Phase I and scintigraphy studies to evaluate safety,tolerability, pharmacokinetics,and lung deposition of inhaled GDC‐0214 in healthy volunteers

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (^99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. ^99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma C_max similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many factors drive asthma pathogenesis, including several cytokines that signal through the Janus kinase 1 (JAK1) pathway. Inhibition of JAK1 is a possible target for asthma treatments, but previous studies show oral JAK1 inhibitors lead to increased risk of severe infections, malignancy and cardiovascular events.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the safety, pharmacokinetics, and lung deposition of GDC‐0214, an inhaled JAK1 inhibitor designed to target the lungs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Inhaled delivery of a JAK inhibitor for 14 days exhibited low systemic exposure, leading to few adverse events and limited systemic toxicity, while demonstrating high deposition in the lungs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Local pulmonary application of JAK inhibitors may be an effective treatment for asthma with limited systemic risks.     

The preventive effect of systemic treatment with interferon-alpha2B for infertility from mumps orchitis.

OBJECTIVE: To evaluate the effect of interferon-alpha2B on mumps orchitis, often caused by postpubertal mumps and which can result in permanent testicular atrophy. PATIENTS AND METHODS: The study included 21 patients with mumps orchitis, treated between May 1990 and June 1997. Patients were randomly assigned into two groups: in group 1, 13 patients received therapy with interferon-alpha2B (3 x 10(6) IU per day) and group 2 did not, acting as controls. All were evaluated by measurements of testis size, mumps virus titre, hormone level and semen analysis. RESULTS: In group 1, the patients' symptoms resolved within 2-3 days and the volume of the testes returned to normal within 11 days; there was no testicular atrophy in any patient during the follow-up. However, asthenospermia continued to be detected in four patients (unilateral in two, bilateral in two). In group 2, the patients' symptoms resolved within 5-6 days and the volume of the testes returned to normal within 10 days; testes atrophied in three patients (unilateral in two, bilateral in one) during the follow-up. Asthenospermia continued in four patients (unilateral in two, bilateral in two). CONCLUSION: These results suggest that treatment with systemic interferon-alpha2B is effective in preventing testicular atrophy when combined with standard symptomatic treatment.     

Evaluation of Femoral Tunnel Positioning Using 3-Dimensional Computed Tomography and Radiographs after Single Bundle Anterior Cruciate Ligament Reconstruction with Modified Transtibial Technique

Background

The purpose of this study is to report a modified transtibial technique to approach the center of anatomical femoral footprint in anterior cruciate ligament (ACL) reconstruction and to investigate the accurate femoral tunnel position with 3-dimensional computed tomography (3D-CT) and radiography after reconstruction.

Methods

From December 2010 to October 2011, we evaluated 98 patients who underwent primary ACL reconstruction using a modified transtibial technique to approach the center of anatomical femoral footprint in single bundle ACL reconstruction with hamstring autograft. Their femoral tunnel positions were investigated with 3D-CT and radiography postoperatively. Femoral tunnel angle was measured on the postoperative anteroposterior (AP) radiograph and the center of the femoral tunnel aperture on the lateral femoral condyle was assessed with 3D-CT according to the quadrant method by two orthopedic surgeons.

Results

According to the quadrant method with 3D-CT, the femoral tunnel was measured at a mean of 32.94% ± 5.16% from the proximal condylar surface (parallel to the Blumensaat line) and 41.89% ± 5.58% from the notch roof (perpendicular to the Blumensaat line) with good interobserver (intraclass correlation coefficients [ICC], 0.766 and 0.793, respectively) and intraobserver reliability (ICC, 0.875 and 0.893, respectively). According to the radiographic measurement on the AP view, the femoral tunnel angles averaged 50.43° ± 7.04° (ICC, 0.783 and 0.911, respectively).

Conclusions

Our modified transtibial technique is anticipated to provide more anatomical placement of the femoral tunnel during ACL reconstruction than the former traditional transtibial techniques.     

Role of Intraoperative Cholangiography in Patients Whose Biliary Tree Was Evaluated Preoperatively by Magnetic Resonance Cholangiopancreatography

Background

Routine performance of intraoperative cholangiography (IOC) during cholecystectomy is controversial. The aim of this study was to evaluate the role of IOC during cholecystectomy in addition to preoperative magnetic resonance cholangiopancreatography (MRCP) in our institution over a 12-year period.

Methods

A total of 425 consecutive patients who underwent IOC during cholecystectomy were included in this study. MRCP was performed preoperatively for bile duct evaluation in all patients. When common bile duct (CBD) stones were detected, they were removed endoscopically before the operation. We estimated the results of IOC in terms of the success rate, the detection rate of anatomic abnormality of the biliary system, and the incidence of residual CBD stones.

