Organ of the
GD Society for Dermopharmacy
The GD's 5th Annual Meeting in Zurich
The Gesellschaft für Dermopharmazie met in the Swiss metropolis
The 5th Annual Meeting of the GD Gesellschaft für Dermopharmazie reflects the society's internationality first of all by the venue Zurich but also by the years of cooperation with European countries. The city, located at the sea bearing the same name, presented itself in a sympathetic way and welcomed the guests on 28 March 2001 with a touch of spring. The theatre past of the fifties is still present on carpets, cups and plates in the small hotel on the edge of the old town in which some of the participants resided. Only a few footsteps lead to the base terminal of the nostalgic Polybahn which the participants enjoyed using in order to get to the university hill for the fee of one swiss franc and after a short walk having the suberb view on the town and finally to arrive at the venue - the venerable university of Zurich.
There is likewise an essential interest on the part of the industry, supporting and sponsoring the GD in a decisive way. It is a major concern and objective of the society, emphasized Kresken, to represent the interests of all those dealing with the issue of prevention and treatment of skin diseases and to implement the achievements of scientific research for the settled dermatologist immediately in the sense of an optimal patient care. It is obvious that the consultation in the pharmacy supporting the dermatologists in a decisive way also plays a key role in this context.
in drug development
In a basic lecture, the pharmaceutical chemist professor Dr. Gerd Folkers, president of the adjunct of the Collegium Helveticum of the ETH Zurich explained the change in a thought process of the drug development already performed to a great extent. What was utopia still yesterday is almost reality today and it is a question of time how long the claim that nearly all effective drugs originate from the lively nature or are derived from its chemical structures will still be valid. Folkers' prognosis is that the development line is so to speak turned upside down. The optimal recognition of a target structure defined on a molecular level of the organism, usually a protein, will be given special emphasis.
The protein itself is the product of a gene fragment correlating with a disease incidence. This "molecular procedure" entails implications and consequences for therapy, patients and markets. Folkers takes the view that the often quoted term "Life Sciences" is integral part for the comprehension of health and also that every form of therapeutical intervention influences the biochemistry of the human organism. The scientist sees connections between the release of short protein fragments in the brain, soothing pain as reaction on the stimulus of an acupuncture needle and the taking of a beta receptor blocking drug to which the body reacts by lowering of the blood pressure. The state of equilibrium of the biochemistry in the brain by interlocutors finding the right words can be influenced in the same way as by "lifestyle" drugs which may be able to "correct" the emotional state. Naturally, the extent depends on the individual disposition. As it is necessary to assess this disposition, a complete research branch within the pharma trade has specialized under the term "Functional Genomics". This combination of roboting, information- and biotechnology allows a recording and evaluating of molecular patterns. That is the reason why drug research and development has already undergone fundamental changes at the time being.
New therapy option for
psoriasis and atopical dermatitis
Im Vortragsblock unter der Überschrift Dermopharmazeutische Chemie" stellte Professor Dr. Anton Stütz, Novartis Forschungsinstitut Wien, die neue antiinflammatorische Substanzklasse der Ascomycine vor.
In the lecture unit entitled "Dermopharmaceutical Chemistry", professor Dr. Anton Stütz, Novartis Forschungsinstitut (Research Institute), Vienna, introduced the new anti-inflammatory substance class of the ascomycines.
Ascomycines are immune-modulating macrocyclic natural materials, isolated for the first time from streptomyces hygroscopicus var. ascomyceticus. Ascomycine binds to macrophiline-12, inhibits calcineurin and hinders the activation of T-cells as well as the synthesis and release of phlogistic cytokines.
From a multitude of substances, examined in models, the Austrian institute chose SDZ-ASM-981 as development substance due to the fact that it has proved highly effective in vivo both after topical and oral administration in dermatitis models, however, only showed a minor potential of systemical immunosuppression as it is the case for cyclosporin A or FK 506.
The good effectiveness and tolerance with patients suffering from atopical dermatitis could already be proven in multi-center studies. Skin atrophy as noticed after the use of corticosteroids did not appear after the application of SDZ-ASM-981. The treatment of up to 90 percent of the body surface was well tolerated and even with infants from an age of three months either no or only minor blood levels have been measured. The substance is effective with atopical dermatitis, allergic contact dermatitis and chronical hand dermatitis as have shown the results of clinical studies involving more than 2000 patients (children and adults). An additional advantage is the possibility of an oral application, tested with patients suffering from medium to severe chronical plaque psoriasis. The administration of 40 to 60 milligrams per day induced an "impressive clinical improvement without noticing side effects", Stütz emphasized. Thus, an alternative of the oral treatment of inflammatory skin diseases as psoriasis and atopical dermatitis is within reach. At present oral SDZ-ASM-981 is subject to testing in phase II in multi-center studies.
