Herbal Treatments for DFUs in the Wound Clinic

Phytopharmacology and phytomedicine are the studies of efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. In remote communities, where modern health care access is limited, there are many reports on the use of plants, fungi or other natural materials that contain bioactive small molecules capable of promoting wound healing, with a number shown to possess potent bioactivity.^1-4
 
Reports by the World Health Organization state that, in some countries, the use of bioactive small molecules from natural sources far outweighs the use of licensed pharmaceutical therapies for their health care needs; natural remedies have been used for a wide range of health care needs:^1-6
 
Although the Food and Drug Administration (FDA) does not evaluate the safety or efficacy of herbal preparations, herbal preparations fall under the Dietary Supplement Health and Education Act of 1994 (Public Law 103-417). This act states that dietary supplements (including herbal preparations) may not make any claims as to the cure, mitigation, treatment, or prevention of diseases. They may make structure and functional claims such as "supports healthy bones and joints". Some herbal supplements that are used in the food or cosmetic industry are listed by the FDA as "Generally Recognized as Safe (GRAS)". Some of the alternative products mentioned in this section do not fall into this list. Any practitioner wishing to utilize alternative therapies for use in patient care should be aware of the various laws regarding their use, and the literature regarding the safety and efficacy of these preparations and be aware whether the manufacturer follows accepted Good Manufacturing Practice (GMP) and that their preparations are marked as Standardized Extracts or Guaranteed Extracts which shows that the product contains a stated amount of what is known or suspected to be the main active ingredient in the preparation.
 
The use of herbal (natural) products is more widely accepted in other countries, most notably in Germany. The German Commission E is a scientific advisory board of the Federal Institute for Drugs and Medical Devices formed in 1978. The commission gives scientific expertise for the approval of substances and products previously used in traditional, folk and herbal medicine. The commission publishes monographs such as Monographien der Kommission E (Phytotherapie, Bundesinstitut für Arzneimittel und Medizinprodukte). The monographs are a collection of official documents compiled over nearly two decades by a committee composed of twenty-four scientific experts that was set up in 1978 to evaluate the safety and efficacy of herbal medicines by reviewing the extant literature. The monographs are available in the United States.⁷
 
Some herbal therapeutics may already be familiar to US practitioners, but the extent to which they have been studied and tested may not be. My intent in this article is to discuss the common herbal therapeutics, their constituents, studies and uses. It is also important to note that many herbal treatments have drug-drug interactions with other nutritional supplements, over the counter, and/or prescription medications.

This article will discuss herbal therapies for diabetic foot ulcers. Subsequent articles will discuss pressure, venous, and arterial ulcers.

A Closer Look at the Research on Mountain Papaya

A study by Tonaco and colleagues assessed the potential of Vasconcellea pubescens A.DC. (formerly Carica candamarcensis), commonly referred to as mountain papaya, on diabetic foot ulcers (Figure 1).⁸ Papaya leaf contains 2% papain and carpain.⁹ Papain is a mixture of enzymes that degrade protein, carbohydrates, and fats.⁹ The efficacy is thought to be due to proteases in the plant, debriding necrotic tissue. Additionally, this proteolytic response may impair or disrupt the formation of biofilms, which affects the chronicity of the wounds. In vitro, both ripe and unripe papaya fruit inhibit the growth of gram-positive and gram-negative bacteria, including Bacillus cereus, Escherichia coli, Proteus vulgaris, Staphylococcus aureus, Streptococcus faecalis, and Shigella flexneri.¹⁰
 
Other in vitro research shows that ethanol and methanol extracts of papaya fruit have antibacterial activity against gram-positive and gram-negative drug-resistant strains of bacteria. Preliminary evidence suggests that papaya has anti-inflammatory properties.^10–14 Early clinical research shows that applying fermented papaya gel reduces levels of the pro-inflammatory cytokines IL-1β and IL-6 and increases levels of anti-inflammatory cytokines IL-10.⁸ The extract demonstrated enhanced wound repair, with 11 and 4 patients for the Vasconcellea group, compared to five and three patients for the control group, respectively, exhibiting 100% or >80% wound closure overall. In addition to a greater proportion reaching 100% wound closure, the timeframe required was significantly reduced with Vasconcellea treatment, compared to controls. Unfortunately, the study did not mention the frequency of application or the dose.
 
