Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient

Treatment of allergic bronchopulmonary aspergillosis with itraconazole is becoming more widespread in chronic lung diseases. A considerable number of patients is concomitantly treated with topical or systemic glucocorticoids for anti-inflammatory effect. As azole compounds inhibit cytochrome P450 enzymes such as CYP3A isoforms, they may compromise the metabolic clearance of glucocorticoids, thereby causing serious adverse effects. A patient with cystic fibrosis is reported who developed iatrogenic Cushing's syndrome after long-term treatment with daily doses of 800 mg itraconazole and 1,600 microg budesonide. The patient experienced symptoms of striae, moon-face, increased facial hair growth, mood swings, headaches, weight gain, irregular menstruation despite oral contraceptives and increasing insulin requirement for diabetes mellitus. Endocrine investigations revealed total suppression of spontaneous and stimulated plasma cortisol and adrenocorticotropin. Discontinuation of both drugs led to an improvement in clinical symptoms and recovery of the pituitary-adrenal axis after 3 mo. CONCLUSION: This observation suggests that the metabolic clearance of buDesonide was compromised by itraconazole's inhibition of cytochrome P450 enzymes, especially the CYP3A isoforms, causing an elevation in systemic budesonide concentration. This provoked a complete suppression of the endogenous adrenal function, as well as iatrogenic Cushing's syndrome. Patients on combination therapy of itraconazole and budesonide inhalation should be monitored regularly for adrenal insufficiency. This may be the first indicator of increased systemic exogenous steroid concentration, before clinical signs of Cushing's syndrome emerge.     

Enhanced cyclosporine-itraconazole interaction with cola in lung transplant recipients

BACKGROUND: Invasive aspergillosis is a major cause of morbidity and mortality in lung transplant recipients (LTR), occurring in up to 15% of patients post-transplant. The 14% aspergillus incidence at the Cleveland Clinic Foundation prompted institution of universal prophylaxis with oral itraconazole (ICZ) in 1997. We report our experience with two protocols of ICZ administration in non-cystic fibrosis LTR and the interaction with cyclosporine (CSA). METHODS: Group 1 patients (n=12) were administered ICZ capsules in a fasting or fed state, with or without a histamine-2 (H-2) receptor antagonist or proton pump inhibitor. Group 2 patients (n=12) received the same protocol as group I, but in a fed state with a carbonated beverage (cola) to increase acidity in the stomach to enhance absorption of ICZ. The ICZ dose was 200 mg/d, given as one daily dose. A historical control group (n=10) did not receive chemoprophylaxis with ICZ. CSA daily doses, dose intervals, concentration, cost, and random ICZ levels were documented over a 4-month period of time and compared using generalized estimating equations. RESULTS: The daily CSA mg/kg/d dose decreased over time in all three groups, but no differences were found between the three groups. The CSA dosing interval over time was significantly prolonged in group 2 compared to group 1 or the control group (p< or =0.003). Over time, there was no difference in CSA concentration between all groups. There was no difference in cost over time between the three groups; however, the mean cost of CSA therapy was significantly lower in group 2 compared to the control group (p=0.025). Group 2 administered ICZ with cola had greater random blood concentrations of ICZ (p=0.019). CONCLUSIONS: ICZ capsules administered in a fed state with a cola resulted in greater random levels of ICZ, a decrease in cost/d of CSA, and a prolongation of CSA dosing interval. Although daily CSA dosage trended lower in group 2, it did not reach statistical significance. We believe these changes in CSA dosing over time reflect increased absorption of ICZ and recommend verifying ICZ absorption with an itraconazole level, especially when CSA intervals are not prolonged.     

Use of 1-Methyl-Pyrrolidone as a Solubilizing Agent for Determining the Uptake of Poorly Soluble Drugs

Pharmaceutical Research -     

Clinical hepatotoxicity associated with antifungal agents

Introduction: Invasive fungal diseases (IFDs) are a leading cause of morbidity and mortality among immunocompromised patients with bone marrow failure syndromes, hematological malignancies, hematopoietic stem cell transplantation (HSCT), those admitted in intensive care units (ICUs) and those with prolonged febrile neutropenia. IFDs occur in a setting of multiple morbidities and are associated with case fatality rates between 30 and 70%. Along with the development of classes and compounds, the last two decades have seen substantial improvements in the prevention and management of these infections and an overall increased use of antifungal agents.

