My favorite new drugs in veterinary dermatology: Parts 1 and 2 (Proceedings)
These are all relatively new therapies or new information about the use of these therapies.
These are all relatively new therapies or new information about the use of these therapies. Much of this information is a review of anecdotal comments or reports, case reports, some controlled studies or personal experience with these therapies.
Cyclosporine (CsA) is a lipophilic cyclic polypeptide, originally isolated from the soil fungus Tolypocladium inflatum. It was initially discovered while investigating fungal metabolites for antibiotic properties. It has received its greatest attention for preventing rejection of organ transplants but has been used in many other diseases due to its unique immunomodulation effects. It has been used in humans to treat autoimmune diseases, asthma, atopic dermatitis, psoriasis, lichen planus and other inflammatory diseases. It has also been used similarly in veterinary medicine for the preventing rejection of organ transplants as well as in cases of autoimmune disease, keratoconjunctivitis sicca, perianal fistulas and atopic dermatitis (AD). Anecdotally it has been used in the canine for contact allergy, dermatomyositis, sterile granulomatous diseases, and proliferative otitis externa. It has also been used in the feline for urticaria pigmentosa, pseudopelade, atopic dermatitis (including allergic asthma) and eosinophilic granuloma complex.
Mechanism of action and metabolism
Cyclosporine is a potent inhibitor of T cell activation. Cyclosporine has low cytotoxicity relative to its immunosuppressive potency. It blocks the proliferation of activated T lymphocytes by inhibiting interleukin2 (IL2), gene activation, and messenger RNA transcription. Cyclosporine is also thought to inhibit, via suppression of calcium-mediated signal transduction, mast cells and IgE-mediated immediate and LPR reactions Numerous studies have demonstrated influences on mast cells, Langerhans cells, keratinocytes, eosinophils and lymphocytes. Cyclosporine has immunosuppressive and antiproliferative affects rather than cytotoxic or myelotoxic effects.
Formulations, dosages and drug interactions
Atopica ®, Novartis is a micro emulsion formulation that improves absorption of the drug and is available in capsules of 10mg, 25mg, 50 mg and 100mg. It is the only current product that is FDA and EPA approved for veterinary use in the canine. The absorption of the drug can be variable; Atopica ® and Neoral® (the human form similar to Atopica) are more readily absorbed than its predecessor Sandimmune ®. Atopica ® is most consistently absorbed when given without food on an empty stomach, although in some dogs when given with food, despite the reduction in absorption the incidence of vomiting and other gastrointestinal problems may be reduced. Several generics have become available; some do not appear to work as effectively as the brand name Atopica. Gengraph and IVAX, are the author's most commonly used generics, which are less expensive, but occasionally do not work as well clinically as brand name Atopica. For this reason the author always starts therapy with brand name and then based on client's choice will try switching to one of the above generics. CsA is metabolized by cytochrome P-450 enzymes. Cytochrome P-450 inducers, such as phenobarbital and rifampin may decrease CsA levels. Likewise, P-450 inhibitors may increase CsA levels. The drugs commonly used that do this include antifungals (ketoconazole, itraconazole and fluconazole), furosemide and calcium channel blockers such as diltiazem and verapamil, metoclopramide, methylprednisolone and Doxycycline. However not all of these drugs inhibit the specific hepatic microsomal cytochrome P-450 (CYP) 3A12 enzyme. Ketoconazole specifically inhibits hepatic microsome cytochrome P-450(CYP) 3A12 enzyme. This is the CYP that metabolizes cyclosporine and dexamethasone. This is why ketoconazole is commonly used concurrently with cyclosporine. It helps lower the dosage, and thus cost, thereby making cyclosporine more cost effective. The author currently utilizes 5mg/kg q24h with concurrent ketoconazole at 2.5 – 5.0 mg/kg q 24h. Studies in both normal dogs and dogs with perianal fistulas have shown a dose sparing effect when given with ketoconazole. This appears to relate to a 50-75% reduction in the dose of cyclosporine needed. A similar study has not documented the value in dogs with atopic dermatitis, but it is very likely based on anecdotal reports. The dose may also be affected by flavonoids from grapefruit juice and erythromycin.
