A novel anti-inflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology

There is a need for safe and effective therapies for inflammatory skin diseases. Current topical and systemic treatment of psoriasis is effective but suffers from side-effects or is inconvenient. The therapeutic armamentarium for atopic dermatitis is very limited and far from satisfactory. In vivo preclinical data are presented for SDZ ASM 981, a novel ascomycin macrolactam derivative with high anti-inflammatory activity. Anti-inflammatory activity was observed in mouse, rat and pig models of allergic contact dermatitis. In the pig model, topical SDZ ASM 981 was as effective as the ultrapotent corticosteroid clobetasol-17-propionate, and when compared with a series of commercial topical corticosteroid preparations, 0.1% SDZ ASM 981 had equivalent efficacy to clobetasol-17-propionate (0.05%), the most potent product on the market. Unlike the corticosteroid, however, SDZ ASM 981 did not cause skin atrophy in pigs. SDZ ASM 981 potently inhibited allergic contact dermatitis in mice and rats when given systemically, and oral treatment was more effective than cyclosporin A in rats. Furthermore, SDZ ASM 981 has a low potential for affecting systemic immune responses, as demonstrated in rat models of localized graft vs. host reaction and allogeneic kidney transplantation. Preclinical results suggest that SDZ ASM 981 has the potential to be a well-tolerated and effective drug for topical as well as oral treatment of inflammatory skin diseases.     

Labeling of penicillamine di sulfide with technetium-99m

OBJECTIVE: To compare the safety and efficacy of 1% SDZ ASM 981 cream and a matching placebo cream in the treatment of patients with moderate atopic dermatitis. DESIGN: A randomized, double-blind, placebo-controlled, right-and-left comparison study. SETTING: Academic referral center. PATIENTS: Thirty-four adult patients with moderate atopic dermatitis. INTERVENTION: Topical 1% SDZ ASM 981 cream was applied twice daily (n=16) or once daily (n=18) and compared with a corresponding placebo cream base. MAIN OUTCOME MEASURES: Efficacy was measured using a 4-point (0-3) scale for erythema, pruritus, exudation, excoriation, and lichenification (Atopic Dermatitis Severity Index [ADSI]). The ADSI score was defined as the sum of these 5 ratings (range, 0-15) and was determined on the pretreatment day (1 to 14 days before day 0) and on days 0, 2, 4, 7, 9, 11, 14, 16, 18, and 21. The percentage change from baseline (day 0) in the ADSI score was calculated on each of these days. Safety was evaluated by monitoring of adverse events, physical examination, hematologic examination, clinical chemistry studies, urinalysis, and measurement of blood levels of SDZ ASM 981. RESULTS: Of the 38 patients recruited, 34 started and 28 completed treatment according to the protocol. Sixteen patients used the cream twice daily, with significant improvement after 2 days of treatment. Within 3 weeks of topical therapy with 1% SDZ ASM 981 cream twice daily, a mean reduction of 71.9% in the ADSI score was observed at the actively treated test sites compared with a mean reduction of 10.3% at the placebo-treated test sites (P<.001). Efficacy was significantly less in the group treated once daily (n=18), with mean reductions of 37.7% and 6.2%, respectively. The efficacy was especially apparent for pruritus and excoriation. There were no clinically relevant drug-related adverse effects. CONCLUSIONS: Treatment with 1% SDZ ASM 981 cream was well tolerated. Twice-daily application of 1% SDZ ASM 981 cream was significantly more effective than use of the corresponding placebo and more effective than once-daily treatment. The new macrolactam ascomycin derivative SDZ ASM 981 is a promising agent for the treatment of patients with atopic dermatitis. More elaborate phase 2 and 3 trials are under way to fully investigate the potential of this medication.     

Myocardial infarction in france: Prognosis improvement?

