Dexpanthenol

This is the continuation of a two-part series that evaluates compounds for the treatment and healing of wounds. Part 1, which included example formulations in the Formulations section, was published in volume 8, issue 4 (July/August 2004) of the International Journal of Pharmaceutical Compounding. This article is a continuation of information on certain compounds to aid in the healing process and the phases and aspects of wound healing that are being affected by the selected agent.

Honey

Honey is a topical agent that has been used for healing wounds since ancient times. It has been shown to possess antibacterial properties as well as to speed wound healing. Honey's antibacterial properties are attributed to a bee enzyme that allows for peroxide formation.1 There are several ideas as to how honey exerts its antibacterial and enhanced wound-healing effects. Both the type of bee and plant source of the honey are vital in determining whether it will be of use topically for wound healing.1 New Zealand Manuka honey has been shown to have excellent antibacterial and wound-healing properties.1 Honey that is used therapeutically must be crude and unsterilizcd because sterilization eliminates much of its antibacterial activity.1 One study by Monks et al2 has shown that honey can increase monocytes' production of pro-inflammatory cytokines that may speed wound healing. A pharmacist from the United Kingdom, J. Topham,3 postulates that honey could be converted into hyaluronic acid when it is placed on the wound, or that it generates an organized matrix similar to hyaluronic acid. This stable matrix for wound healing would be more organized than the typical collagen matrix and allow for faster epithelialization and reduced scar formation.3

In a study by Al-Waili and Saloom,4 topical crude honey was applied every 12 hours to infected postsurgery wounds. Its efficacy in wound healing and as an antibacterial was compared with that of 70% ethanol and povidone-iodine used to treat similar wounds. The infected wounds were either due to gram-positive or gram-negative organisms and both treatment arms received identical systemic antibiotic regimens. Use of honey resulted in resolution of the infection an average of 8.8 days earlier than in wounds treated with 70% ethanol and povidone-iodine. The average time for wound healing was nearly 12 days shorter in the honey-treated group. Finally, the scars in the honey-treated group were significantly smaller. None of the patients experienced any adverse reactions to topical honey treatment.

Another study performed by Cooper et al5 investigated honey for its ability to kill Pseudomonas infections isolated from burn wounds. This study used two therapeutic honeys from New Zealand. The minimum inhibitory concentrations of the two honeys were calculated to be 7.5% and 6.8%. Both types of honey were able to kill Pseudomonas, including a strain that was resistant to ciprofloxacin, piperacillin, cefuroxime, amoxicillin, trimethoprim, imipenem and Augmentin.

In a study conducted by Subrahmanyam,6 the healing properties of honey on burns was compared with silver sulfadiazine. Silver sulfadiazine was reapplied daily for 21 days after dressings and honey was reapplied every other day for the same time frame. Epithelialization and granulation tissue formation were assessed at days 7 and 21. On day 7, 84% of the patients' honey-treated wounds had undergone epithelialization and granulation tissue formation compared with 72% of those treated with silver sulfadiazine. By day 21, 100% of the patients' honey-treated wounds had undergone epithelialization, while this occurred in only 84% of the patients treated with silver sulfadiazine. Other notable differences between the two treatment groups were the significantly reduced scarring and wound odor in the honey group as compared with the silver sulfadiazine group.

Honey is an effective topical agent for wound healing that is largely free of adverse effects. Compounding pharmacists may be able to make use of this agent by incorporating it into topical dosage forms containing other active ingredients.

Hyaluronic Acid

Hyaluronic acid is a macromolecule that is part of the extracellular matrix and is produced in higher quantities during the proliferation phase of wound healing.7 Besides providing structural support in the wound, topical hyaluronic acid has been shown to speed healing of skin wounds in animal models.7 It has also improved healing rate in chronic venous leg ulcerations. Hyaluronic acid plays a role in the inflammatory phase of wound healing by up-regulating the production of pro-inflammatory cytokines as well as enhancing the chemotaxis of fibroblasts to the wound.7 Low-molecular-weight hyaluronic acid used as a topical cream has been shown to protect newly formed granulation tissue from oxidative damage by functioning as a free-radical scavenger.8 Finally, hyaluronic acid that is esterified can be produced into molded preparations to fit the shape of the wound and function as a tissue implant to promote healing. The preparation is biodegradable and can be left in the wound, as it promotes healing.9