Side effects and adverse reactions
A high incidence of nephrotoxicity and hepatic toxicity is seen in humans but has not been observed in dogs.. Dogs may experience vomiting, diarrhea, bacteruria, bacterial skin infection, anorexia, nephropathy, hepatopathy, hirsutism gingival hyperplasia, papillomatosis and a lymphoplasmacytoid dermatosis. At the author's practice the incidence of vomiting is approximately 25% with most cases responding to dosage reduction or giving the drug as it done with humans with food. However this again can reduce effective serum levels. . The author has also had vomiting respond to the addition of Gastro Calm ®, IVX Animal Health or metoclopramide (0.1 – 0.5mg/kg BID). The papillomatous hyperplasia associated with cyclosporine was recently examined and 2/9 dogs were positive on immunohistochemistry for was for PV antigens. One dog was infected with canine oral PV (COPV) and one was infected with a newly described PV. It was concluded that CsA is an uncommon cause of PV lesions. However, we have been cautioned about an increased incidence of infections especially viral. There are anecdotal reports of upper respiratory infections in cats on cyclosporine. Screening prior and during therapy for toxoplasmosis is also recommended, as there are some concerns related to disseminated infections in cats treated with cyclosporine. In humans there is an increased risk for malignancy with cyclosporine use, especially skin neoplasia. In the canine there is one poorly substantiated report of lymphoma developing in a dog treated with cyclosporine for perianal fistulas after 4 weeks of therapy. Another report looked at correlations of cyclosporine for use in AD and development of mycosis fungoides and leukemia. There were no correlations made however the average length of therapy was only 4.3 months, too short of a period to evaluate long-term effects. Longer-term studies will need to be evaluated to properly address this concern. Lastly as cyclosporine also inhibits the p-glycoprotein pump, caution should be used in treating animals on cyclosporine with avermectins.
Monitoring serum levels of cyclosporine has been evaluated. In the authors experience as well as others, the serum levels of cyclosporine generally do not correlate with clinical responses. However there may be some limited value to monitor these levels when clinical responses are not seen. If levels are still in the low therapeutic range dosages can be increased in an attempt to obtain a response. The author commonly performs pre-cyclosporine lab work and monitors cases on an every 3 – 4 month basis with complete blood counts, chemistry profiles and urinalyses.
There are a number of specific disease entities that have been CsA responsive. The following is a partial list of these diseases.
There are now several reports demonstrated the efficacy of CsA for the treatment of AD in the canine. All studies indicated that CsA at 5mg/kg/d led to decreased clinical symptoms of canine AD. Most studies utilized standardized grading systems, Canine Atopic Dermatitis Extent and Severity Index (CADESI) and Pruritus Visual Assessment Scale (PVAS). Significant reductions in the CADESI and PVAS have been seen in most studies. Some studies show equal effectiveness to standard antipruritic dosages of prednisolone and methylprednisolone. Many specialty practitioners have reported high degrees of success utilizing CsA, with approximately 65% of the cases showing good to excellent responses. This has also been the success seen at the author's practices.. More recent reports have shown the ability to reduce cyclosporine dosing to every-other-day administration in 40% of the dogs after 4 weeks and after 12 weeks, approximately 20% of the dogs can be treated twice weekly. CsA case selection should be based on several factors. At the author's practices, CsA is selected as a therapy after a complete discussion about the effectiveness and potential side effects of the drug with the client. This is done in conjunction with a review of the patients' history, physical findings, diagnostic testing and previous responses and side effects from other forms of therapy.
Cyclosporine has made perianal fistulas a potentially medically manageably disease. Cyclosporine has showed statistical significant responses in many studies. Most show that after 4 weeks of therapy that a noticeable improvement is achievable. Some cases have been able to reduce dosing or even discontinue therapy. Some have been transitioned to a topical counterpart drug, tacrolimus. The author uses cyclosporine at 5mg/kg/d with ketoconazole at 5mg/kg/d and if necessary will double the cyclosporine dose if limited response is seen after 4 weeks. The results of treatment have be comparable with, if not better than, the surgical alternatives. As mentioned previously there is one report in the literature of a dog that was treated with cyclosporine and ketoconazole with perianal fistulas that subsequently developed lymphoma after 4 weeks of therapy. It is a poorly substantiated case.
Cyclosporine has been used for sebaceous adenitis with variable success. The author has seen good responses to Atopica. In the author's experience, short-coated dogs appear to respond more completely than long-coated dogs. In a recent publication by Linek, 12 dogs with SA were treated with cyclosporine A at 5mg/kg/d for 12 months and re-evaluated every 4 months. Clinical scores were calculated based on alopecia and follicular casting in 17 body locations. After 12 months of treatment, clinical scores were significantly reduced in 10/12 dogs. Most dogs showed their most dramatic improvement within the first 4 months. Histologically inflammation was decreased as were numbers of macrophages, CD3 + cells and MHC II expressing cells. Also, the percentage of hair follicles with sebaceous glands was increased, suggesting regeneration of sebaceous glands. In another recent report by Patterson, the topical application of cyclosporine liquid formulation diluted 1:10 in water as a spray on rinse followed by the application of an emollient produced very impressive results in a large group of dogs treated in the United Kingdom. In the limited number of cases treated by the author with this protocol, the results have not been as an impressive, but some clinical responses have been seen.
