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General review
Annales de dermatologie et de v?n?r?ologie 2001; 128: 229-237
? Masson, Paris, 2001Calcipotriol
J.-J.?Guilhou?(1)
(1)Service de Dermatologie-Phl?bologie, H?pital Saint-Eloi, 80, avenue Augustin Fliche, 34295 Montpellier Cedex 5.Tir?s ? part : J.-J.?GUILHOU , at the above address. E-mail: jj-guilhou@chu-montpellier.fr
SUMMARY
Calcipotriol, a vitamin D derivative, was synthesized by Laboratoires L?o in 1985. Its mode of action is identical to that of 1-25 vitamin D3 (calcitriol), namely regulating expression of vitamin D-responsive genes. Calcipotriol decreases keratinocyte proliferation, induces their differentiation, and has strong immunomodulating effects.
Toxicology studies have demonstrated that abnormal calcium-phosphate metabolism is observed only with doses exceeding those recommended for clinical use (maximal topically-applied dose of 100 g per week). The half-life of calcipotriol is shorter than that of calcitriol, and its metabolites are inactive. Its effects on calcium-phosphate metabolism are therefore lesser than those of calcitriol.
Therapeutic trials in psoriasis have demonstrated the superiority of calcipotriol over vehicle, class 2 topical corticosteroids, tar and short contact therapy. Coadministration with topical corticosteroids increases efficacy and reduces side effects. In association with phototherapy, cyclosporine, or retinoids, efficacy is further enhanced and the cumulative doses of these treatments can therefore be reduced. Calcipotriol is effective in certain disorders of keratinization (ichthyosis), but its benefit in the treatment of scleroderma and vitiligo is uncertain.
At recommended doses, side effects are limited to local skin irritation in 20 p 100 of cases. Allergic contact dermatitis is rare. Photosensitization is occasionally observed when calcipotriol is initiated in patients already undergoing UVB phototherapy.
In France, treatment of plaque-type psoriasis involving up to 40 p 100 of the body surface area is an approved indication for calcipotriol. Several studies have demonstrated the efficacy and safety of calcipotriol in children at total weekly doses up to 50 g per m2 body surface area. Contraindications include hypercalcemia, pregnancy, and lactation.
All three forms of topical calcipotriol (0.005 p 100 ointment, cream, and lotion) may be administered twice daily, alternated with application of a topical corticosteroid, or used in conjunction with systemic treatments for psoriasis. The benefit of maintenance therapy has not been determined.
R?SUM?
Le calcipotriol
J.-J.?GuilhouLe Calcipotriol est un d?riv? de la vitamine D synth?tis? en 1985 par les Laboratoires L?o. Son mode d'action est identique ? celui de la 1-25 vitamine D3 (Calcitriol), essentiellement par le contr?le de l'activit? de g?nes capables de r?pondre ? la vitamine D. Il entra?ne une diminution de la prolif?ration des k?ratinocytes, induit leur diff?renciation, et a d'importantes fonctions immuno-modulatrices.
Les ?tudes toxicologiques n'ont montr? des anomalies du m?tabolisme phosphocalcique que pour des quantit?s appliqu?es sup?rieures ? celles pr?conis?es en clinique (100 g par semaine). La demi-vie du Calcipotriol est nettement inf?rieure ? celle du Calcitriol et ses m?tabolites sont inactifs. Ses effets sur le m?tabolisme phosphocalcique sont de ce fait nettement inf?rieurs ? ceux du Calcitriol.
Les essais th?rapeutiques dans le psoriasis ont montr? la sup?riorit? du Calcipotriol sur son excipient, sur les dermocortico?des de classe 2 et les r?ducteurs. L'association aux dermocortico?des augmente l'efficacit? et diminue les effets secondaires. L'association ? la phototh?rapie, ? la Cyclosporine ou aux r?tino?des entra?ne une am?lioration plus compl?te des l?sions et permet de diminuer les doses cumulatives de ces traitements. Le Calcipotriol s'est av?r? efficace dans certains troubles de la k?ratinisation (ichtyoses) et, de fa?on plus incertaine, dans les scl?rodermies localis?es et le vitiligo.
