New drug therapies in veterinary dermatology (Proceedings)

Veterinarians are always in search of the "magic bullet" to treat their dermatologic patients. This desire to obtain better treatments has lead to the discovery of many new therapies and new dermatological applications for older medications. Many of the newer treatments that we will discuss been recognized in veterinary medicine because of successes being reported anecdotally. Many of these drugs are used without scientific studies to back them up. Despite the lack of scientific studies for many of these drugs and drug applications, these drugs deserve consideration and discussion.

Antimicrobial therapies

Azithromycin (Zithromax)

Azithromycin is an orally or parenterally administered azalide macrolide that has been a mainstay for treating upper respiratory bacterial infections in humans. Recently, this drug has been used in dogs and cats for respiratory and pyodermas. Azithromycin is a bacteriostatic antibiotic that inhibits protein synthesis by penetrating the cell wall and binding to the 50S ribosomal subunits in susceptible bacteria.

Azathithromycin has a relatively broad spectrum. It has in vitro activity (does not necessarily indicate clinical efficacy) against gram-positive organisms such as Streptococcus pneumonia, Staphylococcus aureus and gram-negative organisms such as Haemophilus influenzae, Bordatella sp., Mycoplasma pnenumoniae, Borrelia burgdorferi and Toxoplasma.

The pharmacokinetics of azithromycin has been described in cats and dogs. In dogs, the drug has excellent bioavailability after oral administration is 97%. Tissue concentrations apparently do not mirror those in the serum after multiple doses and tissue half-live in the dogs may be up to 90 hours. Greater than 50% of an oral dose is excreted unchanged in the bile. In cats, oral bioavailability is 58%. Tissue half-lives are less than in dogs, and range from 13 hours in adipose tissue to 72 hours in cardiac muscle. As with dog, cats excrete the majority of a given dose in the bile. When compared to erythromycin, azithromycin has better absorption characteristics, longer tissue half-lives, and higher concentrations in tissue and white blood cells.

Azithromycin with its relative broad spectrum and favorable pharmacokinetic profile may be useful for a variety of infections in veterinary species (probably not Mycoplasma haemofelis or Chlamydophilia felis in cats). It has been suggested as being useful for such infections as cryptosporidiosis, toxoplasmosis (with pyrimethamine), Lyme disease, or those caused by Mycobacterium leprae or Mycobacterium avium-intracellulare and in combination with atovaquone to treat babesiosis. However, little data is published at this time on the use of this drug in veterinary species.

Azithromycin is contraindicated in animals hypersensitive to any of the macrolides and should be used with caution in patients with impaired hepatic function. Although not proven scientifically, azithromycin is thought to be safe in pregnancy.

Azithromycin can cause vomiting in dogs at high doses. However, when compared to erythromycin, azithromycin probably will cause significantly fewer GI side effects. Other adverse effects, particularly those associated with liver, may become apparent in dogs and cats as more experience is attained. Although the intravenous medication is not commonly used in veterinary medicine, intravenous administration of azithromycin has been associated with local reactions.

Drug interactions between azithromycin and other drugs occur. Cisapride should not be administered concurrently with azithromycin in cats. In dogs and cats, azithromycin may potentially increase cyclosporine blood levels so cyclosporine doses should be adjusted down when both drugs are given at the same time. In addition, oral antacids may reduce the rate of azithromycin absorption so the dose for azithromycin should be increased when antacids are used.

Recommended drug doses for dogs and cats generally range from 5 to 15 mg/kg once to twice daily for 3 to 20 days. Subsequent doses every 3 to 5 days if continued treatment is required may be effective. As more experience is gained with this agent, the appropriate dose for azithromycin should be clarified. Cost has been a major issue for use in animals, a 250 mg tablet costs around $6 to 7, but the drug has just recently become available generically and so the cost should decrease.

Terbinafine (Lamisil)

Terbinafine is a synthetic allylamine antifungal that inhibits the synthesis of ergosterol which is a component of fungal cell walls. Terbinafine also inhibits the conversion of squalene to sterols and causes accumulation of squalene. Both these effects are thought to contribute to its antifungal actions. Terbinafine's mechanism for inhibiting ergosterol is different from the azole antifungals. Unlike the azole agents, terbinafine does not significantly affect the cytochrome P-450 enzyme system, and therefore, it does not have the drug interaction concerns associated with azoles (ie ketoconzole, itraconazole, etc).

Terbinafine primarily has fungicidal activity against dermatophyte organisms and may only be fungistatic against yeast. It appears that terbinafine may be useful for treatment of Malassezia dermatitis in dogs and Microsporum canis infections in dogs and cats. Terbinafine also has activity against Aspergillis, Blastomyces, and Histoplasma. At this time, it is usually not used for infections cause by these organisms except in pet birds.

