EDITORIAL ESPAÑOL
==================
Hola Amigos de la red, DERMAGIC de nuevo con ustedes. EL PIMECROLIMUS Y LA DERMATITIS ATOPICA. 

Hace 4 años el DERMAGIC se inicio en la red con su primera revisión que fue EL TACROLIMUS, droga no esteroidea que se popularizo en el tratamiento de la dermatitis atopica y otras enfermedades. Esta medicina hasta el día de hoy no ha sido comercializada en nuestro país (Venezuela). 

Hace unas semanas recibí la visita del LABORATORIO NOVARTIS en mi oficina y me presentaron el producto ELIDEL (PIMECROLIMUS), por lo cual considere interesante averiguar en la red sobre el mismo. 
EL PIMECROLIMUS crema al 1% (ELIDEL), nombre código (SDZ ASM 981), es un derivado de la ascomicina y al igual que el TACROLIMUS es una droga no esteroidea inhibidor selectivo de las citoquinas inflamatorias, que ha demostrado ser efectivo en el tratamiento de la dermatitis atopica. 

El PIMECROLIMUS se une a una enzima denominada calcineurina, la cual es vital para la activación de las células helper 1 y 2. y también es un inhibidor de los mastocitos provocando así una disminución de la inflamación en la piel. 

Hasta el presente las drogas de primera línea contra la dermatitis atopica son los ESTEROIDES TÓPICOS, los cuales son efectivos cuando se usan por cortos periodos de tiempo, sin embargo, el uso a largo plazo puede ocasionar atrofia cutánea y resistencia a la terapia debido a efectos supresivos en el tejido conectivo. 

EL PIMECROLIMUS viene a representar la primera DROGA EN NUESTRO PAÍS como alternativa a los esteroides tópicos para el tratamiento de la dermatitis atopica. Sus efectos secundarios son realmente pocos, parece una droga segura y confiable según los estudios realizados incluso en niños pequeños, VALE LA PENA probarla. !!! 

En las referencias los hechos... 

Saludos a todos. 

Dr. José lapenta R. 


EDITORIAL ENGLISH
=================
Hello Friends of the net, DERMAGIC again with you. Today THE PIMECROLIMUS AND THE ATOPIC DERMATITIS. 
Four (4) years ago the DERMAGIC beginning in the net with its first review that was THE TACROLIMUS, non esteroidal drug that popularizes in the treatment of the atopic dermatitis and other diseases. This medicine until today's day has not been marketed in our country (Venezuela). 

Some weeks ago I received the visit of the NOVARTIS LABORATORY in my office and they presented me the product ELIDEL (PIMECROLIMUS), reason why consider interesting to search in the net on the same one. 

THE PIMECROLIMUS Cream 1% (ELIDEL), name code (SDZ ASM 981), it is an ascomicyn macrolactam derivative, and the same as the TACROLIMUS it is a non steroidal drug, selective inhibitor of inflammatory cytokines that has demonstrated to be effective in the treatment of the atopic dermatitis. 

The PIMECROLIMUS binds to an enzyme denominated calcineurin, which is vital for the activation of the helper T cell type 1 and 2, and it is also an inhibitor of the mast cells causing this way to decrease of the inflammation in the skin. 

At present, the first-line drugs for treating atopic dermatitis are topical corticosteroids. They are effective when used short-term; however, long-term use of the corticosteroids is associated with suppressive effects on the connective tissue, seen as skin atrophy or resistance to therapy.

THE PIMECROLIMUS comes to represent the first DRUG IN OUR COUNTRY like alternative to the topical steroids for the treatment of the dermatitis atopica. Their secondary effects are really few, it seems a sure and reliable drug according to the studies even carried out in small children, it is WORTHWHILE to prove it. !!! 

In the references the facts... 

Greetings to all. 

Dr José lapenta R. 
===========================================================
REFERENCIAS BIBLIOGRÁFICAS / BIBLIOGRAPHICAL REFERENCES
=========================================================== 
1.) Pimecrolimus inhibits up-regulation of OX40 and synthesis of inflammatory cytokines upon secondary T cell activation by allogeneic dendritic cells.
2.) Combination therapy and new directions for managing atopic dermatitis.
3.) Platelet aggregation and intracellular calcium mobilisation responses are enhanced by cyclosporin A but not by pimecrolimus (SDZ ASM 981).
4.) Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug.
5.) Gateways to Clinical Trials. June 2002.
6.) Spotlight on topical pimecrolimus in atopic dermatitis.
7.) Topical noncorticosteroid immunomodulation in the treatment of atopic dermatitis.
8.) Pimecrolimus 1% cream (Elidel) for atopic dermatitis.
9.) Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children.
10.) [The skin as an immunological organ]
11.) Pimecrolimus. Novartis.
12.) Immunomodulatory macrolactams for topical treatment of inflammatory skin diseases.
13.) Topical pimecrolimus (Elidel) for treatment of atopic dermatitis.
14.) [Pimecrolimus (SDZ ASM 981). Current state of research]
15.) [New horizons in the treatment of atopic dermatitis]
16.) Topical pimecrolimus: a review of its clinical potential in the management of atopic dermatitis.
17.) Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents.
18.) Topical tacrolimus and pimecrolimus are not associated with skin atrophy.
19.) [Constitutional eczema; the possibilities of local treatment]
20.) Low systemic exposure after repeated topical application of Pimecrolimus (Elidel), SD Z ASM 981) in patients with atopic dermatitis.
21.) Tacrolimus and pimecrolimus: from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis.
22.) Recent advances in dermatology.
23.) Topical tacrolimus and pimecrolimus: future directions.
24.) Pimecrolimus cream 1%: a new development in nonsteroid topical treatment of inflammatory skin diseases.
25.) Safety of the new macrolide immunomodulators.
26.) Pimecrolimus (Elidel, SDZ ASM 981)--preclinical pharmacologic profile and skin selectivity.
27.) Tacrolimus and pimecrolimus. Introduction.
28.) Macrolactam immunomodulators for topical treatment of inflammatory skin diseases.
29.) The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils.
30.) Treatment of immune-mediated skin diseases: future perspectives.
=============================================================== 
=============================================================== 
1.) Pimecrolimus inhibits up-regulation of OX40 and synthesis of inflammatory cytokines upon secondary T cell activation by allogeneic dendritic cells.
===============================================================
Clin Exp Immunol 2002 Oct;130(1):85-92 

Kalthoff FS, Chung J, Stuetz A.

