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Veterinary Dermatology 2004, 15, 61– 74
Blackwell Publishing, Ltd. Cyclosporin A: a new drug in the field of canine dermatology
ERIC GUAGUÈRE*, JEAN STEFFAN† and THIERRY OLIVRY‡ *Clinique Veterinaire Saint Bernard, 598 Avenue de Dunkerque, 59160 Lomme, France †Novartis Animal Health, CH 4002 Basle, Switzerland ‡Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27606, USA (Received 16 July 2003; accepted 14 October 2003) Abstract
In the last few years, there has been growing interest in the use of cyclosporin to treat canine skin dis- eases. Cyclosporin exhibits potent immunomodulating properties that reflect its ability to block the transcriptionof cytokines genes in activated T lymphocytes. Cyclosporin also inhibits a number of immune allergic reactionsthat occur after activation of mast cells, Langerhans cells, eosinophils and keratinocytes. In randomized control-led trials, cyclosporin has proven to be as effective as glucocorticoids for treatment of canine atopic dermatitisat the inducing dosage of 5 mg kg−1. The drug has also proven beneficial for the treatment of perianal fistulas indogs. Other potential applications are suggested from small pilot open trials using dogs affected with variousimmune-mediated dermatological diseases. The pharmacokinetic properties of cyclosporin are very similar indogs and man, but its safety margin is much wider in dogs. Therefore, routine cyclosporin blood level monitoringdoes not appear necessary. Although in man renal impairment and hypertension are often seen, even at low doses,these effects are not observed in dogs. Adverse reactions consist mainly of transient emesis and diarrhoea occur-ring during the first days of treatment. Other adverse reactions, such as gingival hyperplasia, verruciform lesionsand hypertrichosis, appear to be dose-dependent, and occur rarely at therapeutic doses. An increased suscepti-bility to infections has not been reported in dogs receiving this drug.
Keywords: anal furunculosis, atopic dermatitis, canine, cyclosporin, dermatology, pharma-cokinetics,pharmacology.
I N T RO D U C T I O N
administered orally as a vegetable oil-based formula-tion is in the range 20 –27% in dogs6–11 and 25 –35% in Cyclosporin A (CsA) is a compound isolated in the early man.12,13 This relatively low bioavailability can be 1970s from extracts of telluric fungi (Tolypocladium explained by the large molecular mass of the drug and inflatum gams).1 This drug has been used for its immu- its low water solubility. In addition, this drug is par- nomodulating properties in humans after organ trans- tially metabolized in the intestines by the cytochrome plantation since 1977.2 In human dermatology, CsA P450-dependent mono-oxygenase (CYP3A isoform) has been shown to be useful for the treatment of psoriasis3 system.14 Absorption is also limited by P-glycoproteins and atopic dermatitis (AD).4 In canine dermatology, that act as a drug efflux pump from the intestinal epi- this drug has been the subject of growing interest over thelial cells by transporting the drug from the intestinal recent years for the treatment of perianal fistulae (PFi) and AD. Its efficacy has been explored in the treatment In veterinary medicine CsA is available in micro- of other immune-mediated dermatoses.5 In addition, data emulsion (ME) in soft gelatin capsules of 10, 25, 50 and have been accumulated on the pharmacokinetic and 100 mg (Atopica®, Novartis Animal Health, Basel, safety profiles of the drug in dogs. This review is aimed Switzerland). In humans, CsA was first developed as a at summarizing the data available on the use of CsA for vegetable oil formulation of 100 mg mL−1 offered as a the treatment of canine skin diseases, with cross-reference drinkable solution or a soft gelatin capsules (Sandim- to the human medical dermatology experience.
mune®, Sandoz-Pharma, Basel, Switzerland) beforethe ME preparation became available. The ME formu-lation was designed to improve bioavailability. On contact C L I N I C A L P H A R M A C O K I N E T I C S
with gastrointestinal fluids, this formulation readilyforms a homogeneous monophasic microemulsion The pharmacokinetics of CsA in dogs and man are that mimics the mixed micellar phase of the standard extremely similar. The bioavailability of the drug formulation. Compared to the initial olive oil formula-tion, the ME is better absorbed. In man, the bioavail-ability of the ME formulation therefore increases from Correspondence: Eric Guaguère, Clinique Veterinaire Saint 20 –30% to 30 – 40%.16 In dogs, the ME formulation Bernard, 598 Avenue de Dunkerque, 59160 Lomme, France. E-mail:[email protected] offers a 35% bioavailability (Novartis AH data on file), 2004 European Society of Veterinary Dermatology Table 1. Mean pharmacokinetic parameters (SD) of cyclosporin A given intravenously to dogs
HPLC: high-pressure liquid chromatography. RIA: radioimmunoassay. FPIA: fluorescence polarization immunoassay (TDx Abbott Diagnostics).