Areas covered: All antifungal agents, including amphotericin B formulations, echinocandins and the triazoles, may cause hepatic toxicity that ranges from mild and asymptomatic abnormalities in liver function tests to substantial liver injury and fulminant hepatic failure.

Expert opinion: The present article reviews incidence and severity of hepatotoxicity associated with different classes and agents to provide a better understanding of this specific end organ toxicity and safer use of antifungal agents A thorough understanding of the distribution, metabolism, elimination and drug-drug interactions of antifungal agents used for management of IFDs in combination with safety data from clinical trials, pharmacokinetic and pharmacodynamic studies may guide the use of antifungal treatment in patients at high risk for the development of hepatic dysfunction and in those with underlying liver damage due to cytotoxic therapy.     

Use of a semi-physiological pharmacokinetic model to investigate the influence of itraconazole on tacrolimus absorption,distribution and metabolism in mice

1.?The aim of this study was to investigate the influence of itraconazole (ITCZ) on tacrolimus absorption, distribution and metabolism by developing a semi-physiological pharmacokinetic model of tacrolimus in mice.

2.?Mice were randomly divided into four groups, namely control group (CG, taking 3?mg kg^?1 tacrolimus only), low-dose group (LDG, taking tacrolimus with 12.5?mg kg^?1 ITCZ), medium-dose group (MDG, taking tacrolimus with 25?mg kg^?1 ITCZ) and high-dose group (HDG, taking tacrolimus with 50?mg kg^?1 ITCZ).

3.?Liver clearance (CL_li) decreased significantly (**p?<?0.01) in LDG (35.3%), MDG (45.2%) and HDG (58.7%) mice compared to CG mice. With respect to gut clearance (CL_gu), significant (**p?<?0.01) decrease was also revealed in LDG (35.9%), MDG (50.2%) and HDG (64.6%) mice. A significant (**p?<?0.01) higher tacrolimus brain-to-blood partition coefficient (K_t,br) was found in MDG (25.3%) and HDG (55.9%) mice than in CG mice. Moreover, a significant (*p?<?0.05) increase (16.3%) was found in the absorption rate constant (K_a) in HDG mice compared to CG mice. There was a significant (**p?<?0.01) association between ITCZ dose and the change in CL_gu (ΔCL_gu, r=??0.790), the change in CL_li (ΔCL_li, r=??0.787) and the change in K_t,br (ΔK_t,br, r?=?0.727), while the association between ITCZ dose and the change in K_a (ΔK_a) was not significant (p?>?0.05).

4.?These findings could be useful in predicting the efficacy and toxicity of tacrolimus, and drug–drug interaction of ITCZ and tarcolimus in human.     

Exploring the feasibility of the use of biopolymers as a carrier in the formulation of amorphous solid dispersions – Part I: Gelatin

Biopolymers have rarely been used so far as carriers in the formulation of amorphous solid dispersions (ASD) to overcome poor solubility of active pharmaceutical ingredients (APIs). In an attempt to enlarge our knowledge on this topic, gelatin, type 50PS was selected. A screening study was initiated in which twelve structurally different poorly soluble biopharmaceutical classification system (BCS) Class II drugs (carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen) were selected for evaluation. Solid dispersions of five different drug loadings of these twelve compounds were prepared by lyophilization and evaluated for their solid state properties by mDSC and XR(P)D, and in vitro dissolution performance. Even without any process optimization it was possible to form either fully amorphous or partially amorphous systems, depending on the API and API to carrier ratio. Hence in this respect, gelatin 50PS behaves as any other carrier. Dissolution of the API from the solid dispersions significantly exceeded that of their crystalline counterparts. This study shows the potential of gelatin as a carrier to formulate amorphous solid dispersions.     

