Effect of CYP3A4 induction and inhibition on the pharmacokinetics of SHR0302 in healthy subjects.

AIMS: SHR0302 is a selective Janus kinase (JAK) 1 inhibitor under clinical investigation for the treatment of rheumatoid arthritis (RA). As SHR0302 is metabolized mainly by cytochrome P450 (CYP) 3A4, clinical studies were performed to evaluate the effects of a strong CYP3A4 inducer, rifampin, and a strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of SHR0302 in healthy subjects. METHODS: Two phase I, open-label, fixed-sequence drug interaction studies enrolled 28 subjects. In Study A, 14 subjects received 8 mg SHR0302 on Days 1 and 10, and 600 mg rifampin once daily on Days 3-11. In Study B, 14 subjects received 4 mg SHR0302 on Days 1 and 8, and 200 mg itraconazole once daily on Days 4-10. Blood samples were collected to measure SHR0302 concentrations. Pharmacokinetic parameters were calculated using non-compartmental analysis. Treatment comparisons were made using mixed-effect models. RESULTS: Co-administration with rifampin decreased the exposures of SHR0302 with geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for AUC0-inf of 0.51 (0.49, 0.54) and Cmax of 0.91 (0.84, 0.98). Co-administration with itraconazole increased the exposures of SHR0302 with GMR (90% CIs) for AUC0-inf of 1.48 (1.41, 1.56) and Cmax of 1.06 (0.982, 1.14). Single oral doses of SHR0302 administered with or without rifampin or itraconazole were generally safe. CONCLUSIONS: Strong CYP3A4 induction and inhibition both resulted in a weak effect on the clinical exposures of SHR0302. These present studies provided valuable information that helps inform SHR0302 dosing instructions and concomitant medication precautions.

Efficacy and safety of bivalirudin during percutaneous coronary intervention in high-bleeding-risk elderly patients with chronic total occlusion: A prospective randomized controlled trial.

OBJECTIVES: To assess the efficacy and safety of bivalirudin during percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) in high-bleeding-risk elderly patients. BACKGROUND: Bivalirudin reduces PCI-related bleeding; however, its efficacy and safety in patients with CTO, especially elderly patients with a high bleeding risk, remain unclear. METHODS: This single-center prospective randomized controlled trial assigned 123 high-bleeding-risk elderly patients with CTO to either the unfractionated heparin (UFH) group (n = 55) or the bivalirudin group (n = 68). The primary efficacy endpoint was the incidence of major adverse cardiac events (MACEs) during hospitalization and at the 6-month follow-up. The safety endpoint was bleeding or procedure (access)-related complications after PCI. RESULTS: MACE incidence was 17.6% and 20.0% in the bivalirudin and UFH groups, respectively (P = 0.82). Bleeding Academic Research Consortium (BARC) type 1-2 bleeding events during hospitalization were comparable between the groups (UFH: 10.9% vs. bivalirudin: 8.8%, P = 0.77). No BARC type 3-5 bleeding events or severe procedure (access)-related complications (subcutaneous hematoma >5 cm) occurred in either group. At the 6-month follow-up, MACE incidence was comparable between the groups (UFH: 3.6% vs. bivalirudin: 1.5%, P = 0.59). The Kaplan-Meier analysis revealed that MACE-free survival rates were comparable between the groups (P = 0.43). One case of BARC type 3-5 bleeding (fatal intracranial hemorrhage) was observed in the UFH group at the 6-month follow-up. CONCLUSIONS: Bivalirudin and UFH showed comparable efficacy and safety in elderly patients with a high bleeding risk, undergoing PCI for CTO lesions.

CHA2DS2-VASC score as a preprocedural predictor of contrast-induced nephropathy among patients with chronic total occlusion undergoing percutaneous coronary intervention: a single-center experience.

