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The Wound Healing Properties of Betulin from Birch Bark from Bench to Bedside
Abstract
With central European approval in January 2016 for a betulin-oleogel (Episalvan), used to accelerate wound closure in partial thickness wounds, the herbal active ingredient triterpene dry extract (betulin), from birch bark, was introduced into therapy for the first time. Clinical evidence of accelerated wound healing was provided in a new study design by means of intraindividual comparison of split-thickness skin graft donor wounds and burn wounds. Clinical results of a phase II study evidencing accelerated wound healing in the rare disease epidermolysis bullosa are also available, and a pivotal multi-centre phase III study is currently being conducted. The mode of action affects all three phases of wound healing (inflammation, migration, and differentiation), and it has been possible, in some cases, to shed light on this down to the molecular level. After temporary stimulation of the inflammatory phase, the keratinocytes migrate more rapidly to the wound closure and, finally, epidermal differentiation is stimulated. With this project, we have shown that scientifically founded new developments in phytotherapy are possible in Europe. The active ingredient is new and its indication is for the first time clearly proven in studies. Betulin-oleogel is the first drug of its indication and is patented until 2030. In addition, it is the first phytotherapeutic agent in surgery, and thus opens up a new therapeutic area for phytotherapy. The birch bark contains about 22% betulin in its cork tissue, meaning that the active ingredient is sustainably available from Northern Europeʼs wood-processing industry on a scale of several 100,000 t/a.
... In the second phase, inflammation subsides as skin cells proliferate and migrate to close the wound. The third and final phase, which is the longest, involves the differentiation, maturation, and remodeling of skin cells to restore the tissue (Scheffler, 2019). Inflammation mediators such as COX-2, IL-6, and IL-8 are temporarily upregulated by the dry extract from birch bark, thanks to its stabilization of their mRNA (half-life increases by a factor of 3.5). ...
... These structures appear as keratinocytes are stimulated to migrate, continuing until they reestablish contact with neighboring cells. Clinically, this manifests in accelerated re-epithelialization (Scheffler, 2019). In the final stage of wound healing, dry extract from birch bark stimulates keratinocyte differentiation markers, promoting the maturation of the skin barrier. ...
... During the early differentiation phase, the expression of involucrin and keratin 10 increases, followed by the upregulation of transglutaminase in the late phase. Ultimately, the birch bark extract specifically triggers terminal differentiation, driving the apoptosis-like transition of keratinocytes into corneocytes (Scheffler, 2019). ...
Skin conditions are a common health concern faced by patients of all ages. For thousands of years, plants have been used to treat various skin conditions, including acne, vitiligo, and psoriasis, to name a few. Today, with increasing patient preference for natural therapies, modern medicine is now more than ever incorporating age-old knowledge of herbal remedies useful in treating skin conditions into modern-day treatments. This review covers various plant-derived therapeutics (polyphenon E [sincatechins], psoralen, salicylic acid, anthralin, podophyllotoxin, and Filsuvez [birch triterpenes, oleogel-S10]) that have demonstrated scientific evidence of clinical efficacy for dermatologic disorders. The discovery, composition, history of use, and current uses in dermatology are summarized for each botanical ingredient.
... HPLC-PDA-MS analyses of the crude extract ( Figure 2) and fractions thereof enabled the elucidation of the rest of the constituents. (7); hesperidin (hesperitin 7-O-rutinoside) (8); rosmarinic acid (9); luteolin 3′-O-glucuronide (10); melitric acid A (12); clinopodic acid I (13); acacetin 7-O-rhamnosylglucoside (14); clinopodic acid O (15); 5,6,3-trihydroxy-7,8,4-trimethoxyflavone (16); acacetin (4′-methylapigenin) (17); melitric acid A methylester (18). ...
... HPLC-PDA-MS analyses of the crude extract ( Figure 2) and fractions thereof enabled the elucidation of the rest of the constituents. (7); hesperidin (hesperitin 7-O-rutinoside) (8); rosmarinic acid (9); luteolin 3 -O-glucuronide (10); melitric acid A (12); clinopodic acid I (13); acacetin 7-O-rhamnosylglucoside (14); clinopodic acid O (15); 5,6,3-trihydroxy-7,8,4trimethoxyflavone (16); acacetin (4 -methylapigenin) (17); melitric acid A methylester (18). (7); hesperidin (hesperitin 7-O-rutinoside) (8); rosmarinic acid (9); luteolin 3′-O-glucuronide (10); depside tetramer-not identified (11); melitric acid A (12); clinopodic acid I (13); acacetin 7-O-rhamnosylglucoside (14); clinopodic acid O (15); 5,6,3-trihydroxy-7,8,4-trimethoxyflavone (16); acacetin (4′-methylapigenin) (17). ...
... (7); hesperidin (hesperitin 7-O-rutinoside) (8); rosmarinic acid (9); luteolin 3 -O-glucuronide (10); melitric acid A (12); clinopodic acid I (13); acacetin 7-O-rhamnosylglucoside (14); clinopodic acid O (15); 5,6,3-trihydroxy-7,8,4trimethoxyflavone (16); acacetin (4 -methylapigenin) (17); melitric acid A methylester (18). (7); hesperidin (hesperitin 7-O-rutinoside) (8); rosmarinic acid (9); luteolin 3′-O-glucuronide (10); depside tetramer-not identified (11); melitric acid A (12); clinopodic acid I (13); acacetin 7-O-rhamnosylglucoside (14); clinopodic acid O (15); 5,6,3-trihydroxy-7,8,4-trimethoxyflavone (16); acacetin (4′-methylapigenin) (17). ...
Satureja pilosa Velen. (Lamiaceae) is a perennial and melliferous aromatic–medicinal subshrub which is range-restricted in adjacent parts of Greece and Bulgaria and locally in Italy, known in Northern Greece as wild oregano (“agriorigani”) and traditionally collected from the wild for culinary purposes. Since the ethnopharmacological data and modern biological activities of Satureja spp. suggest promising applications in skin conditions, the present study aimed to investigate the hitherto unknown phenolic content of cultivated S. pilosa and its potential biological activities, focusing mainly on wound-healing and anti-inflammatory effects. An HPLC-PDA-MS-targeted phytochemical investigation, along with NMR, allowed for the isolation and characterization of the main constituents, resulting in 18 compounds. Representative extracts and purified compounds were tested for wound-healing activity on NIH/3T3 fibroblasts. The butanol extract exhibited a significantly higher cell migration rate (73.4%) compared to aqueous (50.6%) and methanolic (49.6%) ones, enhancing the cell migration more rapidly at both concentration levels, whilst rosmarinic acid was the most potent among the isolated compounds, with a migration rate of 64.0% at the concentration level of 10−5 mg/mL, followed by 3,4-dihydrophenyllactic acid (54.7%). Moreover, potential effects on endothelial activation processes were explored, including the leukocyte–endothelial cell interaction during inflammatory processes and the migratory capacity during angiogenic actions, since these processes are commonly associated with skin diseases. Finally, extracts and purified compounds demonstrated weak antibacterial potential against two important pathogens (Staphylococcus aureus and Pseudomonas aeruginosa), suggesting that further investigation is warrented.
... To address this generic shortfall, Amyrt Pharma has developed Oleogel-S10, composed of 10% birch triterpene extracts, which have been shown to accelerate wound healing by modulating inflammation, stimulating keratinocyte migration, and imparting an antimicrobial effect. 136,137 The active components have previously been used in burn and split-thickness skin graft wounds, and found to accelerate wound healing. 136,137 In 2017, a prospective, placebo-controlled phase II trial in EB showed clinical improvements, where 5 of the 12 treated wounds showed faster re-epithelialization albeit without statistical significance. ...
... 136,137 The active components have previously been used in burn and split-thickness skin graft wounds, and found to accelerate wound healing. 136,137 In 2017, a prospective, placebo-controlled phase II trial in EB showed clinical improvements, where 5 of the 12 treated wounds showed faster re-epithelialization albeit without statistical significance. 138 Recently, a phase III double-blind, randomized, vehicle-controlled trial (EASE) showed that topical Oleogel-S10, applied at least every 4 days, led to complete wound healing in 41% of the patients within 45 days compared to 29% in the vehicle arm. ...
Dystrophic epidermolysis bullosa (DEB) is one of the major types of EB, a rare hereditary group of trauma-induced blistering skin disorders. DEB is caused by inherited pathogenic variants in the COL7A1 gene, which encodes type VII collagen, the major component of anchoring fibrils which maintain adhesion between the outer epidermis and underlying dermis. DEB can be subclassified into dominant (DDEB) and recessive (RDEB) forms. Generally, DDEB has a milder phenotype, while RDEB patients often have more extensive blistering, chronic inflammation, skin fibrosis, and a propensity for squamous cell carcinoma development, collectively impacting on daily activities and life expectancy. At present, best practice treatments are mostly supportive, and thus there is a considerable burden of disease with unmet therapeutic need. Over the last 20 years, considerable translational research efforts have focused on either trying to cure DEB by direct correction of the COL7A1 gene pathology, or by modifying secondary inflammation to lessen phenotypic severity and improve patient symptoms such as poor wound healing, itch, and pain. In this review, we provide an overview and update on various therapeutic innovations for DEB, including gene therapy, cell-based therapy, protein therapy, and disease-modifying and symptomatic control agents. We outline the progress and challenges for each treatment modality and identify likely prospects for future clinical impact.
... The wound was washed daily with saline solution, and appropriate treatment was applied. On days 1, 3,5,7,10,13,15,20,25, and 30, the wound was measured, and photographs were taken prior to the application of the cream. ...
... In addition, it gels oils, thanks to which it creates thixotropic gels, the durability of which is higher at body temperature than at Pharmaceutics 2023, 15, 633 5 of 31 room temperature. After receiving excellent results in toxicology and pharmaceutical safety studies, the era of clinical trials began to clarify the indications where triterpene birch bark extract could be used [20]. ...
