PDF hosted at the Radboud Repository of the Radboud University Nijmegen

Transcription

1 PDF hosted at the Radboud Repositoy of the Radboud Univesity Nijmegen The following full text is a publishe's vesion. Fo additional infomation about this publication click this link. Please be advised that this infomation was geneated on and may be subject to change.

2 Bitish Jounal of Dematology 1996; 135: Tacalcitol ointment in the teatment of psoiasis vulgais: a multicente, placebo-contolled, double-blind study on efficacy and safety M.VAN DE KERKHOF, T.WERFEL,* U.F.HAUSTEIN, + T.LUGER,i B.M.CZARNETZKI, R.NIEMANNK AND V.PLANITZ-STENZELH Univesity Hospital Nijmegen, Depatment of Dematology, 6500 HB Nijmegen, the Nethelands *Medical School Hannove, Dematological Clinic Linden, Hannove, Gemany t Univesity Hospital Leipzig, Depatment of Dematology, Wpzig, Gemany $ Univesity Hospital Ministe, Depatment of Dematology, 4SI49 Münste, Gemany ^Univesity Hospital Belin, Depatment of Dematology, Belin, Gemany THERMAL Kut Hemann, Reinbek, Gemany Accepted fo publication 23 Mach 1996 S u m m a y Tacalcitol is a vitamin D analogue which has been developed fo the theapy of psoiasis vulgais. teatment with a twice daily application of 2 ug/g ointment andomized left compaison ition of a 4 wg/g ointment male and female d desquamation was influenced significantly moe by tacalcitol ointment than by placebo < ) at evey contol point, stating fom week 2. With egad to the individual symptoms desquamation, infiltation and eythema, the teatment with tacalcitol was also supeio to cebo teatment beginning at week 2. Qualitatively, the same esults wee obtained with the ifeence assessment of both teated body sides and also the global assessments of efficacy and lefit. Symptoms of local skin iitation which may be elated to the active compound o the ointment base wee epoted by 12-3% of patients. In only one patient, iitation equied discontinuation of tacalcitol teatment. Laboatoy citeia, including seum calcium, seum phosphate and seum levels of calcitonin, paathomone, 1 a,24-dihydoxy vitamin 1), and 25- hydoxyvitamin D3, did not eveal Futhemoe, the dob al assesvsment teatment. c \ \ demonstate that the once daily application of a 4 /tg/g an efficacious theapy fo psoiasis vulgais in Caucasian patients, and that its toleance is good, wheeve the lesion is located, including on the face. Seveal antipolifeative o immunomodulatoy dugs, such as dithanol, topical coticosteoids, methotexate, cyclospoin A, o psoalens with UVA, 0 have poven to be effective in the theapy of psoiasis but each of them is associated with diffeent disadvantages. Theefoe, new pinciples of theapy ae desiable. Recently, attention has again been focused on the teatment of psoiasis with vitamin D analogues. Inteest fist aose when a patient s psoiasis impoved while his osteopoosis was being teated with 1 a-hydoxy-vitamin D3. Seveal studies have demonstated that active inflammation."' In view of the fea of the potential of vitamin I) 3 deivatives, which implies the isk of seious advese events such as the calcification of such psoiatic teatment with vitamin D had to wait until new analogues with a educed calcipotopic potential became available. In many counties, caldpotiol has been intoduced fo the teatment of psoiasis. This vitamin D analogue also inhibits the polifeation of keatinocytes and induces thei diffeentiation but has a much less ponounced effect on the calcium metabolism. 5 Tact vitamin D3 inhibits epidemal polifeation, enhances (la,24-dihydoxy vitamin fo eview nomal keatinization and intefees with cutaneous et al.4) is anothe synthetic of 758 {( ) 1996 Bitish Association of Dematologists