Pantothenic Acid (Vitamin B5)

Pantothenic acid in the stable alcohol form of dexpanthenol has been shown to hasten wound healing, improve epithelialization and induce the proliferation of fibroblasts.10 Dexpanthenol can be prepared in varying strengths between 2% to 5% and can be formulated in creams, ointments or solutions or as an emulsion for topical application. Wounds treated with 5% dexpanthenol once a day for 5 days showed improved tissue strength and less wound redness than wounds treated with vehicle only or first aid cream, or wounds that were untreated.10 Pantothenic acid is thought to stimulate healing by inducing epithelialization as part of its actions as a cofactor of coenzyme A.10 Burns treated topically with 5.4% dexpanthenol have shown better epithelialization than untreated wounds.10 Finally, a German study10 has shown that 5% dexpanthenol will speed the process of wound healing by 1.52 times.

Pentoxifylline

Pentoxifylline (PTX) is a phosphodiesterase-inhibiting drug that has been used orally to reduce blood viscosity and also has been used to treat Raynaud's disease. It has also shown promise topically in wound healing. In correspondence with pharmacist Matthew Kopacki, he reports improved rates of healing using 10% PTX in combination with calcium channel blockers in Pluronic lecithin organogel (PLO) gel. One theory behind this is that PTX may act as a penetration enhancer to allow the calcium channel blocker to better reach the wounded tissue.

Phenytoin

The traditional use of phenytoin (PTN) has been as an anticonvulsant. One of its classic side effects is gingival hyperplasia, and this is the basis behind the hypothesis that PTN can stimulate wound repair.11 However, the mechanism behind PTN's actions on wound healing is still unknown. A study performed by DaCosta et al12 investigated the effects of topical PTN in healing skin wounds in rats. Each rat in the study was wounded in four places; two wounds were treated with 10 mg of PTN in 200 µL of 0.9% sodium chloride solution and the other two were treated with just 200 µL of 0.9% sodium chloride solution. Therefore, each animal served as its own control. The PTN or 0.9% sodium chloride solution was applied to the wounds on the same day as the animals were wounded, and then again 3 and 6 days later. Three days after wounding, the wounds treated with PTN had increased fibroblasts and angiogenesis compared with the untreated wounds. Six days after wounding, fibroblasts proliferation and angiogenesis were significantly more advanced than that of untreated wounds where fibroblast infiltration and angiogenesis had just began. Wounds treated with PTN had significantly greater amounts of collagen (due to greater number of fibroblasts), as well as greater tensile strength, than untreated wounds.

Thomas Johnson, a compounding pharmacist using topical PTN in his practice, has reported13 that topical PTN can cause decreased wound drainage and increased speed of wound healing. He reports that wounds treated with topical PTN will be healed within 1 to 3 weeks instead of 6 to 8 weeks. The major side effect to the use of topical PTN is burning upon its first application. Most of the clinical trials involving PTN have applied PTN powder directly to the wound. This is acceptable if the wound is small; application of PTN powder directly to a larger wound is impractical. Johnson reports13 success with the use of PTN compounded in Unibase cream to achieve a final concentration of 20 mg of PTN per gram of cream. This cream is much easier to apply to a wound and appears not to cause as much initial burning as a powder application.

Repifermin

Repifermin is an investigational drug that shows promise in promoting faster wound healing.14 Repifermin is a recombinant form of human keratinocyte growth factor 2 (KGF-2). Significant amounts of KGF-2 are not expressed in unwounded skin; however, its expression is highly up-regulated in skin wounds. Repifermin causes keratinocytes to proliferate and move to promote new tissue growth. A recent phase II trial14 investigated the efficacy of repifermin in healing chronic venous leg ulcers. The study14 used 4-mg/mL spray and applied 20 µg/cm^sup 3^ 60 µg/cm^sup 3^ or placebo to leg ulcers. Both the 20-µg/cm^sup 3^ and 60-µg/cm^sup 3^ repifermin treatment groups showed14 significantly more wound closure following 12 weeks of treatment compared with placebo. Used topically, repifermin appears to be tolerated well, with the primary adverse effect being pruritis. Repifermin looks to be a promising new agent in wound care.