Pimecrolimus is a new non-steroidal inhibitor of T cell and mast cell activation. In the present study, we compared the potency of pimecrolimus and cyclosporin A (CyA) to inhibit cytokine synthesis of alloantigen-primed T cells and the expression of CD134 (OX40), an inducible co-receptor molecule thought to be critical for the survival and expansion of inflammation-mediating T cells. To mimic the physiological situation of recurrent antigenic stimulation, we have used dendritic cells (DC) as stimulators of purified CD4+ T cells in the primary and secondary allogeneic mixed lymphocyte culture (allo-MLC). Pimecrolimus inhibited surface expression of OX40 and prevented the up-regulation of CD25 and CD54 with a 10-fold higher potency compared to CyA. Similarly, 50% inhibition of allo-DC-mediated T cell proliferation by pimecrolimus was obtained at 0.55 nm, compared to about 12 nm for CyA. Furthermore, pimecrolimus blocked the increase of OX40 on primed T cells restimulated on day 10 in secondary allo-MLC. Allo-DC-primed T cells showed a restricted cytokine profile characterized by the production of TNF-alpha, IFN-gamma and IL-2 but low to undetectable levels of IL-4 and IL-10. The synthesis of TNF-alpha and IFN-gamma and the up-regulation of OX40 on T cells after secondary allogeneic stimulation were almost entirely blocked by 10 nm pimecrolimus. Taken together, pimecrolimus inhibits T cell proliferation and Th1 cytokine synthesis and also prevents the up-regulation of the OX40 co-receptor on primed T cells indicating its potential in the therapy of chronic inflammation and autoimmunity.

=============================================================== 
2.) Combination therapy and new directions for managing atopic dermatitis.
=============================================================== 
Allergy Asthma Proc 2002 Jul-Aug;23(4):243-6 

Boguniewicz M.

Division of Pediatric Allergy-Immunology, National Jewish Medical and Research Center, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado, USA.

Atopic dermatitis is a common skin disease with a complex immunopathology that has a significant impact on the quality of life of patients and their families. Although topical corticosteroids have been the cornerstone of therapy, safety concerns, especially in children, with potent preparations or with chronic use have prompted treatment with various adjunctive therapies. Recently, topical calcineurin inhibitors, including tacrolimus and pimecrolimus, have been shown effective as monotherapy for this chronic relapsing disease.

=============================================================== 
3.) Platelet aggregation and intracellular calcium mobilisation responses are enhanced by cyclosporin A but not by pimecrolimus (SDZ ASM 981).
=============================================================== 
Platelets 2002 Jun;13(4):213-8 

Fox SC, Judge HM, Allen BR, Heptinstall S.

Centre for Vascular Research, University of Nottingham, Cardiovascular Medicine, Queen's Medical Centre, Nottingham NG7 2UH, UK.

It has been shown previously that cyclosporin A enhances platelet aggregation responses, particularly to adenosine diphosphate (ADP). In this investigation platelet responses to ADP in the presence of cyclosporin A and pimecrolimus (SDZ ASM 981), a new cell selective inhibitor of inflammatory cytokines, were determined. Measurements were performed in whole blood using a sensitive platelet counting method and in platelet-rich plasma (PRP) using a Biola laser aggregometer. The latter monitors both aggregate formation and aggregate size. In vitro studies were performed using recombinant hirudin as anticoagulant in order that physiological concentrations of divalent cation concentrations were maintained. Studies using both methods confirmed an enhanced aggregation response to ADP in the presence of cyclosporin A. In contrast, aggregation responses were not enhanced in the presence of pimecrolimus, either in PRP or in whole blood where a slight reduction of ADP-induced aggregation was seen at concentrations of pimecrolimus >10(-6) M. The effects of cyclosporin A and pimecrolimus on ADP-induced calcium mobilisation in platelets were determined using a flow cytometric method. A significant increase in intracellular calcium mobilisation was seen in the presence of cyclosporin A but not in the presence of pimecrolimus. Enhanced platelet aggregation responses to ADP observed in the presence of cyclosporin A may be a consequence of enhanced ADP-induced calcium mobilisation.

=============================================================== 
4.) Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug.
=============================================================== 
J Allergy Clin Immunol 2002 Aug;110(2):277-84 

Kapp A, Papp K, Bingham A, Folster-Holst R, Ortonne JP, Potter PC, Gulliver W, Paul C, Molloy S, Barbier N, Thurston M, de Prost Y; Flare Reduction in Eczema with Elidel (infants) multicenter investigator study group.

Department of Dermatology and Allergology, Hannover Medical University, Ricklingerstrasse 5, D-30449 Hannover, Germany.

BACKGROUND: Pimecrolimus cream 1% (Elidel, SDZ ASM 981), a nonsteroid selective inhibitor of inflammatory cytokines, is effective in the treatment of atopic dermatitis (AD). In this study we compared early intervention with pimecrolimus cream with treatment with a vehicle control. OBJECTIVE: The purpose of this investigation was to assess whether early treatment in infants of AD signs/symptoms with pimecrolimus could influence long-term outcome by preventing disease flares. METHODS: In this 1-year, double-blind controlled study, 251 infants aged 3 to 23 months with AD were randomized 4:1 to a pimecrolimus-based regimen (n = 204) or a conventional treatment regimen (n = 47). Both groups used emollients for dry skin. Early AD signs and symptoms were treated either with pimecrolimus cream to prevent flares or, in the control group, with vehicle. Vehicle was used to maintain blinding conditions. In the event of flares, moderately potent corticosteroid was permitted in both groups. The primary efficacy end point was the incidence of flares at 6 months. RESULTS: Pimecrolimus significantly reduced the incidence of flares compared with control treatment (P <.001), with 67.6% versus 30.4% of patients completing 6 months with no flare and 56.9% versus 28.3% completing 12 months with no flare. Overall corticosteroid use was substantially lower in the pimecrolimus group: 63.7% versus 34.8% of patients did not use corticosteroids at all during the study. Pimecrolimus was also more effective than control treatment in the long-term control of pruritus and the signs of AD. There were no clinically significant differences in incidence of adverse events between the 2 treatment groups. CONCLUSIONS: Treatment with pimecrolimus of early signs and symptoms significantly modified the disease course in infants by reducing the incidence of flares and improving overall control of AD. Pimecrolimus was safe and well tolerated.

=============================================================== 
5.) Gateways to Clinical Trials. June 2002.
=============================================================== 
Methods Find Exp Clin Pharmacol 2002 Jun;24(5):291-327 

Bayes M, Rabasseda X, Prous JR.