Autoimmune skin diseases
The author has used cyclosporine to treat cases of lupus erythematosus, pemphigus foliaceus and pemphigus erythematosus with variable degrees of success. In some cases the responses are quite impressive and can also serve as an alternative therapy to high dose glucocorticoids and other immunosuppressive drugs. When used for such diseases typical starting dosages are higher, usually 10mg/kg/d with some cases being treated with dosages as high as 20mg/kg/d. Responses in cases of feline pemphigus foliaceus have been even more impressive and good responses have been seen at lower dosages of 5 –10mg/kg/d.
Otitis externa and proliferative end stage ear disease
In a pilot study by Hall, five client-owned dogs were treated with oral cyclosporine at 5 mg/kg twice daily for a minimum period of 12 weeks. All dogs were re-evaluated clinically every four weeks to monitor progress. All five cases showed significant clinical improvement based on owner and clinical assessments. Individual owners also commented on improved disposition, hearing and quality of life. Although bacterial colonization was noted on ear cytology, adjunctive ear medications were not required. More detailed placebo-controlled studies are needed. The author has also seen success in not only chronic end stage cases but also in early cases of allergic otitis externa. Many dogs that are treated with Atopica for their generalized atopic dermatitis symptoms commonly have similar improvement in their otitis.
Many drug reactions have an immunological basis and often require treatment with immunomodulation therapy. Cyclosporine's unique mechanism of action on T lymphocytes and inhibition of interleukin2 (IL2), gene activation, and messenger RNA transcription makes it a logical choice for a variety of drug reactions. The author has seen responses to cases of confirmed erythema multiforme, contact reactions and drug-induced vasculitis.
Feline allergies, feline asthma and eosinophilic granuloma
Although not used as frequently or in as many cases as in the canine, use of cyclosporine is gaining popularity in the feline. It appears to be an excellent alternative to glucocorticoids in a variety of allergic hypersensitivity disorders in the feline. The author and others have seen very impressive responses in feline atopic dermatitis, all forms of eosinophilic granuloma complex and even in cases of feline asthma. It is dosed at 5 – 10mg/kg/d without the use of ketoconazole. Some gastrointestinal side effects and anorexia can be seen in a limited number of cases (Vercelli, Raviri et al. 2006).
Tacrolimus is a 23-member macrolide produced by Streptomyces tsukabaensis , it is available as an oral formulation (ProGraf®) used extensively as an immunosuppressive in human transplants that has very similar actions to cyclosporine. Side effects preclude this form from use in dogs and cats. Protopic® is a topical formulation available as a 0.1% ointment. This drug was the first FDA approved drug of a type now referred to as topical immunomodulators (TIMs). This type of drug has topical anti inflammatory effects without the atrophogenic effects and metabolic effects of topical glucocorticoids. It was recently approved for the treatment of atopic dermatitis in humans and is also beneficial in psoriasis and possibly alopecia areata. Large multicenter human studies indicate it is a very safe drug with minimal systemic absorption. However there are recent concerns associated with increase risk for neoplasia in humans. This is currently being further evaluated. Its mechanism of action is similar to cyclosporine but 10 to 100 times more potent. It works by calcineurin inhibition, resulting in suppression of antigen presenting T cells, inhibition of the production of multiple cytokines from T cells (IL-2, IL-3, IL-4, IFNγ, GMCSF, and TNF-α), down-regulates cytokine expression in other cells including mast cells, basophils, eosinophils, keratinocytes and Langerhans cells, inhibition of eosinophil recruitment.
It has been reported effective in perianal fistulas, although at a lower rate than systemic cyclosporine. It can be used once there is significant response to systemic cyclosporine for the final therapy or maintenance of perianal fistulas. It appears to have some efficacy in atopic diseases and other possible indications include localized lesions associated with: discoid lupus erythematosus, pemphigus erythematosus, pemphigus foliaceus.(Griffies, Mendelsohn et al. 2004) It is being tried anecdotally for a wide number of veterinary dermatologic diseases when lesions are localized and the author has used is it for pinnal vascular disease, alopecia areata and vitiligo.