BACKGROUND: Cyclosporine for the treatment of psoriasis constitutes a new approach. Alternative systemic cyclosporine derivatives have been studied to find an immunosuppressive drug with fewer adverse effects. Tacrolimus is one of these new immunosuppressive drugs. Systematically, it has been proven effective in treating psoriasis. A topical formulation of tacrolimus is attractive because it has fewer adverse effects and is useful for a large group of patients. We report for the first time on the efficacy of nonocclusive topical tacrolimus in the treatment of psoriasis. OBSERVATIONS: After a washout phase of 2 weeks, patients were randomized to receive 0.005% calcipotriol ointment twice daily, placebo ointment once daily, or 0.3% tacrolimus ointment once daily. One psoriatic plaque was treated with a surface area of 40 to 200 cm2. Efficacy was estimated using the local psoriasis severity index. The reduction in the local psoriasis severity index score after 6 weeks was 62.5% in the calcipotriol group, 33.3% in the tacrolimus group, and 42.9% in the placebo group. CONCLUSIONS: There was no statistically significant difference between the efficacy of tacrolimus and placebo ointment (P = .77). Calcipotriol ointment, applied twice daily, had a better effect than tacrolimus ointment and placebo ointment once daily.     

Use of a purse string suture to close a percutaneous access site after hemodialysis graft interventions

BACKGROUND: Weekend therapy with superpotent topical corticosteroids has been used for the long-term treatment of psoriasis. Recently, calcipotriene ointment has been added to this regimen for use on weekdays, but there are no long-term studies of that combination. OBJECTIVE: The purpose of this study was to determine whether the addition of weekday calcipotriene to a pulse therapy regimen of weekend superpotent corticosteroids results in a longer duration of remission of plaque psoriasis. SUBJECTS: This was a double-blind, placebo-controlled, parallel-group study. Forty-four patients with mild to moderate psoriasis were treated with calcipotriene ointment in the morning and halobetasol ointment in the evening for 2 weeks. Thereafter, 40 patients who were at least moderately (50% or greater) improved were randomized to 2 treatment groups. After 2 weeks of treatment with calcipotriene ointment in the morning and halobetasol ointment in the evening, 20 patients were randomized to receive halobetasol ointment twice daily on weekends and calcipotriene ointment twice daily on weekdays, and 20 patients were randomized to receive halobetasol ointment twice daily on weekends and placebo ointment twice daily on weekdays. RESULTS: Seventy-six percent of patients applying halobetasol ointments on weekends and calcipotriene ointment on weekdays were able to maintain remission for 6 months compared with 40% of patients applying halobetasol ointment on weekends only with the vehicle on weekdays. CONCLUSION: The addition of calcipotriene ointment applied on weekdays to a weekend pulse therapy regimen of superpotent corticosteroids can increase the duration of remission of psoriasis.     

The effects of topical calcipotriol on systemic calcium homeostasis in patients with chronic plaque psoriasis

BACKGROUND: Calcipotriol is an effective treatment of chronic plaque psoriasis. We have previously demonstrated that it has a small effect on systemic calcium homeostasis even at recommended doses. OBJECTIVE: We attempted to determine the mechanism of the effect of calcipotriol on systemic calcium homeostasis so we could assess the possible consequences of long-term use. METHODS: Sixteen patients with extensive chronic plaque psoriasis were hospitalized and treated with high-dose topical calcipotriol. Up to 360 gm of calcipotriol (50 micrograms/gm) ointment was applied per week for 2 weeks under controlled conditions. RESULTS: There was a dose-dependent rise in intestinal absorption of calcium. No effect on bone turnover was demonstrated over this short period. Five patients became hypercalcemic, and there was a dose-dependent rise in serum total adjusted calcium, serum ionized calcium, serum phosphate, urine calcium, and urine phosphate. There was a dose-dependent fall in serum parathyroid hormone and serum 1,25 dihydroxyvitamin D3. CONCLUSION: Calcipotriol exerts its effects on systemic calcium homeostasis by increasing intestinal absorption of calcium and probably phosphate. This results in suppression of parathyroid hormone and 1,25 dihydroxyvitamin D3.     

In-vitro photobactericidal activity of aminoacridines

We report four patients with severe erythrodermic, pustular psoriasis, or plaque-type psoriasis, who were treated with a combination of acitretin and bath PUVA. After 4 weeks out-patient treatment, the psoriasis in all patients had improved by > or = 90%. No patient had relapsed when reviewed at 3 months. No significant side-effects were seen with the combined retinoid/bath PUVA treatment. Acitretin and bath PUVA may be safely combined for the treatment of severe psoriasis.     