[email protected]

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, https://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, abarelix, abciximab, alicaforsen sodium, almotriptan, alteplase, amlodipine, amoxicillin trihydrate, amprenavir, argatroban monohydrate, aspirin, atorvastatin calcium, azathioprine; Baclofen, benidipine hydrochloride, benserazide, BMS-214662, bosentan, botulinum toxin type B; Candesartan cilexetil, carbamazepine, carbidopa, carboplatin, ceftriaxone sodium, celecoxib, cetirizine hydrochloride, clarithromycin, clavulanate potassium, clopidogrel hydrogensulfate, clozapine, CPI-1189, cyclophosphamide, cytarabine; Darbepoetin alfa, denileukin diftitox, dexamethasone, dipyridamole, droperidol, DW-166HC; Ebastine, efalizumab, efavirenz, eletriptan, enalapril maleate, enfuvirtide, enoxaparin sodium, enrasentan, entacapone, epoetin, eprosartan mesilate, etanercept, etoricoxib; Fenofibratefexofenadine hydrochloride, filgrastim, fludarabine phosphate, fluoxetine hydrochloride fluvoxamine maleate, frovatriptan, furosemide; Gabapentin, galantamine hydrobromide, gatifloxacin, gefitinib, ghrelin (human), glatiramer acetate; Haloperidol; Ibuprofen, ibuprofen, guaiacol ester, idarubicin hydrochloride, imipramine hydrochloride, imiquimod, interferon beta, interferon beta-1a, interferon beta-1b, interferon omega, irbesartan, itraconazole; Ketorolac, ketorolac tromethamine; Lamifiban, lamotrigine, lanoteplase, lansoprazole, leflunomide, leuprorelin acetate, levetiracetam, levocetirizine, levodopa, lisinopril, loratadine; Manidipine, methylprednisolone, metronidazole, mirtazapine, mizolastine, modafinil, morphine sulfate; Naproxen sodium, naratriptan hydrochloride, nifedipine, NSC-683864; Ofloxacin, olanzapine, omalizumab, omapatrilat, ondansetron hydrochloride, oxcarbazepine; Paclitaxel, parecoxib sodium, paroxetine hydrochloride, phenytoin sodium, pimecrolimus, pramipexole hydrochloride, pravastatin, prednisone, pregabalin; Quetiapine fumarate; Ranitidine hydrochloride, rasburicase, ritonavir, rivastigmine tartrate, rizatriptan benzoate, rofecoxib; Saquinavir mesilate, sertraline, sildenafil citrate, simvastatin, sumatriptan succinate; Tacrolimus, tiagabine hydrochloride, ticlopidine hydrochloride, tirofiban hydrochloride, tolvaptan, topiramate, tretinoin; Valproic acid, valsartan, venlafaxine hydrochloride, verapamil; Warfarin sodium; Ximelagatran; Zanamivir, ziconotide, zolmitriptan, zonisamide.

=============================================================== 
6.) Spotlight on topical pimecrolimus in atopic dermatitis.
=============================================================== 
Am J Clin Dermatol 2002;3(6):435-8 

Wellington K, Jarvis B.

Adis International Inc., Langhorne, Pennsylvania 19047, USA. [email protected]

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, is a nonsteroid, has anti-inflammatory activity, and has demonstrated efficacy in reducing symptoms of atopic dermatitis in adult and pediatric patients when applied topically. Compared with vehicle, topical pimecrolimus 1.0% cream was significantly more effective at reducing symptoms of atopic dermatitis, as measured by the Eczema Area and Severity Index (EASI), in infants aged 3 to 23 months, children aged 2 to 17 years, and adults. The median reductions from baseline in the total EASI score in adults after treatment with pimecrolimus 1.0% or corresponding vehicle twice daily for 3 weeks were 47 and 0%, respectively. In infants and children, treatment with pimecrolimus 1.0% twice daily for 6 weeks resulted in significant decreases in mean EASI scores compared with vehicle. The severity of pruritus was significantly reduced in patients of all age groups after topical treatment with pimecrolimus 1.0% cream. Compared with vehicle, the incidence of eczematous flares was also reduced by intermittent long-term use of topical pimecrolimus 1.0% in adults, children and infants. Sixty-one percent of children treated with pimecrolimus for 1 year completed the first 6 months of treatment without experiencing a flare, compared with 35% of patients who received vehicle. Furthermore, the use of topical corticosteroids for the treatment of uncontrolled flares in adults, children and infants was lower in the pimecrolimus groups than in the vehicle groups. Topical pimecrolimus 1.0% cream is well tolerated in atopic dermatitis patients of all age groups. There were no clinically relevant systemic adverse events reported from any of the studies in patients with atopic dermatitis. The most frequently reported adverse events pertained to application site reactions, such as burning and a feeling of warmth. In conclusion, topical pimecrolimus 1.0% cream has shown efficacy in the treatment of mild to moderate atopic dermatitis in infants, children and adults. Although tolerability data concerning infants and children have not yet been published in full, the drug appears to be well tolerated in all age groups, and there have been no reports of clinically relevant systemic adverse events. Furthermore, pimecrolimus has shown no potential for skin atrophy, a problem commonly associated with treatment with topical corticosteroids. Topical pimecrolimus 1.0% provides a promising and well tolerated treatment option in the management of infants, children and adults with mild to moderate atopic dermatitis.

=============================================================== 
7.) Topical noncorticosteroid immunomodulation in the treatment of atopic dermatitis.
=============================================================== 
Am J Clin Dermatol 2002;3(6):381-8 

Reitamo S, Remitz A, Kyllonen H, Saarikko J, Granlund H.

Department of Dermatology, Hospital for Skin and Allergic Diseases, University of Helsinki, Helsinki, Finland. [email protected]

At present, the first-line drugs for treating atopic dermatitis are topical corticosteroids. They are effective when used short-term; however, long-term use of the corticosteroids is associated with suppressive effects on the connective tissue, seen as skin atrophy or resistance to therapy. Currently, two topical noncorticosteroid immunomodulators tacrolimus (FK506) and pimecrolimus (SDZ ASM 981) are under development, or already on the market in some countries for atopic dermatitis. These two compounds show structural similarity. In T lymphocytes they bind to the same cellular receptor, the FK-binding protein (FKBP) or macrophilin-12. Tacrolimus shows a 3-fold greater affinity to FKBP compared with pimecrolimus. The tacrolimus/ pimecrolimus-FKBP complex further binds to calcineurin, an enzyme vital for the early activation of T cells. The consequence of calcineurin binding is a lack of activation of both T helper cell types 1 and 2. Further effects of these compounds have been suggested on other inflammatory cells, such as Langerhans cells and mast cells/basophils. In contrast to corticosteroids, no suppressive effects on connective tissue cells have been observed. Taken together, treatment of inflammation results in healing of the barrier function of the skin. This again results in reduced bioavailability of the drug, as compared with systemic use. Placebo-controlled studies have shown the efficacy of both tacrolimus (at 0.03 and 0.1%) and pimecrolimus (at 0.6 and 1%). The main adverse event in these studies has been a burning sensation and increased pruritus at the site of application. Typically, these adverse events are observed only during the first days of treatment. Long-term safety studies, of up to one year, have not revealed any new adverse events. So far, long-term use of topical noncorticosteroid compounds has not been associated with signs of immune deficiency. Although there is currently no evidence for clinically relevant, prolonged adverse effects, some of these, such as an increased risk of photocarcinogenesis, need to be monitored. There is evidence from tacrolimus studies that monotherapy results in better long-term results when compared with combination therapy with corticosteroids. Tacrolimus and pimecrolimus could replace topical corticosteroids as the first-line treatment of atopic dermatitis.

