米托坦
米托坦 (Mitotane，又稱 o,p'-DDD) 是一種腎上腺細胞毒性劑，在獸醫學中主要用於內科治療犬隻的**腦下垂體依賴型腎上腺皮質機能亢進 (PDH)** (庫興氏症候群)。其化學結構與殺蟲劑 DDT 相似。 由於它能引發腎上腺皮質的靶向性壞死，因此能有效減少過量皮質醇的產生。它也可用於人類和犬隻腎上腺癌的姑息性治療。 **臨床要點：** 治療通常分為兩個不同階段：*誘導期* (每日給藥以快速破壞增生的腎上腺組織，直到達到臨床終點) 和 *維持期* (每週或每兩週給藥以防止腎上腺皮質重新生長)。由於過度治療可能導致醫源性腎上腺皮質機能低下 (艾迪生氏症)，因此必須進行嚴密的監測。
作用機制: Mitotane acts as a targeted **adrenocortical cytotoxic agent**. * It causes severe, progressive necrosis and atrophy of the **zona fasciculata** and **zona reticularis** of the adrenal gland → drastically reducing the synthesis of glucocorticoids (cortisol). * It relatively spares the **zona glomerulosa**, meaning mineralocorticoid (aldosterone) synthesis is usually unaffected, though clinically significant effects on aldosterone production can occasionally occur. * The exact intracellular mechanism of cytotoxicity is not fully understood, but it is believed to involve metabolic activation within the adrenal mitochondria, leading to irreversible binding to cellular macromolecules and subsequent cell death.
各物種劑量
- Hyperadrenocorticism · 30-50 mg/kg · PO · q24h · to effect · Efficacy in cats is very variable, with many showing no response at non-toxic levels. Not recommended.
- Medical treatment of hyperadrenocorticism · 50 mg per ferret PO once daily for one week, then 50 mg PO 2-3 times per week · PO · q24h then 2-3 times/week · Long-term · Have a compounding pharmacy make 50 mg capsules. Can be coated with Nutrical.
- Pituitary-dependent hyperadrenocorticism (Induction - Protocol A) · 25 mg/kg twice a day, PO with food · PO · q12h · Until clinical endpoints occur (usually 4-9 days) · Reduce food by 1/3 the day before. Stop therapy if water consumption approaches 60 mL/kg/day, appetite reduces, vomiting, listlessness, or diarrhea occurs.
- Pituitary-dependent hyperadrenocorticism (Maintenance - Protocol A) · 25-50 mg/kg per week · PO · Divided in as many doses as possible weekly · Long-term · Adjust based on ACTH stimulation test results.
- Pituitary-dependent hyperadrenocorticism (Induction - Protocol B) · 30-50 mg/kg/day PO with a meal once daily or divided q12h · PO · q24h or q12h · 7-10 days · Goal is basal and post-ACTH cortisol between 1-5 micrograms/dL.
- Pituitary-dependent hyperadrenocorticism (Maintenance - Protocol B) · 35-50 mg/kg per week in 2-3 divided doses · PO · Divided weekly · Long-term
- Pituitary-dependent hyperadrenocorticism (Induction - Protocol C) · 50 mg/kg divided q12h · PO · q12h · Until water consumption decreases to <100 mL/kg/day or adverse signs observed (usually 3-7 days) · Max 5-7 days prior to ACTH stim test if water consumption cannot be monitored.
給藥途徑
禁忌症
- Known hypersensitivity to mitotane
- Pregnancy (FDA Category C in humans; Class D in veterinary medicine - embryotoxic/teratogenic)
- Patients that are not eating well (should never be administered to anorexic animals)
- Not recommended in cats (trilostane is more effective and mitotane efficacy is highly variable)
不良反應
- Lethargy
- Ataxia
- Weakness
- Anorexia (loss of appetite)
- Vomiting
- Diarrhea
- Neurologic signs (uncommon)
- Liver changes (congestion, centrolobular atrophy, fatty degeneration)
- Iatrogenic hypoadrenocorticism (requiring long-term glucocorticoid/mineralocorticoid replacement in ~5% of dogs)
- Anorexia
- Diarrhoea
- Acute-onset neurological signs (2-3 weeks post-initiation)
- Iatrogenic hypoadrenocorticism
藥物相互作用
- CNS Depressants · Additive depressant effects may be seen if used concomitantly. · moderate
- Insulin · Diabetic dogs receiving insulin may have their insulin requirements rapidly decreased when mitotane therapy is instituted. · major
- Phenobarbital · Can induce enzymes and reduce the efficacy of mitotane; conversely, mitotane can induce hepatic microsomal enzymes and increase the metabolism of phenobarbital.
- Spironolactone · Has been demonstrated to block the action of mitotane in dogs; an alternate diuretic is recommended. · major
- Barbiturates · Increases the hepatic metabolism of mitotane · moderate
- Corticosteroids · Increases the hepatic metabolism of mitotane · moderate
監測
- Physical exam and history (especially water consumption, food consumption, and weight)
- ACTH response test (crucial for dose adjustment)
- Serum electrolytes (Na+/K+)
- BUN
- CBC
- Liver enzymes
- Blood glucose
- Appetite (daily during induction)
- ACTH stimulation test (to monitor treatment efficacy)
- Blood glucose (in diabetic patients)
- Clinical signs of weakness, vomiting, or neurological changes
過量
Because of the drug's toxicity and very long half-life, acute overdosage should be managed aggressively. * **Decontamination:** Emptying the stomach and administering activated charcoal and a cathartic should be considered after a recent ingestion. * **Monitoring & Treatment:** The patient must be closely monitored. Administer systemic glucocorticoids (e.g., dexamethasone or prednisone) and IV fluids if signs of acute hypoadrenocorticism (Addisonian crisis) develop.
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