Diethylstilbestrol
Diethylstilbestrol (DES) is a synthetic, nonsteroidal estrogen primarily used in veterinary medicine for the management of **estrogen-responsive urinary incontinence** in spayed female dogs. It has also been utilized for benign prostatic hypertrophy in male dogs and estrus induction. > **Clinical Pearl:** Due to the severe risk of bone marrow toxicity (fatal aplastic anemia) and its classification as a potential carcinogen and teratogen, DES is strictly prohibited in food-producing animals. Because of human health concerns and market withdrawals, DES is no longer commercially available as an FDA-approved manufactured product and must be obtained through veterinary compounding pharmacies. In modern practice, safer alternatives like estriol (Incurin) or phenylpropanolamine (PPA) are often preferred as first-line therapies for sphincter mechanism incompetence.
กลไกการออกฤทธิ์: DES acts as a potent agonist at **estrogen receptors (ER-α and ER-β)**. Upon binding, the receptor-ligand complex translocates to the cell nucleus, where it binds to estrogen response elements (EREs) on DNA, altering mRNA transcription and subsequent protein synthesis. * **Urinary Incontinence:** Estrogens upregulate the expression and sensitivity of **α-adrenergic receptors** in the internal urethral sphincter. This increases the sphincter's responsiveness to endogenous norepinephrine, thereby increasing resting urethral closure pressure and preventing urine leakage. * **Reproductive/Systemic Effects:** Promotes growth and development of female sex organs, increases cervical/vaginal mucosal thickness, and causes endometrial proliferation. It also accelerates epiphyseal closure, increases calcium deposition in bone, and inhibits pituitary gonadotropin release via negative feedback.
ขนาดยาตามชนิดสัตว์
- Estrogen-responsive incontinence (females) · 0.1-1 mg (total dose) PO once daily for 5 days, then 1 mg once a week · PO · Once daily for 5 days, then weekly · Long-term maintenance · Doses of 2.2 mg/kg per day have caused death in cats secondary to bone marrow toxicity.
- Primary sphincter mechanism incompetence (Option A) · 0.1-1 mg (total dose) per dog PO for 5 days followed by maintenance of 1 mg/week or a maximum of 0.1 mg/kg/week. Minimum effective dose should be used for maintenance. Do NOT give more than recommended. · PO · Once daily for 5 days, then weekly · Long-term maintenance · As an alternative to phenylpropanolamine.
- Primary sphincter mechanism incompetence (Option B - females) · 0.1-1 mg (total dose) PO once daily for 5 days, then 1 mg once a week · PO · Once daily for 5 days, then weekly · Long-term maintenance
- Primary sphincter mechanism incompetence (Option C) · 0.5-1 mg (0.02 mg/kg; maximum dose of 1 mg) for 3-5 days as an induction dose and then periodically decreased to every other day and then to the lowest dose that will maintain continence. · PO · Daily initially, then tapered · Long-term maintenance · In difficult cases, may be used with phenylpropanolamine. Note: Conjugated estrogens (e.g., Premarin) are sometimes used as a substitute (e.g., 20 mcg/kg PO every 4 days).
- Estrus induction · DES at 5 mg/day for a tentative 7 days. The first day of vulvar swelling is designated as Day 1. Continue DES on DAY 1 and Day 2. If no effect is seen in 7 days, give DES at 10 mg/day for another tentative 7 days. If vulvar swelling and bleeding detected, DES is continued on Day 1 and Day 2. If no effect seen in these 14 days, discontinue and restart in 30 days. Once proestrus initiated, on Day 5 give 5 mg of Luteinizing hormone (LH) if obtainable. If LH unavailable, give GnRH 3.3 micrograms/kg IM and FSH 10 mg IM in its place. Bitch is bred on Day 13. · PO · Daily · 7-14 days · Adjust dosages of LH and FSH for animal size-the above dosages are for a dog weighing 50-60 lbs.
วิธีการให้ยา
ข้อห้ามใช้
- Food-producing animals (FDA prohibited)
- Pregnancy (teratogenic; causes fetal genitourinary malformations)
- Patients with preexisting anemias or leukopenias
- Females with estrogen-sensitive neoplasms
อาการไม่พึงประสงค์
- Bone marrow suppression (thrombocytopenia, leukopenia, fatal aplastic anemia)
- Cystic endometrial hyperplasia
- Pyometra (in intact females)
- Mammary neoplasia
- Feminization (in males)
- Signs of estrus (in females)
- Pancreatic, hepatic, and cardiac lesions (reported in cats)
- Malignant ovarian adenocarcinomas (experimental)
อันตรกิริยาระหว่างยา
- Azole Antifungals (itraconazole, ketoconazole, etc.) · May increase estrogen levels
- Cimetidine · May decrease metabolism of estrogens
- Corticosteroids · Enhanced glucocorticoid effects may result; estrogens may alter protein binding or decrease metabolism of corticosteroids
- Erythromycin, Clarithromycin · May decrease the metabolism of estrogens
- Warfarin · Oral anticoagulant activity may be decreased; increases in anticoagulant dosage may be necessary
- Phenobarbital · May decrease estrogen concentrations
- Phenytoin · May decrease estrogen concentrations
- Rifampin · May induce hepatic microsomal enzymes and decrease estrogen levels
การติดตาม
- Packed Cell Volumes (PCV)
- White blood cell counts
- Platelet counts
- Liver function tests (at baseline, one month after therapy begins, and repeat 2 months after cessation if abnormal)
การได้รับยาเกินขนาด
Acute overdosage in humans with estrogens has resulted in nausea, vomiting, and withdrawal bleeding in females. In veterinary patients, acute overdose information is limited, but **chronic overdosage or high doses** are well-documented to cause severe, potentially fatal **bone marrow suppression** (aplastic anemia, thrombocytopenia, neutropenia). Doses of 2.2 mg/kg per day have caused death in cats. Treatment of overdose should involve immediate discontinuation of the drug and aggressive supportive care (e.g., blood transfusions, broad-spectrum antibiotics for neutropenia).
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