Pimecrolimus (Elidel) is an ascomycin macrolactam derivative that acts similar to Tacrolimus though a recent study in mice showed it is different. (Vollset, Larsen et al. 1986) In contact hypersensitivity induced in mice pimecrolimus did not impair the primary immune response, although both cyclosporine and tacrolimus did while all three drugs effectively inhibited the secondary phase. It is used similar to Protopic though has had less of an irritant effect in some cases. No comparisons have been done in dogs but anecdotal reports have suggested similar or lower efficacy than tacrolimus
Pentoxifylline is a member of a class of drugs that inhibit phosphodiesterase enzymes (PDE) and are referred to as PDE inhibitors. Pentoxifylline makes the red blood cell more pliable and effectively decreases blood viscosity, decreases fibronectin, decreases the production of cytokines (TNF alpha, IL1, IL6, IL8), decreases leukocyte response to IL1 and impairs T-lymphocyte binding to keratinocytes, and decreases fibroblast activity and with long term use may decrease fibrosis. Pentoxifylline has been shown to be beneficial in a variety of canine skin diseases. Its effectiveness may be due to any one or a combination of its different actions on the immune response. The initial use described in dogs was for the treatment of dermatomyositis. Since then it has been evaluated best in atopic dermatitis and reported effective in dermatomyositis, contact dermatitis, idiopathic onychomadesis and has been anecdotally recommended for vasculitis, ischemic dermatopathy, pinnal thrombovascular necrosis, idiopathic mucinosis, erythema multiforme and as an adjunctive therapy for immune mediated dermatoses, fibrosing deep pyoderma and pododermatitis. Initially many veterinarians dosed it at 10 mg/kg q8-12hr. Recently it was suggested that q8h dosing might be preferable for some diseases such as atopic dermatitis. There were anecdotal reports of 20 - 30 mg/kg being more effective. One study showed a good response in 11/11 dogs with dermatomyositis but the average dose needed was 46.5 +/- 8mg/kg q12 h and took 4-10 weeks to see response with a median time to respond of 6 weeks.(Rees, Boothe et al. 2002) A pharmacokinetic study in dogs showed that 30mg/kg dosing should be effective, as therapeutic human concentrations (1,000 ng/ml) were reached and persisted for 510 minutes (+/- 85min). This would suggest that q12h dosing may be effective at that dose. However, one caution is that bioavailability varied from approximately 25-75%. Another question is the use of generic forms of the drug as there are no comparative studies but anecdotal reports of better responses to the brand name Trental ®.
In general no serious effects have been reported with any frequency in dogs. Vomiting and diarrhea are the major concerns and in humans are dose related. Two dogs on pentoxifylline reportedly developed erythema multiforme.(White and Papich 2002) This is particularly interesting, as the drug has been used to treat erythema multiforme with some cases showing a beneficial effect in my experience.
Interferons (INF) are a group of glycoprotein cytokines produced by a variety of inflammatory cells and fibroblasts that have numerous immunologic effects. There are several recognized interferons and they do vary in their immunologic effects. The main uses are based on antiviral and antineoplastic properties but they may also be beneficial in a variety of dermatologic disorders. The initial commercial form of interferon is the recombinant human INF alpha-2b (Roferon-A) and more recently a veterinary product became available. The recombinant feline INF-omega (Virbagen Omega) has been shown effective in canine parvoviral infection. All veterinary dermatologic uses are based solely on anecdotal information or recently three pilot studies suggesting some possible efficacy. Uses are described in the canine oral papilloma viral infections, recurrent pyoderma, and mycoses fungoides and most recently a pilot study by Carlotti et al (WCVD 5) suggests efficacy of Virbagen for atopic dermatitis. A study using recombinant canine interferon K-100 compared its efficacy to topical diphenhydramine (DH) in atopic dogs where 63 were treated with K-100 and 29 with DH. The KT-100 was given SQ 3x a week on alternating days for 4 weeks and the DH was given orally twice a day. The efficacy rates of the KT-100 was 72.1% for pruritus, 73.8% for excoriations, 75.4% for erythema and 60.7% for alopecia compared to the DH group 20.7% pruritus, 27.6% for excoriations, 24.1% for erythema and 24.1% for alopecia.(Olivry, Marsella et al. 2007) The most cost effective treatment is utilizing low dose oral therapy. The high potency Roferon comes as a 3 million IU/ml solution and is diluted in 999ml Lactated ringers solution and then divided into 30 ml ampoules (1000 IU/ml) that anecdotally will remain stable if frozen. Once the ampoules are thawed they can be kept refrigerated for thirty days. The current recommended dosage is 1ml daily given orally. The oral administration is done by injecting the solution in the buccal cavity as it is believed the absorption is from the upper oral mucosa. This regimen has been used for canine papilloma virus but also has been evaluated in a pilot study for recurrent pyoderma. (Thompson, Grieshaber et al. 2004) This study did not definitively prove efficacy but suggests there may be some benefit. In the feline, herpes virus, idiopathic facial dermatitis, atopic dermatitis and eosinophilic ulcers may also respond to low dose oral therapy.
