Griseofulvin is the only FDA-approved systemic antifungal for veterinary use. Griseofulvin is a systemic antifungal agent effective against the common dermatophytes. It is practically insoluble in water and only slightly soluble in most organic solvents. Particle sizes of griseofulvin vary from 2.7 mcm (ultramicrosized) to 10 mcm (microsized).
抗真菌活性
动物灰黄霉素作用机制
Dermatophytes concentrate griseofulvin via an energy-dependent process. Griseofulvin then disrupts the mitotic spindle by interacting with the polymerized microtubules in susceptible dermatophytes. This leads to production of multinucleate fungal cells. The inhibition of nucleic acid synthesis and the formation of hyphal cell wall material also may be involved. The result is distortion, irregular swelling, and spiral curling of the hyphae. Griseofulvin is fungistatic rather than fungicidal, except in young active cells.
真菌对动物灰黄霉素耐药机制
Dermatophytes can be made resistant to griseofulvin in vitro.
动物灰黄霉素抗真菌谱
Griseofulvin is active against Microsporum, Epidermophyton, and Trichophyton spp. It has no effect on bacteria (including Actinomyces and Nocardia spp), other fungi, or yeasts (including Malassezia and Candida).
药代动力学特征
动物灰黄霉素吸收
Plasma levels peak ~4 hours after oral administration of griseofulvin, but absorption from the GI tract continues over a prolonged period. Absorption is highly variable and influenced by a number of factors. The rates of disaggregation and dissolution in the GI tract limit the bioavailability of griseofulvin; thus, microsized and ultramicrosized particles are usually used. High-fat meals, margarine, or propylene glycol significantly enhance GI absorption of griseofulvin and are indicated if the microsized particles are used.
动物灰黄霉素分布
Griseofulvin is deposited in keratin precursor cells within 4–8 hours of oral administration. Sweat and transdermal fluid loss appear to play an important role in griseofulvin transfer in the stratum corneum. When these cells differentiate, griseofulvin remains bound and persists in keratin, making it resistant to fungal invasion. For this reason, new growth of hair, nails, or horn is the first to become free of fungal infection. As the fungus-containing keratin is shed, it is replaced by normal skin and hair. Only a small fraction of a dose of griseofulvin remains in the body fluids or tissues.
动物灰黄霉素生物转化与药代动力学
Depending on the species, 10%–50% of a griseofulvin dose is excreted almost exclusively as metabolites in the urine, and the remainder in the feces for ~4–5 days after administration. The elimination half-life of griseofulvin is ~24 hours in several species; however, its pharmacokinetics have not been described in ruminants, horses, or avian species. The drug can be detected in 48–72 hours at the base level of the skin, in 6–12 days in the lower quarter, and in 2–19 days in the middle section of the horny layer.
适应症与给药剂量
Griseofulvin is administered for dermatophyte infections in dogs, cats, calves, horses, and other domestic and exotic animal species. Most dermatophytes are sensitive; however, certain species present greater therapeutic challenges than others. Griseofulvin has also been shown to be effective against sporotrichosis andTrichophyton equinum ringworm in horses. Several dermatophytes may require higher dose rates for satisfactory control.
General dosages for griseofulvin are listed in Dosages of Griseofulvin. The dose rate and frequency should be adjusted as needed for the individual animal.
灰黄霉素给药剂量
Species | Dosage, Route, and Frequency |
|---|---|
Dogs, cats | Microsized: 10–50 (up to 130) mg/kg/day, PO, or divided q 8–12 h Ultramicrosized: 5–20 (up to 50) mg/kg/day, PO |
Horses, ruminants | 5–10 mg/kg/day, PO, for 3–6 weeks, or longer if required 15 mg/kg/day, PO, for 2-4 weeks (foals) |
Rodents, rabbits, fur animals | 25–50 mg/kg/day, PO, for 30 days |
临床特殊注意事项
动物灰黄霉素不良反应和毒性
Adverse effects induced by griseofulvin are rare. Nausea, vomiting, and diarrhea have been seen. Hepatotoxicity has also been reported. Animals with impaired liver function should not be administered griseofulvin because its biotransformation will be decreased and toxic levels may be reached.
Idiosyncratic (Type B or Type II adverse reaction) toxicity in cats has been reported. Neutropenic reactions are more common in cats with feline immunodeficiency virus (FIV), and therefore FIV testing prior to treatment is recommended. Adverse reactions appear to be more common in Siamese, Himalayan, Persian, and Abyssinian cats. Clinical signs are neurologic, GI, and hematologic. Griseofulvin is contraindicated in kittens less than 12 weeks of age and in pregnant animals because it is teratogenic. Due to its carcinogenic and teratogenic potential, griseofulvin should be administered with caution in food-producing animals, and greatly extended withdrawal intervals should be anticipated after its extra-label use.
动物灰黄霉素相互作用
Lipids increase GI absorption of griseofulvin. Barbiturates decrease its absorption and antifungal activity. Griseofulvin is a microsomal enzyme inducer and promotes the biotransformation of many concurrently administered drugs. The combined use of ketoconazole and griseofulvin may lead to hepatotoxicity.
动物灰黄霉素对实验室检测干扰
Treatment with griseofulvin increases alkaline phosphatase, AST, and ALT. Proteinuria may be detected.
