特比萘芬与复方酮康唑治疗皮肤真菌病的比较

目的 :特比萘芬与复方酮康唑治疗皮肤真菌病的疗效比较。方法 :患浅部真菌病病人 6 0例 ,男性 4 1例 ,女性 19例 ,年龄 (2 9±s 9)a ,随机分为特比萘芬组 30例 ,应用特比萘芬软膏外涂患处 ,bid× 2wk ;复方酮康唑组 30例 ,外用复方酮康唑霜剂 ,bid× 2wk ;在停药时及停药 2wk后观察疗效。结果 :治疗结束时 ,特比萘芬组总有效率为 73% (2 2 /30 ) ,复方酮康唑组为 57% (17/30 ) ,P >0 .0 5;停药 2wk后 ,特比萘芬组总有效率为 97% (2 9/30 ) ,复方酮康唑组为 4 7% (14/30 ) ,P <0 .0 5。治疗结束时 ,特比萘芬组真菌清除率为 83% ,复方酮康唑组为 53% ,P <0 .0 5,停药 2wk后 ,特比萘芬组真菌清除率为 97% (复方酮康唑组为 37% ,P <0 .0 1)。 2组均未见不良反应。结论 :特比萘芬治疗浅部真菌病优于复方酮康唑。     

伊曲康唑联合萘替芬酮康唑乳膏治疗复发性真菌性外耳道炎

摘 要 目的：观察伊曲康唑与萘替芬酮康唑乳膏联用治疗复发性真菌性外耳道炎的疗效及安全性。方法：复发性真菌性外耳道炎患者48例随机分为两组。对照组24例给予萘替芬酮康唑乳膏外用,qd,连续2周。观察组24例在对照组基础上,加用伊曲康唑胶囊200 mg,po, qd,连续2周。比较两组近期及远期疗效,并评价安全性。结果：用药两周后,观察组总有效率为100.0%,明显优于对照组的83.3%（P<0.05）。治疗结束后6个月随访,观察组无1例复发,对照组复发率为20.0%;观察组复发率明显低于对照组（P<0.05）。治疗期间,两组患者均未见药品不良反应发生。结论：萘替芬酮康唑乳膏与伊曲康唑联用治疗复发性真菌性外耳道炎效果显著、安全性好。     

The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole

AIMS

Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated.

METHODS

This was a two-period, single-sequence crossover study in 18 healthy subjects. They received a single 50 mg oral dose of sotrastaurin in period 1 followed by a 14-day inter-treatment phase. In period 2 they received ketoconazole 200 mg twice daily for 6 days and a single 50 mg dose of sotrastaurin on the fourth day of ketoconazole administration.

RESULTS

Co-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin C_max by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 ± 128 to 678 ± 189 ng ml⁻¹ and increased AUC by 4.6-fold (4.1, 5.2) from 1666 ± 808 to 7378 ± 3011 ng ml⁻¹ h. Sotrastaurin half-life was nearly doubled from 5.9 ± 1.7 to 10.6 ± 2.5 h. The AUC of the active metabolite N-desmethyl-sotrastaurin was increased by 6.8-fold. Sotrastaurin did not alter ketoconazole steady-state predose plasma concentrations.

CONCLUSIONS

The strong CYP3A4 inhibitor ketoconazole increased sotrastaurin AUC by 4.6-fold. A compensatory reduction in the dose of sotrastaurin is warranted when strong CYP3A4 inhibitors are co-administered.     

