查看Ch61 Antifungal Agents的源代码

=== Itraconazole (伊曲康唑) ===

Itraconazole is a triazole that lacks the corticosteroid suppression associated with ketoconazole while retaining most of ketoconazole’s pharmacological properties and extending the antifungal spectrum. Importantly, itraconazole has activity against Aspergillus spp., whereas imidazoles do not. Itraconazole has been supplanted by other triazoles in the treatment of invasive mold infections but remains an important prophylactic agent in the prevention of mold infections in some patients (e.g., patients with chronic granulomatous disease [CGD]).

伊曲康唑是一种三唑类药物，缺乏与酮康唑相关的皮质类固醇抑制，同时保留了酮康唑的大部分药理学特性并扩展了抗真菌谱。重要的是，伊曲康唑对曲霉属有活性，而咪唑类则没有。伊曲康唑在治疗侵袭性霉菌感染方面已被其他三唑类药物取代，但在某些患者（例如，慢性肉芽肿病 [chronic kineomatous disease， CGD] 患者）中，伊曲康唑仍是预防霉菌感染的重要预防剂。

<b style=color:#0cf>【注】</b>三唑类抗真菌药物原理皆为：使14 - 脱甲基酶系失活，导致麦角固醇（真菌细胞膜重要成分）合成受阻。


'''ADME''': Itraconazole is available as a tablet, capsule, and a solution in hydroxypropyl-β-cyclodextrin for oral use. The capsule form of the drug is best absorbed in the fed state, but the oral solution is better absorbed in the fasting state, providing peak plasma concentrations more than 150% of those obtained with the capsule. The tablet formulation is approved only for onychomycosis. Super-bioavailable (SUBA)-itraconazole, a reformulation with enhanced GI absorption, has recently been approved by the FDA (U.S. Food and Drug Administration). Itraconazole is metabolized in the liver. It is both a substrate for and a potent inhibitor of CYP3A4. Itraconazole is present in plasma with an approximately equal concentration of a biologically active metabolite, hydroxy-itraconazole. The native drug and metabolite are more than 99% bound to plasma proteins. Neither appears in urine or in CSF. The t1/2 of itraconazole at steady state is about 30 to 40 h. Steady-state levels of itraconazole are not reached for 4 days and those of hydroxy-itraconazole for 7 days; thus, loading doses are recommended when treating deep mycoses. Severe liver disease will increase itraconazole plasma concentrations, but azotemia and hemodialysis have no effect.

'''ADME'''： 伊曲康唑有片剂、胶囊和口服羟丙基-β-环糊精溶液。药物的胶囊形式在进食状态下吸收最好，但口服溶液在空腹状态下吸收最好，提供比胶囊获得的血浆峰值浓度高 150% 以上。该片剂制剂仅被批准用于甲癣。超级生物可利用度 （SUBA）-伊曲康唑是一种增强胃肠道吸收的重新配方，最近已获得 FDA（美国食品和药物管理局）的批准。伊曲康唑在肝脏中代谢。它既是 CYP3A4 的底物，也是 CYP3A4 的有效抑制剂。伊曲康唑存在于血浆中，与生物活性代谢物羟基-伊曲康唑浓度大致相等。天然药物和代谢物与 Plasma 蛋白结合的 99% 以上。均未出现在尿液或 CSF 中。伊曲康唑在稳态下的 t1/2 约为 30 至 40 小时。伊曲康唑的稳态水平在 4 天内未达到，羟基 - 伊曲康唑在 7 天内未达到稳态水平;因此，在治疗深部真菌病时，建议使用负荷剂量。严重的肝病会增加伊曲康唑血浆浓度，但氮质血症和血液透析没有效果。


'''Therapeutic Uses''': Itraconazole is the drug of choice for patients with indolent, nonmeningeal infections due to B. dermatitidis, H. capsulatum, P. brasiliensis, and Coccidioides immitis. The drug also is useful in the therapy of indolent invasive aspergillosis outside the CNS, particularly after the infection has been stabilized with amphotericin B. Approximately half of the patients with distal subungual onychomycosis respond to itraconazole (Evans and Sigurgeirsson, 1999). Although not approved for these uses, itraconazole is a reasonable choice for the treatment of pseudallescheriasis, an infection that does not respond to amphotericin B therapy, as well as cutaneous and extracutaneous sporotrichosis, tinea corporis, and extensive tinea versicolor. HIV-infected patients with disseminated histoplasmosis or penicilliosis have a decreased incidence of relapse if given prolonged itraconazole “maintenance” therapy. Itraconazole is not recommended for maintenance therapy of cryptococcal meningitis in HIV-infected patients because of a high incidence of relapse. Long-term itraconazole therapy has been used in non–HIV-infected patients with allergic bronchopulmonary aspergillosis to decrease the dose of glucocorticoids and reduce attacks of acute bronchospasm (Salez et al., 1999). Itraconazole solution is effective and approved for use in oropharyngeal and esophageal candidiasis. Because the solution has more GI side effects than fluconazole tablets, itraconazole solution usually is reserved for patients not responding to fluconazole. Finally, itraconazole is also used as Aspergillus prophylaxis in patients with CGD.

