Ulcers

Simpson, Kunz and Slafta, New York State Journal of Medicine (1965), 344 reported that PHT promoted the healing of leg ulcers. The study contained double blind and crossover controls. Thirty hospitalized psychiatric patients (age range forty to seventy-seven years) were chosen for the project. The sole criterion for the patient selection was that all had chronic leg ulceration. The ulcers had been present for from two to fifteen years. Occasional healing had taken place but this was minimal and most of the patients had an area of ulceration present at all times despite the fact that they received standard topical treatment and occasional bed rest. Repeated measurements were carried out under double-blind conditions. Measurements were made by means of a planimeter reading of the ulcer area as well as the actual scaling area around the ulcer. A clinical rating was also given. All three indices measured showed improvement in the PHT group compared with the placebo group. Statistical analysis of the actual ulcer areas demonstrated a difference at better than the 0.05 level of significance between the two groups. Small doses such as 200 mg a day were found to be associated with better healing than were larger doses.

344. Simpson, G. M., Kunz, E., and Slafta, J., Use of sodium diphenylhydantoin in treatment of leg ulcers, New York J. Med., 65: 886-888, 1965.

Strean, Chemical Abstracts (1966),669 reported PHT effective in promoting the complete healing of an antecubital ulcer, a diabetic ulcer and two peptic ulcers, all of long duration. It was found that PHT provided for the regeneration of healthy tissue in the denuded zone.

669. Strean, L. P., Treatment of ulcers, Chem. Abst. Biochem. Sec., 65: 11219c, 1966 (Merck & Co., Inc. Application for patent, Belg., May 12, 1965).

Taylor, Personal Communication (1969),730 reported a twenty-four-year-old patient with typical oral and genital ulcerations of Behcet's syndrome. The patient also had involvement of the temporomandibular joints (Costen's syndrome). Clenching the jaw produced pain typical of the syndrome. In addition, she suffered with conjunctivitis, urethritis, vaginitis and arthritis. By the sixth day, with treatment with PHT, 100 mg/day, the ulcerated areas had healed and all other symptoms disappeared. The patient remained symptom-free when seen five months later.

730. Taylor, A. S., Behcet’s syndrome treated with DPH, Personal communication, 1969.

Rodriguez-Noriega, Esparza-Ahumada, Andrade-Perez, Espejo-Plascencia and Chapa-Alvarez, Investigacion Medica Internacional (1983),2911 studied forty patients with venous stasis, diabetic and other soft tissue ulcers. They compared the use of PHT, topically, in twenty patients with conventional treatment in a control group of twenty patients. The average time to healing or grafting in the PHT-treated group was twenty-one days, compared to forty-five days in the control group. Biopsy of the PHT-treated ulcers showed more rapid infiltration of fibroblasts and greater collagen deposition, as well as increased new blood vessel formation. Bacterial cultures of the ulcer surface improved more rapidly, and more stable scar formation was also seen in the PHT group. (See also Ref. 2690).

2911. Rodriguez-Noriega, E., Esparza-Ahumada, S., Andrade-Perez, J. S., Espejo-Plascencia, I., Chapa-Alvarez, R., Treatment of ulcerations in soft tissues with topical diphenylhydantoin, Invest. Med. Int., 10: 184-6, 1983.
2690. Lasker, S. E., Lee, B. Y., Madden, R. E., Jetter, R. B., Topical use of 5,5-diphenyl-2,4-imidazolidinedione (diphenylhydantoin) inducing rapid granulation of chronic skin ulcers, Clin. Res., 31(3): 677a, 1983.

Barba Rubio, Presented at the XII Mexican Congress of Dermatology (1985),2308 presented a report on the use of topical PHT in the treatment of trophic lower extremity ulcers in seven leprosy patients. The ulcers were chronic and had been refractory to previous forms of treatment for up to fifteen years. With PHT, three of the patients had complete healing of their ulcers within six weeks. The remaining four patients had good results consisting of diminished exudate, appearance of healthy granulation tissue, reduction in ulcer size, and suitability for skin grafting.