Little veterinary specific pharmacokinetic information is available in animals. In humans, terbinafine given orally is greater than 70% absorbed and after a first-pass metabolism it is about 40% bioavailable. Food may enhance absorption somewhat. Terbinafine is distributed to skin and into the sebum. Over 99% of drug in the plasma in bound to plasma proteins. Drug in the circulation is metabolized in the liver and the effective elimination half-life is about 36 hours. Terbinafine may persist in adipose tissue for very long periods (2 to 3 weeks).

The manufacturer does not recommend terbinafine use in human patients with active or chronic liver disease or in the patients with significantly impaired renal function. Therefore, terbinafine should be used with extreme caution in veterinary patients with severely impaired liver or renal function. If terbinafine needs to be used in these patients a dosage adjustment needs to be performed. High dose studies in pregnant rabbits and rats have not demonstrated overt fetotoxicity or teratogenicity, but the drug enters maternal milk at levels 7 times that found in the plasma.

Terbinafine appears to be well tolerated in veterinary patients. However, this drug has been used in a limited number of veterinary cases. Therefore, with more documented cases, the true number and types of side effects will be better understood. Side effects reported in humans include: GI (inappetence, vomiting and diarrhea), liver failure, neutropenia and skin reactions (severe drug reactions such as toxic epidermal necrolysis).

Terbinafine can interact with other drugs. Terbinafine reportedly inhibits CYP2D6 (in people) and therefore terbinafine may reduce the metabolism of tricyclic antidepressant, MAO-B inhibitors (selegiline), beta-blockers, and SSRI's (fluoxetine, etc). Terbinafine may increase the clearance of cyclosporine and cimetidine may reduce the clearance of terbinafine. Rifampin may increase the clearance of terbinafine.

Recommended dosages (oral) for dermatophytic infections in dogs and cats generally are in the 30 to 40 mg/kg once daily ranges. Because of the persistence of the drug in skin and hair follicles, this agent may be amenable to short-term therapy (2 to 3 weeks?), where in spite of positive cultures at the end of treatment clinical cures can occur over the next few months. Pulse or cycle therapy with terbinafine may also prove to be effective. Terbinafine is available only as 250 mg oral tablets (approximately $6 to 7) so treatment costs can rapidly escalate. It is also available as a topical 1% cream or spray.

Immunotherapies

Cyclosporine (Atopica, Neoral)

Cyclosporine is naturally produced calcineurin inhibitor immunosuppressant agent. Commercially, cyclosporine is available in several dosage forms including an oral liquid, capsules and a concentration for injection. To increase oral absorption, a micro-emulsion forming human-labeled preparation (Neoral) is also available in capsules and oral liquid. The veterinary product, Atopica is a micro-emulsion product similar to Neoral.

Cyclosporine is an immunosuppressant that focuses on cell-mediated immune response, but it has some humoral immunosuppressive action. While cyclosporine's exact mechanism of action is not known, it is believed to act by specific, reversible inhibition of immunocompetent lymphocytes in the G0 or G1 phase of the cell cycle. T-helper lymphocytes are the primary target, but T-suppressor cells are also affected. Lymphokine production and release (including Interleukin-2, T-cell Growth Factor) are inhibited by cyclosporine.

Cyclopsorine may be useful clinically as an immunosuppressant for immune-mediated, perianal fistulas and as part of a protocol to reduce the rejection allographs in transplant medicine in dogs and cats. Atopic is labeled for use in dogs only as a treatment for atopic dermatitis.

Oral cyclosporine (Atopcia) in dogs is rapidly, though poorly and erratically absorbed and bioavailability varies from 23 to 45% (Atopica). Presence of food in the GI tract can reduce bioavailability by 20%. The given dose and dosage recommendations change accordingly. Neoral and Sandimmune are NOT bioequivalent. It has been reported that Atopica is closest to the Neoral formulation. Cyclosporine is distributed in high levels into the liver, fat and blood cells (RBC's, lymphocytes). It does not appreciably enter the CNS. The drug is primarily metabolize in the liver via the cytochrome P450 system and excreted into the bile. Less than 1% of a dose is excreted unchanged into the urine. Elimination half-life in the dog is approximately 9-12 hours.

Cyclosporine is contraindicated in patients hypersensitive to it or any component (i.e. the castor oil found in the injectable and veterinary products). It is labeled as contradindicated in dogs with a history of malignant neoplasia. Cyclosporine should be used with caution in any patients with hepatic or renal disease. It has been shown to be fetotoxic and embryonic in rats and rabbits at dosages 2 to 5 times normal and should be used during pregnancy only when the benefits the risks.

In dogs, vomiting, anorexia and diarrhea are most commonly seen; gingival hyperplasia and papillomatosis have been described, particularly when higher dosage is used. Increased shedding is often reported that dogs with diarrhea may benefit from changing from product containing castor oil to one that does not. Cats with high blood levels (1,000 ng/ml) may develop anorexia. While nephrotoxicity and hepatotoxicity are potentially an issue in dogs and cats, it appears that extremely high blood levels (greater than 3000 ng/ml) are necessary before this is a problem. Animals that have levels greater than 1000 ng/ml persisting for weeks or month may be more susceptible to bacterial or fungal infections. Long-term, particularly in combination with other immunosuppressants (corticosteroids), may predispose the patient to developing neoplastic or infectious diseases. A recent-report of fatal Toxoplasmosis infection in a cat receiving cyclosporine has been published. Increase hair growth has been noted in feline patients on cyclosporine. The drug reportedly tastes badly and compliance may be an issue.