3 TACALCITOL IN PSORIASIS 759 (la,2 5-dihydoxy vitamin D3), the most active metabolite of vitamin D. The affinity of tacalcitol to the vitamin D ecepto in human keatinocytes is slightly highe than that of natually occuing vitamin D. The effect that tacalcitol exets on the polifeation and diffeentiation of cultued epidemal cells is also compaable with o slightly moe ponounced than that of calcitiol. This has been shown in muine epidemal cells as well as in nomal human keatinocytes and in those deived fom andomized left compaison. Befoe the stat of teatment, a 2-week wash-out peiod was equied fo all patients. Teatment consisted of a once daily, andomized application of eithe tacalcitol ointment o the base without active substance (heeafte efeed to as placebo) to the selected psoiatic test lesions. Lesions wee teated until they cleaed but fo not moe than 8 weeks. Thee was a post-teatment follow-up peiod lasting psoiatic lesions. Clinical studies have shown good until the onset of a elapse o fo a maximum of 4 theapeutic efficacy in Japanese psoiatics with a twice daily application of a 2 /ig/g tacalcitol ointment weeks. Thee wee contols at weeks - 2,0, 2,4, 6, 8 (o at the end of teatment) and 1 2 (o at the onset of a elapse). Medical ethical committee appoval was obtained in each study cente and patients wee included afte having given infomed consent. With egad to safety, thee wee neithe changes in the tested laboatoy citeia no wee thee any seious dug-elated advese events when studies wee pefomed with a maximum teatment duation of 1 2 weeks. Dug-elated advese events wee also not obseved in two clinical studies whee a 4 yug/g tacalcitol ointment was applied twice daily fo up to 4 weeks.13,14 Futhemoe, in a safety confimation study 1 c whee up to 80/^g/g tacalcitol wee applied once daily in an ointment fo 7 consecutive days to the skin of both healthy adults and psoiasis patients, no elevant fluctuations wee obseved in the level of seum calcium, seum phosphate o seum ceatinine. Tacalcitol was detected in the blood of one healthy voluntee but was at below the detection limit (25 pg/ml) in all othe cases. No effect on intinsic vitamin D metabolism was obseved.15 Patient selection Male and female patients, aged yeas, with stable plaque psoiasis wee consideed fo enty into the study. Females wee not allowed to be o to become pegnant duing the tial. Patients with an inceased seum calcium o seum phosphate level (>10-5 mg/ 100 ml and/o >4-5 m g/100 ml, espectively) wee excluded, as wee patients who had eceived systemic o topical antipsoiatic teatment ove a peiod of 2 months o 4 weeks espectively, pio to the stat of the study. Othe exclusion citeia wee seious diseases, the The objective of the pesent double-blind, placebo- necessity fo concomitant theapy contolled clinical study was to show whethe tacalcitol ointment is also efficacious and safe in the theapy of Caucasian psoiatics, as the above-mentioned data wee deived fom Japanese patients. Futhemoe, it was desiable to educe the fequency of application fom twice daily to once daily in ode to enhance patients compliance. A concentation-finding study,1(1 pefomed as a psoiasis plaque test, evealed that a once daily application of an ointment containing 4 /ig/g below), known allegy to any ingedient of the study medication, paticipation in anothe clinical tial within 4 weeks pio to the stat of this study, o expected poo compliance (e.g. dug addiction). No calcium supplements o dugs influencing the calcium metabolism 2d. The use of, babituates, phenytoin and non-steoidal anti-inflammatoy dugs wee also pohibited. The test aeas wee only allowed to be teated with eithe white petolatum o an emolo moe povided the best efficacy. The wash-out and the follow-up ointment has