Imiquimod (Aldara) is a new drug that has a lot of potential in veterinary dermatology. It is topically applied, has few side effects and appears to stimulate natural immune function. Therefore, it is being tried on a wide variety of human diseases and will undoubtedly find more uses in veterinary medicine as well. Diseases recently reported on in human dermatologic therapy include: decreasing recurrent rates of keloids, other viral induced warts and molluscum contagiosum (human pox virus), and epithelial pre-malignant or neoplastic diseases such as squamous cell carcinoma in situ, extra mammary Paget's disease, actinic keratosis and basal cell carcinoma. These observations suggest it may be a valuable therapy for a variety of cutaneous viral lesions such as feline herpes virus dermatitis but also epithelial diseases seen in cats, particularly actinic keratosis and squamous cell carcinoma and Bowen's disease. For most diseases it is applied two to three times a week for various intervals, with most cases showing responses within 4 weeks of therapy. Adjustments on frequency of application are made based on burning or irritant reactions, which can be quite significant in some cases.
Imiquimod had been used successfully, but in uncontrolled situations, to treat two forms of canine papilloma virus, feline herpes and papilloma viruses. Feline Bowen's disease has been associated with papilloma virus and the author has seen excellent responses to several cases treated with Imiquimod. The author has also successful treated 3 cases of equine sarcoids with Imiquimod. Side effects so far have included significant tissue necrosis and irritation or burning. The drug may be helpful for solar dermatitis and pre-cancerous solar induced lesions in dogs and cats if lesions are localized.
Trilostane is a synthetic, orally active steroid analogue. It can act as a competitive inhibitor of the 3 hydroxysteroid dehydrogenase enzyme system and thereby inhibit the synthesis of several steroids, including cortisol and aldosterone. This blockade is reversible and seems to be dose-related. In dogs peak trilostane concentrations are seen within 1.5 hours and decrease to baseline values in about 18 hours (Arnolds Veterinary Products Limited, UK). The efficacy and safety of trilostane in the treatment of canine PDH were evaluated in a multicenter study at the Royal Veterinary College in London, the Veterinary Teaching Hospital in Dublin and Small Animal Hospital in Glasgow. Seventy-eight dogs with confirmed PDH were treated with trilostane for up to 3 years. The starting dose varied from 1.8 to 20 mg/kg (mean = 5.9 mg/kg). Trilostane appeared to be well tolerated by almost all dogs with only 2 dogs developing signs and biochemical evidence of hypoadrenocorticism. The low prevalence of side effects compared favorably to those reported with mitotane. However, the author has seen a few Addison cases in the first 20 cases where the drug was used. One of which remained permanently. Trilostane was found to be nearly as effective as mitotane in resolving the signs of hyperadrenocorticism. Polyuria, polydipsia and polyphagia had dissipated in 40 dogs within 3 weeks after starting trilostane. Within 2 months, a further 20 dogs showed decreases in their water and food consumption. These improvements were maintained as long as the dogs remained on adequate doses of trilostane. Skin changes resolved in 24 out of 39 (62%) of dogs that initially presented with dermatological signs. All of these improvements were maintained as long as the dogs remained on adequate doses of trilostane. Only 8 dogs that were treated with trilostane for more than 2 months showed poor control of clinical signs. In contrast, mitotane is effective in about 80% of cases of pituitary dependent hyperadrenocorticism (PDH). The mean survival of all trilostane treated dogs was 661 days. Direct comparison with mitotane was difficult as 65% of the dogs were still alive at the time of censor and therefore the mean survival may still increase. By comparison, the mean survival of mitotane treated dogs has been reported to be 810 to 900 days. (Barker, Campbell et al. 2005)
Trilostane has also been advocated as one of the most successful treatments for Alopecia X, particularly in the Pomeranian dog. Sixteen Pomeranians and eight miniature poodles presenting with clinical signs of alopecia X, elevated blood concentrations of 17-hydroxyprogesterone post stimulation with adrenocorticotropic hormone and increased urinary cortisol/creatinine ratios were treated with trilostane. Trilostane was given once or twice daily at a mean dose of 10.85 mg kg/d. Adrenal function was evaluated with a follow-up of 28 months in the Pomeranians and 33 months in the miniature poodles. Treatment with trilostane led to complete hair re-growth in 85% of the Pomeranians and in all of the miniature poodles within 4 to 8 weeks. No adverse events attributed to treatment with trilostane were recognized. The hair re-growth might have been the result of a down-regulation of adrenal steroids and/or of the noncompetitive inhibition of the estrogen receptors at the hair follicle level.(Cerundolo, Lloyd et al. 2004). The author has not seen the same response in clinical cases treated in the US, with closer to 50% showing response and often not complete hair regrowth.
