Calcipotriol cream combined with twice weekly broad-band UVB phototherapy: a safe, effective and UVB-sparing antipsoriatric combination treatment. The Canadian Calcipotriol and UVB Study Group.

BACKGROUND: Calcipotriol has been combined with a number of systemic antipsoriatric treatments, improving efficacy or reducing the systemic treatment required. Although studies on calcipotriol and UVB have also been performed, there are no data on the UVB-saving effect of calcipotriol combined with broad-band UVB to reduce overall UVB exposure, while maintaining efficacy. OBJECTIVES: To assess the efficacy and safety of calcipotriol cream (50 microg/g) combined with twice weekly broad-band UVB and to determine if this treatment would require fewer UVB treatments and lower cumulative UVB irradiance when compared to a standard 3 times weekly broad-band UVB regime in patients with extensive psoriasis. METHODS: This multicentre, prospective, randomised, parallel-group, vehicle-controlled, single-blind (investigator) study consisted of a 1-week wash-out phase, 12-week treatment phase and 12-week follow-up phase. Broad-band UVB equipment was standardised and calibrated prior to the study. The UVB starting dose was based on the patient's minimal erythema dose. Assessments included PASI, extent, severity and investigator and patient's overall assessments of the psoriasis. RESULTS: Fewer exposures (12 vs. 19) and less cumulative UVB irradiance (1,570 vs. 5,430 mJ/cm(2)) were required by the calcipotriol + twice weekly UVB group to achieve 80% reduction in PASI (p < 0.001). Similarly, fewer exposures (22 vs. 25) and less cumulative UVB irradiance (4,147 vs. 9,670 mJ/cm(2)) were required by this group to achieve total clearance (p < 0.001). There was no difference in the PASI, patient's and investigator's overall assessments and number of adverse events recorded by either group for both the treatment and follow-up phases. CONCLUSION: Calcipotriol cream + twice weekly broad-band UVB phototherapy is an effective and safe antipsoriatric treatment, resulting in fewer UVB exposures, lower cumulative irradiance and a saving of time.

Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2.

Angiogenesis inhibitors are a novel class of promising therapeutic agents for treating cancer and other human diseases. Fumagillin and ovalicin compose a class of structurally related natural products that potently inhibit angiogenesis by blocking endothelial cell proliferation. A synthetic analog of fumagillin, TNP-470, is currently undergoing clinical trials for treatment of a variety of cancers. A common target for fumagillin and ovalicin recently was identified as the type 2 methionine aminopeptidase (MetAP2). These natural products bind MetAP2 covalently, inhibiting its enzymatic activity. The specificity of this binding is underscored by the lack of inhibition of the closely related type 1 enzyme, MetAP1. The molecular basis of the high affinity and specificity of these inhibitors for MetAP2 has remained undiscovered. To determine the structural elements of these inhibitors and MetAP2 that are involved in this interaction, we synthesized fumagillin analogs in which each of the potentially reactive epoxide groups was removed either individually or in combination. We found that the ring epoxide in fumagillin is involved in the covalent modification of MetAP2, whereas the side chain epoxide group is dispensable. By using a fumagillin analog tagged with fluorescein, His-231 in MetAP2 was identified as the residue that is covalently modified by fumagillin. Site-directed mutagenesis of His-231 demonstrated its importance for the catalytic activity of MetAP2 and confirmed that the same residue is covalently modified by fumagillin. These results, in agreement with a recent structural study, suggest that fumagillin and ovalicin inhibit MetAP2 by irreversible blockage of the active site.

Management of psoriasis with calcipotriol used as monotherapy.