Topical calcitriol in the treatment of chronic plaque psoriasis: a double-blind study

A randomized, double-blind, left-right, vehicle-controlled study to assess the therapeutic efficacy and safety of twice daily application of 15 micrograms/g calcitriol ointment for a period of 6 weeks was performed in 32 patients suffering from bilateral, symmetrical, severe chronic plaque psoriasis. Twice daily 15 micrograms/g calcitriol ointment significantly improved erythema, induration, scaling and global severity of psoriatic plaques, and was much more effective than vehicle ointment. The difference in overall clinical efficacy between calcitriol and vehicle was statistically significant from week 1 onwards, and was maintained over the entire study. On completion of the study, clearance of psoriatic lesions was found in 47% of calcitriol-treated sides and in 13% of vehicle-treated sides. Skin histopathology of calcitriol-treated sides revealed a return to normal keratinization, with decreased inflammatory cell infiltration in the dermis and disappearance of the inflammatory infiltrate from the epidermis. Three patients had asymptomatic hypercalcaemia during the study. Mean serum levels of total calcium, albumin-adjusted total calcium, phosphorus, 25-hydroxyvitamin D and calcitriol did not show statistically significant changes in the baseline/end-point comparisons.     

Acute cerebellar ataxia after subclinical hepatitis A infection

Infection is a well-recognized triggering factor for both guttate and chronic plaque psoriasis. We investigated prospectively 13 patients with recalcitrant psoriasis exacerbated by recurrent tonsillitis, who underwent tonsillectomy between 1990 and 1993. There were 12 female patients and one male, with a mean age of 17 yr (range 6-28). Six patients had guttate psoriasis resistant to standard treatments and seven patients had chronic plaque psoriasis exacerbated by tonsillitis that was severe enough to warrant at least one admission to hospital. Patients were followed by chart review and postal questionnaire. Psoriasis was cleared completely after tonsillectomy in five out of the six patients (83%) with guttate psoriasis and was improved in one patient. Two out of seven patients with plaque psoriasis (29%) were cleared, two (29%) were improved and three (42%) were unchanged. We conclude that tonsillectomy may be a successful treatment modality in selected patients with recalcitrant guttate or chronic plaque psoriasis.     

Tacalcitol ointment in the treatment of psoriasis vulgaris: a multicentre, placebo-controlled, double-blind study on efficacy and safety

Tacalcitol is a vitamin D analogue which ahs been developed for the therapy of psoriasis vulgaris. The treatment with a twice daily application of 2 micrograms/g ointment is efficacious and safe in Japanese patients. The objective of this randomized, placebo-controlled, intraindividual right-left comparison was to investigate the efficacy and safety of 8 weeks' therapy with a once daily application of a 4 micrograms/g tacalcitol ointment in Caucasian psoriatics. The data on 122 male and female patients were analysed. The score sum of erythema, infiltration and desquamation was influenced significantly more by tacalcitol ointment than by placebo (P < 0.0001) at every control point, starting from week 2. With regard to the individual symptoms of desquamation, infiltration and erythema, the treatment with tacalcitol was also superior to placebo treatment beginning at week 2. Qualitatively, the same results were obtained with the preference assessment of both treated body sides and also the global assessments of efficacy and benefit. Symptoms of local skin irritation which may be related to the active compound or the ointment base were reported by 12.3% of patients. In only one patient, irritation required discontinuation of tacalcitol treatment. Laboratory criteria, including serum calcium, serum phosphate and serum levels of calcitonin, parathormone, 1 alpha, 24-dihydroxyvitamin D3 and 25-hydroxyvitamin D3, did not reveal any changes of clinical relevance during or after treatment. Furthermore, the global assessment of tolerance was good or very good in more than 90% of cases. The results of this study demonstrate that the once daily application of a 4 micrograms/g tacalcitol ointment is an efficacious therapy for psoriasis vulgaris in Caucasian patients, and that its tolerance is good, wherever the lesion is located, including on the face.     