Retinoids

Typically used to treat acne or psoriasis, the retinoids have potential as topical wound-healing agents. Orally, retinoids have been shown15 to promote the formation of granulation tissue as well as reverse impaired wound healing due to administration of corticosteroids. Topical treatment with retinoids has shown13 benefit in wound healing, but, for the most part, this benefit is derived from application prior to wounding. In a diabetic mouse model, Kitano et al15 compared effects of all-trans-retinoic acid pretreatment between diabetic and normal mice. These mice were diabetic due to a genetic mutation that impaired the production of KGF. Diabetic and control mice were pretreated with 0.1% all-trans-retinoic acid or empty vehicle for 5 days; 2 days later punch biopsies were performed. Diabetic mice treated with all-trans-retinoic acid displayed significant epidermal hypertrophy that was absent in control mice. One day following punch biopsy diabetic mice treated with all-trans-retinoic acid had significant inflammatory cell migration into the wound, but diabetic mice treated with vehicle only did not. Fourteen days after punch biopsy, 89% of diabetic mice treated with all-trans-retinoic acid had completely healed wounds compared with 22% of diabetic mice treated with empty vehicle. All-trans-retinoic acid also up-regulated KGF expression in diabetic mice. Due to the mechanism of action of all-trans-retinoic acids it would be of interest to see if use of all-trans-retinoic acid and repifermin would display a synergistic effect.

Treatment with retinoids has been investigated in human chronic leg ulcers. In a study performed by Paquette et al,16 a solution of 0.05% tretinoin was applied to leg ulcers from five patients for 10 minutes and then the solution was washed away. The application was limited to a few minutes because tretinoin is very irritating to wounded skin. One week after tretinoin treatment, patients showed more granulation tissue; and, after 4 weeks, there was increased granulation tissue and collagen as well as angiogenesis.

Sucralfate

Sucralfate (SUC) comprises both aluminum hydroxide and sucrose octasulfate.17 It is most commonly used orally as a protective agent for the mucosal layer for patients suffering from peptic ulcer disease. However, other dosage forms of SUC have exhibited17 use in wound healing. SUC is thought to promote wound healing by inhibiting inflammatory cytokine release. It can also stimulate angiogenesis, the formation of new blood vessels, by stabilizing basic KGF.17 SUC cream 7%, when used to treat second-degree burns, has been shown17 to cause faster epithelialization than other topical agents, such as silver sulfadiazine. One small study17 showed an average time to epithelialization of 18.8 days in second-degree burn patients treated with 7% SUC cream compared with an average time of 24.6 days in second-degree burn patients treated with other topical drugs. This same study17 showed that third-degree burn patients treated with 7% SUC cream developed granulation tissue on average 6.6 days earlier than patients treated with other topical burn agents. Serum monitoring throughout therapy with SUC cream showed no presence of absorbed aluminum.

Topical SUC has also been used successfully to treat the bleeding and diarrhea caused by radiation-induced proctitis. In a small study,18 use of a 10% SUC enema twice a day was able to significantly reduce bleeding in 76.9% of patients after 4 weeks of treatment. This response was improved to 92.3% of patients after 16 weeks of therapy. The patients in the study were followed for an average of 45.5 months after treatment with 10% SUC enemas, and 70.83% of the patients had no relapses in bleeding. In all of the patients who did relapse, re-initiation of SUC therapy stopped bleeding. Both of these dosage forms of SUC can easily be prepared by the compounding pharmacist to help these types of patients.

Conclusion

Options in the topical treatment of wounds have expanded in the past few years. Only a decade ago glyceryl trinitrate was the leading topical drug to treat anal fissures. Calcium channel blockers have now taken the lead. Recombinant DNA technology has also driven research in this area, and likely several recombinant growth factors and cytokines involved in the regulation of wound healing will be available as drugs. The number of opportunities the compounding pharmacist has in creating topical formulations for wound care is enormous. Not only can certain medications be compounded in dosage forms to specifically meet patient needs but these drugs can also be combined in one dosage form to simplify a patient's drug regimen and improve compliance. The use of calcium channel blockers and PTN in PLO is just one of numerous combination medications the pharmacist can compound. These medications have the potential to have an incredible impact on the lives of patients suffering from slow-healing wounds, especially wounds that threaten amputation. Topical medications such as calcium channel blockers and becaplermin have shown dramatic reductions in the time needed to reach complete healing. The arena of topical medications to treat wound healing is an excellent niche for the compounding pharmacist to market his or her skills to both patients and physicians.

