Immunotherapeutic strategies against HPV disease

Symposium S24. What’s new in pharmaceutical research creased risk of progression to CIN 3, especially HPV 16 showed a significant correlation (p < 0.01). Lesions with high CD8 cell counts in the adjacent stroma had an significantly increased risk to progress to CIN3 (p < 0.001). Furthermore current smoking, high CD4 cells counts in the epithelium were weak risk factors. HPV-types and local immune response differed significantly between regressing, persisting and progressing cervical lesions. [ S23-5 1 lmmunotherapeutic disease

strategies

against

HPV

C.J.N. Lacey. Imperial College School of Medicine, London, UK Human papillomavirus infections cause a spectrum of genital pathology. Common clinical manifestations include genital warts and pre-cancer and cancer of the cervix. A variety of treatments are available including anti-proliferative, destructive and surgical modalities. However, in recent years advances in immunology and latterly in basic papillomavirus research have opened new avenues towards immunotherapeutic approaches to treatment. These can be conceptualised as non-antigen specific and antigen-specific. Non-antigen specific therapies include the interferons for which the best efficacy has been demonstrated by intra-lesional administration. Nevertheless only modest efficacy and cost have limited their utility. Imiquimod is a new topical immunomodulator which acts via local induction of a cytokine cascade, although the final effector mechanisms remain to be clarified. Antigen-specific therapies in development include a tecombinant HPV 6 L2E7 vaccine for genital warts in phase II, a recombinant HPV 16 E6E7L2 vaccine for CIN in preclinical and vaccinia-bearing HPV 16/18 E6E7 in phase II. These data will be discussed.

S24.

S24-1

What’s new in pharmaceutical research Cutaneous drug delivery in vivo measured by microdialysis: State and perspective

J. Serup, L. Groth, E. Benfeldt. Department of Dermatological Research, Leo Pharmaceutical Products, Ballerup, Copenhagen; Department of Dermatology, Gentofre Hospital, Hellerup, Denmark In vitro methods in skin pharmacology include Franz cells and release chambers. In vivo methods include tape stripping, suction blister, skin biopsy and measurement in the excretes and recently microdialysis. A 0.2 mm dialysis fibre is inserted in the dermis and perfused, with chemical analysis of the outlet perfusate. Free and diffusible drugs are determined. Advantages and limitations of the microdialysis method will be outlined. Influence of barrier function and vehicle on the penetration can easily be determined. Barrier disruption such as experimental contact dermatitis enhances the drug penetration markedly. Cutaneous blood flow also influences drug levels in the dermis. Conclusion: Microdialysis is a promising new technique in skin pharmacology, however, one method among others, each having their pros and cons.

S24-2

S37

New and unexpected data concerning the efficacy/toxicity ratio of the HI antagonists

I. Ramboer. VCB Pharma Sector; R&D, Braine-I’Alleud, Belgium HI antagonists drugs have been used successfully for nearly 60 years in the treatment of allergic diseases. Many papers have been published on the clinical efficacy of the 2”d generation antihistamines in both rhinitis and CIU. This new generation has brought the advantage of fewer sedating side effects that lead to a better therapeutic index. The description of rare but severe arrhythmias under terfenadine and astemizole administration lead to a reappraisal of the new drugs according to a larger series of basic quality criteria. Among them, we find: (a) a lack of metabolism via the cytochrome P 450 systems in order to avoid drug-drug interactions and interindividual variability. (b) a lack of activating and/or inhibiting effect on CYP 450. (c) A lack of inhibiting effect on P-glycoproteins involved in MDR. (d) a lack of inhibiting effects on ion channels. (e) a low volume of distribution in order to avoid drug accumulation into non targeted cells and tissues. All these quality criteria could be linked to particular well defined physico-chemical properties of these drugs. 1S24-3

Ascomycin macrolactam SDZ ASM 981: A new option for treatment of inflammatory skin diseases

A. St&z’, M. Graebe?, M. Grassbergert, E Kalthofft, J.G. Meingassner ‘. ‘Novartis Research Institute Vienna, Austria; ‘Novartis Pharma, Basle, Switzerland SDZ ASM 98 1 has been shown to be highly effective in various animal models of skin inflammation. In the DNFB-induced allergic contact dermatitis in pigs, topical SDZ ASM 981 and clobetasol-17-propionate demonstrated comparable inhibition of erythema/induration. In addition, histopathology revealed similar reduction in CD4Y. CD2+ cells and of CD25+ (IL2R+), CD8+ cells 24 h and 72 h, respectively, for both drugs. Different to clobetasol, SDZ ASM 981 does not induce skin atrophy when applied to pig skin. Using a T helper cell clone isolated from the skin of an atopic dermatitis patient, SDZ ASM 981 inhibited the proliferation as well as the cytokine release after unspecific and specific activation at low nanomolar concentrations. In preliminary studies, SDZ ASM 981 was effective in plaque psoriasis (under occlusion), established allergic contact dermatitis to nickel and in atopic dermatitis. Results from ongoing clinical phase II will be reported. S24-4

Clinical screening of efficacy and tolerability of D-vitamin analogues treatment of psoriasis vulgaris I

for the

V. Tetens, M.B. Milsgaard, S.B. Jensen, J. Setup. Leo Pharmaceutical Products, Ballerup, Denmark Objective:

To validate a new psoriasis plaque Lt

design for