Results

MRCP preoperatively identified 6 (1.4?%) patients with abnormal biliary systems and 56 with CBD stones, which were endoscopically removed. The success rate of IOC was 93.8?% (399/425). Abnormalities of the biliary system were detected in 12 patients (12/399, 3.0?%) and CBD stones in 8 (8/399, 2.0?%). Of the eight patients with stones, seven had been examined by endoscopy preoperatively and found to have CBD stones. The detection rate of bile duct stones in patients with preoperative endoscopic removal of CBD stones (7/56, 12.5?%) was significantly higher than those with CBD stones first detected during IOC (1/365, 0.3?%) (p?<?0.01). Moreover, no residual CBD stones were detected in patients who were operated on within fewer than 12?days from endoscopic treatment to the operation.

Conclusions

IOC is indicated even after preoperative sphincterotomy for CBD stones. In our study, it resulted in a 12.5?% incidence of persistent stones after sphincterotomy. IOC plays an additional role in detecting CBD stones and in revealing abnormalities of the biliary tree in patients whose biliary tree was preoperatively evaluated by MRCP.     

改良导尿管在尿道成形术患儿中的应用

目的 探讨改良导尿管对小儿尿道成形术后引流尿液,缓解患儿排尿疼痛,减少术后并发症的作用.方法 将120例尿道成形术后患儿随机均分为两组.对照组按常规方法,在新成形尿道内置一管径8～10F的多侧孔短硅胶支架管.观察组则应用8～12F改良导尿管引流尿液,即在导尿管中、下段剪多个侧孔,持续导尿10 d左右后将改良导尿管中段多侧孔段下移至新建尿道处作为短支架管,指导患儿自控排尿.结果 观察组术后排尿疼痛评分显著低于对照组,术后并发症发生率显著低于对照组(均P＜0.01);两组术后尿培养均为阴性,无尿路逆行感染.结论 应用改良导尿管引流尿液能有效缓解小儿尿道成形术后排尿疼痛,减少手术并发症.     

2016/2018中国麻醉领域临床实践指南质量评价

[目的]采用AGREE-China指南质量评价工具对我国2016/2018麻醉领域临床实践指南进行质量评价,以期了解我国麻醉领域临床实践指南现状。[方法]登录中国知网(CNKI)、万方数据(Wanfang)、维普(VIP)和中国生物医学文献数据库(CBM)4个中文期刊数据库,检索我国近3年制订的麻醉领域相关临床实践指南,检索时限为2016-01-01/2018-12-31。由2位评价员按照纳入与排除标准独立完成文献筛选和资料提取,并采用AGREE-China对纳入指南进行质量评价。[结果]共纳入19部指南或共识,其在AGREE-China 5个领域平均得分如下:科学性与严谨性为19.79%,有效性与安全性为52%,经济性为0,可用性与可行性为68.42%,利益冲突为0。[结论]我国麻醉领域相关临床实践指南较倾向于临床实用性,但总体质量不高,大部分缺乏循证医学证据。在今后指南制订中要特别注重指南制订的科学严谨性、安全有效性和经济性,提高对利益冲突领域的关注,并及时对指南进行更新修订。     

Computed tomography arterial portography for assessment of portal vein injury after blunt hepatic trauma

PURPOSE

Intrahepatic portal vein injuries secondary to blunt abdominal trauma are difficult to diagnose and can result in insidious bleeding. We aimed to compare computed tomography arterial portography (CTAP), reperfusion CTAP (rCTAP), and conventional computed tomography (CT) for diagnosing portal vein injuries after blunt hepatic trauma.

METHODS

Patients with blunt hepatic trauma, who were eligible for nonoperative management, underwent CTAP, rCTAP, and CT. The number and size of perfusion defects observed using the three methods were compared.

RESULTS

A total of 13 patients (seven males/six females) with a mean age of 34.5±14.1 years were included in the study. A total of 36 hepatic segments had perfusion defects on rCTAP and CT, while there were 47 hepatic segments with perfusion defects on CTAP. The size of perfusion defects on CT (239 cm³; interquartile range [IQR]: 129.5, 309.5) and rCTAP (238 cm³; IQR: 129.5, 310.5) were significantly smaller compared with CTAP (291 cm³; IQR: 136, 371) (both, P = 0.002).