poven to have vey good skin Y peiod,, 2-3% salie m (Meye-Rohn et al, il communication). Thus, the white petolatum, t peequisites wee fulfilled to pefom a phase III study with the aim of investigating the efficacy and safety of a once-daily application of a 4 /ig/g tacalcitol ointment in the theapy of psoiasis vulgais in Caucasian patients. illowed to be applied to psoiatic lesions othe than the test aeas thoughout the whole study peiod. Psoiatic lesions chosen as test aeas wee allowed to be localized anywhee but on the scalp. They wee to have a scoe sum of >5 of Methods scoes see below) fo eythema, infiltation and desquamation, and at least modeate intensities (scoe 2 ) fo eythema and desquamation. The diffeence of the scoe sums 5 fo tacalcitol and placebo The study was designed as a multicente, double-blind, teatment had to be ^ 1. The test lesions also had to be (( ) 1996 Bitish Association ofdematologists, Bitish Jounal of Dematology, 135,

4 760 P.C.M.VAN DE KERKHOF et a l compaable with egad to localization (almost symmetical) and aea (fo each teatment up to 1 0 % of total body suface). (McNema) was used fo binay data, and the paied Wilcoxon test was used fo categoized data with odeed categoies. The laboatoy data wee analysed by the Sign test, Wilcoxon anking test o Stuat- Maxwell test and patly by the i-test. Thee was a Study medication and evaluation The placebo consisted of paaffin oil, diisopopyl adipate and white petolatum. Tacalcitol ointment additionally contained é/âg/g tacalcitol (la-24-dihydoxycholecalcifeol). At the beginning of the study (week - 2 ) demogaphic data (sex, age, height and weight) and anamnestic data (diagnosis, localization and aea of lesions, outbeak of disease, duation of last attack, pevious teatment, othe diseases and thei teatment) wee gatheed. Futhemoe, the paametes fo the efficacy and safety evaluations (see below) wee assessed. Wheneve the seveity was descibed, the following scoing system was applied: 0, none; 1, slight; 2, modeate; 3, sevee; 4, vey sevee. The pimay efficacy citeion was the scoe sum of eythema, infiltation and desquamation, which was assessed befoe the stat of teatment (week 0 ) and at statistical analysis of all andomized patients with at least one post stat of teatment measuements ( intention-toteat ) and of all patients who wee teated accoding to potocol ( pe potocol ). The safety assessment compised: (i) advese dug events, assessed at weeks 2, 4, 6 and 8 ; (ii) global assessment of toleance by investigato and patient ( 1, vey good; 2, good; 3, modeate; 4, poo), made at week 8; (iii) haematology (white blood cell count, ed blood cell count, platelet count, haemoglobin, haematocit) evaluated befoe and at the end of teatment; (iv) blood chemisty (seum calcium, seum phosphate, seum ceatinine, SGOT, alkaline phosphatase, LDH), evaluated at weeks 2, 0, 2, 4, 6 and 8 ; (v) seum calcitonin, paathomone, 1 o;,25-dihydoxyvitamin Dj and 25- hydoxy vitamin D 3 assessed at fou centes befoe and teatment evey contol visit duing the teatment peiod (weeks 2, 4, 6, 8). This citeion was chosen as it is pat of the PASI scoe but does not include the localization and Results extent which was not consideed to be useful in an intaindividual compaison with a maximum aea of 1 0 % of total body suface. The seconday efficacy citeia wee: (i) individual scoes fo eythema, infiltation, desquamation and puitus; (ii) pefeence assessment (left bette than ight, left equal to ight, left wose than ight); (iii) time to complete healing; (iv) aea of test lesions; (v) global assessment of efficacy made by investigato and patient (1, vey good; 2, good; 3, modeate; 4, poo); (vi) assessment of benefit based on the patient s expeience (scale