References

1. Lusby PE, Coombes A, Wilkinson JM. Honey: A potent agent for wound healing? J Wound Ostomy Continence Nurs 2002; 29(6): 295-300.

2. Tonks AJ, Cooper RA, Jones KP et al. Honey stimulates inflammatory cytokine production from monocytes. Cytokine 2003; 21(5): 242-247.

3. Topham J. Why do some cavity wounds treated with honey or sugar paste heal without scarring? J Wound Care 2002; 11(2): 53-55.

4. Al-Waili NS, Saloon KY. Effects of topical honey on post-operative wound infections due to gram positive and gram negative bacteria following caesarean sections and hysterectomies. Eur J Med Res 1999; 4(3): 126-130.

5. Cooper RA, Halas E, Molan PC. The efficacy of honey in inhibiting strains of Pseudomonas aeruginosa from infected burns. J Burn Care and Rehabil 2002; 23(6): 366-370.

6. Subrahmanyam M. A prospective randomised clinical and histological study of superficial burn wound healing with honey and silver sulfadiazine. Burns 1998; 24(2): 157-161.

7. Chen WY, Abatangelo G. Functions of hyaluronan in wound repair. Wound Repair Regen 1999; 7(2): 79-89.

8. Trabucchi E, Pallotta S, Morini M et al. Low molecular weight hyaluronic acid prevents oxygen free radical damage to granulation tissue during wound healing. Int J Tissue React 2002; 24(2): 65-71.

9. Ballard K, Cantor AJ. Treating recalcitrant diabetic wounds with hyaluronic acid: A review of patients. Ostomy Wound Manage 2003; 49(4): 37-49.

10. Ebner F, Heller A, Rippke F et al. Topical use of dexpanthenol in skin disorders. Am J Clin Dermatol 2002; 3(6): 427-433.

11. Talas G, Brown RA, McGrouther DA. Role of phenytoin in wound healing- A wound pharmacology perspective. Biochem Pharmacol 1999; 57(10): 1085-1094.

12. DaCosta ML, Regan MC, al Sader M et al. Diphenylhydantoin sodium promotes early and marked angiogenesis and results in increased collagen deposition and tensile strength in healing wounds. Surgery 1998; 123(3): 287-293.

13. Johnson TJ. Use of topical phenytoin for wound care. S D J Med 1998; 51(101:387-388.

14. Robson MC, Phillips TJ, Falanga V et al. Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor-2) to accelerate wound healing in venous ulcers. Wound Repair Regen 2001; 9(5):347-352.

15. Kitano Y, Yoshimura K, Uchida G et al. Pretreatment with topical all-trans-retinoic acid is beneficial for wound healing in genetically diabetic mice. Arch Dermatol Res 2001; 293(10): 515-521.

16. Paquette D, Badiavas E, Falanga V. Short-contact topical tretinoin therapy to stimulate granulation tissue in chronic wounds. J Am A cad Dermatol 2001; 45(3): 382-386.

17. Banati A, Chowdhury SR, Mazumder S. Topical use of sucralfate cream in second and third degree burns. Burns 2001; 27(5): 465-469.

18. Kochhar R, Sriram PV, Sharma SC et al. Natural history of late radiation proctosigmoiditis treated with topical sucralfate suspension. Dig Dis Sci 1999; 44(5): 973-978.

Address correspondence to: Bruce Biundo, Professional Compounding Centers of America, 9901 South Wilcrest, Houston, TX 77099. E-mail: bbiundo@pccarx.com

Christopher D. Helmke

Professional Compounding Centers of America

Houston, Texas

Copyright International Journal of Pharmaceutical Compounding Sep/Oct 2004
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