The diabetic ulcer II / La ulcera diabetica II

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****** DATA-MÉDICOS *********
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ULCERA DIABÉTICA (II) / DIABETIC ULCER (II)
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***** DERMAGIC-EXPRESS No 15 *********
****** 12 NOVIEMBRE 1.998 ***

EDITORIAL ESPAÑOL:
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Hola Amigos, Dermagic de nuevo con ustedes. Han salido al mercado varios productos nuevos para el tratamiento de la ulcera diabética, el REGRANEX, CYTOLEX, DERMAGRAFT, BIAFINE Y APLIGRAF. Alli estan las referencias.

A partir del día de hoy DERMAGIC será montado en la lista ACADERM-L perteneciente al Dr. Art C Huntley, para su difusión en USA, una vez a la semana.

Hasta una próxima edición colegas,,, saludos,,,

Próximas ediciones: * ONICOMICOSIS BLANCA,,, * EL SOLARASE

Dr. José Lapenta

EDITORIAL ENGLISH:
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Hello friends, Dermagic again with you. They have left to the market several new products for the treatment of diabetic ulcer, the REGRANEX, CYTOLEX, DERMAGRAF, BIAFINE AND APLIGRAF. I, am sending the references on these products.

Starting from today's day DERMAGIC will be mounted in the list ACADERM-L belonging to the Dr. Art C Huntley, for their diffusion in USA, once a week.

Dermagic is also mounted in DERMLIST, Brazil, (Dr. George Leal), and FUNGI (Dr. Paulo Taborda), and diffused in Colombia, Peru, Argentina, Panama, Venezuela, etc.

Until a next edition colleagues,,,, greetings

Next editions: * WHITE ONYCHOMYCOSIS,,, * THE SOLARASE

Dr. José Lapenta

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DERMAGIC/EXPRESS(15)
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ULCERA DIABÉTICA (II) / DIABETIC ULCER (II)
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ULCERAS EN LA WEB//ULCER IN THE WEB
1.) Cytolex Cream Heals Diabetic Foot Ulcers Well as
Oral Antibiotic
2.) FDA Panel Recommends Dermagraft For Diabetic Foot Ulcers
3.) Regranex Gel Approved In U.S. For Diabetic Foot Ulcers
4.) Biafine Now Packaged For Dermal Wounds And Radiodermatitis
5. FDA Advisory Panel Recommends Unconditional Approval of Apligraf TM for Treatment of Venous Leg Ulcers
6.)Ténica para la aplicación de Apligraf.//Technique to use APLIGRAF

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1.) Cytolex Cream Heals Diabetic Foot Ulcers Well as Oral Antibiotic
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PLYMOUTH MEETING, Pa., March 18, 1997 -- Magainin Pharmaceuticals
Inc. (Nasdaq: MAGN) today announced the successful results of its second, pivotal Phase III clinical trial of Cytolex(TM) 1% topical antibiotic cream (MSI-78) for the treatment of infection in diabetic foot ulcers.

The Company's analysis of the study showed statistical equivalence between MSI-78 and orally administered ofloxacin, with respect to the study's primary endpoint of clinical response of infection at day 10 of treatment, and at subsequent time points through day 28, and at follow-up. Floxin(R) (ofloxacin) is a quinolone antibiotic indicated for the treatment of skin and soft tissue infections. The study enrolled 342 patients.

As a secondary endpoint, MSI-78 and ofloxacin were comparable with respect to overall assessments of microbiological improvement.

Preliminary analyses of adverse events in the study suggest a favorable profile for MSI-78. Both drugs were well tolerated, however, treatment with ofloxacin was associated with a significant excess of adverse events related to the central nervous system, particularly as it relates to insomnia.

Magainin previously announced successful results of its initial, pivotal trial of MSI-78 for the treatment of infection in diabetic foot ulcers in September 1996.

"This is a strong confirmation of the efficacy and safety results observed in our initial pivotal study," said Jay Moorin, Chairman, President and Chief Executive Officer of Magainin. "Our two studies represent, to our knowledge, the largest database of clinical data for infected diabetic foot ulcers that has been assembled. If approved for marketing by the U.S. Food and Drug Administration ("FDA"), we expect that MSI-78 will be the first antibiotic specifically labeled for the treatment of infection in diabetic foot ulcers, and will provide physicians an important alternative to systemic therapy."

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2.) FDA Panel Recommends Dermagraft For Diabetic Foot Ulcers
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LA JOLLA, CA -- January 29, 1998 -- The United States Food and Drug
Administration's general and plastic surgery devices panel of the medical devices advisory committee has recommended that the agency approve Advanced Tissue Sciences, Inc.'s Dermagraft(TM), a living human dermal replacement for the treatment of diabetic foot ulcers, with the condition that the company perform a post-marketing study.