Les effets secondaires sont purement cutan?s aux doses pr?conis?es avec irritation l?sionnelle et p?ri-l?sionnelle dans environ 20 p 100 des cas. Les dermites de contact sont rares. Des ph?nom?nes de photosensibilit? peuvent etre observ?s lorsque le Calcipotriol est appliqu? chez des malades qui ?taient en cours de phototh?rapie UVB.
L'AMM comporte le psoriasis en plaques atteignant moins de 40 p 100 de la surface cutan?e. Plusieurs ?tudes ont montr? l'efficacit? et l'inocuit? du Calcipotriol chez l'enfant dans la mesure o? la r?gle des 50?g par semaine et par m2 de surface corporelle est respect?e. Les contre-indications sont repr?sent?es par les ?tats d'hypercalc?mie, la grossesse et l'allaitement.
Les modalit?s d'administration des trois formes gal?niques (pommade, cr?me et lotion, toutes concentr?es ? 0,005 p 100) sont variables?: deux applications par jour, applications altern?es avec un dermocortico?de ou association aux traitements syst?miques du psoriasis. Le traitement d'entretien n'est pas codifi?.
In 1985, Morimoto reported the remarkable improvement in psoriasis of a Japanese patient treated with 1-alpha hydroxy-vitamin D3 for osteoporosis, and he later demonstrated the efficacy of vitamin D derivatives [1]. In view of the potential side effects with oral therapy, particularly the risk of hypercalcemia, research focused on topical vitamin D preparations and on analogs with less effect on calcium-phosphate metabolism. This led to the synthesis of calcipotriol in 1985 by L?o laboratories, and it was made commercially available in France in various pharmaceutical forms (Daivonex?) in 1992.
Since the first publications of Kragballe [2] in 1988, numerous studies have demonstrated the efficacy of calcipotriol in the topical treatment of psoriasis. Other cutaneous diseases with aberrant keratinization, keratinocyte hyperproliferation, or immunologic cutaneous manifestations also improve with calcipotriol.
Pharmacodynamics
Chemical structure fig.?1
Calcipotriol is derived from 1-24 dihydroxy-vitamin D3 and is differentiated by the presence of a double bond and a cyclopropane ring on the side chain. Calcipotriol is hydroxylated in the 1-position and on the side chain, as is characteristic of the most active derivatives of vitamin D, particularly the natural form 1-25 dihydroxy-vitamin D3 (calcitriol). Tacalcitol, or 1-24 dihydroxy-vitamin D3, which has been used for many years in Japan, has recently been launched in France (Apsor?, Laboratoire Lipha).
Mechanisms of action
Molecular mechanism fig.?2
Calcipotriol has the same mechanisms of action as other vitamin D derivatives, and these mechanisms involve both genomic and non-genomic pathways. The non-genomic mechanism is due to the capacity of vitamin D to increase intracellular calcium concentration, likely through hydrolysis of phosphatidyl inositol phosphate, leading to production of diacylglycerol and inositol triphosphate with subsequent release of intracellular calcium stores. The intracellular calcium concentration regulates a number of cellular functions including proliferation and differentiation.
The genomic effects of vitamin D analogues are mediated by nuclear vitamin D receptors (VDRs), members of the family of nuclear hormone receptors. These receptors are vitamin D-regulated transcription factors. Vitamin D binds to the VDR and activates it, whereupon the VDR binds to a vitamin D response element (VDRE), situated within the promoter region of numerous genes. By this mechanism the VDR can increase or decrease expression of the nearby genes. The VDREs contain two conserved hexameric core sequences separated by a varying number of nucleotides. The core sequences can be arranged head-to-tail as direct repeats (DR) or head-to-head as inverted palindromes (IP). The VDREs are bound by a dimer of two receptor molecules, either a VDR homodimer (VDR-VDR), or more often a VDR heterodimerized with another nuclear receptor, particularly the RXR retinoic acid receptor (VDR-RXR). Since retinoic acids are vitamin A derivatives, combinations of vitamin A and vitamin D analogues, mediated through numerous possible configurations of the response elements and receptors for vitamin D (VDR) and vitamin A (RXR) result in a complex signaling network [3]. It is possible that particular combinations of dimers and response elements may correspond to distinct cellular effects. Therefore, for example, the presence of an inverted palindrome-type VDRE bound by a VDR-RXR heterodimer may preferentially regulate cell proliferation [3].