2308. Barba Rubio, J., Diphenylhydantoin in leprosy. Its topical application in ulcers and plantar trophic ulcers, Presented to XII Mexican Congress of Dermatology, Oaxaca, Oct. 9-12, 1985.

Pasolini, Pancera, Manganoni, Cetta and Zanaboni, Giornale Italiano di Dermatologia e Venereologia (1988), describe a thirty-year-old patient with prolidase deficiency and chronic leg ulcers present since puberty. Almost complete healing of the cutaneous ulcers lesions) resulted from oral phenytoin treatment (50 mg on alternate days).

El-Zayat, Military Medicine (1989), conducted pilot clinical trials (at Basra Teaching Hospital, Basra, Iraq) to evaluate topical phenytoin's effectiveness in treating decubitus ulcers resulting from war-related wounds. Topical phenytoin treatment was compared to that of normal saline. Prompt pain relief, decreased wound exudate and bacterial contamination, enhanced granulation tissue formation, and more rapid healing characterized the PHT group. The fifteen PHT-treated patients experienced complete healing of their decubitus ulcers in one to three weeks (one patient required a skin graft), while the control group required six to eight weeks to achieve similar results. Furthermore, five of these patients required skin grafts.
An additional twenty patients with missile wounds were treated with PHT in an open trial. All twenty patients with intractable missile wounds healed within two to four weeks. Six of eleven positive wound cultures became negative after five days of treatment. Three of the remaining five cultures were negative after ten days of treatment.
The author emphasizes that topical PHT is not only effective in promoting wound healing, but is also readily available, safe, inexpensive, and easy to use.

Modaghegh, Salehian, Tavassoli, Djamshidi and Shiekh Rezai, International Journal of Dermatology (1989), report on the topical phenytoin sodium treatment of nineteen patients with war-related missile wounds and six patients with refractory civilian ulcers. With phenytoin treatment applied daily over a four-week period, twenty-two of the twenty-five patients had complete wound healing within two to four weeks. Three other patients had good granulation responses, but still required skin grafting for final wound closure. The mean healing time was two weeks for missile wounds, compared to six to eight weeks for historical controls. The civilian ulcers had been unresponsive to any treatment over the previous five months. Although no antibiotics were given, the positive wound cultures of seventeen patients became negative after one week of PHT treatment.
The authors recommend wider use of this safe, inexpensive, readily available and easy-to-use agent because of its positive effect on wound healing and rapid pain relief.

Bogaert, Saleta, Sanchez and Garcia, International Journal of Dermatology (1990), treated twenty leprosy patients with thirty-three trophic ulcers of the leg and plantar area with topical phenytoin for three to six weeks. Seven additional patients with seven ulcers were treated with both topical and systemic PHT, 100 mg po daily. The ulcers were debrided of necrotic tissue, washed with soap and antiseptic and a thin dusting of PHT powder and a dry gauze dressing were applied. The patients' ulcers were examined weekly and photographs were taken at the beginning of treatment and at two-week intervals. When examined at one week, all ulcers showed diminished exudate and abundant new granulation tissue. By three to six weeks, twenty patients had major improvement -- complete healing of small lesions (2-4 cm diameter) and markedly enhanced granulation tissue formation in larger lesions (> 4 cm). Seven patients had moderate improvement. None worsened.

