and the body's capacity to counteract them. With their antioxidant properties, Birch triterpenes help counteract oxidative stress by scavenging free radicals. This can prevent cellular damage and contribute to the overall maintenance of cellular health. The protective role of antioxidant activity is essential in shielding cells from the detrimental consequences of oxidative stress, a factor implicated in various diseases, including neurodegenerative disorders and cardiovascular conditions.

• Anticancer Potential: Betulinic acid, a prominent Birch triterpene, has shown promise in cancer research. Studies indicate that Betulinic acid induces apoptosis in cancer cells. Apoptosis is a programmed cellular self-destruction process vital for preserving normal cellular balance. By triggering apoptosis in cancer cells, Betulinic acid may contribute to inhibiting the growth and spread of certain types of cancer. The mechanism of action may involve interference with signaling pathways that regulate cell survival.

• Antimicrobial Activity: Birch triterpenes may exhibit antimicrobial properties, making them effective against certain microorganisms. These antimicrobial effects could be attributed to the ability of triterpenes to disrupt the cell membranes of bacteria or fungi, leading to their inhibition or destruction. This antimicrobial activity is of interest for potential therapeutic applications, such as in developing antimicrobial agents or herbal remedies with antibacterial or antifungal properties.

Pharmacokinetics:

Absorption:

• Specific Compound Variability: The absorption of Birch triterpenes in the gastrointestinal tract is influenced by specific compounds, such as betulin and betulinic acid. Different compounds may exhibit varying degrees of absorption due to differences in their chemical structures.

• Solubility and Formulation: Solubility in the gastrointestinal fluids and the formulation of the Birch triterpenes (e.g., as part of an extract or in a specific dosage form) play a crucial role in determining absorption efficiency. Lipophilic compounds may be absorbed more readily.

Distribution:

• Tissue Distribution: Once absorbed, Birch triterpenes can be distributed throughout the body. The extent of distribution to various tissues is influenced by factors such as the lipophilicity of the compounds. Lipophilic substances tend to distribute into fatty tissues more readily than hydrophilic ones.

• Protein Binding: The binding of Birch triterpenes to plasma proteins can affect their distribution. Binding to proteins may impact the bioavailability and the amount of free, active compounds available for therapeutic effects.

Metabolism:

• Hepatic Metabolism: Birch triterpenes, especially betulin, undergo metabolism in the liver. Enzymatic processes within the hepatic cells may transform the parent compounds into various metabolites. The liver's role in metabolism is crucial for detoxifying and eliminating these compounds.

Elimination:

• Liver and Kidney Clearance: The liver and kidneys significantly eliminate Birch triterpenes and their metabolites. The liver processes these compounds, and the resulting metabolites are often excreted via the kidneys. Biotransformation processes in the liver may convert lipophilic compounds into more water-soluble forms for easier renal clearance.

• Biotransformation: Biotransformation involves enzymatic modifications that make the compounds more suitable for elimination. Conjugation reactions, such as glucuronidation, sulfation, and methylation, may contribute to forming water-soluble metabolites.

Half-Life:

• Variability: The half-life of Birch triterpenes can vary widely among individuals. Factors such as the specific compound being studied, individual variations in metabolism, and the dosage form used can all influence the half-life.

• Dosage Form Impact: The formulation of the Birch triterpenes, such as whether they are administered as an extract, capsule, or another form, can impact the rate at which the compounds are absorbed, metabolized, and eliminated, thus affecting the overall pharmacokinetics.

Clinical Studies And Efficacy:

The safety profile of Birch triterpenes was assessed in the EASE trial, a randomized, double-blind, multicenter, placebo-controlled study involving 223 participants with inherited epidermolysis bullosa (EB), including both adults and pediatric subjects. The study comprised a 90-day double-blind segment, wherein participants were randomly assigned to receive either Birch triterpenes or a placebo gel for the topical treatment of partial-thickness wounds at intervals ranging from one to four days. Non-adhesive dressings were applied to the treated wounds. Subsequently, all participants received Birch triterpenes for an additional 24 months in the open-label phase. Here are the key points regarding adverse reactions observed during the double-blind phase:

Adverse Reactions in ≥ 2 % of Subjects:

• Application site reactions, including application site pruritus, administration site pain, and administration site pruritus, occurred in seven percent of subjects treated with Birch triterpenes, compared to six percent in the placebo gel group.