=============================================================== 
8.) Pimecrolimus 1% cream (Elidel) for atopic dermatitis.
=============================================================== 
Skin Therapy Lett 2002 Apr;7(4):1-3 

Bernard LA, Bergman JN, Eichenfield LF.

Pediatric and Adolescent Dermatology, Childrens' Hospital and Health Center, San Diego, CA, USA.

Pimecrolimus is an immunomodulating medication that inhibits production of inflammatory cytokines in the skin and this compound was specifically developed for the treatment of inflammatory skin diseases. Phase II and III clinical trials with the topical formulation of pimecrolimus (Elidel cream, Novartis) have shown that it is safe and effective for use in patients with atopic dermatitis (AD). The US FDA recently approved Elidel for use in patients >or=2 years of age and older with mild to moderate atopic dermatitis (AD).

=============================================================== 
9.) Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children.
=============================================================== 
Pediatrics 2002 Jul;110(1 Pt 1):e2 

Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, Dobozy A, Paul C, Molloy S, Hultsch T, Graeber M, Cherill R, de Prost Y; Flare Reduction in Eczema with Elidel (Children) Multicenter Investigator Study Group.

Department of Pediatric Pneumology and Immunology, Charite, Humboldt University, Berlin, Germany. [email protected]

OBJECTIVE: Pimecrolimus cream (SDZ ASM 981), a nonsteroid inhibitor of inflammatory cytokines, is effective in atopic dermatitis (AD). We assessed whether early treatment of AD signs/symptoms with pimecrolimus could influence long-term outcome by preventing disease flares. METHODS: Early intervention with pimecrolimus was compared with a conventional AD treatment strategy (ie, emollients and topical corticosteroids). In this 1-year, controlled, double-blind study, 713 AD patients (2-17 years) were randomized 2:1 to a pimecrolimus-based or conventional regimen. Both groups used emollients for dry skin. Early AD signs/symptoms were treated with pimecrolimus cream or, in the conventional treatment group, vehicle to prevent progression to flares. If flares occurred, moderately potent topical corticosteroids were mandated. The primary efficacy endpoint was ranked flares at 6 months. Safety was monitored clinically, and a skin recall-antigen test was performed at study completion. RESULTS: BASELINE CHARACTERISTICS OF THE PATIENTS: The mean age for both groups was approximately 8 years, and the majority of patients had moderate disease at baseline. PATIENT FOLLOW-UP AND EXPOSURE TO STUDY MEDICATION: The mean duration of follow-up (+/-standard error) was 303.7 (+/-5.30) days in the pimecrolimus group and 235.2 (+/-9.40) days in the control group. The discontinuation rate was significantly higher in the control group than in the pimecrolimus group (51.5% vs 31.6% at 12 months), and proportionately more patients with severe or very severe disease discontinued in the control group. The main reason for the higher discontinuation rate in the control group was unsatisfactory therapeutic effect (30.4% vs 12.4%). This resulted in a substantially higher mean number of study medication treatment days in the pimecrolimus group compared with the control group: 211.9 (69.8% of study days) versus 156.0 (66.3% of study days). Of those patients who completed 12 months on study, 14.2% and 7.0% of patients in the pimecrolimus and vehicle groups, respectively, used study medication continuously. EFFICACY: Patients in the pimecrolimus group experienced significantly fewer AD flares than those in the control group, according to the primary efficacy analysis on ranked flares of AD (Van Elteren test). The proportion of patients who completed 6 or 12 months with no flares was approximately twice as high in the pimecrolimus group compared with control (61.0% vs 34.2% at 6 months; 50.8% vs 28.3% at 12 months). Fewer flares were observed in the pimecrolimus group regardless of baseline disease severity, so even severe patients derived benefit from the treatment. The analysis of time to first flare showed that treatment with pimecrolimus was associated with a significantly longer flare-free period (log- rank test). Covariate analysis indicated a statistically significant effect on time to first flare of baseline Eczema Area and Severity Index score, and whether patients had "severe" or "very severe" disease at baseline according to the Investigators' Global Assessment, although patients in all baseline disease severity subgroups benefited from treatment. Age had no significant effect. Fewer patients in the pimecrolimus group required topical corticosteroid therapy compared with control (35.0% vs 62.9% at 6 months; 42.6% vs 68.4% at 12 months), and patients in the pimecrolimus group spent fewer days on topical corticosteroid therapy (57.4% vs 31.6% [pimecrolimus vs control, respectively] spent 0 days on topical corticosteroid therapy, 17.1% vs 27.5% 1-14 days, and 25.5% vs 41.0% >14 days over the 12 months of the study). This steroid-sparing effect of pimecrolimus was evident despite pimecrolimus-treated patients being on study longer than patients in the control group. The average proportion of study days spent on second-line corticosteroids was 4.08% in the pimecrolimus group and 9.10% in the control group. Analysis of Eczema Area and Severity Index over time showed significantly lower median scores, thus indicating better disease control in the pimecrolimus group compared with the control group. Similar results were obtained from analysis of the Investigators' Global Assessment (not shown). The treatment groups were well balanced with respect to the number of patients using antihistamines during the study (57.2% vs 62.9%, pimecrolimus vs control, respectively). SAFETY: There were no appreciable differences between treatment groups in the overall incidence of adverse events. The most frequent adverse events were common childhood infections and ailments, including nasopharyngitis, headache, and cough. The incidence of suspected drug-related adverse events was not significantly different in the pimecrolimus group (24.7% vs 18.7%--pimecrolimus vs control), and the incidence of serious adverse events was low (8.3% vs 5.2%--pimecrolimus vs control). Life-table analysis of incidence of adverse events revealed no significant differences between the treatment groups, except for cough. Local tolerability was good in both treatment groups. The most common application site reaction reported was sensation of burning (10.5% vs 9.3%--pimecrolimus vs control). There were no major differences between treatment groups in the duration or severity of application site reactions, most of which were mild-to-moderate and transient, occurring within the first week of treatment. Skin infections were reported in both groups. There were no between-group differences in the life-table analysis of time to first occurrence of bacterial skin infections nor in the adjusted incidence of bacterial skin infections. Although there were no significant differences between treatment groups in the incidence of individual viral skin infections, the incidence of grouped viral skin infections (12.4% vs 6.3%--pimecrolimus vs control) showed a slightly higher incidence in the pimecrolimus group. Laboratory values and vital signs showed no significant between-group differences. There were no significant differences between treatment groups in response to recall antigens in those patients who remained on study for 12 months. CONCLUSIONS: Treatment of early AD signs/symptoms with pimecrolimus was effective in preventing progression to flares in more than half the patients, reducing or eliminating the need for topical corticosteroids. The benefits were consistently seen at 6 months across important disease severity subgroups and with respect to the various predefined efficacy endpoints. Furthermore, these benefits were sustained for 12 months, providing evidence that long-term treatment with pimecrolimus leads to better control of AD. Treatment with pimecrolimus was well tolerated and was not associated with clinically relevant adverse events compared with the conventional treatment group. The results reported here offer the prospect of effective long-term management of AD with reduced need for topical corticosteroids.