Various parts of the papaya plant are used for diabetes. Papaya seed extract inhibits the enzymes alpha-amylase and alpha-glucosidase in vitro. In animal research, papaya seed extract inhibits postprandial hyperglycemia.^15,16 Papaya also has antifungal activity. In vitro, papaya latex induces fungistatic effects against Candida albicans by causing cell wall degradation.¹⁷ Theoretically, patients allergic to latex might also be allergic to papaya. People who are allergic to latex should use papaya or papaya-containing products with caution due to the risk for cross-reactivity.^18–21

What You Should Know About French Maritime Pine

A bark extract showing wound-healing potential is Pycnogenol^® (Horphag Research), which is the registered name for an extract from a French maritime pine, Pinus pinaster (Figure 2). Pinus is also found in Spain, Portugal, Italy, Croatia, and Morocco.²² Pycnogenol contains several active constituents including flavonoid monomers such as catechin, epicatechin, and taxifolin. It also contains condensed procyanidins (also called flavonoids or proanthocyanidins) such as procyanidin B1, B3, B6, and B7, which are dimers, oligomers, and polymers of catechin and epicatechin.^23,24

A clinical study was performed to evaluate the wound-healing response of Pycnogenol on diabetic ulcers. The treatment groups consisted of an oral capsule containing Pycnogenol, a topical treatment involving the powder from the capsule applied to the ulcer, and a combination of both the oral and topical treatments. Interestingly, the combination treatment of oral and topical application induced a greater healing response, with 89% of ulcers successfully healed, compared to 61% healed in the untreated controls.²⁵ All 4 groups received the same level of ulcer care. Treatment with Pycnogenol significantly reduced the ulcer area within 6 weeks across all 3 treatment groups.

Various studies have investigated the anti-inflammatory effects of maritime pine bark extract. In humans, a standardized extract of maritime pine bark has been shown to inhibit NF-kappa activation,²⁶ and cyclooxygenase (COX)-1 and COX-2 activity,²⁷ and reduce C-reactive protein (CRP) levels.^28–29 Other clinical research shows that taking this specific extract decreases erythrocyte sedimentation rate (ESR) and reduces interleukin (IL)-6.²⁹ Maritime pine might have hypoglycemic effects. Taking maritime pine with other products with hypoglycemic potential might increase the risk of hypoglycemia. One clinical study shows that maritime pine bark extract can decrease blood sugar.³⁰ Maritime pine might have antiplatelet activity; use with caution in patients with bleeding conditions. Clinical research suggests that maritime pine bark extract inhibits platelet aggregation.^31–33 Tell patients to discontinue maritime pine at least 2 weeks before elective surgical procedures.

Can Marigolds Have a Positive Effect on DFUs?

Calendula (Figure 3) is a flowering plant commonly known as marigold.³⁴ It is native to Asia and southern Europe and has been traditionally used in Ayurvedic and Unani systems of medicine for tropical ailments, and as an antispasmodic, antipyretic, and emmenagogue. It was also commonly used as a food dye and flavoring.³⁴C. officinalis is part of a genus of plants that has a long history of medicinal use, in particular as an anti-inflammatory treatment.^35,36 The applicable part of calendula is the flower. The flower petals contain coumarins, esculetin, scopoletin, umbelliferon (7-hydroxycoumarin), tocopherols, alpha-tocopherolquinone, and calenduloside B.³⁷ At least eight bioactive triterpendiol monoesters have been identified in the extracts of dried calendula flowers.³⁸Calendula also contains minerals, carbohydrates, lipids, phenolic acids, flavonoids, tannins, coumarins, sterols and steroids, monoterpenes, sesquiterpenes, triterpenes, tocopherols, quinones, amino acids, and resins.³⁹
 
A study was performed assessing the effect of Calendula officinalis L. hydroglycolic extract on diabetic foot ulcers. Calendula is used for wound healing due to its potential anti-inflammatory effects.^38,40 The faradiol monoester is believed to play an important role in the anti-inflammatory activity. Some evidence suggests the water-soluble flavonoids might also be responsible for the wound-healing effects.⁴¹ In animal models, Calendula extracts combined with allantoin improved epithelialization of experimentally inflicted skin wounds.⁴² As a prospective pilot study, all 41 patients enrolled into the study were treated with C. officinalis hydroglycolic extract; 78% of patients exhibited complete wound closure within 30 weeks of treatment, with a mean time of 15.5 weeks.³⁵ The presence of colonized bacteria within the ulcers was significantly decreased following also reduced following treatment.³⁵
 
An in vitro study aimed to determine the effect of C. officinalis on fibroblast proliferation and migration responses, with platelet-derived growth factor (PDGF) used as a positive control due to its role in wound healing, in particular, fibroblast chemotaxis to wound site.⁴³ The use of a scratch wound assay demonstrated an increased presence of fibroblasts within the scratch site following treatment with C. officinalis extracts, comparable to the positive control, PDGF. The use of an antiproliferation agent, mitomycin C (5 µg/mL), produced equivalent responses, indicating that C. officinalis extracts induce wound repopulation responses through stimulating fibroblast migration.⁴³ Histopathological and biomechanical restorations in the group treated with 7% gel were significantly more than the placebo and control group. Upper and lower doses seem to be less effective, although the reasons for this remain unclear.⁴⁴Calendula may cause an eczematous allergic reaction in individuals sensitive to the Asteraceae/Compositae family.^45,46 Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs.