T : elimination half life. MRT: mean residence time. Vss: volume of distribution at steady-state.
compared with 20 –25% with the vegetable oil formula-tion.6–11 The ME formulation also decreases the inter-individual variability of drug absorption due to theincreased absolute bioavailability and from the lack ofeffect of bile secretion on absorption. As a vegetable oilformulation, the absorption of CsA is very much influ-enced by bile secretion emulsifying the solution. Indogs, bile diversion results in a 75 – 80% decrease in drugabsorption if given as vegetable oil formulation.11,17 Asthe bioavailability of CsA is not influenced by bilesecretion when the drug is offered as ME the decreaseof absorption after feeding is reduced in man.18 How-ever, in dogs, even as ME formulation, the absorptionis slightly delayed when the drug is given with food, Figure 1. The feeding effect was tested in a cross-over study on eight
and the individual variability is increased (Fig. 1). It is beagles receiving each the gelatine capsule and the solution as ME therefore recommended that the drug is administered formulation with or without food. The variability of the drug either 2 h before, or after feeding. The clinical relevance absorption was increased when the CsA ME was given with food.
of variations of blood concentrations when CsA is Very low levels were observed in 5 of the 16 dogs receiving the drug given with food during long-term treatment of canine with food. Cyclosporin was analysed using fluorescence polarizationimmunoassay (TDx).
skin diseases has not yet been determined.
In dogs and man, the drug is metabolized mainly in the liver and intestines. The same cytochrome P450 There is a low passage of CsA from blood to brain.
enzymes CYP3A4 are involved in both intestinal and In dogs, concentrations in the cerebrospinal fluid hepatic metabolism.14 Hepatic metabolism of CsA remain 10 –100 times lower than in blood, even follow- tends to be three times more active in dogs than in ing repeated high-dose intravenous infusions.26 Like humans19 but this is compensated for by a lower rate of ivermectin the ATP-binding transporters P-glycoproteins, metabolism in the liver than the intestine. With the liver especially the B1 cassette (PgP, MDR1 gene product) playing a key role in the drug metabolism, it is not sur- play a major role in preventing CsA, from crossing the prising that a 70% hepatectomy reduces the drug clear- blood–brain barrier and accumulating in the brain.27 ance rate by ≈ 50%, and thus increases the elimination When applied epicutaneously, CsA has a poor skin half-life to the same extent.11 However, as drug absorp- penetration despite being very lipid soluble.28 In man, tion is also reduced after hepatectomy, drug exposure moderate to poor efficacy is obtained after topical is only increased by 20%.11 Therefore, hepatic dysfunc- application for treatment of AD.4 The poor skin pene- tion is expected to impact minimally on the drug safety.
tration is suspected to be related to the high molecular Despite the complex structure of CsA, the reactions mass of the compound. High lipophilicity may also involved in biodegradation of this molecule are limited slow the movement of the compound from the lipid- to hydroxylations and demethylations, which results in rich stratum corneum to the hydrated lower epider- ≈ 25 metabolites.20,21 It is generally accepted that the mis.28 However, recent studies and anecdotal reports metabolites are devoid of pharmacological activity.22 suggest that the topical application of CsA could be Being lipophilic, CsA distributes widely in the tissues.
beneficial for treatment of PFi in dogs.29 The concentration of CsA in the skin is up to 10 times Elimination of CsA is mainly biliary with minimal higher than blood concentrations in laboratory ani- renal excretion in all species (Table 1). The unchanged mals and man.23,24 In dogs, the same magnitude of the fraction of CsA eliminated by the kidneys is only 1– 6% skin to blood concentration ratio has been found.25 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 61– 74
Table 2. Comparison of pharmacokinetic parameters of cyclosporin A in dog and man after oral administration
Data obtained following the administration of vegetable oil based formulations and using an HPLC assay (excluding Ref. 8). 1For references see text. 2References 12 and 13. Cl: clearance. F: absolute bioavailability. T : time of maximum concentration. T : elimination half-life. MRT: mean residence time. *Vegetable oil formulation. †Microemulsion formulation.
Table 3. Pharmacokinetic interactions with cyclosporin A
Well–documented report of interaction with Ketoconazole
Fluconazole
Itraconazole
Diltiazem
Erythromycin
Clarithromycin
Norfloxacin
Phenytoin
Metoclopramide
Vitamin E‡
Methylprednisolone Cimetidine Vitamin E† Nonsteroidal anti-inflammatory drugs Fluoroquinolones* Beta Lactam antibiotics Text in italics: Interactions documented in dogs, in plain letters, interactions documented in man. Text in bold: increase or decrease by > 100% compared with to normal levels. Regular text: increase or decrease of 50–100% compared with normal levels.
*Except Norfloxacin; †with the CsA ME formulation (Atopica); ‡with the CsA vegetable oil formulation (Sandimmune).
In man: data from Campana et al.34 review, in dogs see text.
B L O O D P RO F I L E S A N D
D R U G I N T E RA C T I O N S
P H A R M A C O K I N E T I C P A RA M E T E R S
In man, numerous interactions between CsA and other The pharmacokinetic parameters reported from several drugs occur because of shared metabolic pathways dog studies6–11,30 are presented in Table 2, and are com- involving cytochrome P450 system (CYP3A4) and /or pared with those observed in man.12,13 It can be noted competition with the ATP-binding transporter P- that, in man, a wider variation of pharmacokinetic glycoprotein (Table 3). P450-inhibiting drugs decrease parameters occurs in comparison with dogs. This larger hepatic clearance of CsA, increase its serum levels, and variability can be explained by the fact that many stud- they could be responsible for toxic effects when very ies were conducted after organ transplantation (mainly high blood concentrations are reached. However, P450 liver or kidney), and these were likely to influence the enzymatic inductors increase the hepatic metabolism pharmacokinetic parameters of the drug. Transplanta- of CsA, and thus decrease its blood concentration.