BACKGROUND: The vitamin D analog calcipotriene/calcipotriol (Dovonex/Daivonex) offers advantages over other forms of topical therapy in some patients with psoriasis. OBJECTIVE: We review the studies of the use of calcipotriol alone in the management of psoriasis. METHODS: The literature concerning topical calcipotriol therapy was reviewed. RESULTS: Calcipotriol compares well with other standard forms of topical therapy for psoriasis. Irritation of the skin may occur but is generally mild. Treatment can often be restarted after the irritation has cleared. CONCLUSION: Treatment with calcipotriol ointment, cream, or solution is effective and safe in many patients with psoriasis.

Long-term use of topical calcipotriol in chronic plaque psoriasis.

BACKGROUND AND DESIGN: A multi-centre, open, prospective study of 12 months duration was performed to assess safety, efficacy and tolerability of topical calcipotriol in the long-term treatment of psoriasis. One hundred and sixty-seven adults with chronic plaque psoriasis who had previously responded to calcipotriol entered the study. Disease activity was monitored using the psoriasis area and severity index (PASI). Calcipotriol ointment 50 micrograms/g was applied twice daily until remission was attained. Treatment was then stopped but reinstituted in the event of relapses. RESULTS: Of the 167 recruited patients, 6 patients did not receive any treatment during the trial. A total of 39 patients were withdrawn: 15 due to inadequate control of their psoriasis, 9 due to irritant reactions, 7 due to defaulting and 8 for miscellaneous voluntary reasons. A further 24 patients either reached the study medication limit of 2,500 g or were considered to have completed the study a few weeks prior to the 12-month period. Accordingly, 98 patients were assessable after 12 months of therapy. Complete clearing was obtained in 26% of subjects, who then used the treatment intermittently. The remaining patients required continuous treatment for 12 months. The mean PASI fell from 8.1 (SD +/- 6.67, n = 167) at baseline to 3.90 (+/- 3.50, 136) at 2 months and 2.71 (+/- 2.12, 98) at 12 months. There was no rise in the mean serum total calcium. CONCLUSION: Calcipotriol ointment was safe, effective and well tolerated.

A dose-response study of UVB-induced suppression of contact photosensitivity in the mouse.

A marked contact photosensitivity (CPS) response to 3,3',4',5 tetrachlorosalicylanilide (TCSA) plus UVA was induced in mice. Cyclophosphamide (Cy), given prior to sensitization, caused a further increase in ear swelling. When UVB radiation was given at a site distant from that used for sensitization it caused a dose-related suppression of CPS. Cy did not eliminate the UVB-induced suppression.

Age-related changes in contact photosensitivity differ among mouse strains.

There are differences among mouse strains in the age-related changes in reactivity to the contact photosensitizer tetrachlorosalicylanilide (TCSA). We found a tendency to lower reactions in older mice, with some strains showing declines from an early age (BALB/cJ, MRL/MpJ +/+, MRL/MpJ lpr/lpr and SJL/J). Others had increasing reactions until about 30-50 weeks of age before declining (DBA/1J, C3H/HeJ, and A/J) and one strain (C57BL/6J) had increased reactivity with age. There are also differences in the role of cyclophosphamide-sensitive T-suppressor cells in these age-related changes. In some mouse strains, BALB/cJ, C57BL/6J, A/J, DBA/1J and C3H/HeJ, age-related changes in reactivity to TCSA are independent of changes in cyclophosphamide-sensitive suppressor cells. In other strains, MRL/MpJ +/+, MRL/MpJ lpr/lpr and SJL/J, the development of cyclophosphamide-sensitive suppressor cells is responsible for the initial, though not later, stages of the age-related decline in reactivity.

Assessment by mouse model of the ultraviolet A protective effect of topical sunscreens.