'''治疗用途'''： 伊曲康唑是由皮炎芽孢杆菌、荚膜嗜血杆菌、巴西假单胞菌和粗球孢子菌引起的惰性、非脑膜感染患者的首选药物。该药物还可用于治疗 CNS 外的惰性侵袭性曲霉病，特别是在用两性霉素 B 稳定感染后。大约一半的远端甲下甲真菌病患者对伊曲康唑有反应（Evans 和 Sigurgeirsson，1999）。虽然尚未批准用于这些用途，但伊曲康唑是治疗假鼻癣（一种对两性霉素 B 治疗无反应的感染）以及皮肤和皮外孢子丝菌病、体癣和广泛花斑癣的合理选择。如果给予长期伊曲康唑“维持”治疗，患有播散性组织胞浆菌病或青霉素病的 HIV 感染患者的复发率会降低。不建议将伊曲康唑用于 HIV 感染患者隐球菌性脑膜炎的维持治疗，因为其复发率高。长期伊曲康唑治疗已用于非 HIV 感染的过敏性支气管肺曲霉病患者，以减少糖皮质激素的剂量并减少急性支气管痉挛的发作（Salez 等人，1999 年）。伊曲康唑溶液有效，并获批用于口咽和食管念珠菌病。由于该溶液比氟康唑片剂具有更多的胃肠道副作用，因此伊曲康唑溶液通常仅用于对氟康唑无反应的患者。最后，伊曲康唑也用作 CGD 患者的曲霉菌预防。


'''Dosage''': In treating deep mycoses, a loading dose of 200 mg of itraconazole is administered three times daily for the first 3 days. After the loading doses, two 100-mg capsules are given twice daily with food. Divided doses may increase the AUC. For maintenance therapy of HIV-infected patients with disseminated histoplasmosis, 200 mg once daily is used. Onychomycosis can be treated with either 200 mg once daily for 12 weeks or, for infections isolated to fingernails, two monthly cycles consisting of 200 mg twice daily for 1 week followed by a 3-week period of no therapy— so-called pulse therapy (Evans and Sigurgeirsson, 1999). Once-daily terbinafine (250 mg), however, is superior to pulse therapy with itraconazole. For oropharyngeal candidiasis, itraconazole oral solution should be taken during fasting in a dose of 100 mg (10 mL) once daily and swished vigorously in the mouth before swallowing to optimize any topical effect. Patients with esophageal thrush unresponsive or refractory to treatment with fluconazole tablets are given 100 mg of the solution twice a day for 2 to 4 weeks. The typical dose for fungal prophylaxis in patients with CGD is 5 mg/kg per day. In pediatric patients, plasma levels are very erratic and therapeutic monitoring should be considered, particularly for patients being treated for systemic fungal infections (e.g., histoplasmosis and blastomycosis) (Downes et al., 2020).

'''剂量'''：在治疗深部真菌病时，前 3 天每天 3 次，每天施用 200mg 的负荷剂量的伊曲康唑。负荷剂量后，每天两次随餐服用两粒 100mg 胶囊。分次给药可能会增加 AUC。对于播散性组织胞浆菌病 HIV 感染患者的维持治疗，使用 200mg 每日一次。甲癣可以用 200mg 每天一次治疗 12 周，或者对于孤立于指甲的感染，两个月一个周期，包括 200mg，每天两次，持续 1 周，然后是 3 周的无治疗期——所谓的脉冲疗法（Evans 和 Sigurgeirsson，1999 年）。然而，'''每日一次的特比萘芬（250mg）优于伊曲康唑的脉冲治疗'''。对于口咽念珠菌病，伊曲康唑口服溶液应在空腹期间以 100mg（10ml）的剂量服用，每天一次，并在吞咽前在口中用力漱口，以优化任何局部效果。对氟康唑片治疗无反应或难治性食管鹅口疮患者每天两次给予 100mg 溶液，持续 2 至 4 周。CGD 患者真菌预防的典型剂量为 5 mg/kg 每天。在儿科患者中，血浆水平非常不稳定，应考虑治疗监测，特别是对于正在接受全身性真菌感染（例如组织胞浆菌病和芽生菌病）治疗的患者（Downes et al.， 2020）。