tion is followed by a reduction in absorption because of Interactions have been investigated extensively in man, the increased activity of intestinal P-glycoprotein because of the relatively low margin of safety and the efflux pump as well as reduced bile secretion.31,32 need to maintain a minimum trough level to prevent In man, it is recommended that the daily dose is divided into two administrations, in spite of the rela- Most of the drug interactions known in man have tively slow elimination of the drug. High CsA peak not yet been documented in dogs. In this species, concentrations are considered to be responsible for interaction with ketoconazole is the most relevant, as it renal functional impairment.12 In dogs, a once daily is often used to treat dermatological conditions. The administration is preferred, because the drug’s margin clearance of CsA is decreased in the presence of of safety is greater. This regimen is used for treatment ketoconazole, leading to higher CSA blood concentra- of AD, but in most studies conducted on PFi, twice tions. The increase is proportional to the ketoconazole daily dosing was proposed. A recent study suggests dose in the range 2–12 mg kg−1.6 This interaction is clin- that a single daily administration also yields satisfac- ically relevant as the daily dose of CsA can be markedly reduced.35,36 However, the extent of the interaction is 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 61– 74
individually variable, and CsA blood concentrations been established between CsA trough concentrations cannot be predicted reliably. Individual dose adjust- and efficacy for treatment of PFi33,35 or AD (Novartis ments are therefore required. Interaction with erythro- mycin, another drug used in veterinary dermatology, is As the dose used in the treatment of AD is lower well documented in man but not in the dog. Other mac- than that prescribed for prevention of organ transplan- rolide antibiotics such as lincomycin or clindamycin tation rejection in humans, and because of the larger are not known to interfere with CsA in man.34 safety margin in dogs, trough-level monitoring does The interaction between CsA and cimetidine, a not appear to be justified in routine practice. Blood type-2 histamine receptor antagonist, has recently been level measurements could be useful, however, when the evaluated in dogs.37 Cimetidine, a potent inhibitor of drug is combined with ketoconazole, or with any other the hepatic microsomal enzymes, delayed but did not drug known to interfere with CsA metabolism, for decrease the absorption rate of CsA. Recently, water- soluble vitamin E polyethylene glycol succinate has As the high-pressure liquid chromatography (HPLC) been reported to enhance CsA bioavailability adminis- method is used often in laboratory studies, it is of limited tered as vegetable oil formulation but not as ME for- value for clinician as it is expensive and time-consuming.
mulation.38 Water-soluble vitamin E is believed to Faster and simpler methods have been developed such improve bioavailability by micelle formation enhanc- as a fluorescent polarization immunoassay (FPIA com- ing the absorption in the intestine.
mercially marketed as TDx by Abbott Laboratories, An interaction between methylprednisolone IL, USA) or radioimmunoassay (RIA, commercially (1 mg kg−1) and CsA (20 mg kg−1) was not found when marketed as CYCLO-Trac, INCSTAR Corp., Stillwater, both drugs were administered concurrently (Novartis MN, USA). However, these two assays employ anti- bodies that cross-react with some CsA metabolites43 Most interactions due to transiently administered and therefore yield higher blood concentrations of medications inducing a small increase in CsA blood CsA than HPLC.6 In dogs, blood concentrations mea- concentrations are believed to be of no clinical rele- sured by TDx assay are ≈ 1.8 times higher than those vance in dogs as CsA is not nephrotoxic.
M O N I T O R I N G B L O O D C YC L O S P O R I N
M O D E O F A C T I O N
CsA acts on different cells, but its main therapeutic The monitoring of CsA blood levels following organ action is on T lymphocytes. Cyclosporin induces rap- transplantation has been established as a routine prac- idly reversible immunosuppression by inhibiting the tice in human medicine. Blood monitoring initially was initial antigen triggered activation phase of CD4+ justified by the large individual variability of the drug T lymphocytes. This immunosuppression comes from blood levels, but was also useful to ensure the success the blocking of the transcription of genes encoding of organ transplantation with minimal adverse reac- several cytokines, in particular interleukin (IL)-2. The tions. In man, the relatively small margin of safety and molecular mode of action involves the specific binding the higher inducing dose require a careful dose adjust- of CsA to an intracellular protein, cyclophilin-1, ment. The minimum trough levels to be maintained for belonging to the immunophilin family. Then the transplant success and minimal renal impairment have cyclophilin–CsA complex thus formed inhibits cal- been evaluated in a large number of studies.39 cineurin, which is an enzyme involved in the nuclear The relationship between blood concentration and translocation of the cytoplasmic component of efficacy has not been established for the treatment of NF-AT, an essential transcription factor of the IL-2 psoriasis in man.40 In a study in which the relationships gene.44 The absence of IL-2 synthesis prevents the among efficacy, dose, trough levels and area-under-the- activation and the proliferation of T lymphocytes in curve (AUC) were analysed,41 a better correlation was addition to the secondary synthesis of other cytokines, found between efficacy and AUC than between efficacy including IL-4, interferon (IFN)-γ and GM-CSF.45,46 and trough levels. A recent systematic review of clinical The immunomodulatory properties of CsA have studies conducted in patients with psoriasis concludes been extensively investigated in rodents and man.