Treating burns remains a challenge for modern medicine, especially in developing countries that cannot afford expensive, advanced therapies. This review article summarises clinical and animal model studies of botanical preparations and their mixtures in treating burn wounds and sunburn. Articles available in electronic databases such as PubMed, Scopus, Web of Science, Science Direct and Google Scholar, published in English in 2010–2022, were considered. In the described clinical trials, it was shown that some herbal preparations have better effectiveness in treating burn wounds, including shortening the healing time and reducing inflammation, than the conventional treatment used hitherto. These herbal preparations contained extracts from Albizia julibrissin, Alkanna tinctoria, Aloe vera, Arnebia euchroma, Betula pendula and Betula pubescens, Centella asiatica, Hippophaë rhamnoides, Juglans regia, Lawsonia inermis, and mixtures of Matricaria chamomilla and Rosa canina. Research on animal models shows that many extracts may potentially benefit the treatment of burn wounds and sunburn. Due to the diverse mechanism of action, antibacterial activity, the safety of use and cost-effectiveness, herbal preparations can compete with conventional treatment. The growing interest in alternative medicine and herbal medicine encourages further research. Not only single preparations but also their mixtures should be taken into account because the research conducted so far often suggests a synergistic effect of the ingredients.
... To date, no approved drug is available on the market using wood extracts as antimicrobial agents. However, in the field of wound repair, the first phytochemical based drug called Episalvan has been approved in 2016 (Scheffler 2019). Episalvan is a drug containing the triterpene-rich, purified dry extract from the bark of Betula pendula and B. pubescens using n-heptane as solvent. ...
... Episalvan is a drug containing the triterpene-rich, purified dry extract from the bark of Betula pendula and B. pubescens using n-heptane as solvent. Its indication includes treatment of superficial skin wounds and II-a-degree burn wounds to the skin of adults (Scheffler 2019). In addition, phase 2 clinical studies are currently performed with Episalvan gel or Oleogel-S10 for faster re-epithelialization of wounds in Epidermolysis bullosa patients (Schwieger-Briel et al. 2019). ...
Wood is an important natural resource, and the extracts of specific wood species might have growth-inhibiting effects on certain microbes. This property can be used in the pharmaceutical industry to develop phytochemical-based medicine to treat skin infections. Thus far, methanol, intrinsically toxic, has been the main solvent used for extraction of soluble wood compounds. In this study, the focus was placed on biocompatible solvents, including dimethyl sulfoxide, distilled water, and glycerin, in addition to methanol used to extract compounds from larch, birch bark, Douglas fir, and alder wood sawdust. Microbial growth was tested on four different bacterial strains and one type of fungi representing species that can affect the skin. The results revealed intrinsic toxicity of biocompatible solvents at low concentrations as well as an additive or synergistic effect of wood extracts. In particular, larch and birch extracts strongly decreased microbial growth. In addition, interference of the extract color on the measurements was observed, which must be taken into account to ensure correct analysis of the data. In conclusion, biocompatible solvents in conjunction with larch and birch extracts exhibited antimicrobial effects. The importance of solvent toxicity and background staining were highlighted to determine potential antimicrobial effects.
... Other disclosed triterpenes of the dry extract include lupeol (LU), erythrodiol (ER), betulinic acid (BA), and oleanolic acid (OA), as shown in Table 1 [10]. However, the low solubility of these triterpenes in polar and non-polar solvents makes formulation a challenging task, which might limit their therapeutic application [7,11,12]. For topical application, only a few formulation concepts are known. ...
... For topical application, only a few formulation concepts are known. These include cosmetic water-in-oil creams, water-in-oil foams [8], and an oleogel consisting of TE and sunflower oil, which received the European marketing authorization in January 2016 [12]. To the best of our knowledge, an aqueous colloidal dispersion of TE has not been described so far. ...
This study investigated the formulation and processing of aqueous colloidal dispersions containing a birch bark dry extract (TE) as the active substance and hydrogenated phospholipids (Phospholipon 90H) as stabilizer, which can be used in the preparation of electrospun wound dressings. Colloidal dispersions manufactured using a two-stage homogenization process had a bimodal particle size distribution, which was most significantly (p < 0.0001) affected by the phospholipid content. The size of the single particles decreased from an average particle size of about 4 µm to a particle size of approximately 400 nm. Dynamic interfacial tension studies performed using a profile analysis tensiometer (PAT) showed that the phospholipids strongly declined the interfacial tension, whereas a further decrease was observed when phospholipids were combined with birch bark extract. Interfacial viscoelasticity properties analyzed using the oscillating drop technique resulted in an increase of both interfacial elasticity and viscosity values. These results indicated that the phospholipids are preferentially located at the lipophilic/water interface and a stable film is formed. Furthermore, the results point to a synergistic interaction between phospholipids and TE. Confocal Raman microscopy (CRM) suggested that the TE is predominantly located in the oil phase and the phospholipids at the interface.
... Отмечается, что береста березы проявляет антибактериальную, антигрибковую и противовоспалительную активность, обладает гидрофобно-стью и является антиоксидантом Scheffler, 2019;Судокова и др., 2023]. Большинство исследователей обосновывают, что данные свойства обусловлены содержанием в коре бетулина и его производных, а также суберина Rizhikovs et al., 2022]. ...
Были получены образцы пластика без связующего (ПБС) на основе древесного наполнителя с различным соотношением бересты березы. Образцы ПБС прессовались в герметичной пресс-форме под давлением 40 МПа и температуре 180 °С с последующим ее охлаждением без снятия давления до 40 °С. У полученных образцов были исследованы показатели плотности, прочности при изгибе, модуля упругости при изгибе, твердости по Бринеллю, ударной вязкости, водопоглощения и разбухания за 24 ч, биостойкости по отношению к почво-грунту за 90 суток и активному грунту за 105 суток. Также осуществлялась оценка гидрофобности по краевому углу смачивания. На основании полученных результатов испытаний было установлено рациональное соотношение пресс-композиции на основе березовых опилок с добавлением бересты 50%. При данном соотношении достигаются следующие показатели материала: плотность – 909 кг/м3 ; модуль упругости – 1566 МПа; прочность при изгибе – 8,9 МПа; твердость по Бринеллю – 17 МПа; ударная вязкость – 3,818 кДЖ/м2 ; водопоглощение за 24 ч – 32%; разбухание – 7%. Выявлена зависимость роста биостойкости ПБС с увеличением содержания бересты в пресс-материале, что объясняется ее высокой гидрофобностью и антисептическими свойствами.
Samples of plastic without resin (PWR) were produced using a wood filler with varying proportions of birch bark. The PWR samples were pressed in a sealed mold under a pressure of 40 MPa and at a temperature of 180 °C, followed by cooling without pressure release until reaching 40 °C. The resulting samples underwent testing for density, flexural strength, flexural modulus of elasticity, Brinell hardness, impact toughness, water absorption, and swelling after 24 hours. Additionally, biostability was assessed in soil for 90 days and in active soil for 105 days. Hydrophobicity was also evaluated based on the contact angle. Based on the test results, the optimal composition ratio for the press material was determined using birch sawdust with a 50% addition of birch bark. At this ratio, the material exhibited the following properties: density – 909 kg/m³, modulus of elasticity – 1566 MPa, flexural strength – 8.9MPa, Brinell hardness – 17 MPa, impact toughness – 3.818 kJ/m², water absorption in 24 hours – 32%, and swelling – 7%. A correlation was found between increased birch bark content in the press material and enhanced biostability, attributed to its high hydrophobicity and antiseptic properties.
... Betulin has anticancer activity [64] and is used for the treatment of wound healing [65,66]. Derivates of betulin stimulate collagen synthesis in normal human fibroblasts [67]. ...
This literature review offers an extensive exploration of Chaga mushrooms (Inonotus obliquus), focusing on their phytochemical composition, health-promoting attributes, and mechanisms of action. The aim was to provide an up-to-date overview of Chaga's significance in the medicinal sector, emphasizing its potential role in diverse health benefits. The review highlights Chaga's remarkable anticancer, antioxidant, anti-diabetic, anti-inflammatory, antimicrobial, and immunomodulating properties. By synthesizing recent findings, this work underscores Chaga's importance in the medicinal industries and provides valuable insights into its pharmacological potential.
... Betula alba (birch bark) has been used within traditional medicine across the northern hemisphere and was first used in wound care by the Native American Ojibwe tribe, who would wrap their wounds with birch bark to accelerate healing [67]. Birch bark's healing properties have since been proven clinically using n-heptane dry extract from the outer bark of the birch; 97% of the extract is pentacyclic triterpenes [68] and the triterpene responsible for wound healing is botulin [69]. Ebeling et al. showed that triterpenes significantly increased wound healing in an ex vivo porcine healing model, demonstrating improved skin barrier and enhanced migration when applied to human keratinocytes, mediated through IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling [70]. ...
Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks, a variety of underlying medical conditions can impair the progression through the stages of wound healing, resulting in the development of chronic, non-healing wounds. Great progress has been made in developing wound dressings and improving surgical techniques, yet challenges remain in finding effective therapeutics that directly promote healing. This review examines the current understanding of the pro-healing effects of targeted pharmaceuticals, re-purposed drugs, natural products, and cell-based therapies on the various cell types present in normal and chronic wounds. Overall, despite several promising studies, there remains only one therapeutic approved by the United States Food and Drug Administration (FDA), Becaplermin, shown to significantly improve wound closure in the clinic. This highlights the need for new approaches aimed at understanding and targeting the underlying mechanisms impeding wound closure and moving the field from the management of chronic wounds towards resolving wounds.
... Continuing with the analysis of innovative therapies, two important therapies, considered orphan drugs for EB ("Orphan drug" is a drug used in rare diseases) are Oleogel S10, also called betulin or birch bark extract, which is known to be topically useful in the healing of EB wounds. The dry extract of birch bark promotes keratinocyte differentiation in vitro and in vivo [72,73]. Allantoin is a substance that has a keratolytic, bactericidal, anti-inflammatory and fibroblast proliferation and synthesis of extracellular matrix [74]. ...
