๋ฉํ ํธ๋ ์ธ์ดํธ
๋ฉํ ํธ๋ ์ธ์ดํธ(MTX)๋ ๊ฐ๋ ฅํ **์ฝ์ฐ ๊ธธํญ์ **๋ก, ์์ ์ข ์ํ์์ ์ฃผ๋ก ๊ฐ์ ๊ณ ์์ด์ **๋ฆผํ์ฆ์์ฑ ์งํ**(์: ๋ฆผํ์ข ) ๋ฐ ํน์ ๊ณ ํ์ ์น๋ฃ์ ์ฌ์ฉ๋ฉ๋๋ค. ํญ์ข ์ ํน์ฑ ์ธ์๋ ์๋นํ **๋ฉด์ญ ์ต์ ** ๋ฅ๋ ฅ์ ๊ฐ์ง๊ณ ์์ด, ํ์ค ํ๋ ๋๋์๋ก ์ด๋ ํด๋ก๋๋ถ์ค ์น๋ฃ์ ๋ฐ์ํ์ง ์๋ ๊ณ ์์ด์ ๋นํ๋์ฑ ๋ด๊ด์ผ/๋ด๊ด๊ฐ์ผ๊ณผ ๊ฐ์ ๋์น์ฑ ๋ฉด์ญ ๋งค๊ฐ ์งํ์ ์ ์ฉํ ์น๋ฃ ์ต์ ์ด ๋ฉ๋๋ค. **์์ ์์ :** MTX๋ ์น๋ฃ ์ง์๊ฐ ๋งค์ฐ ์ข๊ณ ์ ์ฅ ๋ฐฐ์ค์ ํฌ๊ฒ ์์กดํ๋ฏ๋ก, ์ฌ๊ฐํ ๋ ์ฑ์ ์๋ฐฉํ๊ธฐ ์ํด ํ์์ ์ํ ์ํ์ ์ ์ฅ ๊ธฐ๋ฅ์ด ๊ฐ์ฅ ์ค์ํฉ๋๋ค. ๋น ๋ฅด๊ฒ ๋ถ์ดํ๋ ์ธํฌ์ ๋งค์ฐ ๋ ์ฑ์ด ๊ฐํ์ฌ ์์ฅ๊ด ์ํผ์ ๊ณจ์๊ฐ ํนํ ๋ถ์์ ์์์ ์ทจ์ฝํฉ๋๋ค.
์์ฉ ๊ธฐ์ : Methotrexate is an **S-phase specific antimetabolite**. It acts by competitively and irreversibly inhibiting the enzyme **dihydrofolate reductase (DHFR)**. * Folic acid โ (via DHFR) โ Dihydrofolate โ (via DHFR) โ **Tetrahydrofolate** (active form). * By blocking DHFR, MTX prevents the reduction of dihydrofolate to tetrahydrofolate. * Tetrahydrofolate is an essential cofactor for the synthesis of purines and pyrimidines (specifically thymidylate). * The depletion of these precursors halts DNA, RNA, and protein synthesis, ultimately leading to apoptosis in rapidly proliferating cells (e.g., neoplasms, bone marrow, GI tract epithelium). > **Note:** DHFR has a much greater affinity for MTX than for folic acid. Therefore, coadministration of folic acid will not reverse MTX toxicity. **Leucovorin calcium** (a derivative of tetrahydrofolic acid that bypasses the blocked enzyme) is required as a rescue agent.
๋๋ฌผ ์ข ๋ณ ์ฉ๋
- For susceptible neoplastic diseases (usually as part of a multi-drug protocol) ยท 2.5 mg/m2 PO 2-3 times weekly; 0.3-0.8 mg/m2 IV every 7 days ยท PO/IV ยท 2-3 times weekly (PO) or every 7 days (IV)
- For non-suppurative cholangitis/cholangiohepatitis (CCHC) syndrome with fibrosis ยท A total dose of 0.4 mg per cat total dose given on one day in three divided doses: 0.26 mg at hour zero, 0.13 mg at the 12 and 24 hour dosing. Repeat every 7-10 days. ยท PO ยท Divided over 24 hours, repeated every 7-10 days ยท Use in conjunction with ursodeoxycholic acid (15 mg/kg PO q24h) and folate (0.25 mg/kg PO q24h).
- As part of the LMP protocol for maintenance of canine lymphoma ยท 2.5-5 mg/m2 PO twice a week ยท PO ยท twice a week ยท Given with Chlorambucil 20 mg/m2 PO every 15 days and Prednisone 20 mg/m2 PO every other day. When Vincristine is added it is at a dose of 0.5-0.7 mg/m2 and is given every 15 days alternating weeks with the chlorambucil.
- In combination with other antineoplastics (per protocol) ยท 5 mg/m2 PO twice weekly or 0.8 mg/kg IV every 21 days; alternatively 2.5 mg/m2 PO daily ยท PO/IV ยท twice weekly, every 21 days, or daily
์ฉ๋์ ๋ฉดํ ์์ ์ ๋ฌธ๊ฐ๋ฅผ ์ํ ์์ ์ฐธ๊ณ ์๋ฃ์ ๋๋ค. ํญ์ ์ต์ ๋ผ๋ฒจ๊ณผ ๊ฐ๋ณ ํ์์ ๋ํด ํ์ธํ์ญ์์ค.