fom 0, not beneficial, though 1 0, exceedingly beneficial ); (vii) post-teatment elapse of Patients' details lesions (by means of the individual scoes fo eythema, and 62 patients to placebo infiltation, desquamation and puitus at week 1 2 ). One hunded and twenty-two patients wee included in the intention-to-teat analysis and the safety analysis, and, as 19 patients wee potocol violatos, 103 patients wee included in the pe-potocol analysis. Potocol viola- :ind/o medic some patient did not etun (thee patients), patient efused futhe paticipation (one patient), temination of study without known eason (one patient). Sixty patients wee andomized to tacalcitol Iealm ent In total 76 male and 46 female patients wee included. The i n 8 ± (mean ± SD) yeas. a body Statistical tests and safety assessment 78-0 ± kg of ± 8 cm. Fo the pimay efficacy citeion, the significance of They had had psoiasis fo 233*5 ± months and diffeence was evaluated by means of the two-sided the duation of the of psoiasis was Wilcoxon matched-pais signed-anks test, the effect size measue being the Mann-Whitney statistic P (X < 7). The Mann-W hitney statistic is assessed as: 0-50, equal; 0.56, small diffeence; 0.64, medium-sized 28-4 ± 74-8 months. On the ight side of the body the test lesions compised 5-6 ± 2-6 %of the total body suface and on the left side they compised 5 5 ± 2 7% of the total body suface. 0.71, lage If P wee calculated fo the seconday citeia, a symmety test In the majoity of patients teatment with tacalcitol 5 %), Lest lesions fo o placebo wee (i 1996 Bitish Association of Dematologists, Bitish Jounal of Dematology, 1 55,

5 TACALCITOL IN PSORIASIS 761 localized on moe than one pat of the body (abitaily divided into face, ams, legs, dosal and vental tunk). The test lesions wee pedominantly localized on ams and/o legs, but in a quate of all patients (24-6%), test lesions wee localized on the face o on the face plus othe pats of the body. those teated with placebo (Fig. 2 ). This diffeence was lage beginning at week 2 fo both the pe-potocol goup and the intention-to-teat goup, (iii) Time to k complete healing could not be assessed as the duation of teatment (8 weeks) was fo most patients too shot to pemit complete healing, (iv) The aea of test lesions changed by less than 1 % duing teatment with eithe of the pepaations. Statistically, thee was a small to medium-sized diffeence at week 8 (data not shown) The peteatment intensity of the individual citeia was judged as sevee o vey sevee in moe than half of the test aeas (59%; desquamation; 65% infiltation; 72%; eythema). Thee was no puitus in 29% of the test which is without clinical elevance in this case, (v) Global assessment of efficacy evealed confomity between the investigato and the patient in 78'6% of cases and was geatly in favou of tacalcitol ointment aeas and in the majoity of cases it was only slightly o vs. placebo (P < 0*0001, P[X < Y 0-82). The data of modeately expessed (about 53%). By the end of teatment (week 8 ), the scoe sum fo the pe-potocol patients ae summaized in Figue 3; the data of the intention-to-teat goup ae qualitatively the eythema, infiltation and desquamation (pimay efficacy citeion) had deceased on aveage by 4*0 scoe points (median: 5-0) afte tacalcitol teatment and by 2-3 scoe points (median: 3-0) afte teatment with Median scoe sum 10 «placebo (pe-potocol goup). The supeioity of tacalci (P tol vs. placebo teatment was significant < ) fom week 2 until the end of teatment. Using the Mann-Whitney effect size measue, it could be shown that the diffeence between the two teatments was lage (P[X < Y] ^ 0-71) at evey contol visit wheeas thee was equality between the test aeas at baseline. This could be