Epidermolysis bullosa (EB) is the overarching term for a set of rare inherited skin fragility disorders that result from mutations in at least 20 different genes. Currently, there is no cure for any of the EB subtypes associated with various mutations. Existing therapies primarily focus on alleviating pain and promoting early wound healing to prevent potential complications. Consequently, there is an urgent need for innovative therapeutic approaches. The objective of this research was to assess the efficacy of various topical treatments in patients with EB with the goal of achieving wound healing. A secondary objective was to analyse the efficacy of topical treatments for symptom reduction. A literature search was conducted using scientific databases, including The Cochrane Library, Medline (Pubmed), Web of Science, CINHAL, Embase, and Scopus. The protocol review was registered in PROSPERO (ID: 418790), and inclusion and exclusion criteria were applied, resulting in the selection of 23 articles. Enhanced healing times were observed compared with the control group. No conclusive data have been observed on pain management, infection, pruritus episodes, and cure rates over time. Additionally, evidence indicates significant progress in gene therapies (B-VEC), as well as cell and protein therapies. The dressing group, Oleogel S-10, allantoin and diacerein 1%, were the most represented, followed by fibroblast utilisation. In addition, emerging treatments that improve the patient’s innate immunity, such as calcipotriol, are gaining attention. However, more trials are needed to reduce the prevalence of blistering and improve the quality of life of individuals with epidermolysis bullosa.
... The resins of P. vera shows a large presence of terpene derivatives, namely monoterpenes (hydrocarbons and oxygenated) in their essential oils, which have previously been successfully tested as wound healing products [27], and not volatile triterpenes. All these metabolites have a wide range of pharmacological effects, including anti-inflammatory, cardioprotective, neuroprotective, hepatoprotective, nephroprotective, antibacterial, antiviral and wound healing properties too [39][40][41][42][43][44]. ...
This study aimed to investigate the phytochemical composition and biological activity of Salsola tetragona Delile. (Amaranthaceae), a medicinal plant. The study evaluated the antioxidant potential of the crude extract and five fractions of S. tetragona using DPPH•, ABTS•+, CUPRAC, and metal chelating assays. The anti-inflammatory activity was determined using a protein denaturation assay, and the antibacterial activity was determined by the Minimum inhibitory concentrations (MICs) for the growth of Escherichia coli and Staphylococcus aureus strains. The MTT test and an in vitro scratch assay evaluated the effects on cell viability and cell migration. The potential anti-SARS-CoV-2 activity was assessed by analyzing the effects on the interaction between ACE2 and Spike protein. The bioactive compounds present in the plant were identified using LC-HR/MS analysis. The crude hydromethanolic extract (STM) and five fractions of S. tetragona, n-hexane (STH), dichloromethane (STD), ethyl acetate (STE), n-butanol (STB), and aqueous (STW) showed significant antioxidant activity in four different tests. In the anti-inflammatory assay, the ethyl acetate fraction exhibited significantly higher activity than Aspirin® (IC50 = 13 ± 5 µg/mL). The crude extract and its fractions showed positive antibacterial activity with similar MICs. In the cytotoxicity assay against the breast cancer cell line MCF7, the dichloromethane fractions (STD) were very effective and demonstrated superiority over the other fractions (IC50 = 98 µg/mL). Moreover, the potential of the extract and fractions as anti-SARS-CoV-2, the ethyl acetate, and dichloromethane fractions demonstrated important activity in this test. LC-HR/MS analysis identified 16 different phenolic compounds, Eleven of which had not been previously reported in the genus Salsola. The results suggest that the extracts of S. tetragona have the potential to become new sources for developing plant-based therapies for managing a range of diseases.
... The powdered triterpenes, in addition to their dermatological action, have a stabilising effect on the preparation. Oleogel-S10 (trade name Episalvan®) was approved by the European Medicines Agency in January 2016 [36][37][38]. ...
Betulin (BN) is a natural lupane-type triterpene extracted from many plant species. Its main source is the outer bark layer of birch trees of the Betulaceae family. BN exhibits a number of biological properties, including anti-inflammatory, antioxidant, anticancer and bacteriostatic effects. The article aimed to present the biological properties of BN and its plausible use in cosmetology and dermatology. BN and its derivatives have significant therapeutic potential, which opens wide possibilities for their use in the treatment of various skin diseases.
... It should be noted that one of the first medicines based on betulin, Episalvan gel, passed clinical trials, and is recently approved for the treatment of skin wounds and burn wounds. 2 A great number of publications are devoted to the pharmacological activity of betulin, which are summarized in reviews of recent years. ...
Betulin, a natural triterpene possessing a wide range of biological activities, has been modified via Steglich esterification to produce a methacrylate derivative capable of participating in radical polymerization. The modification is intended to increase the solubility of betulin, which is almost insoluble in water, by incorporating into the composition of an amphiphilic copolymer. The resulting solubility of betulin in water increased from 8·10 ⁻⁵ mg/mL to more than 10 mg/mL per betulin. For this, well‐defined biocompatible thermoresponsive copolymers with high betulin content have been synthesized through the conventional and RAFT copolymerizations of betulin methacrylate (BeMA) with methoxy oligo(ethylene glycol) methacrylate (MOEGMA). BeMA was more reactive in the BeMA‐MOEGMA pair; the resulting copolymers were slightly enriched with BeMA units (r 1 = 1.70, r 2 = 0.93). The copolymers exhibited LCST‐type behavior. LCST was tuned by balancing the hydrophobic betulin and hydrophilic OEG fragments. The molecular weight characteristics of polymers and their behavior in aqueous and organic solutions have been studied. Copolymers obtained by conventional polymerization had lower cloud points than RAFT copolymers of the same composition. The copolymers are characterized by low critical micelle concentrations that decrease as the BeMA fraction in the copolymers increases. RAFT copolymers were shown to form unimolecular micelles resistant to dissociation, which is promising for their use in targeted drug delivery.
... A prime example is the clinically proven wound healing efficacy of birch bark extract with its active ingredient betulin, a pentacyclic triterpene. Episalvan ® (Niefern-Öschelbronn, Germany), a birch bark extract with betulae cortex as the main active substance, received approval by the EMA for the treatment of superficial skin wounds and IIa-degree skin burn wounds in adults in 2016; however, it was withdrawn by the European union as a medicine in 2022 [165,166]. A new medicine, Fisuvez ® (Niefern-Öschelbronn, Germany), a dry extract from birch bark using n-heptane as the extraction solvent, has recently been approved by the EMA for the treatment of epidermolysis bullosa [23]. ...
Plant species have developed effective defense strategies for colonizing diverse habitats and protecting themselves from numerous attacks from a wide range of organisms, including insects, vertebrates, fungi, and bacteria. The bark of trees in particular constitutes a number of components that protect against unwanted intruders. This review focuses on the antioxidative, dermal immunomodulatory, and antimicrobial properties of bark extracts from European common temperate trees in light of various skin pathogens, wound healing, and the maintenance of skin health. The sustainability aspect, achieved by utilizing the bark, which is considered a byproduct in the forest industry, is addressed, as are various extraction methods applied to retrieve extracts from bark.
... Karonen and co-workers (Karonen et al. 2011) used hydrophilic interaction chromatography (HILIC) to study the polycyanidins mixture from birch inner bark. Betulin from birch bark has been studied in numerous medical application articles where they have used betulin for among others cancer therapy (So et al. 2018), wound healing (Scheffler 2019), and skin care (Metelmann et al. 2013 to modify the surface of cellulose fiber (Li et al. 2015b(Li et al. , 2015a. Indeed, all bark contains cellulose, hemicellulose and lignin which are the most abundant components but in different amounts (Isikgor andBecer 2015, Pásztory et al. 2016). ...
Many of the amphiphilic molecules, or surfactants, are produced from fossil-based raw materials. With the increasing awareness of the climate situation, focus has shifted toward more environmentally friendly solutions to replace fossil-based products. This has led to more interest towards the forest. The circular bioeconomy is focused on making use of residues and waste and on optimizing the value of biomass over time via cascading. Nowadays, bark is seen as a waste product by industries and mainly incinerated as solid fuel. The bark contains interesting compounds but some of these are only available in low amounts, less than 1 % in the bark, while other components are present in several percentages. However, some of these components are potential candidates for the manufacture of amphiphiles and there seems to be a strong match between bark availability and surfactant demand. The global amount of bark available is approximately 359 million m3 and more than 10 million m3 of industrial bark are generated annually in Sweden and Finland. The bark of Norway spruce, Scots pine and silver birch contains approximately 25–32 % of extractives and part of these extractives has a potential as a surfactant backbone. This matches the global surfactant demand of about 15.6 million tons. Therefore, industrial bark has a significant potential value as a raw material source for amphiphilic molecules and polymers. This review focuses on betulin, condensed tannin and suberin. These compounds have been studied on individually and methods to extract them out from the bark are well investigated, but to utilize them as amphiphilic compounds has not been explored. With this review, we want to emphasis the potential of using bark, what today is seen as a waste product, as a raw material for production of amphiphiles. Moreover, a techno-economic analysis has been performed on betulin, tannins and suberin.
... Nowadays, birch bark is clinically proven to be effective for wound healing. Oleogel-S10 (Episalvan ® ) is a drug containing triterpene-rich extract from birch bark which had been approved for treatment of partial thickness wounds in adults in the European Union (Scheffler, 2019). Mechanism studies conducted in primary human keratinocytes revealed that birch bark triterpene extract could upregulate various mediators involved in the inflammatory phase of wound healing, resulting in a temporary inflammation (Ebeling et al., 2014). ...
