双戊烯对酮康唑透皮吸收促进作用

目的：研究双戊烯的透皮促进作用。方法：采用自制透皮扩散装置。以离体小白鼠背部皮肤为透皮屏障，紫外分光光度法测定含不同浓度双戊烯和氮酮对酮康唑的促透效果。结果：不同浓度促进剂对酮康唑的促透效果顺序为3％双戊烯＞2％双戊烯＞3％氮酮＞1％双戊烯。结论：实验证明，3％双戊烯对酮康唑具有较好的促透作用，与其它浓度的双戊烯和不同浓度的氮酮相比具有显著性差异（P＜0．05）或极显著性差异（P＜0．01）。     

Epidemiology, clinical features and prognostic value of HIV-1 related oral lesions

Between February 1987 and February 1990, we studied 737 antibody anti HIV-1 positive (AbHIV+) subjects referred to the Infectious Diseases Institute of the University of Turin (Italy) in order to evaluate types, prevalences, relations with clinical stages, distributions in risk-groups and prognostic significances of HIV-1 related oral lesions. The study evidenced the high prevalence of oral lesions, especially mycoses, in the investigated population: 40.3% of the patients showed, in fact, HIV-1 related oral lesions. The 37 months follow-up of 55 AbHIV+ with oral hairy leukoplakia (HL) and 101 patients with oral candidiasis (OC), demonstrated that the probability of developing AIDS in patient with HL was 0.381 at 15, 0.635 at 25 and 0.824 at 37 months. In the patients with OC the probability was 0.294 at 15 months, 0.524 at 25 and 0.781 at 37 months.     

The epidemiology of pseudallescheriasis complicating transplantation: nosocomial and community-acquired infection

The epidemiology of two cases of pseudallescheriasis in organ transplant patients are described and the disease in that population is reviewed. Disseminated hospital-acquired infection occurred in a liver transplant recipient and was fatal despite therapy with miconazole. A heart transplant recipient developed localized disease following soil contamination of soft tissue trauma which was cured with surgical resection and miconazole therapy. Itraconazole showed in vitro activity against Pseudallescheria boydii and should be evaluated in pseudallescheriasis. P. boydii infections are important complications of transplantation and should be considered in the differential diagnosis of community-acquired as well as nosocomial fungal infections in this population.     

Biotransformation and in vitro assessment of metabolism-associated drug–drug interaction for CRx-102, a novel combination drug candidate

CRx-102 is an oral synergistic combination drug which contains the cardiovascular agent, dipyridamole (DP) and a very low dose of the glucocorticoid, prednisolone (PRED). CRx-102 works through a novel mechanism of action in which DP selectively amplifies the anti-inflammatory activity of PRED without replicating its side effects. CRx-102 is in clinical trials for the treatment of osteoarthritis. Here we delineate the in vitro metabolism and explore the potential for a drug–drug interaction between the active agents in CRx-102. Our study using human hepatocyte suspensions showed that both DP and PRED were metabolized by CYP3A4 isozymes, resulting in the formation of diverse arrays of both oxidative and oxidative-reduced metabolites. Within phase 1 biotransformation, CYP3A4 was one of the pathways responsible for the metabolism of PRED, while phase 2 biotransformation played a significant role in the metabolism of DP. Glucuronidation of DP was substantial and was catalyzed by many UGT members, specifically those in the UGT1A subfamily. Based on the tandem mass (MS/MS) product ion spectra (PIS) acquired, the major metabolites of both agents, namely, monooxygenated, mono-N-deethanolaminated, dehydrogenated and O-glucuronidated metabolites of DP and the monooxygenated (e.g., 6-hydroxyl), dehydrogenated (prednisone) and reduced (20-hydroxyl) metabolites of PRED, were identified and elucidated. The affinities for DP biotransformation, including CYP3A4-mediated oxidative pathways and UGT-mediated O-glucuronidation, appeared high (K_m < 10 μM), as compared with the modest affinities of PRED biotransformation catalyzed by CYP3A4 (K_m ∼ 40–170 μM). DP, but not PRED, exerted a minimal inhibitory effect on the drug-metabolizing CYP isoforms, including CYP3A4, which was determined using a panel of CYP isoform-preferred substrate activities in pooled human liver microsomal (HLM) preparations and microsomal preparations containing the recombinant enzymes (K_i ∼ 2–12 μM). Using the DP maximal plasma concentration (C_max) observed in the clinic and a predictive mathematical model for metabolism-associated drug–drug interaction (DDI), we have demonstrated that there is little likelihood of a pharmacokinetic interaction between the two active agents in CRx-102.     