that trough levels are not even useful for monitoring Cyclosporin inhibits skin mast cell counts,47 mast cell the level of renal impairment.42 In dogs, a minimum survival,48 mast cell secretory response after stimula- trough level required for efficacy in PFi is recom- tion,49 mast cell histamine release50,51 and the secretion mended by some authors, but these values are based on of cytokines IL-4, IL-5, tumour necrosis factor (TNF), data established for human and animal patients receiv- ing organ transplants. In addition, trough levels estab- Cyclosporin A inhibits eosinophil survival,55 release lished in human medicine are 12 h concentrations as of toxic granules,56,57 cytokine secretions58 and recruit- the drug is administered twice a day, but 24 h trough ment to the sites of allergic inflammation.59 levels should be established for dogs when the drug is Cyclosporin A decreases the number of epidermal given once daily. At this time, a relationship has not Langerhans cells and inhibits the lymphocyte-activating 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 61– 74
functions of these antigen-presenting cells.60–63 Cyclo- increased blood pressure are the most troublesome side sporin A also reduces the cytokine secretion by effects in humans.77–79 The mechanisms involved in the induction of nephropathy and increased blood pres- Finally, CsA inhibits IgE and mast cell-dependent sure are complex. Cyclosporin is responsible for renal cellular infiltration at the sites of cutaneous inflamma- arteriolar vasoconstriction causing a reduction in tion by preventing TNF-medicated late-phase reac- kidney blood flow and glomerular filtration rate.80 tions in man and dogs. These findings have been Vasoconstriction of the afferent artery results from corroborated by the demonstration that CsA reduces endothelin and thromboxane release and activation of the severity of allergen-induced, late-phase, asthmatic the rennin–angiotensin–aldosterone system.81 Primary renal impairment is therefore secondary to modifica- In dogs, few studies have been conducted, but it is tions of intrarenal haemodynamics. Hypertension also likely that more information will be generated over the seems to be induced by other mechanisms such as an next years. In dogs, as in man, it was found that CsA increased activity of the sympathetic nervous system81 also inhibits T-lymphocyte activation66,67 and cytokine the inhibition of nitric oxide and an increase in intra- production. Mast cell histamine release is also reduced cellular Ca2+ leading to vascular reactivity to vasocon- strictors agents.82 More recently, it has been suggested Cyclosporin A does not inhibit the secretion of IgA, that nephrotoxicity could result from the inhibition of IgG and IgM in dogs67 as is the case in other species. It the adaptative responses to hypertonicity that occurs is well recognized that CsA does not alter humoral during the urine concentration mechanism.82 Pro- immunity. Cyclosporin A had no significant effect on longed treatment with CsA is associated with chronic serum allergen-specific IgE levels and intradermal tests renal damage because of reversible lesions of the renal when administered at 5 mg kg−1 for 21 days to dogs parenchyma. In the long term, proximal tubular with experimentally induced flea allergy dermatitis.69 In another study evaluating the effect of high-dose CsA In dogs, pharmacological studies conducted with (20 mg kg−1) on vaccination in dogs, no effect on vac- high-dose CsA (20 –30 mg kg−1) show only moderate cinal antibody titres could be found (Novartis Animal renal effects, such as a reduction of the rate of urine Health, data on file). Cyclosporin treatment should not flow and a reduction of sodium excretion, all without interfere with vaccination as long as the protection is changes in renal clearance.84,85 Moreover, in toxicolog- obtained mainly via a humoral response.
ical studies conducted in dogs, signs of nephrotoxicity Cyclosporin A also has nonimmunological effects have not been noted clinically or histologically, even at on nonimmunological cells.70 In vitro, at a concentra- the high dosage of 45 mg kg−1 given for 52 weeks.72 tion of 1–10 µg mL−1, CsA reversibly inhibits the pro- This finding has been confirmed in safety studies liferation and synthesis of normal and neoplastic employing dosages up to 33 mg kg−1 for 90 days keratinocyte DNA. This antiproliferative activity plays (Novartis Animal Health: data on file), as well as in a major role in the treatment of psoriasis, which is a clinical studies.74–76 None of the clinical trials revealed disorder characterized by epidermal hyperprolifera- increases in blood creatinine levels. Therefore, it appears tion. Cyclosporin A has been also shown to induce that the dog is much less sensitive than other species, the synthesis of tumour growth factor (TGF)-β that such as rats or man, to the kidney-damaging effect of stimulates cells to increase their extracellular matrix CsA. Such variation in the toxic effects of this drug deposition and decreases the production of degrading could be explained by the excretion of intracellular proteases, therefore inducing a fibrogenic state.45 CsA from the tubular cells by P-glycoprotein,86 thereby TGF-β secretion is probably responsible for the renal preventing toxic effects, and /or by the absence of effect fibrosis observed in rats and man, and the gingival of CsA on calbindin D protein.87 In man and rats, the hyperplasia and verruciform lesions occasionally seen concentration of this protein in kidney tubular cells in dogs. The increased secretion of TGF-β could also decreases during treatment with CsA, which results in contribute to the skin healing process, which in con- calcium accumulation and tubular cell dysfunction.78 trast to glucocorticoids is not inhibited by CsA.71 In dogs, this protein function is not inhibited.87 Studies conducted with isolated arteries show increased blood pressure in dogs when high doses of CsA are perfused,88 but in intact dogs, the oral admin-istration of CsA at dosages of up to 33 mg kg−1 for In dogs, the safety profile of CsA is now well documented 90 days did not induce any change in systemic arterial through toxicological72 and safety studies in this spe- blood pressures (Novartis Animal Health: data on file).