Dermagraft is produced by culturing human dermal fibroblasts (a type of cell commonly found in the dermal layer and in connective tissue) onto a biosynthetic scaffold. As the fibroblasts proliferate on the scaffold, they secrete important structural proteins and growth factors, generating a three-dimensional human dermis. Dermagraft is then frozen for storage and shipment to the treating physicians for implantation into patients.

In the U.S., diabetic foot ulcers affect approximately 15 percent of the 16 million diabetic patients in their lifetime.

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3.) Regranex Gel Approved In U.S. For Diabetic Foot Ulcers
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RARITAN, NJ -- December 17, 1997 -- The United States Food and Drug
Administration (FDA) has granted marketing clearance for Regranex(R) (becaplermin) Gel 0.01%, the first biologic proven to increase the incidence of complete healing in diabetic foot ulcers.

When used as an adjunct to good ulcer care, Regranex Gel is indicated for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. Diabetic foot ulcers are one of the most difficult types of wounds to heal. This new Topical gel, which contains genetically-engineered platelet-derived growth factor, is the first prescription biologic that actively stimulates the body to grow new tissue to heal these wounds.

Clinical trials demonstrated that a once daily topical application of Regranex Gel plus good ulcer care healed more diabetic ulcers than placebo gel plus good ulcer care. Good ulcer care practices, including initial sharp debridement (removal of dead tissue), daily dressing changes, pressure relief and treatment of infection if present, are required to achieve the best results with Regranex Gel. The product will be available in early 1998.

More than two million people with diabetes will develop foot ulcers during their lifetime. Foot ulcers often go undetected since other ailments associated with diabetes -- such as nerve damage and visual and circulatory problems -- make it difficult for patients to feel or see the ulcer as it develops. These open sores often don't heal and may lead to serious complications including severe infection and amputation.

"Diabetic foot ulcers are a serious problem in this country, resulting in 67,000 amputations each year," said Mayer Davidson, M.D., president of the American Diabetes Association. "Diabetic foot disease costs the nation more than $1 billion each year."

"Wound healing is a complex process that, until now, only Mother Nature could influence," said David Steed, M.D., professor of surgery, University of Pittsburgh, and a clinical trial investigator. "Now, with Regranex Gel, we have something that no drug has ever offered before, a simple, easy-to-use treatment that actually stimulates the body to heal more diabetic ulcers."

Regranex Gel was well tolerated in all clinical trials. Incidence of adverse events was similar in patients treated with Regranex Gel, placebo gel or good ulcer care alone.

The active ingredient in the product is becaplermin, a genetically-engineered, platelet-derived growth factor that mimics a protein that occurs naturally in the body. The growth factor stimulates the migration of cells to the ulcer site, encouraging the patient's body to grow new tissue that heals these open wounds. becaplermin is produced by recombinant technology in yeast cells and is not derived from blood.

Regranex Gel was developed by the R.W. Johnson Pharmaceutical Research Institute and will be marketed in the United States by Ortho-McNeil Pharmaceutical, Inc.

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4.) Biafine Now Packaged For Dermal Wounds And Radiodermatitis
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WASHINGTON, MD. -- October 15 -- Medix Pharmaceuticals Americas,

Inc. said its wound management emulsion, Biafine(R), is now separately packaged in the United States specifically for two applications: Biafine Wound Dressing Emulsion (WDE) for the management of dermal wounds and burns and Biafine Radiodermatitis Emulsion (RE) for protection against skin reactions induced by radiation therapy and management of these reactions. The products are cream emulsions, available without a prescription, that work by providing an optimum environment for the skin's healing process.

The application of Biafine WDE and Biafine RE result in the recruitment of macrophages to the wound site, which facilitate healing through all phases of the healing process. Macrophage recruitment assists in debridement, the removal of dead cells and tissue. Biafine's physical structure of oil in water also aids in the removal of dead tissues and its emollient action helps liquify these tissues. The emulsion provides a protective physical barrier against external contamination as well as a moist environment and aids in the absorption of exudates, the fluids that result from a wound.

Adequate hydration is essential to the healing process. Because its water Content is highly available to the wound site, Biafine WDE and Biafine RE provide deep dermal hydration: 41 percent of their water content is absorbed deep in the skin within the first hour of application. Biafine, a leading wound, radiodermatitis and burn care product in Europe, has been used for more than two decades by physicians, fire departments, emergency room personnel and radiation therapy facilities.