Cellular effects
Many cell types in the skin have vitamin D receptors, including keratinocytes and lymphocytes. Calcipotriol and 1-25 vitamin D3 have equivalent affinities for these receptors. In addition to its effects on calcium-phosphate metabolism, vitamin D regulates proliferation and differentiation as well as immune response. Like calcitriol, calcipotriol inhibits proliferation and induces the differentiation of normal and malignant keratinocytes in culture [4]. Vitamin D has also been shown to induce normal differentiation in neoplastic epidermis reconstructed from tranfected keratinocytes, thus confirming potential anti-neoplasic effects of vitamin D [5]. Like other vitamin D derivatives, calcipotriol has immunomodulatory effects including alteration of antigen presentation by dendritic cells, inhibition of T-cell proliferation, and reduction of cytokine levels, in particular IL-6 and gamma interferon [6, 7]. This may explain the beneficial effects of calcipotriol in various inflammatory dermatoses.
Although the effects of calcipotriol on proliferation and differentiation are similar to those of 1-25 vitamin D3, it has less effect on calcium metabolism. After oral or intra-peritoneal administration of calcipotriol to rats, the changes in blood and urine calcium levels are 100 to 200-fold less than the changes induced by 1-25 vitamin D3 [4].
Cutaneous effects in vivo
Most studies have focused on psoriasis and have confirmed the capacity of calcipotriol to regulate epidermal proliferation, differentiation, and the local immune environment. During treatment with calcipotriol, the levels of proliferation markers keratins 6, 16, and 18 decrease, keratins 1 and 10 reappear, levels of IL-8 are reduced, IL-10 levels increase, and the inflammatory infiltrate, particularly the T-lymphocytes population, becomes sparse [8, 9]. Furthermore, calcipotriol increases the expression of vitamin D receptors in the basal keratinocytes [10].
Toxicology studies
Animal toxicology
The risk of acute calcipotriol toxicity is very low in view of the doses required for clinical response. The LD50 of calcipotriol is 15 to 40 mg/kg in the mouse and rat. Chronic or subacute toxicity is observed in the kidney at high doses (54 mg/kg per 24 hours). Mutagenesis and teratogenesis studies in the rat and the rabbit have been negative [11].
Studies of toxicity due to topical administration in the rat yielded discordant results. One study confirmed that calcipotriol was 60-fold less calcemic than 1-25 vitamin D3, that it induced less inhibition of parathyroid hormone, and that the incidence and severity of kidney complications was lower [12]. However, another comparative study revealed that calcipotriol had a greater effect on calcium-phosphate metabolism after 4 days of administration in the rat [13]. These discordant results may be related to differences in the vehicles used and consequent differences in penetration and systemic absorption of calcipotriol.
Human toxicology
Toxicity in humans was observed when quantities applied were greater than the recommended maximal dose of 100 g of topical substance per week, or during trials conducted with quantities of ointment up to 360 g/week. At doses of 100 g/week, an increase in urinary calcium was occasionally noted [14]. In the study by Bourke [15] with higher doses, a dose-dependent increase in urinary and blood calcium and phosphate was observed with a concomitant decrease in parathyroid hormone and serum 1-25 dihydroxy vitamin D3. Hypercalcemia is observed in less than 2 weeks during administration of calcipotriol ointment in amounts greater than 5.6 g/kg/week. It therefore appears that calcipotriol interferes with calcium homeostasis when administered at doses significantly higher than recommended, whereas at recommended doses alterations of calcium balance are exceptional and primarily observed in patients with impaired renal function or altered calcium-phosphate metabolism.
Pharmacokinetics
Systemic administration [16]
The pharmacokinetics of systemically administered vitamin D analogues are of little interest to the dermatologist today, since only topical administration is used. In the rat, the half-life of calcipotriol is 4 minutes, with monophasic elimination. 1-25 vitamin D3 has a longer half-life (3 hours) and its elimination is biphasic. Autoradiographs show that calcipotriol is concentrated in the liver, the kidneys, and the intestine. The two principle metabolites of calcipotriol, MC1046 and MC 1080, result from oxidation of carbon 24 of the side chain. These metabolites have little biologic activity, since they lose their capacity to bind the vitamin D receptor. These studies show that calcipotriol is rapidly metabolized, likely because of its low capacity to bind its vitamin D binding protein, in contrast to the high binding of 1-25 dihydroxy vitamin D3.