cies (Novartis Animal Health; data on file). Moreover, The absence of effect on haemodynamic parameters is the safety profile of the drug has been established in confirmed in other studies in which the mean arterial recent controlled clinical studies that included more blood pressure84 or systemic vascular resistance and than 200 dogs treated for up to 4 months.33,35,36,73–76 cardiac output were measured.89 It is suspected that the In contrast to similar pharmacokinetics existing rennin–angiotensin–aldosterone system could be less between dogs and humans, the safety profile of CsA is responsive to the effect of CsA in dogs compared to different between the species. Nephrotoxicity and 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 61– 74
An increase in the activity of plasma liver enzymes is subjects receiving CsA during transplantation immuno- reported as a common adverse reaction following CsA suppression. This effect has led to therapeutic trials administration in man. In contrast, hepatotoxicity has in alopecia areata and in androgenic alopecia in not been observed in any of the safety studies or clini- humans.98 In dogs, hypertrichosis is rarely reported, but hair shedding has been observed sometimes in clin- The most frequently observed adverse reactions in ical trials,99 probably because of new shafts pushing dogs in both toxicological and clinical studies were out old ones. The molecular mechanisms of the CsA digestive signs, such as vomiting and diarrhoea. In clin- action on epithelial cells are not well elucidated.
ical trials, vomiting occurred in 14 – 42% of the dogs, Cyclosporin has been shown to inhibit insulin secre- mainly in the early phase of the treatment, it appeared tion in in vitro tests100 and in vivo in glucose-stimulation intermittently and was of short duration. Diarrhoea, tests.101–103 The inhibition is dose-dependent and well which was observed in 16 –18% of the dogs, occurred correlated with CsA blood levels. However, dogs eating more frequently but for short periods at the initiation normal diets remain normoglycaemic when receiving CsA even at 20 mg kg−1 for 3 weeks.104 In toxicological Other adverse drug events are reported in both dogs and target animal safety studies (Novartis Animal and man. Cutaneous and mucosal effects, such as gin- Health: data on file) and in clinical trials, glycaemias gival hypertrophy and hypertrichosis, are observed in also remained within normal values.72,74–76 at least 2% of human patients, and they are reversible In summary, results from toxicological, safety and upon cessation of CsA administration.79 In dogs, swell- clinical studies do not provide evidence to recommend ing of the gums is rarely seen at the doses employed.
the routine performance of biochemistry and haema- This anomaly occurred only in 3% of the dogs in one tology tests in the absence of signs suggesting any alter- clinical study,76 and it was mostly seen in subjects treated with higher dosages.72 Gingival hyperplasia is The safety of long-term administration of CsA in reversible within a few weeks of discontinuation of dogs is not yet well documented. However, in a recent administration.90 It is hypothesized that such hyper- retrospective study,105 a trend for an increased inci- plasia is caused by CsA-mediated inhibition of colla- dence of adverse reactions over time was noted in dogs gen degradation due both a stimulation of fibroblast receiving CsA for 6 –30 months. Further studies are proliferation91 and low collagenase expression.92 Papilloma-like skin lesions have also been reported in dogs receiving CsA at high dosages (30 – 45 mg kg−1)during safety and toxicological studies,72,93 but it was I N D I C A T I O N S
reported only in one dog given CsA at the therapeuticdose.74 In none of these cases did histology, immuno- In canine dermatology, CsA is used for treatment of histochemistry,69,71,83 electron microscopy69 or poly- immune-mediated dermatoses, especially AD and Pfi.
merase chain reaction94 permit the identification ofany papillomavirus.