Topical 2% ketoconazole cream monotherapy significantly improves adult female acne: A double‐blind,randomized placebo‐controlled trial

The emergence of bacterial resistance is a global crisis. Prolonged use of antibiotics especially in acne is one issue of concern among dermatologists. Ketoconazole (KTZ) cream, a topical antifungal with anti‐inflammatory and antiandrogenic actions, can decrease lipase activity of Cutibacterium acnes in vitro. We evaluated the efficacy and safety of KTZ cream in mild adult female acne (AFA) by conducting a randomized, double‐blind, placebo‐controlled trial using KTZ 2% and placebo cream twice daily for 10 weeks. We assessed the improvement of clinical severity, measured by AFA score graded by investigators and participants, and the change of acne count. Forty‐one participants enrolled in our study. The proportion of participants with acne improvement from baseline (42.9% vs 9.5%, P = 0.015) and the success rate (45.0% vs 14.3%, P = 0.043) in the KTZ group were significantly higher than that of the placebo group. The most common adverse events were dryness and itching. The percentage change of acne count decreased significantly compared with baseline but did not differ statistically between the two groups (P = 0.268). We concluded that the KTZ monotherapy showed a plausible effect in improving AFA with excellent safety profile. It should be considered as a viable option for mild AFA treatment.     

Effect of a single administration of ketoconazole on total and physiologically free plasma testosterone and 17β-oestradiol levels in healthy male volunteers

Summary The effect of a single oral dose of 400 mg ketoconazole, given as an 80 mg/ml suspension, on total and physiologically free (i.e. non-sex hormonebound) testosterone and 17-oestradiol has been investigated in 6 healthy male volunteers. The two steroids fell to nadir levels of 18 and 60% of their respective initial concentrations 6 hours after drug intake, and then completely recovered. Although in vitro slight displacement of testosterone from the sex-hormone binding globulin, by high doses of ketoconazole was found, the physiologically free concentration of testosterone in vivo was closely correlated with that of the total hormone, suggesting that there is no direct interference with sex-hormone binding globulin in vivo. Plasma LH and FSH were not significantly modified by treatment. The effect of ketoconazole on plasma oestradiol levels was less pronounced and was not clearly related to a block of the aromatase system, as reported in vitro.This work was presented in part at the International Symposium on the Regulation of Androgen Actions, Montreal, 29th June–1st July 1984     

Effects of Ketoconazole on the Pharmacokinetic Properties of CG100649, A Novel NSAID: A Randomized,Open-Label Crossover Study in Healthy Korean Male Volunteers

Background

CG100649, a novel selective cyclooxygenase-2 inhibitor that also inhibits carbonic anhydrase I/II, is expected to reduce the cardiovascular risk typical of other NSAIDs. Concurrent medications may influence the activities of the cytochrome P450 (CYP) 3A enzyme through which CG100649 is metabolized.

Objectives

This study was designed to evaluate the influence of ketoconazole, a known strong inhibitor of CYP3A, on the pharmacokinetic properties of CG100649.

Methods

This randomized, open-label, 2 × 2 crossover study was conducted in healthy Korean male volunteers. Each subject received the following 2 treatments in a randomly allocated sequence, separated by a washout period of 42 days: single oral dose of CG100649 6 mg, and concurrent dosing of CG100649 6 mg and ketoconazole 400 mg followed by ketoconazole 400 mg/d over 4 days. Blood samples for pharmacokinetic analysis were collected at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 240, 384, and 480 hours after dosing of CG100649 in each sequence. Tolerability assessments were performed throughout the study.

Results

Thirty subjects participated, and 26 subjects completed the study. Seventeen adverse events (AEs) were reported in 10 subjects, and all AEs were recovered without any sequelae. No serious AEs were reported. Six subjects receiving the single dose of CG100649 had 9 AEs, and 7 subjects receiving the combination of ketoconazole and CG100649 had 8 AEs. The C_max of CG100649 with CG100649 only and with concurrent administration of CG100649 + ketoconazole were similar (10.7 and 11.0 ng/mL, respectively). The CG100649 AUC_last with concurrent ketoconazole was 1.29-fold greater than that with CG100649 only (2074.0 and 2685.8 ng · h/mL) and demonstrated a statistically significant difference (P < 0.05). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or AEs between treatments.

Conclusion

Although the AUC of CG100649 increased by 29% with the concurrent medication of ketoconazole, it is considered that concurrent administration of CG100649 with ketoconazole would not change the safety profile of CG100649. ClinicalTrials.gov identifier: NCT01154764.     

酮康唑β-环糊精包合物的制备

 目的 探讨应用β-环糊精包合技术提高酮康唑溶解度和稳定性的方法。方法 采用混合搅拌法制备酮康唑β-环糊精包合物,经薄层色谱、X-衍射及差热分析图谱等鉴定,确证为包合物。结果 制备包合物的最佳主客分子摩尔比为1∶1,最佳搅拌时间为5 h,6批包合物包合率在71.59%～73.63%之间。结论 酮康唑β-环糊精包合物可提高酮康唑的溶解度和稳定性。