The majority of clinical trials have concerned psoriasis, and the first controlled studies were initiated in 1988. The vast body of clinical trials published since cannot be referenced and analyzed in detail within the scope of this review. A recent review of this literature was recently published in the British Medical Journal [18].
Topical pharmacokinetics
In humans, after a single application of radiolabeled calcipotriol in ointment, serum concentration is maximal within 6 hours and disappears within 48 hours [11]. The maximum quantity of radioactivity detected in urine is 0.2 p 100 of the total amount applied, whereas it is 0.45 p 100 in stool. Another study reported percutaneous absorption of 5 to 6 p 100 of the dose applied, with rapid transformation of calcipotriol into inactive metabolites in the blood [17]. However, it should be noted that the protocols measured absorption after a single topical administration, in contrast to the twice daily applications of calcipotriol for weeks or months in common practice.
Clinical trials
Calcipotriol and psoriasis
The majority of clinical trials have concerned psoriasis, and the first controlled studies were initiated in 1988. The vast body of clinical trials published since cannot be referenced and analyzed in detail within the scope of this review. A recent review of this literature was recently published in the British Medical Journal [18].
Calcipotriol in monotherapy
Studies comparing calcipotriol ointment against a placebo with twice daily applications over a period of 6 to 8 weeks in adults showed the superiority of calcipotriol ointment compared with vehicle [2, 19]. The reduction in PASI scores in these studies varied from 54.5 p 100 to 68.8 p 100. Similar studies with calcipotriol cream are less numerous and yield similar results, albeit with less effect on PASI scores (47.8 p 100 to 53.7 p 100) [20, 21, 22]. To date, no study has compared calcipotriol cream with calcipotriol ointment. Furthermore, single daily application of calcipotriol is less effective than twice daily applications [21].
Most studies comparing calcipotriol against class 2 topical corticosteroids demonstrated the superiority, to varying degrees, of calcipotriol ointment [23, 24] or cream [20].
Comparative studies against applications of tar or anthralin short contact therapy clearly favor calcipotriol [25, 26].
The efficacy of calcipotriol compared with other vitamin D derivatives has rarely been studied. However, it appears that calcipotriol ointment is more effective than calcitriol ointment (3 mg/g, 2 applications per day) [27]. Topical agents containing calcitriol are not marketed in France yet. Comparison with tacalcitol (Apsor?, Laboratoire Lipha) showed that twice daily applications of calcipotriol ointment were more effective than once daily application of tacalcitol ointment after two weeks of treatment [28].
Long-term studies showed no post-treatment rebound nor tachyphylaxis [31].
Calcipotriol in association with other modalities
Coadministration with topical corticosteroids
Alternating applications of calcipotriol and topical corticosteroids (each product applied each day) in ointment [32] or cream form [21] was slightly more effective and showed better tolerance than calcipotriol monotherapy. Other combination regimens might be appropriate in prolonged therapy, for example application of calcipotriol on weekdays and topical steroids on weekends [33], or alternating weeks of each product [34].
Phototherapy
Association with broad spectrum UVB phototherapy administered two or three per week leads to better results than UVB or calcipotriol monotherapy, with earlier improvement and fewer sessions required for clearing [35, 36]. Narrow band UVB (TL01) 5 times per week combined with calcipotriol has an even greater benefit after two weeks' therapy [37]. However, in a recent study [38] the association of calcipotriol and UVB TL01 administered 3 times per week did not give better results than TL10 phototherapy alone.
Combination PUVA and calcipotriol therapy was assessed in a Franco-Belgian study in which the patients were first administered calcipotriol or vehicle for 2 weeks, followed by PUVA therapy. The results indicate greater efficacy, decrease in the number of sessions required for clearance, and reduction of cumulative UVA by 30 p 100 [39]. A recent study also demonstrated the benefit of combining calcipotriol with topical psoralen + UVA therapy [40].
Cyclosporine [41]
Addition of calcipotriol to low dose cyclosporine (2 mg/kg/day) led to a clear increase in percentage of patients with complete remission at 6 weeks (50 p 100 vs. 11.8 p 100) and a greater reduction in mean PASI scores (80.5 p 100 vs. 57.7 p 100).