In dogs, there is no evidence of an increased fre- Several clinical studies73–76 have established the activity quency of infections during CsA therapy when given of CsA for the treatment of AD in dogs. All trials have either for treatment of PFi or AD. In one study com- been recently analysed106 in a systematic review of the paring CsA with glucocorticoids for treatment of pharmacotherapy of canine AD. It was concluded that canine AD, the frequency of bacterial skin infections all trials provided good evidence of the high efficacy of was found to be lower, albeit not significantly, in dogs CsA administered at 5 mg kg−1 once daily for up to receiving CsA compared with those treated with meth- 16 weeks (Table 4, Fig. 2). A reduction in pruritus and ylprednisolone.76 A 6-day course of 3.5 mg kg−1 of CsA skin lesions was seen after 4 weeks of treatment. In half and glucantime in dogs with leishmaniasis was well tol- of the dogs with AD, the dose could be tapered after erated without worsening of the clinical signs of this 4 weeks to every-other-day administration, followed later disease.95 Similarly, in man, there has been no reports in some patients by twice-a-week dosing. Tapering the of diseases associated with bacterial infections in dose by increasing the intervals between administra- patients administered CsA for AD or psoriasis. The tions or decreasing daily doses appears to yield similar risk of opportunistic infections and lymphomas in responses.107 However, increasing the intervals between these patients seems to be low, compared with that doses is likely to be associated with higher compliance observed in transplant-receiving patients. This is prob- ably because doses prescribed for skin diseases are Two studies compared CsA with glucocorticoids.74,76 lower than those used for prevention of rejection of Both medications resulted in a similar improvement organ transplants, and also because CsA is rarely, if in skin lesions and pruritus. The median or mean re- ever, combined with other immunosuppressing drugs duction from baseline of lesion score was 58 and 69% for treatment of dermatological diseases.96 in CsA- and glucocorticoid-treated dogs, respectively, CsA stimulates hair growth, probably by inducing in one study,74 and 52 and 45% in the other.76 Similarly, the hair follicle anagen phase.97 This reversible effect is the reduction in pruritus score was 78 and 81% in the the cause of the hypertrichosis observed in human first study and 36 and 33% in the second. The lower 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 61– 74
Table 4. Studies evaluating cyclosporin in the treatment of AD
Mean /median reduction in lesional scores Mean /median reduction in pruritus scores lesional scores% dogs with = 50% reduction in control of pruritus in the later experiment is possiblyexplained by the dose-tapering regimen. However,the overall assessment of efficacy given by both invest-igators and pet owners was significantly better inCsA-treated dogs, 76% of the responses were evaluatedas excellent or good compared with 63% in glucocorticoid-treated dogs.76 Perianal fistulasA number of trials33,35,36,99,108–111 have tested the effi-cacy of CsA for treatment of PFi, and they are summa-rized in Table 5. In a randomized placebo-controlledtrial,99 the efficacy of CsA was clearly established.
Lesions of all CsA-treated dogs, but none of placebo- Figure 2. (IT) Intention to treat analysis: all dogs included into the
receiving dogs, scored subjectively improved after study are evaluated whether or not they complete the study. Missing 4 weeks. Mean total surface area and mean PFi depth values are replaced with the last observed value (last value carryforward procedure). PP: Per protocol analysis: dogs that drop out decreased 78 and 62%, respectively, in the CsA group from the study for efficacy, safety or compliance reasons are no but increased 29 and 11%, respectively, in the control longer included in the analysis. In all studies the inducing dose was 5 mg kg−1 CsA microemulsion. The dose was tapered by every other Other uncontrolled studies evaluated doses of CsA day administration after 4 weeks and twice a week administration that ranged from 2 mg kg−1 to 10 mg kg−1, given once after 8 weeks according to the clinical response in the study bySteffan et al.76 or twice daily, for durations of 9–20 weeks. However,the most effective therapeutic dosing regimen has notyet been clearly established. In most studies, CsA wasgiven twice daily but data from recent studies35,111 sug- The co-administration of ketoconazole was consid- gest that once daily administration could be as benefi- ered to decrease the dose of CsA needed to induce cial as twice daily dosing. When several dosages were remission. A dosage of 1 mg kg−1 of CsA combined compared,35,111 lesion resolution was faster with the with 10 mg kg−1 of ketoconazole was found to be effec- higher dosages, but clinical signs also improved with tive.35 Perianal lesions improved in all dogs within dosages ranging from as low as 2 to 5 mg kg−1. The rate 2 weeks of treatment. Ninety-three per cent (13/14) of of relapse and the time to relapse following cessation of dogs achieved complete remission at the end of the therapy were variable. Short protocols with high dos- trial. Seven dogs (50%) exhibited no recurrence even ages resulted in fast remission and high recovery rates, after 1 year without treatment. A similar study,36 eval- but they were likely to be followed by relapses of uated the effect of combining oral CsA (initial dosage clinical signs after the discontinuation of treatment.
of 2.5 mg kg−1 twice daily in eight dogs and 4 mg kg−1 Blood levels were not predictive of disease recurrence.35 once daily in four dogs) and ketoconazole (8 mg kg−1 Treatments longer than 13 weeks reduced the rate of once daily). Clinical signs disappeared in all dogs within 9 weeks after the beginning of treatment, but a 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 61– 74
Table 5. Clinical response in dogs with anal fistula treated with CsA
Dose, frequency of administration and and Improvement after one week in 9/9 (100%) dogs Remission for 6 to over 18 months after treatment cessation All dogs improved under CsA, none under placebo Surface area decreased by 78%, depth by 62% under CsA; increase of these parameters under placebo Total resolution in 17/20 (85%) dogs, 3/20 improved Recurrence in 7/17 (41%) of dogs following Lesion reduction by 50–90% within one week, Recurrence in one dog within 8 weeks following treatment cessation Faster clinical improvement in the dogs receiving 7.5 mg kg−1 than lower doses. Higher complete resolution rate at the highest dose (4/6) as compared to lower doses (2/18).
y, 15
Longer remission (> 12 months) in dogs treated for longer than 13 weeks No consistent relationship between CsA blood levels and efficacy Significant Improvement of lesions obtained with both doses.
Complete resolution of lesions in 7/10 dogs receiving 5 mg kg−1, and complete resolution of clinical signs in 8/10 dogs after 12 weeks.