=============================================================== 
10.) [The skin as an immunological organ]
=============================================================== 
Tidsskr Nor Laegeforen 2002 Mar 20;122(8):793-6 

[Article in Norwegian]

Bjerke JR.

Hudavdelingen Ulleval universitetssykehus 0407 Oslo.

BACKGROUND: The skin is our largest organ. Its physico-chemical properties are adapted to its function as a non-specific general defense line against infections and injury from the environment. Through evolution the skin has developed a second line of highly specific immune defense comprising epidermal Langerhans cells, T lymphocytes and keratinocytes as the most distinct cellular elements. MATERIAL AND METHODS: On the basis of available research data and reviews, an overview on the skin as an immunological organ is presented. RESULTS AND INTERPRETATION: Antigens penetrating into the epidermis are bound to dendritic Langerhans cells, processed and presented to T lymphocytes. Certain memory T cells are able to remember where they first encountered antigen. Skin homing T cells are CLA+ and circulate between the skin, peripheral blood and skin draining lymph nodes. Keratinocytes produce a wide spectre of cytokines, in particular interleukin-1, which has a key role in the skin immune function. The most common inflammatory skin disorders are mediated by T lymphocytes, usually Th1 cells, as in psoriasis, or Th2 cells, as in atopic dermatitis. Systemic treatment with T cell specific suppressive drugs, such as cyclosporine, has been successful in certain dermatoses. Promising cyclosporine analogues for topical treatment (tacrolimus and pimecrolimus) have been developed and may soon be introduced.

=============================================================== 
11.) Pimecrolimus. Novartis.
=============================================================== 
Curr Opin Investig Drugs 2002 May;3(5):720-4 

Schopf RE.

Johannes Gutenberg University, Department of Dermatology, Mainz, Germany. [email protected]

Pimecrolimus, an ascomycin macrolactam derivative, is an inhibitor of T-cell and mast-cell activation, developed and launched by Novartis for the potential treatment of psoriasis and allergic, irritant and atopic dermatitis. The topical formulation had been launched in the US by February 2002 for mild-to-moderate atopic dermatitis in patients aged two years and older. At that time, an oral formulation was in development for which launch was anticipated for 2006. In March 2002, pimecrolimus was approved in Denmark, becoming the first non-steroid prescription cream approved for patients from as young as 3 months of age through to adulthood. At this time, Novartis planned to seek approvals in other European countries during 2002 under the Mutual Recognition Procedure, and elsewhere around the globe. In December 2000, Merrill Lynch predicted sales of SFr 100 million in 2002, rising to SFr 330 million in 2004, and in February 2001, the analysts predicted sales of SFr 120 million in 2002, rising to SFr 574 million in 2005. Later in August 2001, Deutsche Bank estimated sales of SFr 150 million in 2002, rising to SFr 550 million in 2005. Following FDA approval in 2002, Morgan Stanley Dean Witter cautiously predicted sales of SFr 60 million rising to SFr 860 million by 2007.

=============================================================== 
12.) Immunomodulatory macrolactams for topical treatment of inflammatory skin diseases.
=============================================================== 
Curr Opin Investig Drugs 2002 May;3(5):708-12 

Bornhovd EC, Burgdorf WH, Wollenberg A.

Ludwig-Maximillians-University, Department of Dermatology and Allergology, Munich, Germany. [email protected]

Tacrolimus (FK-506; Fujisawa Pharmaceutical Co Ltd) and pimecrolimus (SDZ-ASM-981; Novartis AG) are topical immunomodulators, which provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Both substances form a complex with cytosolic immunophilins. The complex blocks calcineurin and inhibits the transcription of NF-AT-dependent pro-inflammatory cytokine genes. Multicenter, randomized, double-blind clinical trials have shown the efficacy of both substances in atopic dermatitis. We review the physicochemical characteristics, mode of action, pharmacokinetic data, side effects, results of the clincal trials and further indications for tacrolimus and pimecrolimus.


=============================================================== 
13.) Topical pimecrolimus (Elidel) for treatment of atopic dermatitis.
=============================================================== 
Med Lett Drugs Ther 2002 May 27;44(1131):48-50 

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

=============================================================== 
14.) [Pimecrolimus (SDZ ASM 981). Current state of research]
=============================================================== 
Dtsch Med Wochenschr 2002 May 31;127(22):1199-203 

[Article in German]

Dissemond J, Goos M, Wagner SN.

Klinik und Poliklinik fur Dermatologie, Venerologie und Allergologie, Essen, Germany.

Publication Types: 
Review 
Review, Tutorial 
=============================================================== 

=============================================================== 
15.) [New horizons in the treatment of atopic dermatitis]
=============================================================== 
Allergol Immunopathol (Madr) 2002 May-Jun;30(3):134-40 

[Article in Spanish]

Ortiz De Frutos FJ.

Servicio de Dermatologia. Hospital 12 de Octubre. Madrid. Spain.

Nearly fifty years after their introduction, corticoids continue to be one of the main pillars of dermatological therapy in general and in atopic dermatitis in particular. However, their use is limited by local and systemic adverse effects.There is enormous demand for anti-inflammatory agents not belonging to the corticoid group that would be useful in the different inflammatory dermatoses.In the last few years the therapeutic arsenal for atopic dermatitis has increased with two distinct groups of drugs: topical immunomodulators and leukotriene inhibitors. Both groups of drugs are new and new compounds belonging to these types of drugs will probably appear in the next few years.Among the alternatives to corticoids are the immunomodulators and the most promising of these are macrolide antibiotics. Tacrolimus (FK 506) and pimecrolimus (ASM 981) belong to this group of substances with a high capacity to inhibit T lymphocyte activation. Although they also act on other cells playing a role in atopic dermatitis (mastocytes, Langerhans' cells, B lymphocytes) their action on T lymphocytes seems to be the most important. In T lymphocytes, these drugs act by inhibiting the action of calmodulin, a vital enzyme in the activation chain of these cells that ends in the production of interleukin 2 and other proinflammatory cytokines.The accumulated evidence of the various publications seems to indicate that tacrolimus is a safe and effective treatment of atopic dermatitis in patients aged 2 years or more. The drug was approved for clinical use 3 years ago in Japan and more than 1 year ago in the United States. The number of randomized clinical trials comparing this drug with placebo or various corticoids demonstrate that its action is overwhelming. Its anti-inflammatory action is similar to that of high-potency topical corticoids. Two doses daily are required and the drug has been tested in patients with moderate-to-severe atopic dermatitis. Published data from more than 10,000 patients guarantee its safety. The most frequent short-term adverse effect is a burning sensation in the site of application lasting a few minutes.Pimecrolimus has not yet been commercialized in any country and is currently undergoing phase III clinical investigations. It has been tested in three clinical trials in patients aged more than 3 months old with mild-moderate atopic dermatitis. Its safety profile is good and similar to that of tacrolimus.The number and quality of the data provided by studies of treatment with leukotriene inhibitors (zafirlukast, montelukast and zileuton) is much lower but these substances seem to warrant further investigation. Only five small series undergoing treatment with these products have been published.