Healing results from a complex series of cellular and biochemical processes. Macrophages are cells which aid the healing process in several ways, including the removal of foreign particles and microorganisms. Macrophages occur in the Walls of blood vessels and are usually immobile until stimulated by inflammation resulting from a wound or infection.

The healing process consists of three phases:

1) inflammation, during which macrophages assist in autolytic debridement, the removal of dead cells and tissue debris from the wound site;

2) proliferation, in which macrophages stimulate the production and activity of fibroblasts, cells responsible for the production of materials essential to healing such as collagen; and

3) maturation, when fibroblast proliferation promotes multiplication and growth of skin cells through chemical messengers such as fibroblast growth factor and macrophage-derived growth factor.

The unique formulation of Biafine recruits macrophages to the wound site During all three phases.

Biafine WDE can be used for a variety of full and partial thickness dermal wounds, including dermal, vascular, arterial, diabetic and pressure ulcers, as well as first and second degree burns. The product is a fluid, yet firm, emulsion that will conform to the contours of a wound and is available in 45-ml and 100-ml tubes. Biafine WDE can be used safely with topical antibiotics.

According to the most recent data available from the National Center for Health Statistics, in 1992, there were a total of 34 million emergency room visits that were injury-related, generating over $9.2 billion US in healthcare costs. Wound care was performed at approximately one-third of these visits.

In addition to wounds resulting from surgery or injury, Biafine WDE can be used for dermal ulcers, which are open sores on any external surface of the body. Diabetics often suffer from dermal ulcers, usually on their feet. Biafine WDE can also be used for pressure ulcers, known more commonly as bedsores. Pressure ulcers occur in five to nine percent of all hospitalized Patients and in 23 percent of all nursing home patients.

Biafine WDE can also be used for chronic or delayed healing wounds. Application of Biafine WDE can renew the healing process in wounds that have not yet healed for years.

In addition, Biafine WDE can be used for the management of first and second degree burns. First degree burns are classified as those that involve only the epidermis (outermost layer of the skin) and are most commonly the result of overexposure to ultraviolet radiation, such as sunburn. Second degree burns Are usually flash burns or the result of scalds.

Radiation therapy is used to treat many kinds of cancer in almost any part of the body. One common side effect of radiation therapy is radiodermatitis, in which the skin in the treatment area begins to look reddened, irritated or burned. Radiation-treated skin may also develop a moist reaction, especially where there are skin folds and may become very sore. Patients given radiation therapy for breast cancer are especially at risk for radiodermatitis. Biafine RE is available in 45-ml and 20-ml tubes as a prophylaxis against radiodermatitis and for the management of the condition.

If a skin reaction occurs after radiation therapy, Biafine RE can be applied as a wound dressing to manage radiodermatitis. In more severe cases of radiodermatitis, it should be applied in thick layers and may be covered with a gauze dressing if necessary.

PR Newswire 1998 Jan, 29
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5.) FDA Advisory Panel Recommends Unconditional Approval of Apligraf TM for Treatment of Venous Leg Ulcers
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CANTON, Mass. (BW HealthWire/ via PRNewsWire/ via NoBlood.com) -
Organogenesis Inc.

(AMEX:ORG) today announced that the General and Plastic Surgery Devices Advisory Panel to the Food and Drug Administration (FDA) recommended unconditional approval of AppliGraf(TM) (Graftskin) Human Skin Equivalent for the treatment of venous leg ulcers. Approximately one million people in the United States -- four million globally -- suffer from venous leg ulcers. Apligraf(TM) is the first manufactured living human organ -- multilayered skin -- to be recommended for approval by an advisory panel to the FDA.

All Panel members stated they were in favor of product approval. The Panel members voted 5 to 4 in favor of approval of Appligraf(TM) without conditions. In its pivotal trial, Apligraf(TM) was found to be highly effective in the treatment of venous leg ulcers. The product was especially effective in difficult-to-heal ulcers: Apligraf(TM) healed more than twice as many ulcers open for a year or longer, and healed them faster, than compression therapy.

Apligraf(TM) was approved for the treatment of venous leg ulcers in Canada in 1997, and was launched there in August 1997 by Novartis Pharmaceuticals Canada Inc. Novartis AG, the world's leading Life Sciences company, has exclusive worldwide marketing rights to Apligraf(TM) and is pursuing other international registrations for the product. Under the agreement, Organogenesis manufactures the product and Novartis is responsible for all sales and marketing activities, as well as post-marketing studies.

"We believe Apligraf(TM) will revolutionize the treatment of venous leg ulcers," said Herbert M. Stein, Organogenesis' chairman and chief executive officer. "The advisory panel's confidence in the product is encouraging, and we are hopeful Apligraf(TM) will soon be available to the one million Americans who suffer from these wounds."