Dose increased to 5 mg kg−1 after 8 weeks in 6/10 dogs receiving 2 mg kg−1 Complete remission is 8 times more likely with the high dose compared to low dose Faster resolution of lesions with 5 mg kg−1 compared to 2 mg kg−1, but 2 mg kg−1 sufficient for clinical signs improvement Complete clinical remission in 14/16 dogs (93%) Remission for one year in 50% of the dogs Resolution of clinical signs resolution within 9 weeks once daily and ketoconazole 8 mg kg−1 once daily recurrence of lesions was present in five of eight dogs.
both drugs are administered concurrently during the The cost reduction of this combined therapy compared induction phase of immune-suppression.
with that of CsA monotherapy varied between 36 and71%. The concurrent administration of ketoconazole required dose adjustment, as there was a large indivi- Nonmicroemulsified CsA, given at 30 mg kg−1 once dual and temporal variation in CsA blood levels.
daily, was used to treat successfully one dog with nasal The administration of CsA, alone or combined cutaneous lupus.113 A good response was obtained with ketoconazole, even in dogs in which PFi were not completely healed, appeared to be beneficial because thesurgical procedures that were required were less exten- Generalized idiopathic sterile nodular panniculitis sive than those that would have been necessary without CsA was used in two dogs with generalized idiopathic sterile nodular panniculitis.115 The dogs were treatedwith CsA at 5 mg kg−1 orally, once daily. Within2 weeks, there was an 80% reduction in the severity of O T H E R P O T E N T I A L A P P L I C A T I O N S , A
skin nodules, and the dogs became afebrile. Treatment L O O K FO R WA RD
was continued for another 3 weeks and lesions werecompletely resolved by the end of 6 weeks of treatment.
The full potential of CsA benefit in canine dermatol- Cyclosporin was continued on an alternate day regi- ogy has not been fully explored yet. A number of pilot men for 1 month. Relapses were not noticed even after studies or anecdotal observations suggest that CsA 8 months following the end of treatment.
could be of interest in a number of diseases. Furtherresearch is warranted to investigate these potential A noticeable response was not observed in two dogswith epitheliotropic lymphosarcomas treated with CsA Treatment with CsA could offer an alternative in thetreatment of cases of granulomatous sebaceous adeni-tis (GSA) refractory to conventional therapy with O T H E R P O S S I B L E F U T U RE U S E S
retinoids. Cyclosporin at 5 mg kg−1 twice daily wasused for treatment of GSA in a dog.112 A good Some anecdotal uses of CsA for treatment of animal response was obtained within 3 weeks with new hair skin diseases have been recently reported.5 These der- regrowth and decrease of scaling severity. Examination matoses included chronic pedal furunculosis, erythema of post-treatment skin sections confirmed the resolu- multiforme, follicular hyperkeratosis of cocker span- tion of sebaceous and perifollicular granulomas and iels, German shepherd dog deep pyoderma, metatarsal the decrease of hyperkeratosis. Adverse drug events fistulae, sterile pyogranulomatous syndrome and ulcer- ative dermatosis of the philtrum of Saint Bernard andNewfoundlands. In the springer spaniel, cairn terrier and West Highland white terrier successful treatment The first report using CsA in vegetable oil for treatment of primary seborrhea was recently mentioned.116 of three dogs with pemphigus foliacae (PF) was pub- Finally, a pilot study indicated that CsA could be effec- lished in 1989.113 Good to complete resolution of tive in end stage proliferative external otitis in cocker lesions was obtained within 4 – 6 weeks in two dogs receiving 25 mg kg−1. In one dog given 15 mg kg−1 a However, recommendation of use of CsA for treat- temporary reduction in clinical signs was observed, but ment of such diseases must await detailed publications lesions did not respond to higher doses when the sever- of treatment efficacy, preferably based on results of prospective randomized controlled trials.
Recently, a pilot study described the results of induc- tion of treatment with ME CsA at a dosage of 5 then10 mg kg−1 once daily in five dogs with PF.114 The C O N C L U S I O N S
administration of CsA was unable to lead to completeremission in any of the enrolled subjects. Moreover The increasing number of clinical trials and case four of five dogs entered in this trial had to be with- reports provides evidence that CsA is a beneficial mol- drawn because of exacerbation of lesional scores. Con- ecule to treat selected immune-mediated canine skin sequently CsA, at these proposed dosages, cannot be diseases. Its usefulness in man is limited by the fre- recommended for therapy of PF in dogs. However, it quency of adverse reactions such as nephrotoxicity and cannot be excluded that higher dosages of CsA could increased blood pressure, but luckily these effects are be more effective than those employed in the studies not seen in the canine species. Additional studies are described herein. Future trials should also investigate required to fully explore the therapeutic potential of whether CsA would be a useful adjuvant medication, this medication. Nevertheless, CsA represents a helping lowering the dose of glucocorticoids when good therapeutic alternative to the administration of 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 61– 74
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Résumé
Ces dernières années, un intérêt grandissant a été noté pour l’utilisation de la ciclosporine dans le traite- ment de dermatoses canines. La cyclosporine présente des propriétés immunomodulatrices puissantes, qui sontliées à sa capacité à bloquer la transcription de gènes de cytokines dans les lymphocytes T activés. La cyclosporineinhibe également un grand nombre de réactions allergiques qui surviennent après activation des mastocytes, descellules de Langerhans, des éosinophiles et des kératinocytes. Dans des essais randomisés et controlés, lacyclosporine s’est révélée aussi efficace que les glucocorticoïdes pour le traitement de la dermatite atopique canineà la dose d’induction de 5 mg kg–1. La molécule s’est également avérée efficace pour le traitement des fistulespérianales chez le chien. D’autres applications potentielles dans des maladies immunologiques variées sont sug-gérées par des études pilotes. Les propriétés pharmacocinétiques de la cyclosporine sont très similaires chez lechien et l’homme, mais la marge de sécurité est beaucoup plus importante chez le chien. C’est pourquoi la mesuredes concentrations plasmatiques de ciclosporine ne s’impose pas en routine chez le chien. Alors que chez l’hommeune insuffisance rénale et une hypertension sont souvent notées, même à des doses faibles, ces réactions ne sont 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 61– 74
pas observées chez le chien. Les effets secondaires dans cette espèce consistent principalement en des vomisse-ments et des diarrhées transitoires pendant les premiers jours de traitement. Les autres effets secondaires, commel’hyperplasie gingivale, l’apparition de lésions verruqueuses et l’hypertrichose semblent dose-dépendantes, etsurviennent rarement aux posologies usuelles. Une susceptibilité accrue aux infections n’a pas été rapportée chezles chiens recevant cette molécule.