We have developed an animal model to assess the ultraviolet A (UVA) protective effect of topical sunscreens with the use of BALB/cJ mice in which contact photosensitivity to 3, 3', 4', 5 tetrachlorosalicylanilide had been induced. The mice were sensitized on the clipped dorsal skin and challenged on the ears. Changes in ear thickness after challenge were used to measure the degree of photosensitivity. The efficacy of two doses of each topical sunscreen was assessed by the degree of suppression of the contact photosensitivity response at challenge. Control studies were performed with the base of each sunscreen. Some but not all sunscreens that contained UVA-absorbing chemicals showed active suppression of contact photosensitivity in this test system. Several sunscreens gave greater suppression at 5 microliters/cm2 than at 2 microliters/cm2, which suggests a dose-related effect. One sunscreen, however, gave greater suppression at 2 microliters/cm2. Several of the bases tested also suppressed the contact photosensitivity response. An unexpected finding was an enhancement of the contact photosensitivity reaction by two of the bases tested.

Optimization of tetrachlorosalicylanilide and ultraviolet A doses at sensitization and challenge for contact photosensitivity in the mouse.

We studied contact photosensitivity (CPS) to tetrachlorosalicylanilide (TCSA) in BALB/cJ mice with various doses of TCSA and UVA at sensitization and challenge. From these studies we recommend the following protocol: sensitization on days 0 and 1 with 50 microliters of 1% TCSA followed by 3 J/cm2 of UVA, and challenge on day 7 with 10 microliters of 3% TCSA followed by 6 J/cm2 of UVA. This gave an ear swelling response of 27.4 +/- 0.6 x 10(-3) (mean +/- standard error). We also demonstrated that there is reciprocity between volume and concentration of TCSA at sensitization but not between TCSA and UVA doses at sensitization.

Gentamicin: systemic exposure to a contact allergen.

A case is presented of an allergic dermatitis provoked by intravenous gentamicin in a patient previously sensitized by topical medications. Patch tests confirmed hypersensitivity to gentamicin and neomycin. The nature of reactions to contact allergens given systemically and the nature of cross-reactions between aminoglycoside antibiotics are reviewed.

Circadian rhythms are suppressed in hyperproliferative mouse epidermis.

We examined the chronically hyperproliferative epidermis of the asebia (ab/ab) mouse for circadian rhythms in cell proliferation and in the rate of DNA synthesis, which is related to S phase duration. The curve for the circadian rhythm in cell proliferation for asebia epidermis was suppressed and distorted in comparison to that for BALB/cJ epidermis and in comparison to a composite curve produced by averaging the results from ten other published studies.

Studies of the action spectrum for induction of photosensitivity to tetrachlorosalicylanilide in mice.

We have developed a new system, using ear swelling in mice, to study the action spectrum for the induction of photosensitivity to tetrachlorosalicylanilide (TCSA). Using narrow-band interference filters, we produced data for action spectra between 250 nm and 421 nm with doses of 0.5 J/cm2 and 0.2 J/cm2. We found that the higher dose generally produced greater reactions. The action spectrum was similar to the absorption spectrum for TCSA in the UVA region. The reduced responses in the UVB and UVC regions may be due to immunological suppression produced by these parts of the spectrum.

Dose response studies for UVA in contact photosensitivity to TCSA in the mouse.

We performed UVA dose response studies for contact photosensitivity (CPS) to 3,3',4',5-tetrachlorosalicylanilide (TCSA) in BALB/cJ mice using the back for induction and the ears for elicitation. The dose of TCSA was kept constant. The challenge procedure in non-sensitized mice produced a phototoxic response at 24 h after challenge. None of the 11 mice tested showed simple contact sensitivity (CS) to TCSA. Vigorous CPS responses were achieved with sensitization doses of UVA as low as 0.5 J/cm2 and the peak reaction occurred at 24 h after challenge. UVA sensitization doses less than 0.5 J/cm2 gave responses that were reduced in a dose-related manner and the peak response was delayed to 48 h or longer after challenge. The maximum elicitation dose of 6.0 J/cm2 UVA gave the greatest response and almost all ears showed vigorous reactions if the sensitization dose was 0.5 J/cm2 or greater. Lower elicitation doses gave lesser reactions in a dose-related manner. Cyclophosphamide (Cy) pretreatment increased the CPS reaction by about 50%.