A randomized double-blind comparison of the effects on systemic calcium homeostasis of topical calcitriol (3 micrograms/g) and calcipotriol (50 micrograms/g) in the treatment of chronic plaque psoriasis vulgaris

Calcitriol and calcipotriol are effective treatments for psoriasis, although the two have never been directly compared. We compared the efficacy and toxicity of each agent in 24 patients with moderately extensive chronic plaque psoriasis, who were randomized in double-blind fashion to apply 90 g per week of either calcitriol (3 micrograms/g) ointment or calcipotriol (50 micrograms/g) ointment over an 8-week period. Mean PASI in patients applying calcitriol fell from 13 to 8.8 (p < 0.05) and in patients applying calcipotriol from 14.9 to 4.7 (p < 0.005). The reduction was significantly greater in the calcipotriol-treated group (p < 0.05). There was a small increase in serum ionized calcium in the calcipotriol-treated group (from 1.21 mmol/L to 1.25 mmol/L, p < 0.05) but no effect on calcium homeostasis in the calcitriol group.     

Open pore biodegradable matrices formed with gas foaming

The aim of the present study was to investigate the efficacy and clinical tolerability of the specific leukotriene B4 receptor antagonist VML295 in the treatment of stable plaque psoriasis. Immunohistochemical and flow cytometrical methods were used to assess the effects on inflammation and epidermal proliferation. VML295 in the treatment of chronic plaque psoriasis was shown to be safe and well tolerated. After treatment, there was a statistically significant difference between patients treated with VML295 and patients treated with placebo with respect to the leukotriene B4-induced CD11b up-regulation on the cell surface of polymorphonuclear leukocytes derived from peripheral blood. Ex vivo CD11b up-regulation in the VML295-treated group was completely inhibited after 7 days of treatment (P = 0.001). This effect persisted until the end of the treatment period (P = 0.004 on day 15 and P < 0.0001 after 4 weeks), whereas CD11b up-regulation in the placebo group remained unaffected. There was no statistically significant difference in the median psoriasis area and severity index between the treatment groups at the end of the treatment period. During treatment, no significant histological changes were observed in the markers for cutaneous inflammation and epidermal proliferation. Although not statistically significant, a tendency for the increased expression of some markers of cutaneous inflammation and epidermal proliferation was observed after 1 week of treatment with VML295, and a decreased expression of these markers was seen after 4 weeks of treatment with VML295. This observation could indicate anti-inflammatory effects of VML295 appearing between 2 and 4 weeks after the start of treatment.     

Skin problems in sugar artists

The antipsoriatic effects of two topical antipsoriatic agents, betamethasone valerate (Betnovate) and calcipotriol (Daivonex), and a pure nanocolloid gel were assessed in 10 patients with chronic plaque-type psoriasis in a modified psoriasis plaque test. Three noninvasive bioengineering methods were applied to measure antipsoriatic effects: chromametry for objective evaluation of erythema; visiometry, a method for profilometry, and 20-MHz skin ultrasound for the measurement of skin thickness as a parameter of inflammatory infiltration and psoriatic hyperproliferation of the epidermis. Regarding inflammation parameters such as skin thickness (infiltration) and erythema (dilatation of vessels and hyperperfusion), the steroid preparation Betnovate proved to be significantly most effective in our study. Daivonex showed significant decreases in the skin roughness parameters, underlining its antiproliferative effect. The nanocolloid carrier was significantly effective in thickness reduction, this effect being most probably due to occlusion. 20-MHz ultrasound, chromametry and visiometry proved to provide multiparameter assessment of treated and untreated psoriatic skin and can be recommended as objective and reproducible measurements for further studies.     

Topical application of 1,25-dihydroxyvitamin D3 (calcitriol) is an effective and reliable therapy to cure skin lesions in psoriatic children

We studied, in vivo, the effects of a calcitriol-containing ointment (3 micrograms of calcitriol per gram of petrolatum) topically applied on skin lesions in children affected by psoriasis vulgaris. Each patient was instructed to apply the ointment, about 1 g once a day at bedtime followed by occlusive dressing with plastic wrap, on one-side lesion (treated) and petrolatum alone on the equivalent controlateral site (placebo) (total weekly dose of calcitriol: approximately 21 micrograms/patient). After 4 weeks of topical treatment all children showed a complete clearing of their skin lesions on the treated side, without appreciable changes on the placebo side. Serum ionised calcium, calcium and calcitriol levels or urinary calcium excretion did not vary significantly throughout the period of therapy. These findings suggest that topical calcitriol may be an effective and safe alternative therapy for psoriasis in children.     