Trilostane has been available in 30mg, 60 mg and 120mg capsules in a veterinary product licensed as Vetoryl® (Dechra Pharmaceuticals, UK). It is also available in 60 mg capsules approved for human use as Modrenal® (Wanskerne Ltd, Billingshurst, West Sussex, UK). It is not currently approved by the FDA; however, Dechra Pharmaceuticals is currently pursuing US FDA approval. Vetoryl can be imported into the US to treat hyperadrenocorticism (Cushing's syndrome) by following the importation procedure listed on Dechra web site http://www.dechra-us.com/page/vetorylreg. With very small dogs, capsules might need to be split into smaller gelatin capsules. A licensed pharmacist should do this; however compounding this drug is also controversial. Trilostane capsules should be stored at room temperature in airtight, light-resistant containers. Pregnant women should wear gloves when handling the drug and all users should wash their hands after handling the capsules. The current suggested starting dose rate for dogs with PDH and alopecia X is 2.5-10 mg/kg once daily. However a recent report suggests twice daily dosing at 1.4mg/kg q 12h to be an effective protocol for control of naturally occurring hyperadrenocorticism (Vaughan, Feldman et al. 2008). This study also suggested better control at twice daily vs once daily dosing, due to the shorter duration of activity when administered once a day. The dosing needs to be adjusted according to clinical signs and serum cortisol values. The drug is given with food. In dogs only minor side effects are commonly seen such as mild lethargy and decreased appetite 2-4 days from start of therapy (potentially due to steroid withdrawal syndrome) and mild electrolyte abnormalities. Overt hypoadrenocorticism seems to be limited but can occur. The drug should therefore not be used in pregnant animals. It is important to monitor the clinical and biochemical effects of therapy and to adjust the trilostane dose to achieve optimal control. Dogs are re-examined and an ACTH stimulation test is performed at 5 – 6 hours after am dosing 10 days after induction and adjustments made accordingly. Follow up monitoring is performed on a case by case basis.
Spinosad, Comfortis®, Lilly
The most impressive new flea product that has been released is the monthly oral chewable beef flavored tablet, spinosad (Comfortis, Lilly). This is only approved for use in the canine and has a novel mode of action at nicotinic acetylcholine D alpha receptors with some effects on GABA resulting in nerve excitation paralysis and death of the flea. Spinosad is felt to be safe in conjunction with all other flea control products and heartworm preventives. There is one interaction that has recently come to note: spinosad can increase the risk of ivermectin side effects when ivermectin is used at the super high doses required to treat skin parasites such as demodicosis. Low doses of ivermectin as used in heartworm prevention are not problematic for this interaction. It does not kill other internal or external parasites. It is for dogs 14 weeks of age an older.
Comfortis® tablets are beef flavored but contain pork protein. That should not be a problem for dogs with beef allergy but could be a problem for a dog with a pork allergy, rare as that might be. It is highly effective and starts working within 30 minutes and has 100% kill rate by 4 hr and lasting 30 days or longer. It is best given with food for the highest C max and longest duration of effectiveness.
It is considered very safe and the spinosad molecule has been awarded an EPA Green chemistry award in 1999 because of its reduced impact on certain predatory beneficial insects. Side effects have been minimal and a low incidence of vomiting has been reported that appears to dissipate on subsequent dosing. Because it kills fleas so rapidly, egg formation does not occur. Clinical trials in dogs have shown excellent results for not only flea control but in flea allergic dogs with reduced clinical symptoms. It is not approved in cats but toxicity work has been done in cats to show that vomiting may occur when ingested at very high dosages. At this point in time no feline product is planned.
Cefovecin, Convenia®, Pfizer
Cefovecin (Convenia®) is a new third generation cephalosporin developed by Pfizer Animal Health for the treatment of aerobic and anaerobic gram negative and gram positive infections of the urinary tract, soft tissue, and periodontal disease. Cefovecin is a bactericidal against Staphylococcus and Streptococcus spp , Escherichia coli , Pasteurella multocida , and Klebsciella and Proteus spp , but is not active against Pseudomonas or Enterococcus spp
Cefovecin has a long half-life of 6.9 days in cats and 5.4 days in dogs and demonstrates prolonged concentrations in extracellular fluid allowing for dosing every 14 days. If required, the dose of 8 mg/kg subcutaneously in dogs and cats can be repeated every 14 days for a total of three doses. Cefovecin is eliminated through renal excretion with up to 25% biliary excretion. No adverse reactions were noted in preliminary studies, but cefovecin should not be given to animals allergic to penicillins or cephalosporins, less than 8 weeks old, if they are pregnant or lactating, or have severe renal dysfunction.