伊曲康唑分散片在健康人体的生物等效性

目的研究伊曲康唑分散片和伊曲康唑胶囊(抗真菌药)在健康人体的生物等效性。方法采用两制剂双周期双交叉随机自身对照试验设计,20名男性健康志愿者分别口服伊曲康唑胶囊0.2g和伊曲康唑分散片0.2g(参比制剂和受试制剂),用HPLC法测定给药后不同时刻伊曲康唑的血药浓度,用DASVer1.0计算药代动力学参数。结果受试制剂与参比制剂的伊曲康唑主要药代动力学参数:t1/2分别为(20.89±4.58)、(21.05±4.37)h,Cmax分别为(244.3±69.8)、(240.2±66.3)ng·mL-1,tmax分别为(4.05±0.91)、(3.98±1.12)h,AUC0-72分别为(2786.5±670.3)、(2802.8±612.3)ng·h·mL-1,受试制剂与参比制剂相比平均相对生物利用度为(96.8±8.7)%。结论2种制剂在人体内具有生物等效性。     

氟康唑和伊曲康唑先后应用致麻疹样疹

1例78岁女性患者因脑出血、右侧中枢性偏瘫、肺部感染住院治疗。入院第21天，尿、便中检出霉菌孢子和菌丝，考虑霉菌感染。给予氟康唑静脉滴注治疗，首日0．4g／d，以后0．2g／d。3d后患者胸腹部出现红色斑疹，轻度瘙痒。停用氟康唑，改用伊曲康唑0．25g，2：L／d静脉滴注。治疗2d后，患者躯干和四肢红色斑疹继续增多，瘙痒显著。停用伊曲康唑，改用大蒜素静脉滴注并口服氯苯那敏抗过敏治疗，5d后皮疹基本消退。     

HPLC测定人血浆中伊曲康唑的浓度及生物等效性研究

 目的建立HPLC测定伊曲康唑人血浆中浓度和评价伊曲康唑分散片的生物等效性。方法18名健康志愿者单剂量po分散片及胶囊2种伊曲康唑制剂(各含伊曲康唑0.1g)后测定不同时间血药浓度,采用Kromail C₁₈色谱柱(4.6mm×250mm,5μm),以乙腈-水(78∶22)为流动相,流速1.0mL·min^-1;检测波长263nm,检测器灵敏度0.01AUFS,20μL定量环进样。结果受试制剂伊曲康唑分散片和参比制剂伊曲康唑胶囊中伊曲康唑的主要药动学参数:达峰时间为(3.89±0.32)和(3.94±0.24)h,达峰时药物浓度为(1601.12±151.03)和(1678.74±200.37)μg·L^-1,消除相半衰期为(16.50±1.80)和(16.43±1.35)h,药-时曲线下面积AUC_0-72为(21194.89±2604.04)和(21795.72±2657.52)μg·h·L^-1,AUC_0-∞为(22418.87±2921.60)和(23060.62±2865.28)μg·h·L^-1。结论2种伊曲康唑制剂具有生物等效性。     

口服伊曲康唑与外用酮康唑洗剂联合治疗糠秕孢子菌性毛囊炎

目的:观察口服伊曲康唑与外用酮康唑洗剂联合治疗糠秕孢子菌性毛囊炎的疗效。方法:选择临床症状典型,经真菌学检查确诊的糠秕孢子菌性毛囊炎病人52例,分为2组。治疗组27例中男性18例,女性9例,年龄(28±s11)a,与餐同服或餐后即服伊曲康唑200mg,qd,连续7d,同时外用2%酮康唑洗剂,qd,连续用药4wk。对照组25例中男性19例,女性6例,年龄(29±10)a,单纯口服伊曲康唑200mg,qd,疗程同上。观察用药后1,4wk,2组疗效。结果:对照组1,4wk有效率分别为52%和68%,治疗组分别为59%和96%,2组1wk疗效差异无显著意义,4wk疗效治疗组优于对照组。结论:口服伊曲康唑与外用酮康唑洗剂治疗糠秕孢子菌性毛囊炎疗效好。