"Apligraf(TM) is a truly novel product and we are pleased to have Novartis leading the world-wide marketing effort," Stein added. "Novartis has extensive experience introducing novel products, from implementing effective medical education and marketing programs to securing reimbursement. Such programs help establish a long-term business base."

"Novartis is delighted that the FDA advisory panel recommends that Apligraf(TM) be approved for marketing," said David Epstein, Vice President, Marketing and Sales, Specialty Business Sector for Novartis Pharmaceuticals Corp. "We look forward to being able to offer Apligraf(TM) to patients suffering with venous leg ulcers."

Apligraf(TM) has a unique profile most similar to human skin. The product is bi-layered, with both an epidermis and dermis, composed of living human epidermal (keratinocytes) and dermal (fibroblasts) cells. The cells are organized as in skin: for example, the epidermal layer is fully differentiated and includes the protective outer stratum corneum. This is achieved via Organogenesis' patented organotypic cell culture technology, which allows the cells to self-establish their optimal three-dimensional arrangement for function, as they do in the body.

In the Apligraf(TM) pivotal trial, it was found that half of venous leg ulcer patients have had their ulcer for a year or longer. It is believed Apligraf(TM) is able to heal persistent ulcers unhealed with standard treatment because the living cells in Apligraf(TM) are believed to actively contribute to wound healing. In contrast, bandages must rely on the patient's own wound healing abilities, which can be compromised in persistently unhealed wounds.

Apligraf(TM) is applied directly to the wound, much the same way as a conventional skin graft. However, as Apligraf(TM) does not require harvesting skin from the patient, it does not require hospitalization. It has been used in over 400 patients without rejection.

Apligraf(TM) use does not require ultra-cold storage facilities or complex thawing regimens: the physician simply schedules the patient, orders the product and Apligraf(TM) is delivered ready-to-use. Treatment of venous leg ulcers is a scheduled, non-emergency procedure.

In addition to venous ulcers, Apligraf(TM) studies have been completed in skin surgery wounds and burn wounds; data from these studies have been published and/or presented. A pivotal trial is underway in diabetic ulcers which is expected to complete in late 1998/early 1999. A pivotal trial in pressure sores is anticipated to begin in the first half of 1998.

Organogenesis Inc. designs, develops and manufactures medical therapeutics containing living cells and/or natural connective tissue components. Organogenesis' product development focus includes living tissue replacements, cell-based organ assist devices and guided tissue regeneration scaffolds. In addition to Apligraf(TM), the company's product portfolio includes the GRAFTPATCHsurgical product (cleared for marketing in the United States), a cell-based liver assist device, a vascular graft for coronary artery bypass procedures and a tissue filler product for female urinary incontinence.

Statements in this press release which express the "belief", "anticipation", "intention" or "expectation," as well as other statements which are not historical fact, and statements as to product compatibility, design, features, functionality and performance insofar as they may apply prospectively, are forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and involve risks and uncertainties.

There can be no guarantee that the FDA will accept the Advisory Committee's recommendation, or that it will render its decision in a timely manner. The company's actual results may differ significantly from the results discussed on this press release or in other forward-looking statements presented by management.

Factors that might cause such a difference include, but are not limited to, development by the company's competitors of new technologies or products that are more effective than the company's, risks of failure of clinical trials, dependence on and retention of key personnel, protection of proprietary technology, compliance with U.S. Food and Drug Administration regulations, continued availability of raw material for the company's products, availability of product liability insurance upon commercialization of the company's products, ability to transition from pilot-scale manufacturing to full-scale commercial production of products, uncertainty as to the availability of additional capital on acceptable terms, if at all, and the demand for the company's products, if and when approved.

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6.) TÉCNICA PARA LA UTILIZACIÓN DE APLIGRAF (The Stuart Maddin Skin Therapy Letter ///Technique to use APLIGRAF
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Preparation of the wound bed, proper application of Apligraf, and patient compliance with underlying therapy for underlying disease are probably the most important determinants of clinical efficacy.1,2

What are the most important things to remember about preparing the wound?1

1. Debride the wound bed so that it is as clean and free of fibrotic/necrotic tissue as possible.

2. After debridement, cleanse the wound bed of debris by irrigating with a sterile, non-cytotoxic saline solution. You may apply gentle pressure to stop bleeding and/or use topical hemostatic agents prior to application.

3. Contain bacterial infection.

4. Control leg edema and heavy wound exudation with elevation and compression of the leg. 5. Implement appropriate therapies for underlying venous insufficiency.

Should antimicrobial agents be used prior to the procedure?