=============================================================== 
16.) Topical pimecrolimus: a review of its clinical potential in the management of atopic dermatitis.
=============================================================== 
Drugs 2002;62(5):817-40 

Wellington K, Jarvis B.

Adis International Limited, Auckland, New Zealand. [email protected]

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, is a nonsteroid, has anti-inflammatory activity, and has demonstrated efficacy in reducing symptoms of atopic dermatitis in adult and paediatric patients when applied topically. Compared with vehicle, topical pimecrolimus 1.0% cream was significantly more effective at reducing symptoms of atopic dermatitis, as measured by the Eczema Area and Severity Index (EASI), in infants aged 3 to 23 months, children aged 2 to 17 years and adults. The median reductions from baseline in the total EASI score in adults after treatment with pimecrolimus 1.0% or corresponding vehicle twice daily for 3 weeks were 47 and 0%, respectively. In infants and children, treatment with pimecrolimus 1.0% twice daily for 6 weeks resulted in significant decreases in mean EASI scores compared with vehicle. The severity of pruritus was significantly reduced in patients of all age groups after topical treatment with pimecrolimus 1.0% cream. Compared with vehicle, the incidence of eczematous flares was also reduced by intermittent long-term use of topical pimecrolimus 1.0% in adults, children and infants. Sixty percent of children treated with pimecrolimus for 1 year completed the first 6 months of treatment without experiencing a flare, compared with 35% of patients who received vehicle. Furthermore, the use of topical corticosteroids for the treatment of uncontrolled flares in adults, children and infants was lower in the pimecrolimus groups than in the vehicle groups. Topical pimecrolimus 1.0% cream is well tolerated in atopic dermatitis patients of all age groups. There were no clinically relevant systemic adverse events reported from any of the studies in patients with atopic dermatitis. The most frequently reported adverse events pertained to application site reactions, such as burning and a feeling of warmth. In conclusion, topical pimecrolimus 1.0% cream has shown efficacy in the treatment of mild to moderate atopic dermatitis in infants, children and adults. Although tolerability data concerning infants and children have not yet been published in full, the drug appears to be well tolerated in all age groups, and there have been no reports of clinically relevant systemic adverse events. Furthermore, pimecrolimus 1.0% cream has shown no potential for skin atrophy, a problem commonly associated with treatment with topical corticosteroids. Pimecrolimus 1.0% cream provides a promising and well tolerated treatment option in the management of infants, children and adults with mild to moderate atopic dermatitis.

=============================================================== 
17.) Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents.
=============================================================== 
J Am Acad Dermatol 2002 Apr;46(4):495-504 

Eichenfield LF, Lucky AW, Boguniewicz M, Langley RG, Cherill R, Marshall K, Bush C, Graeber M.

Pediatric and Adolescent Dermatology, Children's Hospital-San Diego, 3020 Children's Way, Mail Code 5092, San Diego, CA 92123, USA. [email protected]

BACKGROUND: The ascomycin derivative pimecrolimus (ASM 981) is a cell-selective cytokine inhibitor, specifically developed for the treatment of inflammatory skin diseases. OBJECTIVE: When applied topically, pimecrolimus cream 1% has shown promise as a treatment for inflammatory skin conditions, including atopic dermatitis (AD) in children and adults, allergic contact dermatitis, and chronic contact irritant hand dermatitis in adults. METHODS: In two independent 6-week, randomized, multicenter studies of identical design, the efficacy and safety of pimecrolimus cream 1% in children with predominantly moderate AD were compared with vehicle. Pooled data from a total of 403 patients were used in the analysis. The primary efficacy parameter was the Investigator's Global Assessment (IGA) score. Secondary parameters included Eczema Area and Severity Index (EASI) and severity of pruritus scores. Subjects were also asked to assess their disease control as uncontrolled, limited, good, or complete. RESULTS: Significant therapeutic benefits relative to vehicle were observed in the pimecrolimus-treated group at the first efficacy assessment, 8 days after initial application of the study medication (eg, relief of pruritus). At each subsequent postbaseline visit, pimecrolimus-treated patients showed significant improvement relative to controls in all efficacy measures. The medication was well tolerated. CONCLUSION: Pimecrolimus cream 1% appears to be a safe and effective alternative to currently used therapies for AD.

=============================================================== 
18.) Topical tacrolimus and pimecrolimus are not associated with skin atrophy.
=============================================================== 
Br J Dermatol 2002 Feb;146(2):342; discussion 343 

Comment on: 
Br J Dermatol. 2001 Mar;144(3):507-13. 

Bos JD.

Publication Types: 
Comment 
Letter 
=============================================================== 

=============================================================== 
19.) [Constitutional eczema; the possibilities of local treatment]
=============================================================== 
Ned Tijdschr Geneeskd 2002 Mar 2;146(9):400-4 

[Article in Dutch]

Sillevis Smitt JH.

Academisch Medisch Centrum/Universiteit van Amsterdam, afd. Huidziekten, Postbus 22.660, 1100 DD Amsterdam. [email protected]

Atopic dermatitis is a common skin disease with a major impact on the quality of life. The cause of this disease is unknown and the diagnosis is made using a set of diagnostic features. In very moderate cases topical treatment of the dry skin may be sufficient. In more severe cases topical treatment with corticosteroids is recommended. Dependent on the steroid used and the severity of the eczema, different application schemes and treatment methods may be used. In exceptional cases, tar derivatives, topical antibacterial compounds and non-steroidal anti-inflammatory drugs may be applied. In the near future, the limited therapeutic arsenal of topically effective substances will almost certainly be extended to include drugs such as tacrolimus and pimecrolimus with an inhibiting effect on inflammatory cytokines.

=============================================================== 
20.) Low systemic exposure after repeated topical application of Pimecrolimus (Elidel), SD Z ASM 981) in patients with atopic dermatitis.
=============================================================== 
Dermatology 2002;204(1):63-8 

Van Leent EJ, Ebelin ME, Burtin P, Dorobek B, Spuls PI, Bos JD.