Chronic and unhealed wound is a serious public problem, which brings severe economic burdens and psychological pressure to patients. Various botanical drugs in traditional Chinese medicine have been used for the treatment of wounds since ancient time. Nowadays, multiple wound healing therapeutics derived from botanical drugs are commercially available worldwide. An increasing number of investigations have been conducted to elucidate the wound healing activities and the potential mechanisms of botanical drugs in recent years. The aim of this review is to summarize the botanical drugs in traditional Chinese medicine with wound healing properties and the underlying mechanisms of them, which can contribute to the research of wound healing and drug development. Taken together, five botanical drugs that have been developed into commercially available products, and 24 botanical drugs with excellent wound healing activities and several multiherbal preparations are reviewed in this article.
... The resins of P. vera shows a large presence of terpene derivatives, namely monoterpenes (hydrocarbons and oxygenated) in their essential oils, which have previously been successfully tested as wound healing products [27], and not volatile triterpenes. All these metabolites have a wide range of pharmacological effects, including anti-inflammatory, cardioprotective, neuroprotective, hepatoprotective, nephroprotective, antibacterial, antiviral and wound healing properties too [39][40][41][42][43][44]. ...
Pistacia vera oleoresin is one of the natural products used traditionally for the management of wounds. However, there were no scientific reports documented so far on the wound healing activities to substantiate the claim. This study assesses the potential of the oleoresin of P. vera collected in Italy and Algeria for wound healing efficacy via in vivo circular wound excision model. Italian and Algerian oleoresins were subjected to purification and successive fractionation to obtain three matrices. The fractions have been characterized using GC-FID and GC–MS analyses. Oleoresins mixed with vaseline (5% w/w) were topically applied on wound excision induced on the dorsum of rabbits. Wound healing effects were evaluated by percent of wound contraction. Biopsies performed after healing were histologically assessed. Phytochemical results showed a high content of terpenoids components inducing an efficient wound healing effect determined by an in vivo study. Italian and Algerian oleoresins ointments showed significant wound contraction from day 8 to day 16 as compared to the negative control. The two ointments have not showed statistically difference as compared to Cicatryl, reference drug. These results have also been confirmed by the histological evaluation of the tissues involved. The absence of signs of toxicity on the skin of rabbits indicated the safety of the ointments. The study showed that both oleoresins have a very high effectiveness as wound healing agents and appear to justify their traditional use in wound healing in several countries and offer a scientific support to the treatment of traditional healers.
... The previously and ongoing large body of work undertaken for the investigation of triterpenes has highlighted several biological activities related to these compounds, including anticancer, anti-inflammatory, antioxidant and antimicrobial effects, while new biological activities including antidiabetic, antiosteoporotic and neuroprotective activities are currently under evaluation. anticancer, antihyperglycemic, antidyslipidemic, anti-inflammatory, antioxidant, antimicrobial [18,19] 2 Betulin (Bet, 3-lup-20(29)-ene-3β, 28-diol) anti-inflammatory, antimicrobial, antifibrotic, antiproliferative, wound-healing properties [20][21][22][23] 3 betulin 3,28-diphthalate (DPhB) no data available [24] 14 Glycyrrhetinic acid (GA, 3beta-Hydroxy-11-oxoolean-12-en-30-oic acid) ...
Triterpenic compounds stand as a widely investigated class of natural compounds due to their remarkable therapeutic potential. However, their use is currently being hampered by their low solubility and, subsequently, bioavailability. In order to overcome this drawback and increase the therapeutic use of triterpenes, cyclodextrins have been introduced as water solubility enhancers; cyclodextrins are starch derivatives that possess hydrophobic internal cavities that can incorporate lipophilic molecules and exterior surfaces that can be subjected to various derivatizations in order to improve their biological behavior. This review aims to summarize the most recent achievements in terms of triterpene:cyclodextrin inclusion complexes and bioconjugates, emphasizing their practical applications including the development of new isolation and bioproduction protocols, the elucidation of their underlying mechanism of action, the optimization of triterpenes’ therapeutic effects and the development of new topical formulations.
... Silver sulfadiazine has been a classic topical drug used in the clinics to treat burn wounds. It mainly contains sulfadiazine and silver ion, so it has the antibacterial action of sulfadiazine and the astringency of silver salt and a powerful inhibitory effect on both Gram-positive coccus and Gramnegative bacillus [17][18][19][20]. But long-term clinical application exposes many disadvantages of silver sulfadiazine. ...
Second-degree burn is the most common type of burn wound in the clinics, which presents a deeper wound, skin blisters, white or red bottom, and thick and clear fluid inside, is sensitive to tenderness, and turns white by compression [1, 2]. The aim of this study is to explore the efficacy of applying silver-zinc bacteriostatic cream to patients with second-degree burn under targeted nursing intervention and its effect on wound healing rate. A total of 110 patients with second-degree burn treated in our hospital from January 2019 to June 2021 were selected as the research object for the retrospective study. Between the experimental group and the control group, no statistical differences in patients’ general information were observed (P>0.05); 1 week, 2 weeks, and 3 weeks after treatment, the visual analogue scale (VAS) pain scores of the experimental group were significantly lower (P<0.05); and the total incidence rate of adverse reactions was remarkably lower in the experimental group (P<0.05). On the basis of targeted nursing intervention, applying silver-zinc bacteriostatic cream obtains an obviously better clinical efficacy than silver sulfadiazine ointment in treating second-degree burn and works better in promoting wound healing, relieving pain sensation, and reducing adverse reactions.
... Triterpene extract (TE) from the outer bark of birch consisting of betulin, betulinic acid, lupeol, erythrodiol, caffeoyl-betulin, and oleanolic acid shows anti-inflammatory, antiviral, antimicrobial, and other pharmacological activities (16)(17)(18). TE and betulin were reported to address the inflammatory phase of wound healing by transient upregulation of several pro-inflammatory mediators and enhance the migration of keratinocytes in the second phase of wound healing (19). TE-based oleogel (Episalvan) can affect all the three phases of wound healing, including inflammation, migration, and differentiation, and promote wound healing in several clinical phase II and phase III studies. ...
Drug-loaded electrospun fibers have attracted increasing attention as a promising wound dressing material due to their capability of preventing from infections and inflammation and maintaining an appropriate environment for wound healing. In this study, polylactic acid (PLA), which is widely used in wound management, was chosen as electrospinnable polymer. A triterpene extract (TE) from the outer bark of birch known for its anti-inflammatory, antiviral, antibacterial, and wound healing effects was chosen to produce TE-loaded PLA electrospun fibers for wound dressing. A binary solvent system of dichloromethane (DCM) and dimethyl sulfoxide (DMSO) was employed, and the ratio of the solvents was optimized for preparing smooth and uniform fibers. The morphology of TE-loaded PLA electrospun fibers was investigated by scanning electron microscopy (SEM). The entrapment of TE in PLA fibers was confirmed by confocal laser scanning microscopy (CLSM). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to analyze the solid state of TE in PLA fibers. The release behavior of TE was assayed by a shaking flask method for a period of 96 h. The results revealed that TE-loaded electrospun PLA microfibers could be reliably prepared and are promising future candidates in wound therapy.
... ABCC1 (MRP1), ABCB1 (MDR1, P-glycoprotein/P-gp), and ABCG2 (BCRP/ MXR) are extensively studies, and are commonly responsible for MDR (18,19). Betulin and betulinic acid derived from birch bark have a broad spectrum of pharmacological activity (11,26). Researchers reported that betulinic acid inhibits ABCB1-, ABCG2-, and ABCB5-mediated MDR with similar effectiveness as counterparts in parental cell lines (12). ...
Betulin is a lupane-type pentacyclic triterpene, which is isolated from birch bark. It has a broad spectrum of biological and pharmacological properties, such as anti-inflammatory, anti-tumor, anti-viral, and anti-bacterial activity. Herein, we explored the factors that may result in betulin resistance, especially with respect to its interaction with ATP-binding cassette subfamily C member 1 (ABCC1). ABCC1 is an important member of the ATP-binding cassette (ABC) transporter family, which is central to mediating multidrug resistance (MDR) in naturally derived anticancer agents. An MTT-based cell viability assay showed that ABCC1 overexpression has the ability to desensitize both cancer cell line and gene-transfected cell line to betulin and that this betulin-induced resistance can be antagonized by a known ABCC1 inhibitor MK571 at 25 μM. Additionally, betulin upregulates the ABCC1 protein expression level in both concentration-dependent and time-dependent manners, also blocks the transport function mediated by ABCC1. Subsequently, a high affinity score of betulin was achieved in a computational docking analysis, demonstrating a strong interaction of betulin with ABCC1.
... Therefore, it is prone to microbial, thermal, mechanical, and chemical threats that can cause acute or chronic wounds. Triterpenes from the outer bark of birch are known for various pharmacological effects, including enhanced wound healing [189,190]. Polymeric nanofibers have been utilized to develop drug delivery systems to treat various diseases, for example medicated wound dressing [191,192]. In this respect, the project of Rolf Daniels (University Tübingen, Tübingen, Germany) aims to use birch bark dry extract to develop a bioactive nanofiber wound dressing including phospholipids as dispersants. ...
This review summarizes the research on phospholipids and their use for drug delivery related to the Phospholipid Research Center Heidelberg (PRC). The focus is on projects that have been approved by the PRC since 2017 and are currently still ongoing or have recently been completed. The different projects cover all facets of phospholipid research, from basic to applied research, including the use of phospholipids in different administration forms such as liposomes, mixed micelles, emulsions, and extrudates, up to industrial application-oriented research. These projects also include all routes of administration, namely parenteral, oral, and topical. With this review we would like to highlight possible future research directions, including a short introduction into the world of phospholipids.
... A topical oleogel with betulin reached a randomized phase III clinical trial that investigated the re-epithelialization of split-thickness skin graft wounds on 219 patients; results showed the ability of this product to accelerate skin healing and re-epithelialization, thus contributing to burn care practice [180]. The oleogel, Episalvan, was approved by EMA in 2016 for therapeutical use in burn and wound healing and is also studied in preclinical trials as an orphan drug against epidermolysis bullosa [181]. Furthermore, a betulin emulsion showed excellent wound healing features for treating severe necrotizing herpes zoster in a case report presenting a 64-year-old male patient with chronic lymphatic leukaemia and type II diabetes; betulin application provided continuous improving in wound depth, inflammation, pruritus, pain and induced a complete healing without scarring within 8 weeks [182]. ...
