不同HIV蛋白酶抑制剂对鼠胰岛素瘤细胞功能的影响

目的：探讨不同HIV蛋白酶抑制剂对胰岛beta-细胞功能的影响。方珐：体外观察不同浓度ritonavir或amprenavir干预48h对鼠胰岛素瘤INS-1细胞葡萄糖刺激的胰岛素释放速率的影响，胰岛素测定采用ELISA法，并用细胞内DNA含量标准化。用苔盘蓝染色细胞计数、MTT试验评估ritonavir或amprenavir对INS-1细胞活力的影响。结果：Ritonavir治疗可以显著降低基础胰岛素分泌速率及葡萄糖刺激的胰岛素释放速率，并呈剂量依赖关系（r分别为-0．861，-0．839，均P〈0．01）。10μmol／L ritonavir分别降低基础胰岛素分泌和葡萄糖刺激的胰岛素释放达46％和47％。Amprenavir对胰岛素释放功能没有影响。结论：不同HIV蛋白酶抑制剂对胰岛beta-细胞功能的影响不同。     

Selective Laser Sintering 3-Dimensional Printing as a Single Step Process to Prepare Amorphous Solid Dispersion Dosage Forms for Improved Solubility and Dissolution Rate

This study reports the development of ritonavir-copovidone amorphous solid dispersions (ASDs) and dosage forms thereof using selective laser sintering (SLS) 3-dimensional (3-D) printing in a single step, circumventing the post-processing steps required in common techniques employed to make ASDs. For this study, different drug loads of ritonavir with copovidone were processed at varying processing conditions to understand the impact, range, and correlation of these parameters for successful ASD formation. Further, ASDs characterized using conventional and advanced solid-state techniques including wide-angle X-ray scattering (WAXS), solid-state nuclear magnetic resonance (ssNMR), revealed the full conversion of the crystalline drug to its amorphous form as a function of laser-assisted selective fusion in a layer-by-layer manner. It was observed that an optimum combination of the powder flow properties, surface temperature, chamber temperature, laser speed, and hatch spacing was crucial for successful ASD formation, any deviations resulted in print failures or only partial amorphous conversion. Moreover, a 21-fold increase in solubility was demonstrated by the SLS 3-D printed tablets. The results confirmed that SLS 3-D printing can be used as a single-step platform for creating ASD-based pharmaceutical dosage forms with a solubility advantage.     

A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir

IntroductionTwo solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored.MethodsAdult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0.ResultsModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1–2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration–time curve (AUC_0–48) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment.ConclusionOral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising.     

Therapeutic Drug Monitoring of Indinavir in HIV-Infected Patients Undergoing HAART

Background: Therapeutic drug monitoring (TDM) of protease inhibitors (PI) is gaining increasing importance for the management of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). The PI indinavir (IDV) is widely used in HAART regimens. Combinations of IDV with ritonavir (RTV) have been used to increase the plasma concentration of IDV. However, the desirable IDV concentration range in clinical practice remains to be elucidated. Patients and Methods: To study the value of TDM for IDV in clinical practice, a retrospective analysis of 501 plasma samples of patients treated with IDV in various dosages was performed. IDV levels were determined during routine outpatient visits. Analysis was performed by high pressure liquid chromatography (HPLC) with UV detection. Results: A widespread range of IDV plasma concentrations was seen both within and between patients. The mean IDV level during therapy with IDV 2.4 g/d was 3,260 ng/ml (95% CI: 2,903 ng/ml; 3,618 ng/ml). IDV levels at a dose of IDV 1.6 g/d in combination with RTV resulted in a mean IDV plasma concentration of 4,191 ng/ml (95% CI: 3,356 ng/ml; 5,016 ng/ml). There was no significant difference between plasma levels at the doses of 2.4 g/d and 1.6 g/d. 35 of all 130 patients treated with IDV reached only suboptimal IDV plasma concentrations below the limit of 150 ng/ml. There was no statistically significant difference between the number of patients below an IDV plasma concentration of 150 ng/ml in the various dosage regimens. Conclusion: During therapy with IDV in a b.i.d. scheme, similar IDV plasma concentrations and a comparable number of patients with subinhibitory plasma concentrations were observed when compared to a therapeutic regimen with t.i.d. dosing. In this study, even at various times of plasma sampling after oral ingestion, TCM facilitated the surveillance of patients compliance. Received: August 07, 2000 · Revision accepted: August 27, 2001     

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.     

Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo

Ritonavir, an HIV protease inhibitor, is successfully used for the prevention and treatment of HIV infections. Ritonavir pharmacokinetics are complicated by inhibition, induction and pharmacogenetics of cytochrome P450 (CYP) enzymes mediating its clearance. This investigation revealed that CYP2J2, along with CYP3A4/5 and CYP2D6, efficiently metabolizes ritonavir, and to a CYP2J2-specific (minor) metabolite. Chemical inhibition of ritonavir metabolism, clearance, K_I/k_inact and abundance of CYP2J2 in liver microsomes were evaluated and then applied to an in vitro–in vivo static scaling model to estimate the contribution of each isozyme, as a function of CYP abundance, activity, and genotype. Disposition of the CYP2J2-specific metabolite was also evaluated in vivo. In plasma, metabolite abundance was well above previously reported levels with circulating concentrations measured at 2 μM for the main hydroxylisopropyl metabolite. Ritonavir and metabolite plasma profiles were simulated using Simcyp^®. A modest (2–6%) contribution of CYP2J2 to ritonavir clearance is predicted which increases to more than 20% in subjects carrying CYP2D6 poor metabolizer polymorphisms and CYP3A4 irreversible inhibition. These results indicate that minor drug metabolizing enzymes could become quantitatively important in RTV clearance if main metabolic pathways are impeded.     

3D方案治疗基因1b型低病毒载量慢性丙型肝炎患者应答疗效研究*

目的 观察3D方案(帕里瑞韦/利托那韦/奥比他韦)联合达塞布韦治疗基因1b型低血清病毒载量的慢性丙型肝炎(CHC)患者的疗效及其血浆γ-干扰素(IFN-γ)和干扰素诱导蛋白10(IP-10)水平的变化。方法 2019年5月～2020年5月在我院接受治疗的基因1b型低血清病毒载量的CHC患者77例(初始治疗者62例,复治患者15例),接受3D方案联合达塞布韦治疗3个月,并随访3个月。采用ELISA法检测血浆IFN-γ和IP-10水平变化。评估早期病毒学应答(EVR)、治疗结束时病毒学应答(ETVR)和随访12周结束时持续病毒学应答(SVR12)。结果 在接受3D方案抗病毒治疗后,初治患者EVR、ETVR和SVR12分别为51.6%、100.0%和100%,经治患者EVR、ETVR和SVR12分别为46.7%、100.0%和100%,两组差异无统计学意义(P>0.05);在治疗1 m、2 m、3 m和随访3 m,77例CHC患者血清HCV RNA转阴率分别为93.5%、98.7%、100.0%和100.0%;血清HCV RNA水平分别为(1.1±0.1)log₁₀IU/ml、(1.1±0.1)log₁₀IU/ml、(1.1±0.1)log₁₀IU/ml、(1.0±0.1)log₁₀IU/ml,显著低于治疗前;血清ALT水平分别为(16.8±4.1)U/L、(15.3±3.9)U/L、(11.1±3.2)U/L和(12.0±3.4)U/L,显著低于治疗前【(151.4±16.0)U/L,P<0.05】,血清AST水平分别为(20.4±4.7)U/L、(17.9±4.4)U/L、(18.0±5.1)U/L和(14.7±4.8)U/L,显著低于治疗前【(153.8±15.9),P<0.05】;血浆IFN-γ水平分别为(46.9±5.8)pg/ml、(50.2±6.3)pg/ml、(57.0±6.9)pg/ml和(51.3±4.6)pg/ml,显著高于治疗前,IP-10水平分别为(100.5±36.1)pg/ml、(72.1±22.8)pg/ml、(66.8±13.4)pg/ml和(68.7±12.5)pg/ml,显著低于治疗前。结论 无论初治还是复治的基因1b型低血清病毒载量的CHC患者,采用3D方案治疗均可取得较好的近期疗效,安全性良好,需要继续随访观察长期疗效。     

Rabdomiólisis y hepatotoxicidad grave por interacción entre ritonavir y simvastatina. ¿Puede emplearse la estatina más coste-efectiva en todos los pacientes infectados por el virus de la inmunodeficiencia humana?

Introduction

Drugs like statins may induce rhabdomyolysis. Simvastatin and lovastatin have a high hepatic metabolism and their potential toxicity could be increased by interactions with other drugs that reduce their metabolism.

Patients and methods

A case-report is presented of an HIV-infected patient treated with antiretroviral drugs who developed a rhabdomyolysis-induced renal failure and liver toxicity when simvastatin was substituted for atorvastatin. A literature review is also presented.

Results

The patient required hospital admission and showed a favorable response after hydration and urine alkalinization. There were 4 additional cases published of which there was one death.

Conclusions

Drug-drug interactions can increase the risk of statin induced rhabdomyolysis. In order to evaluate them properly, physicians at all levels of clinical care should be aware of all drugs prescribed to their patients and the contraindicated combinations.