Other combination therapies
Coadministration of calcipotriol with etretinate (40 mg/d) or with acitretin (20 to 70 mg/d) improved the therapeutic effects of the oral retinoid, with a higher response rate, better PASI scores, and lower cumulative doses of retinoids [42, 43].
Calcipotriol-methotrexate therapy is under study.
These studies reveal that combination therapies with calcipotriol and systemic treatments for psoriasis allow greater improvement of the lesions and permit a reduction in daily or cumulative doses with consequently lesser potential side effects.
Calcipotriol in particular forms of psoriasis
Psoriasis of the scalp
A solution of calcipotriol was more effective than its placebo [44] but less effective than betamethasone [45].
Inverse or intertriginous psoriasis
Many authors discourage application of calcipotriol to skin folds because of irritation (see below). However, a study using calcipotriol ointment (open study, not controlled) demonstrated its efficacy despite minor irritation [46]. It may be preferable to use the cream form, which has not been assessed in this indication.
Ungual psoriasis
In a controlled study of 58 patients treated for 3 to 5 months for ungual psoriasis, calcipotriol ointment was as effective as combination treatment with betamethasone dipropionate and salicylic acid [47].
Acrodermatitis
The efficacy of calcipotriol in acrodermatitis is not known, but three cases of acrodermatitis continua of Hallopeau are reported to have greatly improved [48, 49, 50].
Psoriasis in children
Two large studies, one open-label [51], the other controlled [52], demonstrated the efficacy of calcipotriol in childhood plaque-type psoriasis. The children were 2 to 14 years old and the quantities of product applied were identical to those recommended in adults but proportional to the body surface area, up to 50 g/m2/week. The safety of prolonged treatments in children has not been assessed..
Other disorders
Disorders of keratinization
In a left-right study against placebo [53], calcipotriol was effective to varying degrees in different ichthyoses, primarily ichthyosis vulgaris, congenital ichthyosiform erythroderma, and X-linked recessive ichthyosis. In the same study, no effect was noted on keratoderma, and Darier's disease was often aggravated. Another study confirmed the efficacy of calcipotriol in ichthyosis and the improvement of bullous congenital ichthyosiform erythroderma [54]. The obstacles in treating these disorders with calcipotriol are the extensive areas involved and the potential for irritation.
Other studies addressing the response of disorders of keratinization to calcipotriol have demonstrated improvement in Grover's disease [55], keratosis lichenoides chronica [56], pityriasis rubra pilaris [57], inflammatory linear verrucous epidermal nevus [58], and actinic porokeratosis [59].
Immune disorders
In localized scleroderma (morphea/linear scleroderma), an open study [60] of 12 patients over a 3-month period demonstrated the efficacy of calcipotriol under occlusion. However, spontaneous resolution of these disorders has been reported.
In cases of vitiligo, partial or total repigmentation was obtained with either calcipotriol monotherapy [61] or calcipotriol combined with PUVA therapy [62]. The latter study, which was a left-right controlled, double blind, randomized study, reported enhanced repigmentation on the areas to which calcipotriol had been applied.
Miscellaneous
A recent publication demonstrated the efficacy of calcipotriol ointment in prurigo nodularis. This left-right double blind study conducted in 10 patients showed greater efficacy of calcipotriol over betamethasone valerate in reducing in the size of the nodules [63].
The anti-neoplastic properties of vitamin D have led to studies reporting a certain degree of efficacy in seborrheic keratosis [64], T-cell lymphoma [65], and breast cancer metastases [66]. However, further studies are required to assess the anti-neoplastic effect of calcipotriol in cutaneous neoplasms.
Side effects
Systemic effects
Effects on calcium-phosphate metabolism may occur with overdose (more than 100 g of product/week) or when the contraindications are not respected (see chapter on toxicology). At recommended doses, no clinical manifestations of hypercalcemia have been reported, and biological assays, even in long-term studies, reveal no abnormalities in calcium-phosphate metabolism. Bone densitometry remains unchanged after 2 months of treatment with 120 g of calcipotriol per week [67].