No future for active
substances without vehicles
Which requirements a topical dermatological vehicle has to come up to differs to a high extent in relation to the respective perspective. Thus, Dr. Christian Surber gave his opinion in his lecture concerning the vehicle theory. He offered for consideration that bio-pharmaceutical, pharmaceutic-technological, pharmacological, physical and cosmetical properties of consumers, patients, dermatologists, pharmacists and galenic physicians are individually assessed and realized. This is why the question arises as to which effects are to be achieved and which structure of a vehicle is accordingly suitable.
In this connection, professor Dr. Claudia S. Leopold, Institut für Pharmazie der Universität (University Institute for Pharmacy), Leipzig, expressed her opinion regarding the pharmacokinetic and pharmacodynamic aspects of a penetration-oriented vehicle optimization. In this context thermodynamic as well as barrier-modifying effects can be of significance. These effects are either assessed by a direct measurement of the active-substance flux in skin or by measurements of active substances by means of drugs producing a quantifiable, pharmacodynamic reaction. The measuring methods introduced by Leopold have practical relevance if planning and implementation of effect measurements regarding a quantification of vehicle effects or the assessment of penetration properties are concerned. The effect is to be ascertainable as rapidly, easily and visually as possible and in addition without requiring a great deal of testing and time.
Such examinations are relevant for example to the FDA Guidance for Industry "Topical dermatologic corticosteroids: in vivo bio-equivalence" in which the implementation of the skin pallor test with glucocorticoids is described by measuring the maximal effect. This guidance is to point out that stationary conditions are to be ensured for an unadulterated quantification of pallor effects and that for the examining of vehicle effects the intrinsic activity of the model active substance has to be known.
Professor Dr. Reinhard Neubert, Institut für Pharmazeutische Technologie und Biopharmazie (Institute for Pharmaceutical Technology and Biopharmacy), department pharmacy at the Martin-Luther-University, Halle-Wittenberg, mentioned in his lecture liposomes, multiple emulsions and nanoparticles as modern vehicle systems for the cutaneous application. While the dermal application of liposomes is controversially discussed in literature, analyses have shown that multiple emulsions in the same way as nanoparticles are in a position to control the penetration of active substances into skin by means of the liberation process and to influence the active substance stability in a positive manner. Also colloid vehicles and micro-emulsions have been examined relating to the mechanism of active-substance penetration. In this connection it could be shown that these vehicle systems feature advantages regarding a transdermal therapy.
more than a 'decorative package'
The lecture unit "Dermocosmetics" showed clearly that the industry has to take an increasing demand by the legislator respectively the consumer into account. Professor Dr. med. Peter Elsner of the Klinik für Dermatologie und Allergologie (Clinic for Dermatology and Allergologie) of the Friedrich Schiller University, Jena, commented the current aspects of the European legislation.
With the sixth amendment of the European Cosmetics Directive 76/768 EEC, the currently valid basis of the cosmetics legislation in Europe, the labeling obligation for the cosmetic ingredients has been introduced, a mandatory safety assessment has been stipulated and for the first time also the term of "effectiveness" of cosmetics has been included. Thus, producers introducing cosmetics on the market, have to prepare a product dossier, proving both safety and the attributed effectiveness. "Correspondingly", Elsner emphasized "the effectiveness proof for cosmetics has become a legal obligation". This legal amendment also considers the obligation for the replacement of animal tests in the safety assessment as far as validated alternative methods are available.
In clinical and professional dermatology skin irritations caused by cleansing agents and washing-up liquids as well as detergents and soaps are a frequently occurring problem. An easy method for the registration of irritation by hand cleansing agents is the corneo-surfametry, expounded by Dr. Bernard Gabard, department Biopharmacy of the Spirig AG, Egerkingen, Switzerland. 19 different syndets and shampoos, all declared as being "mild", "skin protective" or "suitable for babies" have been tested in his working group regarding their skin tolerance by means of the elbow-washing tests, the soap chamber tests and the corneo-surfametry. For a precise evaluation of the skin tolerance, an irritation index has been suggested (IOI). The results of the corneo-surfametry lead to a classification of the products in three categories with increasing impairment of the horny layer of epidermis. A relevant classification of cleansing products relating to their skin tolerance is thus possible in a rapid, easy and cost-saving manner. "Nevertheless", Gabard qualified his statement, "results of the bio-engineering measuring methods have shown that certain products are able to induce skin reactions, e.g. an erythema, which are not covered by an in-vitro examination as the corneo-surfametry.