CONCLUSION

Perfusion defects measured by CTAP were significantly greater than those determined by either rCTAP or CT in cases of blunt hepatic trauma. This finding suggests that CTAP is superior to rCTAP and CT in evaluating portal vein injuries after blunt liver trauma.The liver is one of the most frequently injured solid abdominal organs in the setting of blunt abdominal trauma (1). Fortunately, most patients with blunt hepatic trauma have relatively stable vital signs and need only supportive treatment or transarterial embolization (TAE) (1–9). Only 15% of patients, who present with hemodynamic instability or fail with nonoperative management, require operative intervention to manage their liver injury.Embolic therapy has been shown to have a high success rate in hemodynamically stable patients with blunt hepatic injury. TAE is associated with decreased abdominal infections, decreased transfusions, and decreased length of hospital stay compared with operative management (2, 3, 7). However, angiography can only detect bleeding from the hepatic artery; it cannot locate bleeding from the hepatic or portal vein. In the literature, portal vein injuries are not commonly described and most are the result of penetrating injuries to the extrahepatic portal veins. Mortality after a portal vein injury due to trauma is primarily due to hypovolemic shock and can be as high as 50% or greater (10, 11).Since the intrahepatic portions of the hepatic and portal veins are low pressure systems, they can bleed insidiously. Nevertheless, this subtle bleeding may require multiple transfusions and result in a prolonged hospital stay. Relative to an extrahepatic portal vein injury, patients with an intrahepatic portal vein injury may have relatively stable vital signs and slowly decreasing hemoglobin levels (10, 11). In addition, traumatic occlusion and/or thrombosis of the portal vein may cause large hepatic parenchymal infarction.Computed tomography arterial portography (CTAP) is a useful method based on portal enhancement of the liver by infusion of contrast material through the superior mesenteric artery for evaluating the portal venous system (12–15) and is widely used in patients with hepatic tumors with portal venous invasion (13, 16, 17). CTAP has a high sensitivity and specificity in the evaluation of portal vein thrombosis due to tumor (90% sensitivity, 99% specificity, 95% positive predictive value, 97% negative predictive value) (14). However, few studies have focused specifically on the utility of CTAP in the evaluation of portal vein injury as a result of trauma.The liver has a dual blood supply and receives between 66% and 75% of its blood supply from the hepatic portal vein with the remainder supplied by the hepatic artery (18). CTAP reflects only portal venous perfusion while reperfusion CTAP (rCTAP) reflects hepatic arterial reperfusion. Both rCTAP and conventional computed tomography (CT) are useful for determining certain liver injuries. However, they do not specifically evaluate the portal vein.The purpose of this study was to compare CTAP, rCTAP, and CT for diagnosing portal vein injuries after blunt hepatic trauma. We hypothesized that CTAP would be superior to rCTAP and CT in assessing portal vein injury after blunt hepatic trauma.     

Is there any correlation between model-based perfusion parameters and model-free parameters of time-signal intensity curve on dynamic contrast enhanced MRI in breast cancer patients?

Objective

To find out any correlation between dynamic contrast-enhanced (DCE) model-based parameters and model-free parameters, and evaluate correlations between perfusion parameters with histologic prognostic factors.

Methods

Model-based parameters (Ktrans, Kep and Ve) of 102 invasive ductal carcinomas were obtained using DCE-MRI and post-processing software. Correlations between model-based and model-free parameters and between perfusion parameters and histologic prognostic factors were analysed.

Results

Mean Kep was significantly higher in cancers showing initial rapid enhancement (P?=?0.002) and a delayed washout pattern (P?=?0.001). Ve was significantly lower in cancers showing a delayed washout pattern (P?=?0.015). Kep significantly correlated with time to peak enhancement (TTP) (ρ?=??0.33, P?<?0.001) and washout slope (ρ?=?0.39, P?=?0.002). Ve was significantly correlated with TTP (ρ?=?0.33, P?=?0.002). Mean Kep was higher in tumours with high nuclear grade (P?=?0.017). Mean Ve was lower in tumours with high histologic grade (P?=?0.005) and in tumours with negative oestrogen receptor status (P?=?0.047). TTP was shorter in tumours with negative oestrogen receptor status (P?=?0.037).

Conclusions

We could acquire general information about the tumour vascular physiology, interstitial space volume and pathologic prognostic factors by analyzing time-signal intensity curve without a complicated acquisition process for the model-based parameters.

Key points

? Kep mainly affected the initial and delayed curve pattern in time–signal intensity curve. ? There is significant correlation between model-based and model-free parameters. ? We acquired information about tumour vascular physiology, interstitial space volume and prognostic factors.     

Enhancing islet engraftment with rosiglitazone

To study the role of a peroxisome proliferator-activated receptor agonist, rosiglitazone, on islet engraftment, streptozotocin-induced diabetic C57BL/6 mice were fed daily rosiglitazone (2.4 mg/kg) for 9 and 31 days starting 2 days before transplantation with 75 and 150 syngeneic islets, respectively. After receiving 75 islets and 9 days of rosiglitazone, half of the treated diabetic mice became normoglycemic at 4 weeks, while none were normoglycemic among those mice that did not receive treatment. After transplanting 150 islets and receiving 31 days of rosiglitazone, 80% of the treated diabetic mice became normoglycemic while the incidence was only 25% for the controls. The insulin content of the islet grafts in the rosiglitazone groups was 0.8 times (75-islet group) and 1.3 times (150-islet group) higher than that of control mice. The insulin content of pancreatic remnants did not differ significantly among all groups. An in vitro study revealed that the glucose-stimulated insulin secretion and insulin content of cultured islets was not different in the presence versus absence of 4.5 or 22.5 micromol/L rosiglitazone. In vitro study revealed that rosiglitazone inhibited the lipopolysaccharide-induced secretion of interleukin-1 beta and interferon-gamma from peritoneal exudate cells. In conclusion, our data suggest that short-term administration of rosiglitazone enhances islet engraftment.