Controlled studies in both cats and dogs show good clinical efficacy. In the treatment of naturally occurring bacterial infections of skin and soft tissues in dogs was evaluated in patients presented to veterinary clinics. Patients were treated with either cefovecin (8 mg/kg bodyweight as a single subcutaneous injection) or with orbifloxacin (5 mg/kg bodyweight by oral administration once daily for seven consecutive days). Prior to treatment, the predominant pathogens identified were Staphylococcus intermedius, Staphylococcus aureus and Proteus mirabilis . The clinical scores recorded pre-treatment and at 7 and 14 days post-treatment were used to calculate an improvement ratio for each animal and dogs were categorized as either "cured", "improved" or "failed" according to the degree of improvement observed. For cefovecin, the clinical success at Day 7 post-treatment was 63.8% (37 out of 58 animals) and at Day 14, 87.5% (49 out of 56 animals); for orbifloxacin clinical success at Day 7 and Day 14 post-treatment was 44.4% (24 out of 54 animals) and 73.3% (33 out of 45 animals), respectively. No adverse events attributable to cefovecin were observed during the study period and no injection site abnormalities were noted in any animals. The results demonstrated that when administered subcutaneously once at a dose of 8 mg/kg bodyweight, cefovecin was effective and safe in the treatment of skin and soft tissue infections in dogs.(Takeshi Fujii, Takatsu et al. 2007). In another study 354 dogs were randomized to treatment and received either cefovecin administered by subcutaneous injection at 14 day intervals, as clinically necessary, or amoxicillin/clavulanic acid as oral tablets twice daily for 14 days. Courses of treatment were repeated at 14 day intervals up to a total of four courses. Cases were evaluated for clinical efficacy at 28 days after initiation of the final course of treatment. Clinical efficacy was assessed by scoring the clinical signs typical of skin infections. Cefovecin was shown to be as effective as amoxicillin/clavulanic acid administered orally in the treatment of bacterial skin infections in dogs. Cefovecin offers the additional benefit of eliminating owner non-compliance.(Stegemann, Coati et al. 2007).
In cats cefovecin was evaluated for the treatment of bacterial abscesses and wounds. 217 cats were randomized to treatment with either cefovecin administered by subcutaneous injection at 14 day intervals or amoxicillin/clavulanic acid as twice-daily oral tablets for 14 days. Treatment courses were repeated at 14 day intervals, when deemed necessary. Cases were evaluated 28 days after initiation of the final course of treatment. Cefovecin was as efficacious as amoxicillin/clavulanic acid, and efficacy was 100 per cent for both treatments. Cefovecin, administered as a single subcutaneous injection repeated at 14 day intervals as required, was shown to be as efficacious as oral amoxicillin/clavulanic acid in the treatment of abscesses/wounds in cats.(Stegemann, Sherington et al. 2007)
Dahlinger, J., Gregory, C., Bea, J. Effect of ketoconazole on CyA dose in healthy dogs. Vet Surg 1998; 27: 64-68.
Kuroha, M., Y. Kuze, et al. (2002). "In vitro characterization of the inhibitory effects of ketoconazole on metabolic activities of cytochrome P-450 in canine hepatic microsomes." American J. Vet. Res 63(No 6): 900-905.
Olivry, T., C. Rivierre, et al. (2002). "Cyclosporine decreases skin lesions and pruritus in dogs with atopic dermatitis: a blinded randomized prednisolone-controlled trial." Veterinary Dermatology 13: 77-87.
Olivry, T., Steffan, J., Roland, D.F., et al. Randomized controlled trail of the efficacy of cyclosporine in the treatment of atopic dermatitis in dogs. J Am Vet Med Assoc 2002; 221 (3): 370-77.
Patricelli, A. J., R. J. Hardie, et al. (2002). "Cyclosporin and ketoconazole for the treatment of perianal fistulas in dogs." J Am Vet Med Assoc 220(No 7): 1009-1016.
Favrot C, Olivry T, Nespeca, G, et al. Causal heterogencity of cyclosporine-induced verrucous skin lesions in dogs. 20th Proceedings of North American Veterinary Dermatology Forum, Sarasota, Florida, 2005:174.
Rosenkrantz, W.S., Griffin, C.E., Barr, R.J. Clinical evaluation of cyclosporine in animal models with cutaneous immune-mediated disease and epitheliotropic lymphoma. J Am Anim Hosp Assoc 1989; 25: 377-84.
Stahelin, H.F. The history of cyclosporine A (Sandimmune®) revisited: Another point of view. Experientia 1996; 52:5-13.
Steffan, J., et al. Comparison of cyclosporine A with methylprednisolone for the treatment of canine atopic dermatitis: a parallel blinded randomized controlled trials. Vet Dermatol 2003:14:11-22.