demonstated fo the pe-potocol patients (n 103 patients; see Fig. 1) as well as fo those in the intention-to-teat goup (n = 122 patients). Futhemoe, these lage diffeences wee maintained when the data of each cente wee analysed sepaately (centes with fewe than fou patients wee pooled). The diffeences wee statistically significant at centes with moe than nine patients. The seconday efficacy citeia chaacteized futhe the esponse to tacalcitol and placebo teatment, (i) The intensity of the individual citeia of eythema, infiltation and desquamation is lowe in the teated with tacalcitol ointment than in those teated with placebo. The supeioity of tacalcitol was confimed by the Mann-Whitney statistic: fo eythema thee was a medium-sized diffeence at week 2 (P[X < Y] which became lage [P[X < Y] = 0-72) fom week 6 ; fo infiltation the diffeence could be qualified as lage fom week 4; fo desquamation thee was a mediumsized diffeence at week 2 and a lage diffeence at week 8. Fo puitus, howeve, thee wee only small diffeences at all contol points afte the stat of teatment, (ii) assessment evealed that the teated with tacalcitol ointment wee bette Weeks Figue 1. Median scoe sum of eythema, infiltation and desquamation duing teatment with tacalcitol (-A -) o with placebo (-- * in pe potocol patients. The diffeence between teatments is lage (P[X < Yj 2* 071) accoding to the Mann-Whitney statistic, and significant (/ < ) at evey time point except baseline (week 0) whee the scoe sums ae equal Bitish Association of Dematologists, Bitish Jounal of Dematology, 135,

6 762 P.C.M.VAN DE KERKHOF et al. same, (vi) By means of a scale wit h the two extemes not beneficial (scoe 0 ) and exceedingly beneficial (scoe 1 0 ), the benefit of tacalcitol ointment was assessed with scoe 7 (median) whee the benefit of placebo was assessed with scoe 4 (median). The diffeence between these assessments is obviously lage and it is statistically significant (P < ). (vii) An exact evaluation of psoiatic elapses could not be made as in most cases the test lesions had not cleaed duing the 8 weeks teatment. Nevetheless, of 97 patients who undewent a follow-up examination, 34 patients (35*1%) had an aggavation and 63 patients (64-9%) had no aggavation at all. The aggavation occued bilateally in 2 8 of these 34 patients and unilateally in six patients (thee tacalcitol, thee placebo). epoted one o moe symptoms of skin iitation. Six patients complained of a buning sensation, seven patients of puitus, thee wee six cases of skin ashes (one with hagades and eosion), and one case of hagades. Skin iitation occued bilateally in fou patients and unilateally in five patients (thee tacalcitol, two placebo). In six cases the body side was not documented. In the thee patients whee only the tacalcitol-teated test aeas wee affected, thee wee complaints of slight to sevee puitus in some of the test aeas. This was accompanied by pustules in some of the test lesions in one patient, by edness and heat sensation in one othe patient. Only one of the 15 patients discontinued teatment of the iitated lesions, but not of the othe test lesions. Five patients of the intention-to-teat goup (4*3%) Toleance and safety epoted an advese event. One patient had diahoea, one suffeed fom nausea, in one case a haematoma was Fifteen of the 122 intention-to-teat patients (12-3%) diagnosed, in one thee was slight ciculatoy eaction % patients 80 and fatigue, and one patient s skin was dy. The symptoms lasted fo seveal days, but did not equie teatment o a withdawal of the study dugs. None of these events was consideed to be dug-elated. Laboatoy investigations evealed no clinically elevant effects. In the haematology paametes the Sign test showed that