ํฌ์ฌ ๊ฒฝ๋ก
๊ธ๊ธฐ
- Preexisting bone marrow depression
- Severe hepatic insufficiency
- Severe renal insufficiency
- Hypersensitivity to the drug
- Pregnancy (Teratogenic/Embryotoxic - FDA Category X)
- Nursing mothers
- Pre-existing severe bone marrow suppression
- Severe renal impairment
- Severe hepatic impairment
- Pregnancy and lactation (teratogenic and embryotoxic)
- Patients with significant third-space fluid accumulations (e.g., ascites, pleural effusion)
์ด์๋ฐ์
- Diarrhea
- Nausea
- Vomiting
- Inappetence (especially in cats)
- GI toxicity (ulcers, mucosal sloughing, stomatitis)
- Hematopoietic toxicity / Myelosuppression (nadir at 4-6 days)
- Hepatopathy
- Renal tubular necrosis
- Alopecia
- Depigmentation
- Pulmonary infiltrates and fibrosis
- CNS toxicity (encephalopathy) if given intrathecally
- Anaphylaxis (rare)
- Myelosuppression (neutropenia, thrombocytopenia, anemia)
- Gastrointestinal toxicity (anorexia, vomiting, diarrhea, stomatitis)
- Hepatotoxicity (elevated liver enzymes)
์ฝ๋ฌผ ์ํธ์์ฉ
- Amiodarone ยท Prolonged PO administration (>2 weeks) may inhibit MTX metabolism
- Asparaginase ยท Given concomitantly with MTX may decrease MTX efficacy
- Azathioprine ยท Potential for increased risk for hepatic toxicity
- Chloramphenicol ยท May displace MTX from plasma proteins increasing risk for toxicity, but also may reduce MTX absorption and enterohepatic recirculation
- Cisplatin ยท May have synergistic action with MTX, but alter the renal elimination of MTX
- Cyclosporine ยท May increase MTX levels
- Folic Acid ยท May reduce MTX efficacy, but folate deficiency increases MTX toxicity
- Neomycin (oral) ยท May decrease the absorption of oral methotrexate if given concomitantly
- NSAIDs / Salicylates ยท Severe hematologic and GI toxicity risk; use caution in dogs also on MTX
- Penicillins ยท May decrease MTX renal elimination ยท moderate
- Probenecid ยท May inhibit the tubular secretion of MTX and increase its half-life ยท major
- Pyrimethamine ยท A similar folic acid antagonist; may increase MTX toxicity and should not be given to patients receiving MTX
๋ชจ๋ํฐ๋ง
- Efficacy of treatment
- Clinical signs of GI irritation and ulceration
- Complete blood counts (with platelets) weekly early in therapy, then every 4-6 weeks (Discontinue if WBC <4000/mm3 or platelets <100,000/mm3)
- Baseline and ongoing renal function tests
- Baseline and ongoing hepatic function tests (liver enzymes)
- Complete Blood Count (CBC) - baseline and prior to each dose (monitor for nadir)
- Renal function panel (BUN, Creatinine, Urinalysis)
- Hepatic enzymes (ALT, AST, ALP, Bilirubin)
- Clinical signs of gastrointestinal toxicity (vomiting, diarrhea, anorexia)
- Hydration status
๊ณผ์ฉ๋
Acute overdosage in dogs is associated with severe exacerbations of adverse effects, particularly **myelosuppression** and **acute renal failure**. Acute tubular necrosis occurs secondary to drug precipitation in the renal tubules. * **Toxicity Thresholds:** In dogs, the maximally tolerated dose is reported to be 0.12 mg/kg q24h for 5 days. A dose of 10 mg/kg is considered lethal if leucovorin rescue is not performed. * **Decontamination:** Empty the gut and prevent absorption using standard protocols if ingestion is recent. Oral neomycin has been suggested to help prevent intestinal absorption. * **Renal Protection:** Forced alkaline diuresis should be considered to minimize renal damage. Maintain urine pH between 7.5-8 by adding 0.5-1 mEq/kg of sodium bicarbonate per 500 mL of IV fluid. * **Antidote:** **Leucovorin calcium** is the specific therapy for MTX overdoses. It must be given as soon as possible (preferably within the first hour, definitely within 48 hours). Dogs treated with leucovorin at 15 mg/m2 every 3 hours IV for 8 doses, then IM q6h for 8 doses were able to tolerate very high MTX doses.
VetSheet ์ฝ๋ฌผ ๋ ํผ๋ฐ์ค๋ ๋ฉดํ ์์ ์ ๋ฌธ๊ฐ๋ฅผ ์ํ ์์ ์์ฌ๊ฒฐ์ ๋ณด์กฐ ๋๊ตฌ์ด๋ฉฐ, ์ ๋ฌธ์ ํ๋จ์ด๋ ์ ์กฐ์ฌ์ ์ต์ ๋ผ๋ฒจ์ ๋์ ํ์ง ์์ต๋๋ค.