Department of Dermatology, Academic Medical Center, University of Amsterdam, The Netherlands. [email protected]

BACKGROUND: Pimecrolimus is a cell-selective inhibitor of inflammatory cytokine release developed specifically for the treatment of inflammatory skin diseases. AIM: The objective of this study was to evaluate blood concentrations and tolerability of pimecrolimus during topical treatment. METHODS: Twelve adult patients with extensive atopic dermatitis were enrolled in an open-label, noncontrolled, pharmacokinetic study. The patients were treated twice daily for 3 weeks with pimecrolimus cream 1% on all lesions. Pimecrolimus blood concentrations were measured at regular time points, and the safety and tolerability were monitored throughout the study. RESULTS: In 78% of the 444 blood samples evaluated, pimecrolimus concentrations remained below the limit of quantitation (0.5 ng/ml). The highest concentration measured was 1.4 ng/ml. There was no indication of drug accumulation. Pimecrolimus was well tolerated locally and systemically. CONCLUSION: The 3-week twice daily treatment with pimecrolimus cream 1% results in consistently low pimecrolimus blood concentrations with no accumulation. Pimecrolimus cream appears suitable for the long-term management of atopic dermatitis. 

=============================================================== 
21.) Tacrolimus and pimecrolimus: from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis.
=============================================================== 
J Am Acad Dermatol 2002 Feb;46(2):228-41 

Nghiem P, Pearson G, Langley RG.

Cutaneous Oncology Unit, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. [email protected]

Tacrolimus ointment, a topical inhibitor of the phosphatase calcineurin, has recently been approved in the United States for use in the treatment of atopic dermatitis. It is the first topical immune suppressant that is not one of the hydrocortisone derivatives, important allies in dermatology for nearly 50 years. Although tacrolimus is less able to penetrate thick skin than glucocorticoids, it does not cause dermal atrophy, an important advantage over the hydrocortisone class. Pimecrolimus (ASM 981), a newer calcineurin inhibitor closely related to tacrolimus, is also being developed for atopic dermatitis therapy. Pimecrolimus has an altered skin penetration profile but the same mechanism of action as tacrolimus. In this review we chronicle the discovery of the calcineurin inhibitors, their presumed evolutionary role as a bacterial "smart bomb" against fungi, molecular and cellular mechanisms of action in the immune system, systemic and topical side effects, efficacy in atopic dermatitis, and future applications within the specialty of dermatology. Particular attention is given to the issues of systemic absorption of tacrolimus, the conditions in which absorption can become a concern, efficacy relative to glucocorticoids, and the choice of 0.03% or 0.1% tacrolimus ointment for use in adults and children.

=============================================================== 
22.) Recent advances in dermatology.
=============================================================== 
Clin Podiatr Med Surg 2002 Jan;19(1):65-78 

Wu SJ, Tanphaichitr A, Ly M.

Division of Dermatology, Ohio State University, Columbus, Ohio, USA. [email protected]

Novel therapies for dermatologic diseases are now widely available to the clinician. The topical immune modulators tacrolimus and pimecrolimus are likely to change the way in which inflammatory dermatoses are treated. Antiviral and antitumor effects of imiquimod, another immune-response modifier, are being studied to determine the ways in which it may affect the treatment of cutaneous viral infections and skin cancers. New topical treatments for onychomycosis and the current lack of effective treatments for nondermatophyte onychomycosis indicate the need for more effective treatment for this common disease. Exciting developments in skin substitutes and growth factors for acute and chronic wound care hold much promise for the future.

=============================================================== 
23.) Topical tacrolimus and pimecrolimus: future directions.
=============================================================== 
Semin Cutan Med Surg 2001 Dec;20(4):268-74 

Ling MR.

Emory University School of Medicine, Atlanta, GA, USA.

Topical tacrolimus ointment and pimecrolimus cream represent the first members of a new class of medications. Topical immunomodulators have been developed for the treatment of atopic dermatitis. Their superb safety profiles and excellent efficacy as anti-inflammatory agents make them attractive candidates to treat a host of other skin disorders. This article reviews published experiences that use them for psoriasis, seborrheic dermatitis, lichen planus, pyoderma gangrenosum and other diseases. Possible modifications to these compounds and novel untested applications are discussed.

=============================================================== 
24.) Pimecrolimus cream 1%: a new development in nonsteroid topical treatment of inflammatory skin diseases.
=============================================================== 
Semin Cutan Med Surg 2001 Dec;20(4):260-7 

Hebert AA, Warken KA, Cherill R.

Department of Dermatology, The University of Texas Medical School, Houston, USA.

Atopic dermatitis (AD) is one of a family of inflammatory skin diseases (psoriasis, irritant contact dermatitis, and allergic contact dermatitis). Dermal inflammation and production of proinflammatory cytokines by activated T cells is a prominent and defining characteristic in all of these conditions. Corticosteroids, though effective and potent immunosuppressants, are associated with a number of systemic and local adverse effects. The ascomycin derivative pimecrolimus (formerly ASM 981) is a nonsteroid with topical anti-inflammatory activity. Pimecrolimus cream 1% is minimally absorbed into the circulation; thus, it has a low bioavailability-reducing the risk for systemic adverse effects. The efficacy and safety of pimecrolimus cream 1% has been well shown in diverse patient populations with inflammatory skin diseases in several well-controlled trials. Significant and rapid amelioration of the signs and symptoms of AD was established in 3 studies lasting 6 weeks each, evaluating 589 pediatric patients. In a 1-year study, pimecrolimus was applied at the first signs and symptoms of eczema to prevent the progression of AD to flares. Flares were prevented in over 50% of patients who used pimecrolimus cream 1%, reducing or completely eliminating the need for topical corticosteroids during a 1-year treatment period. Results in pimecrolimus studies in chronic irritant hand dermatitis and chronic hand dermatitis of mixed causes indicate potential for use in these important diseases, and further study in these indications is warranted.

=============================================================== 
25.) Safety of the new macrolide immunomodulators.
=============================================================== 
Semin Cutan Med Surg 2001 Dec;20(4):242-9 

Robinson N, Singri P, Gordon KB.

Department of Dermatology, Northwestern University, Chicago, IL 60611, USA.

With the wide acceptance of cyclosporine in the treatment of skin disease, there has been an effort to find new immunomodulating agents with superior safety profiles for use in dermatology. Among the most promising of the classes are the new macrolide immunomodulators, including tacrolimus and pimecrolimus. Of these, only tocrolimus has had widespread use for nondermatologic indications, primarily solid organ transplantation. Both of these agents have been studied for inflammatory diseases of the skin. In this article, we review the systemic and topical toxicities of these macrolide immunomodulators.

=============================================================== 
26.) Pimecrolimus (Elidel, SDZ ASM 981)--preclinical pharmacologic profile and skin selectivity.
=============================================================== 
Semin Cutan Med Surg 2001 Dec;20(4):233-41 

Stuetz A, Grassberger M, Meingassner JG.