thee wee no impotant changes fom baseline. With egad to the blood chemisty citeia, the Sign test did not eveal any impotant changes fom baseline, wheeas the Stuat-Maxwell test showed a although clinically ielevant deviation fom nomal in alkaline phosphatase at week 2, In addition to the statistical analysis, the data of each patient wee analysed and did not show any clinically elevant changes. The seum calcium levels ae shown I»»1 «yi.h» Vey good a I ft*" Good IOB Modeate I-* Poo W eeks Figue 2. Pefeence assessment. This was made by means of a ight left compaison of the test lesions in all pe-potocol patients. tacalcitol bette; W, equal; Ü, placebo bette % Figue 3. Global assessment of efficacy. The assessment of efficacy of teatment with tacalcitol ointment ( ) o placebo (El) in the pepotocol goup as made by the investigato is given. (C) 1996 Bitish Association of Dematologists, Bitish jounal of Dematology, 13 5,

7 TACALCITOL IN PSORIASIS 763 a) mmol/l 2*7-2*6 2-5 i» i patients and its supeioity vs. the base without the active substance. It was possible to show the efficacy by means of a set of diffeent citeia which eithe descibe the symptoms impession 2*4 2*3 > i i >. i -X- of the disease. Most of the citeia evealed a lage diffeence between the tacalcitol teatment and the placebo teatment, fequently appaent fom the fist 2*2 i f i i «i i-?»» contol visit. By means of statistical analysis pe study cente it could be shown that only 1 2 patients wee 2*1 demonst 2 Week /end diffeence between teatments. The influence of tacalcitol on puitus and aea of test lesion was only slightly bette than that of placebo. Howeve, these small diffeences b) wee without clinical elevance. Fo the aea of the test 150-?S 70 1*0 75 /{> lesions an indiect could have been expected though the action on the efficacy citeia. Howeve, 85 the duation of teatment in this study might have been 30«60 S / 'Sii y ; I MS m m i I'.-' >, ; W: m p. i*/: i< >! i { I >* il $é :;?i i Vi5 II Ü Pi ty'é iit?. > p ' & : 1ÍV'ñ y,"* M m ü i v ma m mm **11m II Sí V &. y. i1 11 ' s', i l m í-!< O W *Ts t! íi : f t ' i Ml V '' 5??.^S= ilíl f I ÍV*Í.!#H II Itel #»A Ìli ïïmiï ' "5 too shot to influence the aea of the test lesions. A ecent publication states18 that individual lesions esolve without decease in aea until cleaance occus. In the pesent investigation, a consistent obsevation was the ponounced eduction of all efficacy scoes including eythema. The intensity of eythema deceased fom mainly vey sevee to mainly modeate o slight afte tacalcitol teatment, wheeas placebo teatment only 0 wook 0 n ^ i i i i 1' hiw i week 87end o educed the eythema to mainly sevee o modeate Figue 4. Indicatos fo calcium metabolism (mean ± standad deviation), (a) Seum calcium levels ( x in 122 patients, all centes), (b) Seum calcitonin (x: jpg/ml ), paathomone (O); [pg/ mlj), 1cv2 5-dihydoxyvitamin l)5( ; [pg/ml]), 2 5-hydoxy vitamin 1), (A; (ng/ml)). The espective nomal anges ae given as bac of the statistical values (of 84 patients, fou centes). in Figue 4a. No significant changes (Sign test) wee With egad to safety, thee wee neithe any dugelated seious advese events no wee thee deviations in the laboatoy paametes which wee of clinical elevance. Fom all safety data, it can be concluded that thee was no indication of any influence on the systemic calcium metabolism. Hypecalcaemia has been obseved duing the 8 weeks teatment peiod. In 84 obseved fo vitamin Dj analogues.1 y F patients seum calcitonin, paathomone, 2 5-hydoxy- vitamin D$ and 1,2 5-dihydoxyvitamin D } wee moni- on the long-tem safety of tacalcitol ae in Symptoms of local skin iitation wee obseved o No changes in case of puitus) by 1 5 patients. In this (Wilcoxon anking