Squamous Cell Carcinoma (SCC):

• Squamous cell carcinoma of the skin (SCC) was reported as an adverse event during the EASE trial's double-blind and open-label periods.

• Four subjects with recessive dystrophic EB, including a 20-year-old male during the double-blind period and three female subjects aged 22, 46, and 49 years during the open-label period, reported one SCC each.

• Two of the four subjects applied Birch triterpenes to where SCC developed.

What Are the Contraindications of Birch Triterpenes?

There are no contraindications present.Warnings and Precautions:

Hypersensitivity reactions, as well as local hypersensitivity and skin responses, have been documented in individuals undergoing treatment with Birch triterpenes. Reported manifestations include conditions such as urticaria (hives) and dermatitis.

Specific Considerations:

Pregnancy:

• Risk Summary: There is insufficient data on the utilization of Birch triterpenes during pregnancy, and no details are provided regarding the potential risks of significant birth defects, miscarriage, or adverse outcomes for both the mother and fetus. Animal studies involving oral administration of Birch triterpenes to pregnant rats during organogenesis showed no effects on reproductive or fetal parameters. The systemic absorption of Birch triterpenes in humans following topical administration is low, and fetal exposure is not anticipated.

• Background Risk: The baseline risk of major birth defects and miscarriage in the general population is unknown for the indicated population. Within the general population of the United States, the anticipated baseline risk for significant birth defects is in the range of two to four percent. In comparison, the risk of miscarriage is estimated to be between 15 and 20 percent.

• Animal Data: Animal studies on pregnant rats did not show maternal toxicity or fetal malformations at doses up to 100 mg/kg/day during organogenesis. Birch triterpenes did not affect development at doses up to 100 mg/kg/day in another study covering prenatal and postnatal development. However, available data does not support direct comparisons of systemic exposure between animal studies and human topical use.

Lactation:

• Risk Summary: There is a lack of information regarding the occurrence of Birch triterpenes or their metabolites in human breast milk, as well as their potential effects on the nursing infant and their influence on milk production. Since systemic exposure to Birch triterpenes in breastfeeding women using the drug topically is expected to be low, adverse effects on the breastfed infant are not anticipated. Nevertheless, given the clinical necessity of Birch triterpenes and their potential consequences for the breastfed infant, it is essential to carefully balance the developmental and health advantages against any possible risks.

Pediatric Use:

• Safety and Effectiveness: Birch triterpenes, specifically Birch triterpenes, are safe and effective for treating dystrophic and junctional EB wounds in pediatric patients six months and older. Evidence supporting its use in this age group comes from a single randomized, placebo-controlled trial involving 156 subjects aged six months to 17 years.

• Age Limitation: The safety and efficacy of Birch triterpenes, including their use in pediatric patients below six months of age, have not been verified.

Geriatric Use:

• The available clinical studies on Birch triterpenes need an adequate representation of subjects aged 65 and older with Epidermolysis Bullosa (EB). Consequently, the data from these studies needs to provide more information to determine whether the responses to Birch triterpenes in this older age group differ from those observed in younger subjects.

The specific impact of Birch triterpenes, including potential efficacy and safety considerations, remains unclear for individuals aged 65 and older with EB. It is important to note that the lack of inclusion of a significant number of elderly subjects in clinical trials is common and may be due to various reasons, including eligibility criteria, potential comorbidities, or specific characteristics of the target population.

Therefore, caution should be exercised when considering the use of Birch triterpenes in individuals 65 and older, as the available evidence is insufficient to conclude the treatment's effects and tolerability in this particular age group. Additional research or specific studies involving elderly populations would be necessary to understand better the implications of Birch triterpenes in managing EB in individuals aged 65 and older.