Lodha, Lohiya, Vyas, Bhandari, Goyal and Harsh, British Journal of Surgery (1991), evaluated topical phenytoin's ability to promote the healing of large abscess cavities in controlled studies of clinical and experimental wounds. Application of phenytoin (200 mg/cm2) to such wounds in twenty patients was compared with to conventional treatment in an additional twenty patients. Phenytoin treatment resulted in earlier separation of slough, decrease in edema, control of pain and overall enhanced healing. The mean rate of reduction of wound area was 2.02 +/-0.48 (SD) cm2/day in the phenytoin group versus 1.58 +/-0.51 cm2/day in controls (p < 0.05) on day 10, and 1.8 +/-0.32 cm2/day versus 1.19 +/-0.21 cm2/day (p < 0.01) on day 20. The mean volume reduction rates at both the 10th and 20th day were 0.48 +/-0.01 cm3/day for phenytoin versus 0.32 +/-0.04 cm3/day for controls (p < 0.005). By day 20, seventeen of the patients treated with phenytoin were rated as having healed completely, compared with only one of the controls.
In a standardized guinea-pig model of the clinical abscess cavity where the abscesses were produced by inoculation with Bacillus proteus and Klebsiella pneumoniae, an enhanced healing rate was also observed (at seven days, 0.40 +/-0.05 cm2/day with phenytoin versus 0.21+/-0.08 cm2/day in controls; p < 0.005). All eight of the animals treated with phenytoin healed by day 21, compared with one of the eight controls. Biopsies of the wounds treated with phenytoin showed less inflammation, no necrosis, and enhanced neovascularization, collagen deposition and fibroblast proliferation, compared to controls. Bacterial colonies also decreased more rapidly with the use of phenytoin.
Based on the results of their experimental and clinical studies, the authors recommend the topical application of PHT to promote healing of abscess cavities. They comment that PHT is not only effective, but also safe, easy to use and inexpensive.

Malhotra and Amin, International Journal of Leprosy (1991), describe a controlled inpatient trial comparing topical phenytoin to topical zinc therapy in the treatment of trophic ulcers in leprosy patients. Fifty patients (forty-one males and nine females) were treated with phenytoin and twenty-two (seventeen males and five females) were treated with zinc cream. The ulcers were on the forefoot, midfoot, heel, leg and other locations. Healthy new granulation tissue appeared in thirty-one of the fifty PHT-treated patients (62%) within seven days. In the zinc-treated group, five of twenty-two patients (23%) showed a comparable response. Ulcer exudate was eliminated much earlier in the phenytoin-treated group. By twelve weeks, thirty of forty-three PHT-treated patients (70%) remaining in the study had complete healing. Four other patients had 50% or greater healing. Of the twenty-two zinc-treated patients, only six had complete healing. The authors comment on the reduced incidence of secondary infection requiring antibiotics in the phenytoin-treated patients, as compared to those receiving zinc treatments.

Muthukumarasamy, Sivakumar and Manoharan, Diabetes Care (1991), in a controlled inpatient study of diabetic foot ulcers, treated fifty patients with topical phenytoin (applied as a thin layer over the ulcer) and fifty control patients with dry, sterile occlusive dressings. The patients were matched for age, sex, ulcer area, depth, chronicity and infection. There was improvement in both groups, but the ulcers treated with topical phenytoin healed more rapidly. Mean time to complete healing was twenty-one days with phenytoin and forty-five days with control. The differences seen were statistically significant (p < 0.05). The authors also noted that the quality of scar formation was better in the phenytoin-treated group.

Xu, Liang, Zhang and Zhang, West China Medical Journal (1992), used topical phenytoin to treat previously refractory ulcers (of 1 - 9-year duration) of three gout patients. The surface areas of the ulcers varied from 0.5 x 0.5 to 4.5 x 6.5 cm2. Two patients had multiple deep fistulas (6 - 16 cm) or sinuses. There was extensive chalky suppurative exudate on the ulcer surfaces and in the sinuses. Bacterial cultures were positive in two cases, one for Pseudomonas aeruginosa, and the other for Staphylococcus aureus. With phenytoin treatment (application of a thin layer over the ulcer area), the ulcer exudate began to diminish after day 5 and disappeared after day 10. Fresh granulation tissue appeared at days 7 - 15, and bacterial cultures became negative by day 24. Two cases healed completely, and one improved markedly. No adverse reactions were observed. The authors suggest that topical phenytoin may be an effective and safe medicine for the therapy of refractory gouty ulcers.