test, i-test) wee found (Fig. 4b). it is elevant to note that the patients wee The toleance of tacalcitol teatment was consideed to teat face "es, i.e. aeas S by ì investigato to o vey in 1 18 of 119 patients (99-2%), and the coesponding value fo the placebo teatment was 98-3%. The patients confimed good o vey good toleance in 113 of 118 cases (95*8%) fo tacalcitol and in cases (94*1%) fo the placebo. ae elatively susceptible fo iitation to vitamin 1)5 analogues. It is possible that the iitations ae elated to the study medication. Nevetheless, they did not occu moe fequently in the taealcitol-teated aeas than in the placebo-teated lesions. It should be noted that puitus is also a symptom of psoiasis. In some patients it was i to -T puitus was Discussion The data demonstate the efficacy of this tacalcitol ointment in the teatment of psoiasis vulgais in Caucasian pat of the manifestation of this disease o a dug-elated advese event. In spite of the epoted local skin iitation, the toleance was assessed as good o vey good in the of cases. It was c fo (c) 1996 Bitish Association of Dematologists, Bitish jounal of Dematology, 135,

8 764 P.C.M.VAN DE KERKHOF cl al. futhe teatment with tacalcitol that the theapy of psoiatic lesions on the lace with this medication was well toleated. Of 30 patients whose test aeas wee also Bokum, Gemany. The pesent study was as a multicente investigation, funded by Hemal, Kut Hemann, Hambug, Gemany. localized on the face, only two e symptoms of local skin iitation thee. Calcipotiol (50/ug/g) in ointment is the vitamin D3 analogue which has been available in many counties fo 3 yeas. This analogue has poven to be effective, has been well accepted although iitation of the skin was a limitation, in up to 25% of the patients. 19,23 In Japan, an ointment with tacalcitol has been available fo 2 yeas and has poven to be effective and well-toleated; less than 1% of the patients showed iitation of the skin.4 Caicitiol (3/ig/g) in ointment twice daily has been epoted to be effective in the teatment of psoiasis. Howeve, again iitation limits the use of this compound in up to 15% of the patients (van de Kekhof, pesonal communication). Up to 3% of the patients had to discontinue teatment due to sevee iitation (van de Kekhof, pesonal communication). It has been difficult to make a diect compaison between the vitamin D3 analogues with espect to efficacy and toleance as no compaative studies ae available to date. Howeve, the pesent study suggests that tacalcitol 4/ig/g in ointment, applied once daily has a elatively low potential to induce iitation. It can be concluded fom the pesent investigation that a once daily topical teatment with a 4/Ug/g tacalcitol ointment is acious in the theapy of psoiasis vulgais in the majoity of Caucasian patients. Of couse it would be desiable to have data of long-tem theapy as well as data of extensive teatment (moe than 10% of body suface). The pesent study, howeve, does not povide any evidence of a modulation of systemic calcium metabolism. In view of the elatively low iitancy and the maked effect on eythema it is attactive to speculate that tacalcitol may become a mainstay in the teatment of flexual and facial psoiasis. Tacalcitol ointment theefoe has the potential to establish itself as a valuable theapeutical option in the spectum of phamaceutics. Refeences 1 Moimoto S, Kumahaa Y. Patient with psoiasis cued by la - hydoxyvitamin D}. Med ƒ Osaka Univ 1985; 35: Noman AW, Bouillon R. Thomasset M (eds). Vitamin D: Gene Regulation Stuctue-Function Analysis, and Clinical Application: Poceedings of the Eight Wokshop on Vitamin D. Belin: de Guyte, Kagballe K, Ivesen L. Calcipotiol: a new typical antipsoiatic. Dematol