Steffan J, Strehlau G, Maurer M, Rohlfs A. Cyclosporin A pharmacokinetics and efficacy in the treatment of atopic dermatitis in dogs. J Vet Pharmacol Ther 27:231-8 2004
Steffan J, Parks C, Seewald, W. Clinical Trial Evaluating the Efficacy and Safety of Cyclosporine in Dogs With Atopic Dermatitis J Am Vet Med Assoc 226:1855-1863, 2005.
Mouatt JG. Cyclosporin and ketoconazole interaction for treatment of perianal fistulas in the dog. Aust Vet J . 2002 Apr;80(4):207-11.
O'Neill-Edwards GA, Holloway S. Efficacy of combined cyclosporine A and ketoconazole treatment in anal furunculosis. J Sm Animal Pract 45(5):238-43, 2004.
Blackwood L, German AJ, Stell AJ, O'Neill T Multicentric lymphoma in a dog after cyclosporine therapy. J Small Anim Pract 45:259-62 2004
Carothers, M.A., et al.: Cyclosporineresponsive granulomatous sebaceous adenitis in a dog. J. Am. Vet. Med. Assoc . 198:1645, 1991.
Linek, M, Boss, C, Haemmerling, R, et al. Effects of cyclosporine A on clinical and histologic abnormalities in dogs with sebaceous adenitis. J Am Vet Med Assoc 2005: 226:59-64.
Patterson, S. Topical cyclosporine for the treatment of sebaceous adenitis. Topical Therapy Workshop, Proceedings from World Congress of Veterinary Dermatology, Vienna, Austria, August 2004, p 64.
Hall, JA. Oral cyclosporine in the treatment of end state ear disease: A pilot study. Proceedings of the 18th Annual Meeting of the American Academy of Veterinary Dermatology and American College of Veterinary Dermatology. Monterey, California 2003: 217.
Vercelli, A., G. Raviri, et al. (2006). "The use of oral cyclosporin to treat feline dermatoses: a retrospective analysis of 23 cases." Vet Dermatol 17(3): 201-6.
Barker, E. N., S. Campbell, et al. (2005). "A comparison of the survival times of dogs treated with mitotane or trilostane for pituitary-dependent hyperadrenocorticism." J Vet Intern Med 19(6): 810-5.
Cerundolo, R., D. H. Lloyd, et al. (2004). "Treatment of canine Alopecia X with trilostane." Vet Dermatol 15(5): 285-93.
Griffies, J. D., C. L. Mendelsohn, et al. (2004). "Topical 0.1% tacrolimus for the treatment of discoid lupus erythematosus and pemphigus erythematosus in dogs." J Am Anim Hosp Assoc 40: 29-41.
Olivry, T., R. Marsella, et al. (2007). "Validation of CADESI-03, a severity scale for clinical trials enrolling dogs with atopic dermatitis." Vet Dermatol 18(2): 78-86.
Rees, C., D. Boothe, et al. (2002). Therapeutic response to pentoxifylline and its active metabolites in dogs with dermatomyositis. AAVD/ACVD, New Orleans.
Stegemann, M., N. Coati, et al. (2007). "Clinical efficacy and safety of cefovecin in the treatment of canine pyoderma and wound infections." J Small Anim Pract 48(7): 378-86.
Stegemann, M., J. Sherington, et al. (2007). "The efficacy and safety of cefovecin in the treatment of feline abscesses and infected wounds." J Small Anim Pract 48(12): 683-89.
Takeshi Fujii, T., S. Takatsu, et al. (2007). "Clinical Efficacy and Safety of an Injectable Formulation of Cefovecin in the Treatment of Bacterial Skin Infections of Dogs
"The Japanese Journal of Veterinary Dermatology 13(2): 81-88.
Thompson, L. A., T. L. Grieshaber, et al. (2004). "Human recombinant interferon alpha-2b for management of idiopathic recurrent superficial pyoderma in dogs: a pilot study." Vet Ther 5(1): 75-81.
Vaughan, M. A., E. C. Feldman, et al. (2008). "Evaluation of twice-daily, low-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism." J Am Vet Med Assoc 232(9): 1321-8.
Vercelli, A., G. Raviri, et al. (2006). "The use of oral cyclosporin to treat feline dermatoses: a retrospective analysis of 23 cases." Vet Dermatol 17(3): 201-6.
Vollset, I., H. J. Larsen, et al. (1986). "Immediate type hypersensitivity in dogs induced by storage mites." Res Vet Sci 40(1): 123-7.
White, S. D. and M. Papich (2002). Update on dermatological therapy. AAVD/ACVD, New Orleans.