The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans

AIMS: The purpose of this human intestinal perfusion study was to investigate the effect of ketoconazole on the jejunal permeability and first-pass metabolism of (R)- and (S)-verapamil in humans. METHODS: A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut(R) perfusion tube in six healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The inlet concentration of (R/S)-verapamil was 120 mg l-1 in both periods, and ketoconazole was added at 40 mg l-1 in period 2. (R/S)-verapamil was also administered as a short intravenous infusion of 5 mg, over a period of 10 min. The appearance ratios of the CYP3A formed metabolites (R)- and (S)-norverapamil were also estimated in the outlet jejunal perfusate. RESULTS: The effective jejunal permeability (Peff) of both (R)- and (S)-verapamil was unaffected by the addition of ketoconazole in period 2 suggesting that ketoconazole had no effect on the P-glycoprotein mediated efflux. However, the appearance ratio of both (R)- and (S)-norverapamil in the outlet jejunal perfusate decreased in the presence of ketoconazole. The rate of absorption into plasma of (R)- and (S)-verapamil increased despite the low dose of ketoconazole added, indicating an inhibition of the gut wall metabolism of (R/S)-verapamil by ketoconazole. CONCLUSIONS: Ketoconazole did not affect the jejunal Peff of (R/S)-verapamil, but it did increase the overall transport into the systemic circulation (bioavailability), probably by inhibition of the gut wall metabolism of verapamil. This might be due to ketoconazole being less potent as an inhibitor of P-glycoprotein than of CYP3A4 in vivo in humans.     

Evaluation of Various Dissolution Media for Predicting In Vivo Performance of Class I and II Drugs

Purpose. In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. Methods. Dissolution behavior of two class I drugs, i,e, acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIF_sp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. Results. Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGF_sp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. Conclusions. As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.     

酮康唑霜的制备与质量研究

本文方法改进了酮康唑霜的配方，并用一阶导致光谱法测定了霜剂中主成分的含量，以３０９ｎｍ为测定波长，可排除基质及尼泊金乙酯、亚硫酸钠等的干扰，快速简便，方法的平均回收率为９９．３％，ＲＳＤ为０．５８％。对制备的酮康唑霜进行稳定性实验以及常温放置９个月观察，外观及主药含量未见明显变化。     

酮康唑酊剂的制备与质控研究

目的：为满足临床需要而研制的一种抗真菌制剂。方法：将酮康唑制剂成酊剂,建立了酸碱度、卫生学、含量测定等质控方法,并进行了刺激性和稳定性方面考察。结果：pH值为7．1－7．3,卫生学检查符合规定,含量测定平均回收率为100．52％,RSD＝0．81％,刺激性较小,稳定性较好。结论：本制剂制备工艺简便,质控方法准确可靠,性质稳定,适合临床应用。     

复方酮康唑软膏的制备及临床应用

目的：复方酮康唑软膏的制备和临床应用。方法：采用二阶导数光谱法和单波长法分别测定酮康唑与依诺沙星的含量。结果：被测组分的平均回收率和相对标准偏差分别为：酮康唑101．6％和0．85％,依诺沙星100．2％和0．26％。结论：方法简便,结果准确,可用于复方酮康唑软膏的质量控制。     

Effects of long-term ketoconazole therapy on serum lipid levels

Summary Serum cholesterol and triglycerides were determined in 36 patients receiving an 8-month course of oral ketoconazole 200 mg/day in order to study its effect on lipid metabolism. The mean serum cholesterol concentration had decreased by 15% (p<0.001) after 1 month, but on continued medication it returned to the pretreatment state; after discontinuation of therapy it increased transiently by 13% (p<0.001). Triglycerides increased during ketoconazole administration and at the end of the trial the mean triglyceride concentration was 48% higher than the baseline value (p<0.02). Although most lipid values during therapy lay within the normal ranges, 6 patients developed transient hypertriglyceridaemia. There was no correlation between the changes in lipids and peak serum ketoconazole levels. In one subject studied in more detail the concentration of very low density lipoprotein triglycerides rose during therapy, whereas high density lipoprotein cholesterol decreased slightly. The lipoprotein lipase activity in muscle and, in particular, in adipose tissue was significantly suppressed during ketoconazole treatment. Serum lipids and, if possible, serum lipoproteins should be carefully monitored in patients receiving long-term oral ketoconazole therapy.     

EMA暂停使用口服酮康唑的受益-风险评估

欧洲药品管理局(EMA)经受益–风险评估后认为,口服酮康唑治疗真菌感染的肝损害风险超过受益。因此,EMA决定暂停这类药品在欧盟的上市许可。建议我国酮康唑口服制剂生产企业做酮康唑口服制剂的受益–风险评估,决定下一步采取的安全性措施,至少应修订药品说明书。在我国销售药品的生产企业应注意不断收集国外药品上市后的再评价信息,并及时采取修订说明书、暂停销售或撤市等适当的风险控制措施,确保用药安全。