The commensals in venous leg ulcers are generally not associated with the kind of frank infection that would preclude the application of HSE. If necessary, oral, topical or injectable antimicrobial agents may be used for one week prior to application.1,2 Several commonly used burn wound antimicrobial agents (including mafenide acetate, polymyxin B sulfate, nystatin and sodium hypochlorite) may have a deleterious effect on HSE. Certain cytotoxic agents (Dakin's solution, mafenide acetate, Scarlet Red dressing, tincoban, zinc sulfate, povidone iodine solution and chlorhexidine) can destroy cellular components of skin and HSE, and following their use, the wound should be thoroughly cleansed with physiological saline before application.1

Use of Apligraf

1. Apligraf is intended for single-use only. It should be kept on its tray on the medium in an incubator (19-31°C) until ready for use. It remains viable for up to five days from the moment it is sealed in the pouch.

2. Before opening the plastic container, check the pH of the mediumby comparing the colour to the colours on the chart provided. The medium is compromised if the colour is purple, and possibly contaminated if the colour is yellow.

3. Handle the Apligraf as little as possible, and use sterile technique.

4. Do not allow the HSE to dry out after opening the package, and place it on the wound bed within 30 minutes.

5. The dermal layer (the glossy layer closest to the medium in the container) should be placed flush with the wound surface. The epidermal layer (matte, dull finish) should be facing up, exposed to the air. Express any trapped air.1 HSE must be trimmed to fit inside the edge of the ulcer margins.

6. If exudateis a problem, slits (pie-crusting) with a scalpel blade, punch biopsies or shredding may help prevent the HSE from floating off the surface of the wound. To prevent contamination, the holes should be made after HSE has been removed from the media well.2

7. It is very important to immobilize the HSE in contact with the wound bed. If securing of the HSE is not complete, staples, sutures or other methods should be used to prevent shear or friction.2 For venous leg ulcers, cover the HSE with a nonadherent primary dressing (e.g. Tegapore® or Mepitel®), then apply a pressure bolster (rolled or folded gauze or a foam plug) and cover the bolster with an elastic wrap/compression bandage.1

8. Within one week of application, HSE may appear translucent and cellophane-like. The graft may degrade partially or completely following the initial application. Degraded HSE may appear yellow and gelatinous, and its similarity to purulent exudate may lead to inappropriate diagnosis of skin infection. In acute or fresh wounds, HSE appears pinkish or whitish-opaque within 1-2 weeks.1

9. In most cases, one to two applications of HSE will be sufficient; in a minority of patients, three applications may be necessary. Reapply within six to eight weeks if less than 50% of the original wound area has closed, or if the HSE has not completely adhered to the wound. Do not disrupt healing tissue or adherent HSE, but gently remove nonadherent remnants of the product.1

In a number of patients, a single application of HSE has converted chronic or non-healing wounds to acute, more responsive wounds. Following the initial application, it may be advisable to wait 8-12 weeks before using a second HSE in order to determine whether or not wound healing has been jump-started and to prevent unnecessary expense.3 Dr Gary Sibbald, Toronto

10.The primary dressing covering the HSE should be inspected and changed at least once a week. Highly exudative wounds may require more frequent changes.1

Information for Patients

Patients should be told to expect some scarring but, generally a return of skin colour and a good cosmetic outcome.4

Venous leg ulcer patients should elevate their feet as much as possible for the first week after application and the underlying venous disease managed aggressively to prevent recurrence. After the ulcer has healed, they should wear elastic compression stockings delivering 30-40 mm Hg of pressure and have follow-up inspections every three months for one year. It is also important that they maintain proper nutrition.1

One of the most exciting benefits of HSE therapy is its ability to dramatically accelerate wound closure, up to two to three times faster than conventional multilayer compression therapy. In the pivotal leg ulcer study, HSE closed as many wounds by eight weeks as conventional therapy did by six months and also resulted in a significantly greater number of patients with 100% wound closure. These differences were even more striking with particulary difficult to heal ulcers (larger or of longer duration).

References

1.Data on file, Novartis Pharma AG.

2.Falanga V, Margolis D, Alvarez O et al. Rapid healing of venous ulcers and lack of rejection with an allogeneic cultured Human Skin Equivalent. Submitted for publication.

3.Sibbald G. Personal communication. July, 1997.

4.Sabolinski ML, Alvarez O, Auletta M et al. Cultured skin as a'smart material' for healing wounds: experience in venous ulcers. Biomaterials1996; 17: 311-320.
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DATA-MÉDICOS/DERMAGIC-EXPRESS No (15) 12/11/98 DR. JOSÉ LAPENTA R.
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