To what extent a satisfactory, skin protective fat restoring is possible for the use of skin cleansing agents, explained professor Dr. med. Wolfgang Gehring of the Dermatological Clinic at the Clinical Center of Karlsruhe. For this purpose investigations of skin cleansing agents as washing solutions, bathing and shower oils as well as shower creams have been carried out the results of which can be looked up in the separate article "A fat restoring is not automatically ensured" (in German).
The fact that the epidermal regeneration can be accelerated by the use of dexpanthenol-containing topical preparations has been confirmed in a study presented by Dr. med. Frank Rippke, Beiersdorf AG, Hamburg. The influence of a cosmetic w/o-emulsion containing five percent dexpanthenol on the epidermal regeneration has been analysed in the human epidermal suck blister model. In this model intra-epidermal skin defects are induced by hypotension (0,4 bar) and subsequently treated with the test products respectively physiological sodium chloride solution as a control. As measurement of the barrier function the trans-epidermal water loss is analyzed every 24 hours. The dexpanthenol-containing test product features in contrast to the control and its active substance-free basis a significant epithelization-promoting effect especially in the early application stage.
A further subject of the Annual Meeting was the professional skin protection. Which skin protective agents resist the repetitive irritation test and are thus suitable for working areas in which a special strain for hands is the case, showed Andreas Klotz, Stockhausen GmbH & Co. KG, with the example of an effectiveness test. The detailed report about the test results of a novel skin protective preparation on the basis of a multiple emulsion can be looked up in the report "Wide-spread field of application for a multiple emulsion" (in German) in this edition.
Dermatopharmacology and -therapy
Interesting aspects of dermatopharmacology and - therapy have been discussed in a subject unit dealing with new and newly discovered methods. Professor Dr. med. Thomas Ruzicka of the Hautklinik (Dermatological Clinic) of the Heinrich-Heine-University, Düsseldorf, informed about the prospects of the genomic analysis of drug effects. In this context it will be possible not only to pursue goal-directed drug development but also to identify and influence wanted and unwanted effectiveness on molecular basis.
For a dermatologic-toxicological evaluation of topical glucocorticoids, the use of which is often inevitable with chronic-inflammatory dermatoses, high-frequency ultrasonics is suitable, as could be shown by Dr. Karl-Heinz Nietsch, Aventis Pharma Deutschland GmbH, Bad-Soden, by means of a study. The study aimed at appraising the risk of the atrophogenic potency of different middle-strong corticosteroids. Experience with conventional halogenized corticosteroids reveals that the anti-inflammatory effect is connected with an identical anti-proliferous potency.
However, with recent, halogen-free corticosteroids as the double-esterifiying prednicarbate, the corresponding benefit-risk evaluation turns out far more positive. In the introduced study 24 testees were applied prednicarbate 0,25 percent as ointment, betamethasone 17-valerate 0,1 percent as ointment and mometasonfuroate 0,1 percent also as ointment over a period of six weeks twice a day on pre-marked fields of the bend of the elbow under strict test conditions (double-blind, randomized, intra-individual). Changes of the skin thickness were measured once a week by means of a skin sonograph.
The maximum decrease of skin thickness after 36 days was the least with prednicarbate 0,25 percent ointment, while it amounted to 17 percent with the equally halogen-free mometasonfuroate and 24 percent with betamethasone 17-valerate. Signs of atrophy or teleangiectasis have not been observed with prednicarbate at none of the testees. There were two cases each of atrophy and teleangiectasis at the treated skin fields treated with mometasonfuroate and betamethason-17-valerate.
Fountains of youth for aged skin?
Whether there is a new fountain of youth for the ageing and old skin, asked professor Dr. med. Isaak Effendy from the Dermatological Clinic of the Philipps-Universität, Marburg. There is an enormous and varied offer of preparations for topical application promising skin-smoothing, - embellishment and -rejuvenation. Special importance is attached to substances with irritation potential as vitamin A-acid or fruit acids. Effendy could prove in own examinations that sodium lauryl sulfate and calcipotriole are in a position to cause comparable bio-physical skin changes and above all an increase of the proliferation rate of the epidermis cells. Future examinations will give further information as to whether hope of an everlasting young skin is justified.