En los últimos años ha habido un creciente interés en el uso de la ciclosporina para el tratamiento de enfermedades cutáneas caninas. La ciclosporina presenta propiedades inmunomoduladoras potentes quemuestran su capacidad de bloquear la transcripción de los genes de citoquinas en linfocitos T activados. Laciclosporina también inhibe algunas reacciones inmunológicas alérgicas que se producen tras la activación demastocitos, células de Langerhans, eosinófilos y queratinocitos. En pruebas clínicas controladas, al azar, laciclosporina ha mostrado ser tan efectiva como los glucocorticoides para el tratamiento de la dermatitis atópicacanina a una dosis inductiva de 5 mg kg–1. El fármaco ha sido también beneficioso para el tratamiento de lasfístulas perianales en perros. Se sugieren también otras aplicaciones potenciales en pruebas clínicas abiertasutilizando perros afectados por diferentes enfermedades dermatológicas inmunomediadas. Las propiedades far-macocinéticas de la ciclosporina son muy similares en perros y en humanos, pero su margen de seguridad esmucho más amplia en perros. Así, la monitorización rutinaria de los niveles sanguíneos de ciclosporina no pareceser necesaria. Mientras en humanos se producen con frecuencia afecciones renales e hipertensión, incluso a dosisbajas, no se observan estos efectos en perros. Las reacciones adversas consisten principalmente en emesis tem-poral y diarrea durante los primeros días del tratamiento. Otras reacciones adversas, como la hiperplasia gingival,las lesiones verruciformes y la hipertricosis, parecen ser dosis-dependientes, y se producen raramente a dosisterapéuticas. No se ha observado una mayor susceptibilidad a las infecciones en perros que reciben este fármaco.
Zusammenfassung
In den letzten Jahren gab es wachsendes Interesse an dem Einsatz von Cyclosporin zur Behandlung von Hauterkrankungen beim Hund. Cyclosporin zeigt beeindruckende immunmodulatorischeEigenschaften, die seine Fähigkeit widerspiegeln, die Transkription von Cytokin-Genen in aktivierten Lym-phozyten zu blockieren. Cyclosporin hemmt ebenso eine Anzahl von allergischen Immunreaktionen, die nachAktivierung von Mastzellen, Langerhans Zellen, Eosinophilen und Keratinozyten auftreten. In randomisierten,kontrollierten Untersuchungen hat sich Cyclosporin in einer Einleitungsdosierung von 5mg/kg zur Behandlungder caninen Atopie als genauso wirkungsvoll erwiesen wie Glukokortikoide. Der Wirkstoff hat auch zur Behand-lung von Perianalfisteln als nützlich erwiesen. Andere potentielle Anwendungsbereiche deuten sich aus einerkleinen offenen Pilotstudie mit Hunden mit verschiedenen immun-mediierten dermatologischen Erkrankungenan. Die pharmakokinetischen Eigenschaften von Cyclosporin sind beim Menschen und Hund sehr ähnlich, dieSicherheitsspanne jedoch ist beim Hund viel breiter. Deshalb scheint die routinemäßige Überwachung desCyclosporinspiegels im Blut nicht notwendig zu sein. Während beim Menschen Schäden und Bluthochdruck inder Niere sogar bei niedrigen Dosierungen häufig festgestellt werden, wird dies beim Hund nicht beobachtet.
Nebenwirkungen bestehen hauptsächlich aus vorübergehendem Erbrechen und Durchfall während derersten Behandlungstage. Andere Nebenwirkungen wie Hyperplasie des Zahnfleisches, warzenähnliche Haut-veränderungen und Hypertrichose scheinen dosisabhängig zu sein und treten bei therapeutischen Dosennur selten auf. Von einer erhöhten Empfänglichkeit für Infektionen wurde bei Hunden, die dieses Medikamenterhalten haben, nicht berichtet.
2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 61– 74

Source: http://www.dermatoclinica.com.br/userfiles/cyclosporin.pdf