'''Adverse Effects''': Itraconazole carries an FDA boxed warning about possible serious adverse effects, including QT prolongation, heart failure, negative inotropic effects, and drug interactions. Serious hepatotoxicity has led, in rare cases, to hepatic failure and death. If symptoms of hepatotoxicity occur, the drug should be discontinued and liver function assessed. In the absence of interacting drugs, itraconazole capsules and suspension are well tolerated at 200 mg daily. Diarrhea, abdominal cramps, anorexia, and nausea are more common than with the capsules. Of patients receiving 50 to 400 mg of the capsules per day, nausea and vomiting, hypertriglyceridemia, hypokalemia, increased serum aminotransferase, and rash occurred in 2% to 10%. Occasionally, rash necessitates drug discontinuation, but most adverse effects can be handled with dose reduction. Profound hypokalemia has been seen in patients receiving 600 mg or more daily and in those who recently have received prolonged amphotericin B therapy. Doses of 300 mg twice daily have led to other side effects, including adrenal insufficiency, lower limb edema, hypertension, and in at least one case, rhabdomyolysis. Doses greater than 400 mg/day are not recommended for long-term use. Anaphylaxis has been observed rarely, as well as severe rash, including Stevens-Johnson syndrome. Itraconazole is contraindicated for the treatment of onychomycosis during pregnancy or for women contemplating pregnancy.

<b style="color:#f80">不良反应</b>：伊曲康唑带有 '''FDA 黑框警告'''，关于可能的严重不良反应，包括 QT 间期延长、<b style=color:#e00>心力衰竭</b>、'''负性肌力作用'''和药物相互作用。在极少数情况下，严重的肝毒性会导致肝功能衰竭和死亡。如果出现肝毒性症状，应停药并评估肝功能。在没有相互作用药物的情况下，伊曲康唑胶囊和混悬液每天 200 毫克的耐受性良好。腹泻、腹部绞痛、厌食和恶心比胶囊更常见。在每天接受 50 至 400mg 胶囊的患者中，'''恶心'''和'''呕吐'''、'''高甘油三酯血症'''、'''低钾血'''症、血清'''转氨酶升高'''和'''皮疹'''发生在 2% 至 10% 的患者中。偶尔，皮疹需要停药，但<b style="color:#0c0">大多数不良反应可以通过减少剂量来处理</b>。在每天接受 600mg 或更多剂量的患者以及最近接受长期两性霉素 B 治疗的患者中，已观察到严重'''低钾血症'''。每天两次 300mg 的剂量导致了其他副作用，包括肾上腺皮质功能减退、下肢水肿、高血压，以及至少一例横纹肌溶解症。大于 400mg/d 的剂量不建议长期使用。很少观察到过敏反应，以及严重的皮疹，包括 Stevens-Johnson 综合征。伊曲康唑禁用于治疗妊娠期甲癣或考虑怀孕的妇女。


'''Drug Interactions''': Tables 61–4, 61–5, and 61–6 list select interactions of azoles with other drugs. Many of the interactions can result in serious toxicity from the companion drug, such as inducing potentially fatal cardiac arrhythmias when used with quinidine, halofantrine (an orphan drug used for malaria), levomethadyl (an orphan drug used for heroin addiction), pimozide, or cisapride (available only under an investigational limited access program in the U.S.). Other drugs may decrease itraconazole serum levels below therapeutic concentrations (Table 61–5).

<b style="color:#f00">药物相互作用</b>：表 61-4、61-5 和 61-6 列出了唑类与其他药物的选择相互作用。许多相互作用可导致伴随药物产生'''严重毒性'''，例如与奎尼丁、氟蒽群（一种用于治疗疟疾的孤儿药）、左旋美沙啶（一种用于海洛因成瘾的孤儿药）、匹莫齐特或西沙必利（仅在美国的研究性限制获取计划下提供）一起使用时，会诱发可能致命的心律失常。其他药物可能会将伊曲康唑血清水平降低到治疗浓度以下（表 61-5）。

<br>