Cutaneous side effects
Depending on the series, side effects are reported in 10-34 p 100 of cases. They are generally benign, most commonly irritation with possible desquamation, and lead to suspension of treatment in 1 p 100 of cases [23, 24]. They are transient and resolve when the calcipotriol is applied less frequently, and they can be minimized or avoided by co-application of topical steroids [21, 32]. The incidence of cutaneous side effects is identical with the ointment or the cream, but no study comparing these two forms has ever been conducted. It is not known whether local side effects are due to the vehicle or to calcipotriol itself [68].
Most publications mention irritation that occurs on the face, but this does not occur in studies in which facial applications were avoided and patients were asked to wash their hands after application [19]. Irritation appears to be dependent on the initial inflammatory state of the psoriatic lesions, particularly on the lower limbs and occasionally in the body folds [68].
A few cases of allergic contact dermatitis with positive patch tests have been reported [69, 70, 71]. However, interpretation of these tests is difficult since calcipotriol and its vehicles are irritants [72].
The association with phototherapy is complex. UVA may degrade calcipotriol [73]. The ointment and cream block UVB if they are applied less than two hours before the session. This effect may be due to the vehicle [74]. Concomitant treatment with UVB does not appear to increase the irritation provoked by calcipotriol [75]. Manifestations of photosensitivity (burns on the lesions treated) have been reported when calcipotriol was introduced during UVB phototherapy [76]. It is therefore preferable to initiate phototherapy in patients already treated with calcipotriol. Finally, hyperactivepigmentation of treated lesions has also been described following phototherapy or topical PUVA therapy [77, 78].
Administration methods
Three pharmaceutical forms of calcipotriol are available in France: ointment, cream, and lotion, all at a concentration of 5 mg per 100 g (0.005 p 100). A preparation containing calcipotriol and betamethasone has been the subject of recent studies and may be commercialized in the near future.
The marketing authorization in 2001 includes the following indications: "topical treatment of psoriasis plaques (psoriasis vulgaris) involving up to 40 p 100 of the body surface area. To enhance efficacy, calcipotriol can be combined with topical corticosteroids and, in more extensive forms, with phototherapy, cyclosporine, or acitretin, respecting the maximum dose of 100 g/week and adjusting the dose in cases in which less than 40 p 100 of skin surface is affected".
In general practice, the indications concern moderately extensive psoriasis in adults, with topical application of less than 100 g/week in order to avoid the unwanted effects on calcium-phosphate metabolism. In children, calcipotriol can be prescribed up to a 50 g maximum of product per m2 of body surface area. Benefits in guttate and pustular psoriasis have not been assessed.
Although psoriasis of the scalp is clearly improved with calcipotriol, its application to the face is debatable. The first publications which contraindicated facial applications were perhaps excessive. If applied prudently, calcipotriol cream can be used on the face, where application of topical steroids presents far more disadvantages. The same is true for psoriasis of the body folds.
Contraindications for calcipotriol therapy include hypercalcemia, pregnancy (although animal studies have revealed no teratogenic effect), and breast feeding (the passage of calcipotriol in maternal milk has not been assessed).
In monotherapy, calcipotriol should be applied twice a day. Single daily applications are less effective. The cream can replace the ointment in the morning if the cosmetic aspect of the ointment is unacceptable.
The benefit of co-administration with topical corticosteroids is appreciated by many dermatologists. This association has often provided greater efficacy and reduced irritation. Association with other systemic treatments of psoriasis, particularly retinoids and cyclosporine, allows greater clinical improvement and lower cumulative doses. The same has been found with phototherapy, with two caveats: calcipotriol must not be applied in the 2 hours before phototherapy, and it should not be initiated in a patient already undergoing phototherapy.
The modalities of maintenance treatment, prescribed as reduced application of calcipotriol, has not been clearly established.
Calcipotriol has an important place in the treatment of psoriasis. In addition to this official indication, it will be valuable to use calcipotriol in cutaneous manifestations with keratinization disorders, particularly certain ichthyoses. The potential efficacy of calcipotriol in scleroderma, vitiligo, and pre-malignant lesions must be confirmed by further controlled studies.
To cite the present paper, use exclusively following reference: Guilhou JJ. Le calcipotriol (full text in english on e2med.com/ad). Ann Dermatol Venereol 2001; 128: 229-37.
Figure 1.
Chemical structure of calcitriol, calcipotriol and tacalcitol.
Figure 2.
Genomic mechanisms of action of calcipotriol.
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