Highly purified omega-3-polyunsaturated fatty acids for topical treatment of psoriasis. Results of a double-blind, placebo-controlled multicentre study

We report the results of a multicentre, double-blind, placebo-controlled study of topical therapy with omega-3-polyunsaturated fatty acids (omega-3-PUFA) in 52 patients suffering from moderate plaque-type psoriasis. In each patient, two similar stable psoriatic plaques served as indicator lesions for the study. One indicator lesion was randomly assigned to treatment with topical preparations of highly purified omega-3-PUFA in one of two concentrations (1 or 10%), and the other was treated with placebo. Efficacy assessment was based on changes in local psoriasis severity index, area involved, erythema, desquamation, induration and pruritus. After 8 weeks of treatment, all indicator lesions had improved significantly, compared with baseline. However, no statistically or clinically relevant differences between the omega-3-PUFA-treated and the placebo-treated lesions were found. Therapy was well tolerated and, apart from one patient who developed perilesional eczema, no clinically relevant adverse events occurred. In conclusion, topical omega-3-PUFA were not effective in a randomized, placebo-controlled, double-blind setting. Results of non-blind trials should be (re-)considered with caution.     

Therapy of resistant psoriasis with topical corticosteroids and dimethylsulfoxide

The sequential application of full-strength dimethylsulfoxide (DMSO) and potent topical corticosteroid preparations was very effective in resistant plaque-type psoriasis. Complete clearing may be achieved in 3-4 weeks. Lower strengths of DMSO were less beneficial. Irritation from the solvent was effectively controlled by corticosteroids and was limited to transient burning or stinging. Resistance to topical corticosteroids may be overcome by the concomitant use of DMSO.     

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A randomized double-blind controlled trial was undertaken to study the efficacy of a cow udder ointment versus petroalatum alone. A total of 30 patients participated in the study. Sixteen patients completed the trial with 8 of 9 patients improving in the active group and 6 of 7 patients improving in the placebo group. This difference was not statistically significant. The use of a cow udder ointment for psoriasis cannot be supported, particularly with the potential for side effects.     

Differences in estimates of percent body fat using bioelectrical impedance

The effect of heliotherapy on psoriasis skin lesions and arthritis was studied in a trial comprising 4 weeks of therapy in the Canary Islands and a 6-month follow-up period. A total of 373 patients participated in the heliotherapy and 361 patients completed the follow-up period. The severity of skin lesions was evaluated using a psoriasis severity index (PSI), and that of the arthropathy by using an arthritis index (AI). During heliotherapy, the PSI decreased significantly from the initial median value of 4.5 to the final value of 0.2. A reduction in the PSI of at least 75% was achieved in 84% of the patients. Guttate psoriasis improved significantly better than plaque-type or erythrodermic psoriasis. There was no correlation between skin type and improvement. Initially, 129 patients had symptoms of arthritis. During heliotherapy, the AI decreased significantly from the initial median value of 6 to the final value of 2. The median time until starting another treatment after heliotherapy was 80 days, and the PSI had returned to its original value in 49% of the patients in 6 months. In patients with joint symptoms the AI returned to the pretreatment level within 6 months. A 4-week heliotherapy period effectively cleared psoriasis, alleviated joint symptoms, and reduced both morbidity and treatment requirement to a considerable extent in the ensuing 6-month period.     

6-month use of 0.2% delmopinol hydrochloride in comparison with 0.2% chlorhexidine digluconate and placebo. (I). Effect on plaque formation and gingivitis