Wounds are among the most common skin conditions, displaying a large etiological diversity and being characterized by different degrees of severity. Wound healing is a complex process that involves multiple steps such as inflammation, proliferation and maturation and ends with scar formation. Since ancient times, a widely used option for treating skin wounds are plant- based treatments which currently have become the subject of modern pharmaceutical formulations. Triterpenes with tetracyclic and pentacyclic structure are extensively studied for their implication in wound healing as well as to determine their molecular mechanisms of action. The current review aims to summarize the main results of in vitro, in vivo and clinical studies conducted on lupane, ursane, oleanane, dammarane, lanostane and cycloartane type triterpenes as potential wound healing treatments.
... 56 Some data from these studies were published subsequently. [100][101][102] Furthermore, more than 2,500 papers have been published on the pharmacological actions of selected triterpene compounds (e.g. betulin, betulinic acid, and lupeol), extracted and isolated from the outer bark of Betula species, for a wide range of human health applications (Brian Garhofer [president and CEO of The Actives Factory] email to T. Smith, January 16, 2020). ...
... The importance of discovering new types of bioactivities for known molecules can be exemplified by betulin, a triterpenoid thought to have limited clinical potential due to its poor bioavailability in humans (Furtado et al., 2017). Recently, a birch bark preparation called Episalvan, containing~80% betulin, was approved as a prescription drug by the European Medicines Agency (EMA) for the treatment of superficial skin wounds (epidermis and upper dermis) and second-degree burn wounds, where it appears to have superior effects compared to other treatments (Scheffler, 2019). In the present study, we characterized and screened extracts, isolated triterpenoids and a water-soluble melanin fraction from I. obliquus in a wide range of immunological, enzymatic and anti-proliferative assays, in order to discover new types of biological activities from these increasingly consumed fungal metabolites. ...
The fungus Inonotus obliquus has historically been used in traditional medicine in Europe and Asia. A melanin fraction and six triterpenoids were obtained from I. obliquus sclerotia, and evaluated in various bioassays including for immunomodulatory, cytotoxicity and enzyme-interacting properties. The water-soluble, nitrogen-free melanin fraction and the triterpenoids 3β-hydroxy-8,24-dien-21-al (1) and inotodiol (2) displayed potent activity in a human complement assay. The melanin fraction inhibited the complement cascade, whereas 1 and 2 activated the same cascade. Compound 2, as well as betulinic acid (3) and betulin (4) had anti-proliferative properties against the colon adenocarcinoma cell line HT29-MTX. Further, the melanin fraction and betulin-3-O-caffeate (6) reduced nitric oxide production in primary murine macrophages. Furthermore, the metabolites were nontoxic against the common gut bacteria E. coli and B. subtilis. The results demonstrate the anti-inflammatory and immunomodulatory effects of I. obliquus melanin and triterpenoids, which could potentially justify the consumption of this increasingly popular “edible” fungus.
... These findings are an initial step in the comprehensive and laborious process from a traditional natural product to a rational phytotherapeutic. Such development starts with extraction optimization, and developing a pharmaceutical formulation, as well as toxicological and pharmacological safety testing, and it culminates in the examination of clinical efficacy, quality, and the mode of action [13]. Re-epithelialization is just a small cutout within the complex process of wound healing, including inflammation, angiogenesis, or granulation. ...
The balm of the Norway spruce (Picea abies) is a well-known traditional herbal medicine used to cure wounds. Even though clinical trials have confirmed its empirical use, the active constituents, their mode of action, and the exact composition of this natural product are still unknown. In this study, the balm was subjected to fractionated extraction and further purified employing flash chromatography, HPLC-PDA-ELSD, preparative and analytical TLC. Hydroxycinnamic acids (
1–
3), the lignan pinoresinol (
4), four hydroxylated derivatives of dehydroabietic acid (DHAA) (
5 –
8), and dehydroabietic acid (
9) were isolated. Their structures were elucidated by LC-MS, 1D- and 2D-NMR. Four extracts, two commercially available resin acids–pimaric acid (
10) and isopimaric acid (
11)–and the isolated compounds were tested for increased re-epithelialization of cell-free areas in a human adult low calcium high temperature keratinocytes monolayer. Lysophosphatidic acid (10 µM) served as positive control and ranged between 100% and 150% rise in cell-covered area related to the vehicle control. Two extracts containing carboxylic acids and non-acidic apolar constituents, respectively, boosted wound closure by 47% and 36% at 10 and 3 µg/mL, respectively. Pinoresinol, DHAA, three of its hydroxylated derivatives, and pimaric and isopimaric acid as well as defined combinations of the hydroxylated DHAA derivatives led to a significantly enhanced wound closure by up to 90% at concentrations between 1 and 10 µM. Overall, lignans and diterpene resin acids, main constituents of Norway spruce balm, are able to increase migration or proliferation of keratinocytes in vitro. The presented data link the phytochemistry of this natural wound healing agent with boosted re-epithelialization.
... The first clinical evidence for the wound healing properties of betulin was achieved in a split thickness wound study with the topical application of a water-free betulin oleogel [80]. Subsequently, several multicentric, controlled, randomized clinical studies on superficial wounds and second degree burns were performed with betulin oleogel [81][82][83] (LOE-A). In 2016, the European Medical Agency (EMA) approved betulin oleogel as a drug for the topical treatment of superficial wounds and burns [84]. ...
Herbal extracts and isolated plant compounds play an increasing role in the treatment of skin disorders and wounds. Several new herbal drugs, medicinal products and cosmetic products for the treatment of various skin conditions have been developed in recent years. In this nonsystematic review, we focus on herbal drugs that were tested in controlled clinical studies or in scientifically sound preclinical studies. The herbal biomedicines are intended to treat atopic dermatitis (St. John's wort, licorice, tormentil, bitter substances, evening primrose), psoriasis (araroba tree, lace flower, barberry bark, indigo, turmeric, olibanum, St. John's wort), actinic keratosis (birch bark, petty spurge), herpes simplex (lemon balm, sage and rhubarb), rosacea (green tea, licorice, tormentil) and acne vulgaris (tea tree oil, green tea, hop), or to improve photo protection (green tea, Dyer's weed, cocoa tree, carotinoids, licorice), aesthetic dermatology (licorice, pine bark, gotu kola) and wound healing (birch bark, onion).
... For example, antiviral effects of BA derivatives were discussed in Sections 3.9.1 and 3.9.2 of this review. Another example is betulin-0leogel (Episalvan), which is recently approved (European Medicines Agency, EU/1/15/1069/001) for the treatment of superficial skin wounds and IIa-degree burn wounds in adults (Frew et al., 2019;Scheffler, 2019). Overall, considering data from the numerous studies discussed in this review, we expect the development of new strategies in the future due to the improvement of B and BA bioavailability and the efficacy for the treatment of human diseases. ...
... The first clinical evidence for the wound healing properties of betulin was achieved in a split thickness wound study with the topical application of a water-free betulin oleogel [80]. Subsequently, several multicentric, controlled, randomized clinical studies on superficial wounds and second degree burns were performed with betulin oleogel [81], [82], [83] (LOE-A). In 2016, the European Medical Agency (EMA) approved betulin oleogel as a drug for the topical treatment of superficial wounds and burns [84]. ...
Botanical extracts have been used for cosmetic and therapeutic purposes in the form of fresh plants or dried or extracted plant material since ancient times. These extracts are often registered as botanical medicine, also referred to as herbal medicine, phytotherapy, or phytomedicine (1). Today, increasing numbers of patients and consumers are asking for plant-based therapeutic preparations as a complementary dermatologic therapy. Botanical therapies are considered as therapeutic alternatives, as agents of safer choice in comparison to conventional therapy, or sometimes as the only effective therapeutic way remaining to treat a certain skin disease. The cosmetic industry is expanding the use of botanicals by introducing plant extracts, herbs, fl owers, fruits, and seed oleates into their products, prom-ising a gentler, more organic approach to beauty. Botanical-based cosmetics are well ac-cepted by the consumers because they are said to possess the ability to detoxify, hydrate, strengthen, stimulate, relax, and balance the skin and hair. These products with active compounds are collectively referred to as "cosmeceuticals" (2)— a portmanteau of cos-metic and pharmaceutical. Because the use of botanicals in dermatologic products is becoming increasingly pop u-lar, clinicians need to learn about their effi cacy and possible side effects. The present chap-ter mainly focuses on botanicals that have been investigated in clinical trials. However, experimental research on botanicals was also considered to a limited extent when it seemed promising for product development in the near future. The present chapter reviews the results of controlled clinical studies on botanicals used in dermatology. Plant-derived single compounds already established in dermatological therapy such as dithranol, salicylates, or podophyllotoxin are also discussed (Table 3.1). In the following sections, the botanicals are discussed under the dermatological indications where they have been studied or would be primarily indicated according to their mode of action (Table 3.2). Most of the studies on botanical extracts have been performed with topical preparations. Where appropriate, studies with botanical food supplements are con-sidered as well. Finally, the most important limitations for the use of botanicals in derma-tology are outlined. Literature references were obtained between December but also "UV-protection" and "sunscreen." To provide the reader with information on the quality of the studies, each study was classifi ed according to the levels of evidence (LOE) A-D suggested by the U.K. National Health Ser vice (3). In brief, LOE-A is assigned to consistent, randomized, con-trolled clinical trials and cohort studies; LOE-B is assigned to consistent retrospective co-horts, exploratory cohorts, outcome researches, case-control studies, or extrapolations from LOE-A studies; LOE-C is assigned to case-series studies or extrapolations from LOE-B studies; LOE-D is assigned to expert opinions without explicit critical appraisal or based on physiology, bench research, or fi rst principles. Whenever possible, the level of evidence was indicated for each study in squared brackets, for example, as [LOE-A].