The 1993; 11: Nishimua M, Hoi Y, Nishiyama S, Nakamizo Y. Topical la-24 (R)dihydoxyvitamin Dj fo the teatment of psoiasis. Review of the liteatue. Eu J Dematol 1993; 3: Matsunaga T, Yamamoto M, Mimua H et al. 1,24 (R)-dihydoxyvitamin Dj, a novel active fom of vitamin D3 with high activity fo inducing epidemal diffeentiation but deceased hypecalcemia activity. ] Dematol 1990; 17: Matsumoto K, Hashimoto K, Kiyoki M et al. Effect of 1,24 R-dihydoxyvitamin D3 on the gowth of human keatlnocytes. JDematol 1990: 17: Kobayashi T, Okumua H, Azuma Y et al. Ict24 R-dihydoxyvitamin D3 has an ability compaable to that of la,2 5-dihydoxyvitamin Dj to induce keatinocyte diffeentiation. J Dematol 1990: 17: Glade CP, van Ep PEJ, van Hooijdonk CAEM et al. Topical teatment of psoiatic plaques with la,24 dihydoxyvitamin D}: a multipaamete flowcytometical analysis of epidemal gowth, diffeentiation and inflammation. Acta Dem Veneeal (Stockh) 1995; 75: Fakas B, Bonnekoh B, Mahle G, Dobozy A. Regulatoy effect of caicitiol, calcipotiol and tacalcitol: a diect compaison in the human keatinocyte line I-IACAT. Ach Dematol Res (In pess). 10 Kimua II, Nishiyama S, Nakamizo Y et al investigation of the usefulness of TV-02 ointment fo patients with psoiasis and left compaison test with betamethasone valeate ointment. Westen Jpn Dematol 1989; 51: Kimua I-I, Nishiyama S, Nakamizo Y et al. Investigation of the clinical effects of TV-02 ointment on psoiasis. Westen ftm Dematol 1989; 51: Eto M, Nishiyama 8, Nakamizo Y et al Study on the efficacy of TV- 02 ointment fo psoiasis esults of a double blind compaative clinical study of the left and ight sides with a placebo (ointment base) as a contol. Nishinihon J Dematol 1991; 53: Nishiyama S, Goto M, Ohkawaa A et al Study fo setting optimal concentation of TV-02 ointment. Nishinihon J Dematol 1989; 51: Kato T, Tadaki T, Teui T, Tagami H. Teatment of psoiasis by Acknowledgments I The following investigatos also paticipated in the study: J.Bath, Desden, Gemany; G.Bug, Züich, Switzeland; E.Chistophes, Kiel, Gemany; R.Happle, Mabug, Gemany; J.ICnop, Mainz, Gemany; D.Lubach, Hannove, Gemany; E.Paul, Nünbeg, Gemany; G.PIewig, München, Gemany; N.Sönnichsen, synthetic bioactive vitamin D}. l«,24-hydoxycholeealdfeol ointment. Acta Dematol (Kyoto) 1989; 84: I 5 Eto M, Nishiyama S, Nakamizo Y et al. Safety confimation study on TV-02 ointment to patients with psoiasis. Nishinihon J Dematol ; SI: Baadsgaad O, Taulsen J, Roed-Petesen ƒ, Jakobsen MB. Optimal concentation of tacalcitol in once-daily teatment of psoiasis. ƒ Dematol Teat 1995; 6: Fedeiksson T, Pettesson U. Sevee psoiasis - oal theapy with a new etinoid. Dematologica 1978; 157: (Q) 1996 Bitish Association of Dematologists, Bitish Jounal of Dematology, 135,

9 TACALCITOL IN PSORIASIS Speight EL, Fa PM. Plaque aea is a poo measue of esponse of psoiasis to teatment. B J Dematol 1994; 131: 443 (Abstact.). 19 Ramsay CA, Beth-Jones J, Bundin G et al. Long-tem use of topical calcipotiol in chonic plaque psoiasis. Dematology 1994; 189: Sauat J-H, Gumowski-Sunek D, Rizzoli R. Topical calcipotiol and hypecalcaemia. Lancet 1991; 337: 1287 (Lette). 21 Hadman KA, Heath DA, Nelson HM. Hypecalcaemia associated with calcipotiol (Dovonex) teatment. B Med ƒ.1993; 306: Hoeck HC, Laubeg G. Laubeg P. Hypecalcaemic cisis afte excessive topical use of a vitamin D deivative. ƒ Inten Med 1994; 235: Poyne T, I-lughes IW, Dass BK, Adnitt PI. Long-tem teatment of chonic plaque psoiasis with calcipotiol. ƒ Dematol Teat 199 3; 4: Langne A, Venjans H, Stapo V et al. lö,25-dihydoxyvitamin D j (caicitiol) ointment in psoiasis. J Dematol Teat 1992; 3: < * (C) 1996 Bitish Association of Dematologists. Bitish Jounal of Dematology, 135,