Novartis Research Institute, Vienna, Austria.

The ascomycin macrolactam derivative pimecrolimus (Elidel, SDZ ASM 981; Novartis Pharma AG, Basel Switzerland) is a cell-selective inhibitor of inflammatory cytokines specifically developed for the treatment of inflammatory skin diseases, such as atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis, and plaque-type psoriasis. It inhibits the production of inflammatory cytokines in T cells and mast cells and prevents the release of preformed inflammatory mediators from mast cells. Topically administered pimecrolimus is as effective as the high-potency corticosteroid clobetasol-17-propionate in a pig model of allergic contact dermatitis (ACD). Unlike clobetasol, however, it does not cause skin atrophy. Given orally, pimecrolimus is as potent or superior to tacrolimus (FK 506) in treating ACD in mice and rats. Pimecrolimus also effectively reduces skin inflammation and pruritus in hypomagnesemic hairless rats, a model that mimics acute signs of atopic dermatitis. Pimecrolimus shows only a low potential to impair systemic immune responses when compared with tacrolimus as shown in rats in (1) the localized graft-versus-host reaction, (2) the antibody formation to sheep red blood cells, and (3) kidney transplantation. Pimecrolimus permeates through pig skin in vitro at a 10-times lower rate than tacrolimus, indicating a lower potential for percutaneous absorption in vivo. The data suggest that pimecrolimus combines high anti-inflammatory activity in the skin with a low potential to impair systemic immune reactions.

=============================================================== 
27.) Tacrolimus and pimecrolimus. Introduction.
=============================================================== 
Semin Cutan Med Surg 2001 Dec;20(4):215-6 

Eichenfield LF.

Children's Hospital, San Diego, CA, USA.

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

=============================================================== 
28.) Macrolactam immunomodulators for topical treatment of inflammatory skin diseases.
=============================================================== 
J Am Acad Dermatol 2001 Nov;45(5):736-43 

Bornhovd E, Burgdorf WH, Wollenberg A.

Department of Dermatology and Allergology, Ludwig-Maximilians University, Munich, Germany.

The immunomodulatory macrolactams provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Tacrolimus (FK506), as well as the newer ascomycin derivative ASM 981 (pimecrolimus), penetrate the inflamed epidermis and are suitable for topical therapy. Both substances inhibit the transcription of proinflammatory cytokine genes such as interleukin 2, which are dependent on the nuclear factor NF-AT. They block the catalytic function of calcineurin, which leads to the inhibition of the transport of the cytoplasmic component of NF-AT to the cell nucleus. Multicenter, randomized, double-blind clinical trials with topical formulations have shown the efficacy of both substances in moderate to severe atopic dermatitis. A review is presented of the biochemical and cell biologic properties, mode of action, pharmacokinetic data, side effects, results of the clinical trials, and further indications for tacrolimus and ASM 981, along with an overview of the related substances cyclosporine and sirolimus (rapamycin).

=============================================================== 
29.) The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils.
=============================================================== 
J Allergy Clin Immunol 2001 Aug;108(2):275-80 

Zuberbier T, Chong SU, Grunow K, Guhl S, Welker P, Grassberger M, Henz BM.

Department of Dermatology and Allergy, Charite, Humboldt University Berlin, Germany.

BACKGROUND: The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) has recently been developed as a novel and cell-selective inhibitor of inflammatory cytokine secretion; it has fewer adverse effects than currently available drugs. OBJECTIVE: In this study, we investigated the capacity of pimecrolimus to directly inhibit in vitro mediator release from human skin mast cells and basophils. METHODS: Purified cutaneous mast cells or basophil-containing peripheral blood leukocytes were obtained from healthy human donors and preincubated with pimecrolimus (0.1 nmol/L to 1 micromol/L) in the absence or presence of its specific antagonist (rapamycin), cyclosporin A (100 nmol/L to 1 micromol/L), or dexamethasone (1 micromol/L) and then stimulated with anti-IgE or with calcium ionophore A23187 plus phorbol myristate acetate. Cell supernatants were kept for analysis of histamine, tryptase, LTC4, and TNF-alpha. RESULTS: Pimecrolimus caused a strong and dose-dependent inhibition of anti-IgE--induced release of histamine from mast cells and basophils (maximally 73% and 82%, respectively, at 500 nmol/L pimecrolimus) and of mast cell tryptase (maximally 75%) and a less pronounced inhibition of LTC4 (maximally 32%) and of calcium ionophore plus phorbol myristate acetate--induced mast cell TNF-alpha release (90% maximum at 100 nmol/L pimecrolimus). In contrast, inhibition achieved during mast cell histamine release was maximally 60% with cyclosporin A and only 28% with dexamethasone. CONCLUSION: These data demonstrate a marked inhibitory capacity of pimecrolimus on mediator release from human mast cells and basophils with a potency exceeding that of cyclosporin A and dexamethasone. Pimecrolimus might thus be expected to be effective in the treatment of mast cell-- and basophil-dependent diseases.

=============================================================== 
30.) Treatment of immune-mediated skin diseases: future perspectives.
=============================================================== 
Eur J Dermatol 2001 Jul-Aug;11(4):343-7 

Luger T.

Department of Dermatology, University of Munster, Von-Esmarch-Str. 56, D-48149 Munster, Germany. [email protected]

In recent years there has been an enormous increase in the understanding of the pathogenesis of immune mediated skin diseases which has led to the development and introduction of new therapeutic regimes. Accordingly, non-specific immunomodulating drugs such as cyclosporin A (CyA), rapamycin, leflunomide, mycophenolat mofetil, tacrolimus, pimecrolimus (ASM981) a.o. proved to be beneficial for a variety of skin diseases. Immunomodulators such as tacrolimus, ASM981 and imiquimod also have been developed for topical application. Specific immunomodulating strategies involve humanized antibodies directed against cytokines or cell surface molecules, receptor antagonists, fusion proteins targeting cytokines or receptors and transcription factor inhibitors. Another interesting approach is to target the appropriate T cell-receptor on autoreactive T cells. Transfection with cytokine genes may represent a useful approach to generate immune deviation and, thereby, treat immune mediated diseases. The value of different vaccination strategies are currently investigated. The first promising results have been obtained by targeting the function of antigen-presenting cells such as dendritic cells (DC). Although, the rapid development of research in immune-mediated diseases has led to the development of several new and more effective therapeutic strategies, in most cases cure is still not possible until the genetics of these diseases are revealed which ultimately may result in gene therapy.

================================================================== 
DATA-MEDICOS/DERMAGIC-EXPRESS No 4-(117)  05/11/2.002 DR. JOSE LAPENTA R. 
=================================================================== 

          Produced by Dr. José Lapenta R. Dermatologist
            Maracay Estado Aragua Venezuela 2.002-2026  
                     Telf.: 04142976087 - 04127766810