Epidermolysis bullosa (EB) is a heterogeneous group of rare inherited disorders that cause skin and mucous membrane fragility. Patients with EB have compromised wound healing due to the underlying genetic defect, which can be further complicated by related comorbidities.
Wound healing in EB patients is challenging due to multiple wounds of varying duration and healing ability. In the absence of a cure, the goal of treatment is to minimize the risk of blister formation, optimize wound care, pain, and itch relief, and address specific complications. However, newly approved therapies like beremagene geperpavec (Vyjuvek) and birch triterpenes (Fisulvez) are paving the way for improved management and quality of life for these patients.
EB is a complex skin disorder that is associated with considerably impaired quality of life. In this review, we discuss wound healing challenges, wound care strategies stratified by EB subtypes, as well as investigational cell-based, protein replacement, and gene therapies. While there are many promising advances, novel and effective treatments are still urgently needed.
Background. Ozonation products of unsaturated fatty acids in fats and oils – 1,2,4-trioxolanes – which contribute to the normalization of oxidative and energy metabolism in various diseases, may be a promising substance for the creation of new combined anti-burn drugs.
The aim. To study the effect of 1,2,4-trioxolanes in a pharmaceutical composition with betulin, which exhibits wound-healing properties, on indicators of oxidative stress and on energy metabolism in the treatment of burns in an experiment onrats. Methods. The experiments were carried out on 50 male Wistar rats with seconddegree skin burns. We assessed the activity of glutathione reductase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, aldehyde dehydrogenase, superoxide dismutase and catalase, as well as the level of lipid peroxidation indicators.
Results. The properties of 1,2,4-trioxolanes were studied and a pharmaceutical composition of 1,2,4-trioxolanes with betulin from birch bark in fish oil was developed. The effect of this composition on oxidative and energy metabolism in rats during the treatment of burns was studied. The activation of NADP/H and NAD/H dependent enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, aldehyde dehydrogenase), as well as superoxide dismutase and catalase, and the normalization of lipid peroxidation parameters under the influence of the studied composition in the treatment of burns were revealed. The effect of the composition on the energy metabolism of erythrocytes was noted, which was assessed by changes in the ratio of lactate dehydrogenase activity in the reverse and direct reactions. Morphohistological studies showed that using the composition under normal conditions and in case of a burn had no effect on the structure of the stomach wall, and also improved the condition of the burn wound on the day 10 compared to the wound condition in animals without treatment.
Conclusion. The proposed composition of 1,2,4-trioxolanes and betulin in fish oil, which allows normalizing oxidative and energy metabolism and improving the condition of a burn wound without toxic effects on the stomach wall, can be used as an element of additional therapy in the treatment of burns.
Birch bark extract (Filsuvez®; also known as the developmental name Oleogel-S10), a topical gel consisting of 10% dry birch bark extract and 90% sunflower oil, is the first therapy approved in the EU and UK for the treatment of partial thickness wounds associated with dystrophic and junctional epidermolysis bullosa (EB) in patients aged ≥ 6 months old. In the pivotal double-blind, randomized, vehicle-controlled, phase III EASE trial in patients with EB, the primary endpoint was met, in which birch bark extract relative to control gel significantly increased the proportion of patients with first complete target wound closure within 45 days. Moreover, patients treated with birch bark extract demonstrated several other positive findings in improving wound burden and wound-associated symptoms. The clinical benefits of birch bark extract were maintained in the 24-month open-label extension period of the EASE trial. Birch bark extract was generally well tolerated in patients with EB, with the tolerability profile being similar to that of control gel. Current evidence indicates that birch bark extract is an effective, emerging treatment option for patients with dystrophic and junctional EB.
There is growing interest in reducing the number of synthetic products or additives and replacing them with natural ones. The pharmaceutical, cosmetic, and food industries are especially focused on natural and bioactive chemicals isolated from plants or microorganisms. The main challenge here is to develop efficient and ecological methods for their isolation. According to the strategies and rules of sustainable development and green chemistry, green solvents and environmentally friendly technologies must be used. The application of deep eutectic solvents as efficient and biodegradable solvents seems to be a promising alternative to traditional methods. They are classified as being green and ecological but, most importantly, very efficient extraction media compared to organic solvents. The aim of this review is to present the recent findings on green extraction, as well as the biological activities and the possible applications of natural plant ingredients, namely, phenolics, flavonoids, terpenes, saponins, and some others. This paper thoroughly reviews modern, ecological, and efficient extraction methods with the use of deep eutectic solvents (DESs). The newest findings, as well as the factors influencing the efficiency of extraction, such as water content, and hydrogen bond donor and acceptor types, as well as the extraction systems, are also discussed. New solutions to the major problem of separating DESs from the extract and for solvent recycling are also presented.
Ethnopharmacological relevance:
Betula pendula subsp. Mandshurica (Regel) Ashburner & McAll. Cortex (birch bark) is a globally traditional medicine for treating multiple inflammatory diseases. Its records are included in the Compendium of Materia Medica and other ancient medical literatures. However, uncovering its chemical profile and exploring novel biologically active compounds from birch bark remains a significant challenge.
Aim of the study:
To uncover the anti-inflammatory, -oxidative, and -proliferative mechanisms and potentially effective compounds of birch bark extract by combing chemical profiling, isolation, identification, together with in vivo, in vitro, and silico evaluation.
Materials and methods:
Ultra-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS/MS) was used to obtain the chemical profile of birch bark extract. The new compounds were obtained via column chromatography and analyzed using X-ray diffraction and electronic circular dichroism for absolute configuration confirmation. The zebrafish caudal fin inflammation-induced model, qPCR, and Western blot analysis were used to explore the effects and underlying mechanisms of birch bark extract. In vitro cytotoxicity assays and kinases screening conducted to gain preliminary insight into the anti-proliferative effects of birch bark extract and its isolated compounds. In addition, in-silico molecular docking was performed to investigate the putative mechanism.
Results:
UPLC-QTOF-MS/MS chemical profiles revealed 105 compounds in birch bark extract, with 80 of these were first reported in B. pendula subsp. Mandshurica cortex. We selected five compounds speculated as novel and isolated three ones (one triterpenoid derivative and two lupine series triterpenoids) for further analysis. Birch bark extract exerted antioxidative and anti-inflammatory effects on zebrafish, as shown by the downregulated reactive oxygen species levels and COX-2α, IL-1β, and TNF-α expression, which occurred through NF-ĸB signaling pathway activation. The in vitro anti-proliferative effects of birch bark extract and compound 44 were also unveiled. Moreover, the putative anti-tumor mechanism of compound 44 was revealed using kinase screening and in-silico molecular docking.
Conclusions:
This study provided a predictable chemical profile and demonstrated the pharmacological effects of birch bark extract, elucidated the mechanism of this traditional Chinese medicine and suggested it as a novel anti-cancer candidate.
In previous studies, lecithin-based nanoemulsions (NEs) have been shown to be skin friendly drug carrier systems. Due to their nontoxic properties, NEs might also be suitable as wound healing agents. Hence, different O/W NEs based on lecithin Lipoid® S 75 and plant oils or medium chain triglycerides were produced and characterised. Two lipophilic natural wound healing agents, a betulin-enriched extract from birch bark (BET) and a purified spruce balm (PSB), were successfully incorporated and their effects on primary human skin cells were studied in vitro. MTT, BrdU and scratch assays uncovered the positive influence of the drug-loaded NEs on cell viability, proliferation and potential wound closure. Compared to control formulations, the NEs loaded with either BET or PSB led to higher cell viability rates of fibroblasts and keratinocytes. Higher proliferative activity of keratinocytes and fibroblasts was observed after the treatment, which is a prerequisite for wound closure. Indeed, in scratch assays NEs with PSB and notably BET showed significantly ameliorated wound closure rates than the negative control (unloaded NEs) and the positive control (NEs with dexpanthenol). Our findings suggest that BET and PSB are outstanding wound healing drugs and their incorporation into lecithin-based NEs may represent a valid strategy for wound care.
Wound healing is an intricate process consisting of four overlapping phases, namely hemostasis, inflammation, proliferation, and remodelling. Effective treatment of wounds depends upon the interaction of appropriate cell types, cell surface receptors, and the extracellular matrix with the therapeutic agents. Several approaches currently used for treating wounds, such as advanced wound dressing, growth factor therapy, stem cell therapy, and gene therapy, are not very effective and lead to impaired healing. Further, repeated use of antibiotics to treat open wounds leads to multi-drug resistance. Today there is considerable interest in plant-based drugs as they are believed to be safe, inexpensive, and more suitable for chronic wounds. For example, a large number of plant-based extracts and their bioactive compounds have been investigated for wound healing. In recent years the structural and mechanistic diversity of natural products have become central players in the search for newer therapeutic agents. In the present review, a thorough critical survey of the traditionally used plant-based drugs used worldwide for wound healing with special reference to the natural products/bioactive compounds isolated and screened is presented. It is hoped that this review will attract the attention of the research community involved in newer drug design and development for wound healing.
Epidermolysis bullosa (EB) is a heterogeneous group of rare inherited blistering skin disorders characterized by skin fragility following minor trauma, usually present since birth. EB can be categorized into four classical subtypes, EB simplex, junctional EB, dystrophic EB and Kindler EB, distinguished on clinical features, plane of blister formation in the skin, and molecular pathology. Treatment for EB is mostly supportive, focusing on wound care and patient symptoms such as itch or pain. However, therapeutic advances have also been made in targeting the primary genetic abnormalities as well as the secondary inflammatory footprint of EB. Pre-clinical or clinical testing of gene therapies (gene replacement, gene editing, RNA-based therapy, natural gene therapy), cell-based therapies (fibroblasts, bone marrow transplantation, mesenchymal stromal cells, induced pluripotential stem cells), recombinant protein therapies, and small molecule and drug repurposing approaches, have generated new hope for better patient care. In this article, we review advances in translational research that are impacting on the quality of life for people living with different forms of EB and which offer hope for improved clinical management.