Numerous drug interactions have been reported with cyclosporine. Therefore, if you are going to use cyclosporine with another drug is important to look up these drug interactions before prescribing another drug. One drug interaction that has been utilized to its full benefit is the drug interaction of cyclosporine and ketoconazole. Ketoconazole increases cyclosporine absorption, therefore lower drug dose for cyclosporine need to be administered when ketoconazole is administered concurrently. The usual dose for ketoconazole is 5- 7.5 mg/kg/day in dogs. It is important to remember that ketoconazole causes side effects in dogs too. Therefore, it is not recommended that these two drugs be used automatically. Owners need to know about the potential side effects concerning both drugs before deciding whether this drug combination is desirable.

Therapeutic drug monitoring may be helpful in adjusting doses or when changing brands. It has been suggested to draw a trough level (12 hours hours after last dose) 24 to 48 hours after starting therapy and then every 2 to 4 weeks; target trough levels have been suggested of 100 to 500 ng/ml in dogs and 250 to 1000 ng/ml for cats for immuosuppression. Different laboratories may use different methodologies so contact your laboratory for evaluation recommendations. Baseline and then periodic (q 3 months after the first month) CBC and biochemistry profiles have been recommended. To maximize absorption, cyclosporine should be give on and empty stomach (one hour before or two hours after meals), but dogs with GI problems may benefit from giving the drug with food (note: dosage may need to be adjusted upwards). It should be stressed to clients the importance of regular dosing being consistent with feeding status; if a dose is missed, the next dose should be administered (without doubling) as soon as possible, but dosing should be no more frequent than once daily.

Endocrine therapies

Trilostane (Modrenal, Vetoryl)

Trilostane is synthetic steroid analog that acts as a competitive inhibitor of 3-beta hydroxysteroid dehydrogenase, thereby reducing synthesis of cortisol, aldosterone and adrenal androgens. Inhibition is reversible and apparently dose dependent.

Trilostane may be useful for treating pituitary-dependent hyperadrenocorticism or adrenal depend hyeradrenocorticism in dogs, feline pituitary-dependent hyperadrenocorticism and equine hyperadrenocorticism (HAC). It may also be useful in treating Pomeranians or miniature poodles with Alopecia X and Alaskan malamutes with adult-onset alopecia.

In dogs, orally administrated trilostane is absorbed rapidly, but erratically absorbed with peak levels occurring between 1.5 to 2 hours post-dose. It is unknown whether the presence of food in the gut significantly alters absorption characteristics. After 18 hours, the drug reportedly returns to baseline levels. Effects on cortisol production apparently last no more than 20 hours after dosing. Trilostane is metabolized in the liver to several metabolites including ketotrilostane, which is active.

Trilostane is contraindicated in animals that are sensitive to it. It should be used in caution in patients with renal or hepatic impairment. Because trilostane significantly reduces the levels of progesterone in vivo, it should not be used in pregnancy. Trilostane is classified by the FDA as a category X drug (contraindicated in pregnancy).

Trilostane appears to be well tolerated in dogs. Lethargy, mild electrolyte abnormalities and inappetence are commonly noted during the first few days of therapy secondary to steroid withdrawal. Vomiting and diarrhea may also be seen. Withholding the drug for a few days and then giving it every other day for a week may help to alleviate the vomiting and diarrhea. Reports of dogs dying acutely or developing hypoadrenocorticism (adrenal necrosis) after receiving trilostane have been reported, but are thought to occur very rarely.

As trilostane can cause hyperkalemia secondary to its effects on aldosterone, potassium-sparing diuretics (ie sprionlactone) may enhance this effect. Potentially, the effects of ACE inhibitors, (ie benzaepril, enalapril) could be enhanced by trilostane. Drugs that also cause decreased cortisol production (mitotane, ketoconazole, aminoglutehimide) could potentiate the effects of trilostane and lead to hypoadrenocorticism.

Usual dosages reported for dogs are 2 to 20 mg/kg PO once daily with food. Doses of up to 50 mg/kg/day divided twice daily have reportedly been given without untoward adverse effects. Treatment is monitored and dosages adjusted via ACTH-stim results, serum electrolytes, clinical response and adverse effects. As the drug is not yet approved in the USA, it must be legally imported through approved FDA mechanism.

Comments and conclusions

A wide variety of medications have been discussed. Each one of these medications has specific applications in veterinary dermatology. Drug doses and side effects vary depending on the drug that you are using. Veterinarians that are familiar with this information can use this information to expand the treatment options that they can offer their pet owners.