****** DATA-MÉDICOS *********

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ULCERA DIABÉTICA (II) / DIABETIC ULCER (II)

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***** DERMAGIC-EXPRESS No 16 ********* 

****** 15 NOVIEMBRE 1.998 ******* 

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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. Allí están las referencias. 

A partir del dia de hoy DERMAGIC sera 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

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, Panamá, Venezuela, etc.

Until a next edition colleagues,,,, greetings 

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

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DERMAGIC/EXPRESS(16)

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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.) TECNICA PARA LA UTTILIZACION DE APLIGRAF (The Stuart Maddin Skin 

Therapy Letter ///Technique to use APLIGRAF

=====================================================================

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 (16) 15/11/1998 DR. JOSE LAPENTA R. DERMATÓLOGO

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Produced by Dr. José Lapenta R. Dermatologist
Venezuela 1.998-2.024

Producido por Dr. José Lapenta R. Dermatólogo Venezuela 1.998-2.0024

Tlf: 0414-2976087 - 04127766810