Triterpenes from the outer bark of birch (TE) are known for various pharmacological effects including enhanced wound healing. Apart from an already authorized oleogel, electrospun nanofiber mats containing these triterpenes in a polyvinyl alcohol (PVA) matrix appear to be an advantageous application form. The effects of PVA molecular weight and concentration on the fiber morphology have been investigated. Three different molecular weights of PVA ranging from 67 to 186 kDa were used. The concentration of PVA was varied from 5 to 20 wt%. Polymer solutions were blended with colloidal dispersions of birch bark extract at a weight ratio of 60:40 (wt.%). The estimated viscosity of polymer solutions was directly linked to their concentration and molecular weight. In addition, both pure and blended solutions showed viscoelastic properties with a dominant viscous response in the bulk. Fiber morphology was confirmed using scanning electron microscopy (SEM). Both polymer concentration and molecular weight were found to be significant factors affecting the diameter of the fibers. Fiber diameter increased with a higher molecular weight and polymer concentration as more uniform fibers were obtained using PVA of higher molecular weight (146–186 kDa). In vitro drug release and ex vivo permeation studies indicated a faster drug release of betulin from electrospun scaffolds with lower PVA molecular weight. Our research suggests that the fabricated TE-loaded PVA electrospun dressings represent potential delivery systems of TE for wound care applications.
Introduction
Skin fragility and recurrent wounds are hallmarks of hereditary epidermolysis bullosa (EB). Treatment options to accelerate wound healing are urgently needed. Oleogel-S10 contains a betulin-rich triterpene extract from birch bark. In this study, we tested the wound healing properties of topical Oleogel-S10 in patients with dystrophic EB.
Methods
We conducted an open, blindly evaluated, controlled, prospective phase II pilot trial in patients with dystrophic EB (EudraCT number 2010-019945-24). Healing of wounds treated with and without topical Oleogel-S10 was compared. Primary efficacy variable was faster reepithelialization as determined by 2 blinded experts. The main secondary outcome variable of the study was percentage of wound epithelialization.
Results
Twelve wound pairs of 10 patients with dystrophic EB were evaluated. In 5 of 12 cases, both blinded reviewers considered epithelialization of the intervention wounds as superior. In 3 cases, only one reviewer considered Oleogel-S10 as superior and the other one as equal to control. Measurements of wound size showed a trend towards accelerated wound healing with the intervention but without reaching statistical significance.
Conclusion
Our results indicate a potential for faster reepithelialization of wounds in patients with dystrophic EB when treated with Oleogel-S10 but larger studies are needed to confirm significance.
The clinical significance of timely re-epithelialization is obvious in burn care, since delayed wound closure is enhancing the risk of wound site infection and extensive scarring. Topical treatments that accelerate wound healing are urgently needed to reduce these sequelae. Evidence from preliminary studies suggests that betulin can accelerate the healing of different types of wounds, including second degree burns and split-thickness skin graft wounds. The goal of this combined study program consisting of two randomized phase III clinical trials in parallel is to evaluate whether a topical betulin gel (TBG) is accelerating re-epithelialization of split-thickness skin graft (STSG) donor site wounds compared to standard of care. Two parallel blindly evaluated, randomised, controlled, multicentre phase III clinical trials were performed in adults undergoing STSG surgery (EudraCT nos. 2012-003390-26 and 2012-000777-23). Donor site wounds were split into two equal halves and randomized 1:1 to standard of care (a non-adhesive moist wound dressing) or standard of care plus TBG consisting of 10% birch bark extract and 90% sunflower oil (Episalvan, Birken AG, Niefern-Oeschelbronn, Germany). The primary efficacy assessment was the intra-individual difference in time to wound closure assessed from digital photographs by three blinded experts. A total of 219 patients were included and treated in the two trials. Wounds closed faster with TBG than without it (15.3 vs. 16.5 days; mean intra-individual difference=-1.1 days [95% CI, -1.5 to -0.7]; p<0.0001). This agreed with unblinded direct clinical assessment (difference=-2.1 days [95% CI, -2.7 to -1.5]; p<0.0001). Adverse events possibly related to treatment were mild or moderate and mostly at the application site. TBG accelerates re-epithelialization of partial thickness wounds compared to the current standard of care, providing a well-tolerated contribution to burn care in practice.
In many clinical trials on cutaneous healing, wound closure is the primary endpoint and single most important outcome parameter, making precise assessment of this time point one of utmost importance. The assessment of wound closure can be performed either by subjective clinical inspection or with a variety of methodologies anticipated to provide more objective data. The aim of this study was to examine intra- and interrater variability of blinded photographic analysis of wound closure of human partial thickness wounds, as well as the reliability of remote photographic analysis of wounds with that of direct clinical assessment.
Two plastic surgeons, a dermatologist, and a maxillofacial surgeon constituted our rater panel. High-resolution images of patient wounds derived from two randomized controlled clinical trials (EU Clinical Trials Register numbers EudraCT 2009-017418-56 (registered 12 January 2010) and EudraCT 2010-019945-24 (registered 13 July 2010)) were individually assessed by the blinded, experienced study raters. The reliability of photographic image analysis was tested using intraclass and interclass correlation. The validity of photographic image analysis was correlated with clinical assessments of documented time to heal from the study centers' files.
The results demonstrated that the mean intraclass correlation coefficient of all four examiners was excellent (r = 0.79; 95% confidence interval (CI), 0.61, 1.00)). The interrater correlation coefficient was good (r = 0.67; 95% CI, 0.57, 1.00)) and therefore acceptable. The agreement between remote visual assessment and clinical assessment at the time of healing was good (r = 0.64; 95% CI, 0.52, 0.76)) with an overall difference of about 1 day.
Remote photographic analysis of cutaneous wounds is a feasible instrument in clinical open-label studies to evaluate time to wound closure. We found that it was a reliable method of measuring wound closure that correlated satisfactorily with clinical judgment, bolstering the potential relevance in the current era of evolving application and dependency in the field of telemedicine.
EU Clinical Trials Register EudraCT numbers 2009-017418-56 (date of registration: 12 January 2010) and 2010-019945-24 (date of registration: 13 July 2010): https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-017418-56; and https://www.clinicaltrialsregister.eu/ctr-search/search?query=2010-019945-24.
Birch bark has a long lasting history as a traditional medicinal remedy to accelerate wound healing. Recently, the efficacy of birch bark preparations has also been proven clinically. As active principle pentacyclic triterpenes are generally accepted. Here, we report a comprehensive study on the underlying molecular mechanisms of the wound healing properties of a well-defined birch bark preparation named as TE (triterpene extract) as well as the isolated single triterpenes in human primary keratinocytes and porcine ex-vivo wound healing models.
We show positive wound healing effects of TE and betulin in scratch assay experiments with primary human keratinocytes and in a porcine ex-vivo wound healing model (WHM). Mechanistical studies elucidate that TE and betulin transiently upregulate pro-inflammatory cytokines, chemokines and cyclooxygenase-2 on gene and protein level. For COX-2 and IL-6 this increase of mRNA is due to an mRNA stabilizing effect of TE and betulin, a process in which p38 MAPK and HuR are involved. TE promotes keratinocyte migration, putatively by increasing the formation of actin filopodia, lamellipodia and stress fibers. Detailed analyses show that the TE components betulin, lupeol and erythrodiol exert this effect even in nanomolar concentrations. Targeting the actin cytoskeleton is dependent on the activation of Rho GTPases.
Our results provide insights to understand the molecular mechanism of the clinically proven wound healing effect of birch bark. TE and betulin address the inflammatory phase of wound healing by transient up-regulation of several pro-inflammatory mediators. Further, they enhance migration of keratinocytes, which is essential in the second phase of wound healing. Our results, together with the clinically proven efficacy, identify birch bark as the first medical plant with a high potential to improve wound healing, a field which urgently needs effective remedies.
It has been shown recently that triterpenes inhibit cancer cell growth of various cell types in vitro. In this work, the effect of highly purified triterpenes (TE) with betulin as the major compound (>80% w/w) on cell proliferation, apoptosis, and differentiation of human keratinocytes was analyzed in vitro, ex vivo, and in vivo. In vitro, TE increased calcium influx into primary keratinocytes and upregulated various differentiation markers including keratin 10. TE also specifically increased the expression of the non-selective transient receptor potential canonical (subtype) 6 (TRPC6) in keratinocytes, and knocking down TRPC6 inhibited keratin 10 upregulation. Ex vivo, in human skin explants TE induced the expression of TRPC6 in the epidermis and increased DNA fragmentation of terminally differentiating keratinocytes. Topical treatment with TE of actinic keratoses, that represent in situ squamous cell carcinomas with disturbed epithelial differentiation, resulted in downgrading of aberrant Ki67 expression and upregulation of keratin 10 in vivo. Our data indicate that TE promotes keratinocyte differentiation in vitro and in vivo. This effect seems to be mediated at least in part by TRPC6.
Zusammenfassung
Das Projekt umfasst die Erschließung des pflanzlichen Wirkstoffs Triterpentrockenextrakt (Betulin) aus der Birkenrinde für die Wundheilung:
▪ mit den weltweit patentierten Erfindungen der „Betulin-Emulsion“ und des „Betulin-Oleogels“,
▪ dem innovativen klinischen Nachweis der beschleunigten Wundheilung,
▪ der publizierten Aufklärung der Wirkweise bei der Wundheilung bis auf die molekulare Ebene
▪ und der zentralen Europäischen Zulassung mit Qualitäts-, Unbedenklichkeits- und Wirksamkeitsnachweis im Januar 2016 für das Arzneimittel Episalvan.