A double-blind, randomised, 6-month clinical trial with parallel group design in 149 patients with gingivitis was conducted to study the efficacy and safety of delmopinol hydrochloride 2 mg/ml (0.2% w/v, Decapinol Mouthwash) used for partly supervised mouthrinsing in comparison with chlorhexidine digluconate 2 mg/ml (0.2% w/v, Hibitane Dental, ICI Pharmaceuticals, UK) and placebo as an addition to normal oral hygiene. Assessments of efficacy were performed using the plaque index and bleeding on probing (BOP). Delmopinol showed 22% lower plaque index scores than placebo after 3 months (p<0.01) and 13% lower scores after 6 months. The corresponding figures for chlorhexidine were 38% (p<0.001) and 38% (p<0.001) after 3 and 6 months, respectively. Bleeding on probing was reduced for delmopinol in comparison with placebo by 11% after 3 months and by 18% (p<0.05) after 6 months. For chlorhexidine the corresponding figures were 18% (p<0.01) and 22% (p<0.01) after 3 and 6 months, respectively. While chlorhexidine showed greater plaque reduction than delmopinol (p<0.01 at 6 months), no statistically significant difference was reached between these two solutions regarding BOP. Both active solutions showed an increased amount of dental calculus in comparison with placebo. A transient anaesthetic sensation in the oral mucosa and taste affection were commonly reported adverse events in both the delmopinol and the chlorhexidine groups. The number of patients withdrawn from treatment due to adverse events or lack of cooperation was 7 in the chlorhexidine group, 4 in the placebo group and 1 in the delmopinol group. The results showed that rinsing with either 0.2% delmopinol hydrochloride or 0.2% chlorhexidine digluconate twice daily for 60 secs for 6 months results in less plaque formation and gingivitis than rinsing with placebo. Mouthrinsing with the 0.2% delmopinol hydrochloride solution was well accepted in this study.     

Narrowband UV-B produces superior clinical and histopathological resolution of moderate-to-severe psoriasis in patients compared with broadband UV-B

OBJECTIVE: To compare the therapeutic effectiveness of daily exposure to narrowband (NB) UV-B vs broadband (BB) UV-B with and without tar. DESIGN: Half-body exposures to NB UV-B or BB UV-B were given daily for 4 weeks in this comparative treatment study. Narrowband UV-B was delivered from TL-01 fluorescent bulbs and BB UV-B from conventional bulbs in the same phototherapy cabinet. Narrowband UV-B was compared using a paired treatment approach to BB UV-B above the waist and to BB UV-B with tar (Goeckerman treatment) below the waist. SETTING: General clinical research center of a university hospital inpatient unit. PATIENTS: Twenty-two patients with moderate-to-severe plaque-type psoriasis completed the study. MAIN OUTCOME MEASURES: Clinical efficacy was measured weekly using psoriasis severity scoring. Therapeutic outcomes after 4 weeks were compared in paired biopsy samples from treated lesions using objective histopathological measures (quantitative reduction in epidermal acanthosis and keratin 16 expression). RESULTS: Clinical resolution of psoriasis was achieved on 86% of paired sites treated with NB UV-B vs 73% treated with BB UV-B. Histopathological resolution of epidermal hyperplasia (marked by keratin 16 expression) was achieved in 88% of lesions treated with NB UV-B vs 59% treated with BB UV-B. Epidermal acanthosis was reduced more completely by NB UV-B treatment. Clinical resolution of psoriatic lesions occurred more rapidly following NB UV-B treatment, with some patients achieving complete resolution after 2 to 3 weeks of treatment. CONCLUSIONS: Narrowband UV-B offers a significant therapeutic advantage over BB UV-B in the treatment of psoriasis, with faster clearing and more complete disease resolution. The erythema response to NB UV-B treatment was significantly more intense and persistent compared with BB UV-B. Considerably more necrotic keratinocytes were observed in histopathological sections of skin treated with NB UV-B after a single 2.0-minimum erythema dose exposure. Treatment should be coupled with obligate minimum erythema dose testing to NB UV-B and close clinical observation during dose increases.     

Bathing suit delivery of 8-methoxypsoralen for psoriasis: a double-blind, placebo-controlled study

Twenty-four patients, 15 men and 9 women, aged 18-70 years with stable plaque-type psoriasis involving more than 20% of the body surface were subjected to a randomized, double-blind, age- and sex-matched, placebo-controlled study. Containers containing 25 mL of either 1% 8-MOP or a color-matched placebo were randomly numbered and stored. To 2 L of water was added 0.8 mL of 1% 8-MOP to obtain a concentration of 3.75 mg/L3, into which a bathing suit was soaked for 5 min. The suits were then gently squeezed to remove excess water and the patients were advised to put on the suit covered by a raincoat for 15 min. Immediately after removal of the raincoat and the suit, patients were irradiated with an initial dose of 4 J/cm2 UVA with increments of 0.5 J/cm2 on alternate days in a whole-body phototherapy unit obtained from the National Biological Corporation, Ohio. Erythema, scaling, and thickness (EST) of the index lesions were assessed on a 3-point scale (Table 1) and photographs were taken before and after completion of the study.