Insights on Using Axihuitl for DFUs

A randomized double-blind study by Romero-Cercecero assessed a 5% cream formulation of the native Mexican plant Ageratina pichinchensis (Figure 4), commonly referred to as Axihuitl, on diabetic foot ulcers.⁴⁷ The active component has been identified as flavonoid, 7-O-(β-D-glucopyranosyl)-galactin. Treatment with A. pichinchensis demonstrated an enhanced wound-healing response, compared to a control treatment of 1% micronized silver sulfadiazine.⁴⁸

A rodent diabetic model also demonstrated the enhanced healing response following A. pichinchensis treatment, compared to both a positive control wound-healing drug (5-methyl-1phenyl-2-(1H) pyridone) and negative control (vehicle only). This was shown by A. pichinchensis treatment inducing a 100% reduction in wound area within 11 days, compared to 70% and 40% for the positive and negative control, respectively.⁴⁹ A 16.8% concentration possesses the highest effectiveness.⁴⁹

Treating DFUs With Honey

Manuka honey was the first naturally derived product to be approved by the Food and Drug Administration (FDA) for use in wound care and indicated for chronic wounds, burn injuries and surgical wounds.^5,50 Honey has been used in wound care for thousands of years, with records of its use in ancient Egyptian times documented on the Edwin Smith papyrus between 2600 and 2000 BCE.^51–53 Honey has been demonstrated to possess numerous beneficial properties, including antibacterial and anti-inflammatory activities.^54–55 These responses are exerted through a variety of parameters, including osmolarity, peroxide activity, sugar content and presence of phytochemical compounds.^55–57 The high sugar content of honey exerts a bactericidal effect through dehydrating the bacterial cells, further aided by the high acidity of honey, which is outside the optimal pH range that bacteria typically grow in. These effects, along with the peroxide activity, are muted slightly at wound sites due to the presence of wound exudate.⁵⁷
 
Some of the benefits of honey in wound healing may be related to its anti-inflammatory effects. There is histological evidence of reduced numbers of inflammatory cells present in wounds dressed with honey.⁵⁸ Although some research disagrees⁵⁹, honey appears to reduce elevated levels of inflammatory proteins such as C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha in humans.^60–61 The antioxidant effects of honey may also play a role in its anti-inflammatory effects as shown in laboratory research.⁶²
 
Manuka honey is a specific variety of honey generated by bees utilizing the flower Leptospermum scoparium (Figure 5) native to New Zealand and Australia.^5,54 Manuka honey gained popularity as a therapy over other honey types due to its antibacterial activity, independent of its ability to release hydrogen peroxide; this ability to possess a non-peroxidase-dependent activity is beneficial, as it can withstand the necessary sterilization process.^58,63 The active component of the non-peroxidase activity attributed to honey is methylglyoxal. Additionally, Manuka honey has been demonstrated to be active against antibiotic-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).^64,65 In comparison to antibiotics used in the treatment of wounds, Manuka honey does not appear to induce resistance in bacteria.^47,65–67
 
A clinical trial assessing the response of Medihoney™ (Integra LifeSciences) on chronic wounds observed successful wound closure in 90% of patients. Another study demonstrated a clinically significant reduction in healing time with Medihoney, compared to standard wound-healing dressings, with 32 days and 46 days, respectively, to reach 50% reduction in wound area.^68,69 Contrary to Jull’s Cochrane Review published in 2015⁵³, O’Meara’s Cochrane Review study in 2014 states that evidence did not support the use of honey.⁷⁰ Honey might inhibit platelet aggregation and increase bleeding time.^71,72 Theoretically, honey might increase the risk of bleeding when used concomitantly with other herbs and supplements that have anticoagulant or antiplatelet effects.

Interactions With Lab Tests

Carica, papaya—none known
Pinus sp., Maritime Pine—none known
Calendula—none known
Ageratina—no information available
Leptospermum scoparium, Manuka honey—none known

Interactions With Other Drugs

Carica – papaya – AMIODORONE (increases effect), DIABETES DRUGS (increases effect), LEVOTHYROXINE (decreases effect), WARFARIN (increases effect).
Pinus sp.- Maritime Pine – ANTICOAGULANT/ANTI-PLATELET DRUGS (increases effect), DIABETES DRUGS (increases effect), IMMUNOSUPPRESSANT DRUGS (decreases effect).
Ageratina – no information available.
Leptospermum scoparium – Manuka Honey – ANTICOAGULANT/ANTIPLATELET DRUGS (may increase, but unlikely), CYTOCHROME P-450 DRUGS (decreases effect), PHENYTOIN (may increase effect).
 
*Although some information about formulation and dosing frequency is not included here, more specific information can be found in individual studies/monographs/reviews of the individual products.
 
Dr. Bozzuto is the NE Section Chair, Wound Care at Geisinger Health System in Scranton, PA.

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