Not quite 'red-handed' but rather accidentally 'caught' has been a phytocosmetic showing positive effects with atopical dermatitis. Undisputed was a rapidly occurring anti-phlogistic and anti-pruritic effect, as explained by professor Dr. med. Andreas J. Bircher of the Allergologische Poliklinik (Allergologic Outpatients' Clinic) of the Kantonsspital Basle. In the first place it was uncertain on what the effect was based, as it could not be assigned to any of the declared ingredients. Only the analysis of the ingredients by means of liquid- and gas-chromatography showed that the cream contained triamcinolonactonideine in concentrations of 16 to 40 microgram per gram. It is true that this value lies below the concentrations of therapeutic preparations (100 - 1000 µg/g), however, as ingredient of a cosmetic corticosteroids are illegal. Bircher summarized that corticosteroids are able to already show a therapeutic effect in even low concentrations, as has been confirmed by this example. For this reason, there is an imperative necessity for OTC-drugs having an amazingly good effectiveness to be examined as to illegal ingredients.
Healing of wounds by
bio-surgery and tissue engineering
A fact already observed during the times of Napoleon and later in World War I has experienced a renaissance since the last century: professor Dr. med. Theo Rufli of the Dermatologische Universitätsklinik (Dermatological University Clinic) at the Kantonsspital Basle reported about healing of wounds by means of maggots (enterobius vermicularis). The reason why even extensive wounds, seized by fly larvae - as noticed accidentally and with repugnance - did not feature infections but healed rapidly without complications, was of interest to the American orthopaedist Baer. After World War I, he began the scientific development of bio-surgery. It is based on the principle that two- to three day-old larvae are applied on the wounds to be purified.
Within three to four days, the necrotic tissue gets preorally predigested by saliva enzymes of the larvae, proteases with strong collagenase activity and then taken in. The bacterial population is reduced both by the excretion of bactericidal peptides and degradation in the intestinal lumen. Rufli can imagine that in this process the excretion of cytokines explains at least a part of the measurable increase in blood circulation and reduction of oedema. Nowadays, this method is considered as being safe and very effective. Although the procedure is connected with considerable pain, which can however be controlled with the corresponding therapy, it is well accepted by the patients. The disadvantages are founded in the logistics, according to Rufli, and also in the fact that it is not that easy to achieve the required sterility of fly larvae.
Lecturer Dr. Matthias Augustin of the Universitäts-Hautklinik (University Dermatological Clinic) Freiburg/Breisgau gave his opinion relating to the pharmaco-economic aspects of the tissue engineering with ulcus cruris and a connected keratinocyte transplantation. Ulcera are not only a considerable financial burden for the Public Health Service but they also signify a major physical and mental burden including a loss of quality of life for the patient. As alternative to the so far established but rather insufficient treatment possibilities, Augustin presented the in vitro cultivation and transplantation of keratinocyte suspensions of autologous and allogenic origin as a bio-technological therapy approach.
Due to the fact that initially increased costs accrue, the question poses whether the tissue-engineering procedure can be useful on a long-term basis also from a pharmaco-economical point of view for the therapy of the chronical ulcera. First comparative data from a meta-analysis and own study results from an investigation involving 42 patients have revealed that costs for the conservative therapy amount to between 15.000 and 30.000 marks per year and patient, compared with 8000 to 20000 marks when applying modern bio-engineering-procedures. These figures are however based on an outpatient treatment and moreover on a distinctly longer recurrence-free time in comparison with the conservative therapy. Augustin admitted that the data position is at present still not satisfactory in order to perform a systematical assessment. On the basis of the present conditions of the German reimbursement system he considers, however, the treatment of the ulcus cruris with keratinocytes-transplants as an interesting alternative for the future compared with the conventional therapy from a pharmaco-economical point of view.
The 5th Annual Meeting of the GD in Zurich ended with a final remark by the GD vice-president, professor Dr. med. Hans Christian Korting, Dermatologische Klinik of the Ludwig-Maximilians-University, Munich. Korting invited as conclusion of his comments to the participation of the 6th Annual Meeting which will take place in the scientific chair of professor Dr. med. Martina Kerscher, Hamburg and professor Dr. Rolf Daniels, Brunswick on 21 March 2002 in the Hamburg university. On the next day, the 3rd Symposium "Health-Economy in Dermatology" will be held at the same venue. The scientific head of this symposium is lecturer Dr. Matthias Augustin. This symposium will be organized for the first time in a cooperation with the Freiburg Dermatological Clinic and the GD. (ghw/jk)
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