Bansul and Mukul, International Journal of Dermatology (1993), compared the wound healing effects of topical phenytoin powder to those of normal saline in a controlled inpatient study of 100 patients with 110 trophic leprosy ulcers of varying chronicity. Fifty patients were assigned to the topical phenytoin group (application of a thin, uniform layer) and fifty, to saline therapy. Ten patients had two ulcers each, and in these cases, one ulcer was treated with phenytoin and the other, with saline. Over the four-week treatment period, healthy granulation tissue appeared earlier and the mean percentage of ulcer volume reduction was greater in the phenytoin group (72.1 +/- 19.9% vs. 55.5 +/- 21.6%) compared to the control group.
The authors conclude that phenytoin is a useful agent for the promotion of healing of trophic leprosy ulcers.

Menezes, Rajendran, Jacob and Vaz, Southeast Asian Journal of Tropical Medicine and Public Health (1993) treated thirty leprosy patients with trophic ulcers of the foot. All thirty patients had supervised bed rest, joint immobilization, ulcer debridement (if required) and oral antibiotic treatment for local infection. The cleansed ulcers of fourteen of these patients were dusted with a thin film of phenytoin powder and covered with a plain dressing. Sixteen patients (the control group) received only daily plain dressings without PHT powder. The ulcers in the two groups were matched for depth as well as surface (planar) dimensions. However, the duration of the ulcers of the patients in the phenytoin group was approximately twice that of those in the control group. Healing patterns were assessed by determining changes in depth and planar (surface) dimensions at weekly intervals over a three-week study period.
Both study groups showed a significant decrease (p < 0.01) in planar dimensions and depth at the end of three-weeks. The rate of decrease in planar dimensions was significantly greater (65%) in the phenytoin group than in controls. Although it was not statistically significant, there was also a marginally greater decrease in ulcer depth in the phenytoin group. The authors conclude that phenytoin is a useful adjunct to rest and immobilization in the treatment of the trophic ulcers associated with leprosy.

Pendse, Sharma, Sodani and Hada, International Journal of Dermatology (1993), conducted a controlled study of seventy-five patients with chronic skin ulcers of various etiologies. Treatment with topical phenytoin (forty patients) was compared to that of normal saline dressings (thirty-five patients) over a four-week period. The treatment protocol was otherwise identical. No antibiotics or vitamin supplements were used during the study. Both groups improved over the four weeks, but the ulcers treated with phenytoin (applied as a thin, uniform layer) healed more rapidly. During the third week of treatment, healthy granulation tissue was obtained in thirty-six of forty (89%) phenytoin-treated ulcers, compared to twenty-four of thrity-five (67%) controls. At the end of three weeks of treatment, the average percent reduction in surface area of the ulcers was 51% in the phenytoin group versus 36% in the control group.
Complete healing of ulcers was obtained in twenty-nine (73%) of the phenytoin group versus ten (28.5%) of the controls. An additional seven phenytoin-treated patients achieved satisfactory wound healing after skin grafting. Seventeen of the controls required skin grafting. Negative wound cultures were obtained earlier in the phenytoin group (twenty-three of twenty-eight patients (82%) versus twelve of twenty-two (54%) in the controls were negative during the second week of treatment.). No local or systemic adverse effects of topical phenytoin were noted. The authors recommend topical use of phenytoin as a safe and inexpensive treatment for a variety of infected and non-infected wounds.

Yadav, Singhvi, Kumar and Garg, Burns (1993) reported the effectiveness of topical PHT as a wound healing agent, compared to both OpSite surgical dressing and a conventional topical antibiotic dressing (Soframycin) in a controlled study of sixty patients (ages 5-70 years) with partial-thickness skin autograft donor sites on the lower extremities. The patients were divided into three treatment groups. For the thirty patients in the PHT treatment group, mean time to complete healing was 6.2 +/- 1.6 days, as compared to 8.6 +/- 2.2 days for the fifteen OpSite patients and 12.6 +/- 3.4 days for the 15 patients treated with Soframycin dressings. By day 6, more than 50% of the donor sites treated with topical PHT were completely healed. None were completely healed at this same time point in either the OpSite or Soframycin groups.