Mit diesem Projekt haben wir gezeigt, dass wissenschaftlich fundierte Neuentwicklungen in der Phytotherapie in Europa möglich sind. Der Wirkstoff ist neu und die Indikation ist erstmals mit Studien evident belegt. Episalvan ist das erste Arzneimittel seiner Indikation und bis 2030 patentgeschützt. Zugleich ist es das erste Phytotherapeutikum in der Chirurgie, erschließt also ein neues Therapiefeld für die Phytotherapie.
Die Birkenrinde enthält in dem weißen Korkgewebe durchschnittlich 22 % Betulin, sodass der Wirkstoff nachhaltig aus der holzverarbeitenden Industrie Nordeuropas im Maßstab von mehreren 100 000 t jährlich zur Verfügung steht. Neben seinem höchsten Wert als Arzneimittel haben wir mit dem Aufbau eines innovativen kontinuierlichen Extraktionsverfahrens eine bisher ungenutzte pflanzliche Feinchemikalie der nachhaltigen industriellen Nutzung deutlich nähergebracht.
The acceleration of wound healing is a major surgical concern. A triterpene extract from birch bark (Betulae cortex) experimentally enhances keratinocyte differentiation in vitro and accelerates wound healing ex vivo. We conducted an open, blind-evaluated, controlled, prospective, randomized (1:1) phase II clinical trial in patients requiring split-thickness skin graft transplantation at two university hospitals in Germany. Donor sites on the upper legs were covered with a moist silicone-coated dressing. Oleogel-S10 ointment containing 10% birch bark extract was randomly applied to the distal or proximal half of the wound, with the other half serving as an intraindividual control, for 14 days after the skin graft surgery. The primary efficacy variable was faster reepithelialization as determined from macrophotographs by independent, blinded experts. Twenty-four patients were randomized and completed the trial. After the 14-day test period, the planned interim analysis revealed a highly significant (p < 0.0001) superiority of Oleogel-S10 in the primary efficacy variable and the trial was terminated early due to ethical concerns. The treatment side was also better reepithelialized and more similar to normal skin after 3 months. In conclusion, Oleogel-S10 significantly accelerated reepithelialization at split-thickness skin graft donor sites. Treatment with Oleogel-S10 was safe and well tolerated. © 2014 S. Karger AG, Basel.
Oleogels are known for their high physical, chemical, and mechanical stability and good in vivo efficacy, which make them appropriate vehicles for dermal drug delivery and skin care for very dry skin. Modern formulation research focusses on well tolerated and sustainable formulation concepts. This paper deals with an innovative oleogel, which is based on a triterpene dry extract from the outer bark of birch (TE). In this formulation TE does not only act as an excipient but provides interesting pharmacological properties at the same time. The oleogel was formulated using solely Simmondsia Chinensis seed oil (jojoba oil) and TE. Fluorescence microscopy and confocal Raman microscopy showed that suspended TE particles arrange in a three-dimensional gel network. Infrared spectroscopy revealed that the formation of hydrogen bonds between TE particles is responsible for the self-assembly of TE in oil. Moreover, the influence of TE concentration and morphology of the TE particles on the viscoelasticity of the resulting oleogels was analyzed. Gel strength increased with TE concentration and was critical to the specific surface area of the TE particles.
Triterpenoids from birch bark, like betulin, seem to have an anticancer potential which needs to be further investigated. Aim of this study was first to explore whether a cyclodextrin-solubilised triterpenoid extract (STE) from birch bark induces selective cytotoxic effects in primary liver cancer cells compared to healthy human hepatocytes. Second, selective cytotoxicity against several tumour cell lines should be analysed. For this purpose, human liver cancer cells derived from mouse xenografts (LIXF 575), healthy human hepatocytes, and 42 different human tumour cell lines were incubated with different concentrations of STE corresponding to 4.3 µM - 137.5 µM betulin (BE). Cytotoxicity was tested with the WST-1 cell proliferation assay, apoptosis with caspase 3/7-activity, and necrosis was determined by the propidiumiodid uptake assay. The pathway of cytotoxic effects was further investigated by immunoblotting of apoptosis inducing factor (AIF) and p53. The monolayer assay was used to analyse selectivity of STE towards different tumour cell lines. STE significantly (p < 0.001) reduced viability and induced apoptosis of LIXF cells in low concentrations corresponding to 8.6 µM BE, while human hepatocytes were affected only in concentrations ≥ 68.8 µM. Cell death occurred in a p53 independent manner, and AIF was not involved. The mean IC50 in the 42 tumour cell lines corresponded to 4.3 µM BE and ranged from 2.05 µM to 8.95 µM BE content. Selectivity was, therefore, rather low. In conclusion, STE exhibits in low concentrations cytotoxicity in a broad spectrum of primary cancer cells and cancer cell lines, which is, at least in LIXF cells, induced by caspase 3/7 mediated apoptosis. STE is far less toxic in hepatocytes. The anticancer potential of STE should be further characterised and also investigated in animal models.
Today cancer treatment is not only a question of eliminating cancer cells by induction of cell death. New therapeutic strategies also include targeting the tumour microenvironment, avoiding angiogenesis, modulating the immune response or the chronic inflammation that is often associated with cancer. Furthermore, the induction of redifferentiation of dedifferentiated cancer cells is an interesting aspect in developing new therapy strategies. Plants provide a broad spectrum of potential drug substances for cancer therapy with multifaceted effects and targets. Pentacyclic triterpenes are one group of promising secondary plant metabolites. This review summarizes the potential of triterpenes belonging to the lupane, oleanane or ursane group, to treat cancer by different modes of action. Since Pisha et al. reported in 1995 that betulinic acid is a highly promising anticancer drug after inducing apoptosis in melanoma cell lines in vitro and in vivo, experimental work focused on the apoptosis inducing mechanisms of betulinic acid and other triterpenes. The antitumour effects were subsequently confirmed in a series of cancer cell lines from other origins, for example breast, colon, lung and neuroblastoma. In addition, in the last decade many studies have shown further effects that justify the expectation that triterpenes are useful to treat cancer by several modes of action. Thus, triterpene acids are known mainly for their antiangiogenic effects as well as their differentiation inducing effects. In particular, lupane-type triterpenes, such as betulin, betulinic acid and lupeol, display anti-inflammatory activities which often accompany immune modulation. Triterpene acids as well as triterpene monoalcohols and diols also show an antioxidative potential. The pharmacological potential of triterpenes of the lupane, oleanane or ursane type for cancer treatment seems high; although up to now no clinical trial has been published using these triterpenes in cancer therapy. They provide a multitarget potential for coping with new cancer strategies. Whether this is an effective approach for cancer treatment has to be proven. Because various triterpenes are an increasingly promising group of plant metabolites, the utilisation of different plants as their sources is of interest. Parts of plants, for example birch bark, rosemary leaves, apple peel and mistletoe shoots are rich in triterpenes and provide different triterpene compositions.
Actinic keratoses (AK) are squamous cell carcinomas in situ and require treatment. Betulin-based oleogel prepared from a standardized triterpene dry extract from birch bark represents a new topical agent with anti-inflammatory and anti-tumor potential.
In the prospective, randomized, monocentric phase 2a study 45 patients with < 10 AK were included and randomly assigned to one of the three treatment groups. Intervention consisted of topical betulin-based oleogel twice daily versus cryotherapy with liquid nitrogen versus the combination of cryotherapy with topical betulin-based oleogel. Treatment response was assessed clinically after three months. The clinical response was graded into complete clearing (100 %), therapy responders (> 75 % clearing of the lesions) and non-responders (< 75 % clearing). Additionally, punch biopsies were obtained from some patients before and at the end of treatment.
Therapy with betulin-based oleogel was well tolerated.Three patients discontinued therapy because of personal reasons. After three months, the 100% (and > 75%) clearing rates of the lesions were as follows: 64% (86%) with betulin-based oleogel (n = 14),79% (93%) with cryotherapy (n = 14),and 71% (71%) with the combined therapy (n = 14). Histological analysis of biopsies taken before and after treatment (n = 8) showed a reduced degree of dysplasia in the epidermis in all study arms.
Betulin-based oleogel seems to be an effective novel approach in the topical treatment of actinic keratoses. However,the clinical and histological findings of the present pilot study have to be verified against placebo with larger case numbers.
As a result of bioassay-guided fractionation, betulinic acid, a pentacyclic triterpene, was identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with athymic mice carrying human melanomas, tumour growth was completely inhibited without toxicity. As judged by a variety of cellular responses, antitumour activity was mediated by the induction of apoptosis. Betulinic acid is inexpensive and available in abundant supply from common natural sources, notably the bark of white birch trees. The compound is currently undergoing preclinical development for the treatment or prevention of malignant melanoma.
Triterpenes are biologically active secondary plant substances that display antimicrobial, hepatoprotective and anti-inflammatory effects. However, the poor solubility of triterpenes in both polar and non-polar solvents as well as expensive purification procedures have prevented the large-scale isolation of these compounds for medicinal purposes. Here, we describe a novel quantitative extraction method of triterpenes from the outer bark of birch (Betula species) in which betulin, a lupan triterpene, predominates. The resulting highly purified triterpene extract (TE) in the form of a dry powder contains betulin as the major compound, but also betulinic acid, lupeol, erythrodiol and oleanolic acid. We have found that this TE is able to form an oleogel, thus providing an opportunity for the topical application of pharmacologically relevant amounts of triterpenes. Furthermore, we have investigated the TE in comparison to its major isolated compounds in cell culture experiments with human immortalized keratinocytes and skin cancer cells. We could demonstrate dose-dependent cytotoxic and apoptosis-inducing effects of TE and betulin. These experimental data support the notion from a previous clinical study that TE from the outer bark of birch might represent a new tool for the topical treatment of skin cancer and skin cancer precursors like actinic keratoses.
Emulsion enthaltend einen Pflanzenextrakt, Verfahren zur Herstellung der Emulsion sowie zur Gewinnung des Pflanzenextraktes
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Das neue Wund-Arzneimittel Episalvan ® : Galenik und Studiendesign
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Regulatory news. Available at www.amrytpharma.com/ investors/regulatory-news
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