Lewis and Rhodes, Annals of Pharmacology (1994), report the lack of measurable serum phenytoin systemic absorption after twelve to twenty-two days of treatment of pressure ulcers with topical phenytoin. Two patients with slow-healing pressure lesions that were deep enough to involve the hypodermis were treated with topical PHT (100 - 200 mg/day). The patients' baseline and post-treatment serum levels were < 0.5 ug/ml indicating the lack of significant absorption of phenytoin through these open lesions.

Adjei, Evans and Asiedu, Transactions of the Royal Society of Tropical Medicine and Hygiene (1998), present three cases of Ghanaian children (ages 8-17) with Buruli ulcers treated successfully with topical phenytoin. The ulcers had been present for periods of three weeks to seven years at the time of treatment. Fresh granulation tissue appeared within two to six weeks of treatment and complete healing was achieved in six to sixteen weeks with the time to healing correlating with ulcer duration. No recurrences were noted.
The authors recommend controlled trials of phenytoin in the treatment of these resistant ulcers caused by Mycobacterium ulcerans to further evaluate its effectiveness.

Rhodes, Heyneman, Culbertson, Wilson and Pkatak, Annals of Pharmacotherapy (2001), report on a study of forty-seven Veterans Administration nursing home patients with stage II decubitus ulcers. The patients, all age 60 years or older, were divided into three treatment groups: eighteen patients in a PHT treatment group, thirteen patients in a topical antibiotic ointment (TAO) treatment group and sixteen patients treated with a DuoDerm collagen dressing. Results indicated that while both the PHT and the standard therapy groups showed progress over the study period, the PHT group showed more rapid results in all aspects of ulcer healing. Within the first two weeks of therapy, all wounds in the PHT group showed greater reduction in ulcer size, appearance of healthy granulation tissue, and reduction in wound exudates. Results demonstrated the effectiveness of topically applied PHT in significantly accelerating the healing of pressure sores. No adverse drug reactions or interactions were noted throughout the study

Carneiro and Nyawawa, East African Medical Journal (2003), evaluated the effectiveness of topical phenytoin compared to that of EUSOL (Edinburgh University solution of lime) with respect to rate of healing and analgesic and antibacterial properties in 102 patients (sixty-seven males and thirty-five females, aged 12-56)) with chronic, non-malignant leg ulcers (duration 3 to 156 weeks) at Muhimbili Medical Center in Dar es Salaam, Tanzania, over a fourteen-month period. Fifty patients were treated with topical phenytoin (application of a thin layer of powder on a daily basis), and fifty-two patients were treated with the daily application of Eusol. All ulcers were dressed daily and followed for a period of twenty-eight days or until the ulcers were epithelialized or were ready for skin grafting.
The authors found that pain reduction was greater in the phenytoin group at days 7 (p<.05) and 14 (p<.01) than for EUSOL. Ulcer discharge also cleared more rapidly with phenytoin (p<.05). The rate of formation of granulation tissue at days 14 and 21 was faster with phenytoin by days 14 and 21 (p<.001), and overall decrease in ulcer area was greater with PHT at a days 7, 14, 21, and 28 (p<.05). The rate of clearance of bacterial colonization was not significantly different in the two groups.
The authors note that phenytoin's low cost, ease of use, and effectiveness in promoting healing offer significant advantages for the treatment of chronic ulcers in resource-poor environments.

Klutse, Adjei, Ampadu and Arthur, Presentation to the 6th WHO Advisory Group Meeting on Buruli Ulcer (2003), reported on their study comparing the effectiveness of topical phenytoin to normal saline dressings, each applied daily for a period of eight weeks, in the healing of Buruli ulcers in fifty-eight patients (29 in each group) in Ghana. Fifty-two patients completed the eight weeks of treatment. Forty-two percent of the PHT-treated ulcers healed completely after eight weeks, compared to only 8% percent of those treated with normal saline. Of the ulcers without complete healing, 60% showed significant improvement (reduction in ulcer size) with phenytoin, compared to 29% with normal saline. Stellate scar formation was also reduced with PHT treatment.
The authors conclude that topical phenytoin is effective treatment for Buruli ulcers.

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