BACKGROUND: The usefulness of the CHA2DS2-VASC risk score (CVRS) in predicting the occurrence of contrast-induced nephropathy (CIN) among patients with chronic total occlusion (CTO) undergoing percutaneous coronary intervention (PCI) remains unclear. METHOD: A total of 239 patients with CTO who underwent PCI were included in this study. They were divided into 3 groups according to the CVRS: low-risk group (1 point, n = 64), intermediate-risk group (2 points, n = 135), and high-risk group (≥3 points, n = 40). Baseline serum creatinine was determined upon admission before the procedure. The serum creatinine level was monitored for 72 h post-procedure to determine the occurrence of CIN. RESULTS: The total incidence of CIN in patients with CTO who underwent PCI was 16.3%. The average CVRS in the CIN group was significantly higher than that in the non-CIN group (3.1 ± 1.2 VS 2.1 ± 1.1, P < 0.001). The incidence of CIN in the high-risk group was 5.6 times higher than that in the low-risk group (37.5% VS 6.3%, P < 0.001). Similar to the Mehran risk score (AUC, 0.754; 95% CI, 0.698-0.810; P < 0.001), the receiver operating characteristic curve analysis showed a good diagnostic value of the CVRS in predicting CIN among patients with CTO who underwent interventional therapy for having CVRS≥3 (sensitivity, 69.2%; specificity, 78.0%; AUC, 0.742; 95% CI, 0.682-0.797; P < 0.001). The multivariate analysis showed that the higher pulse pressure and contrast volume, lower baseline glomerular filtration rate, and CVRS ≥3 were independent predictors of CIN. CONCLUSIONS: The CVRS can be used as a simple pre-procedural predictor of CIN among patients with CTO undergoing PCI.

Application of Acoustic Radiation Force Impulse Imaging for Diagnosis of Female Bladder Neck Obstruction.

OBJECTIVES: To determine the application value of combined transperineal sonography and Virtual Touch tissue quantification (Siemens Medical Solutions, Mountain View, CA) on acoustic radiation force impulse imaging as a scanning method for diagnosis of female bladder neck obstruction. METHODS: Transperineal sonography and Virtual Touch tissue quantification were combined to depict the bladder neck and observe its sonographic characteristics in 36 patients with female bladder neck obstruction and 30 healthy adults in a case-control study. We measured the thickness and shear wave velocity (SWV) of the bladder neck's anterior and posterior lips. RESULTS: There was a statistically significant difference in the thickness and SWV of the bladder neck between the healthy women and those with bladder neck obstruction, whose SWV was higher (P< .05). For the anterior lip, an SWV of 2.11 m/s was the best cutoff point for differentiating bladder neck obstruction from a normal bladder neck; for the posterior lip, an SWV of 2.06 m/s was the best cutoff point. The mean thicknesses of the anterior and posterior lips ± SD were 0.66 ± 0.05 and 0.68 ± 0.05 cm in the group with bladder neck obstruction versus 0.45 ± 0.07 and 0.52 ± 0.09 cm in the normal group. There was a significant difference between them (P < .05). CONCLUSIONS: The bladder neck's anatomic structure can be observed visually by perineal sonography. Virtual Touch tissue quantification on acoustic radiation force impulse imaging can quantitatively reflect the bladder neck stiffness and change in texture. It could provide a quantitative indicator for clinical diagnosis of female bladder neck obstruction and etiology research and display important clinical values.

Effects of basic fibroblast growth factor dose on traumatic tympanic membrane perforation.

OBJECTIVE: To compare the healing outcomes of higher and lower doses of basic fibroblast growth factor (bFGF) on human traumatic tympanic membrane perforation (TMP). STUDY DESIGN: Prospective clinical study. METHODS: All patients with traumatic TMP were treated by direct application of bFGF, and were sequentially allocated into one of two groups: lower-dose group (2-3 drops of bFGF solution daily, approximately 0.1-0.15 mL) and higher-dose group (5-6 drops of bFGF solution daily, approximately 0.25-0.3 mL). The results of closure rate, closure time, and rate of otorrhea between the higher- and lower-dose groups were compared at 3 months. RESULTS: In total, 126 patients were included in this study. The higher-dose group showed significantly improved purulent otorrhea rate compared with the lower-dose group (p < 0.01) for perforations of the same size, although the closure rate of the middle-sized perforations did not differ significantly between higher- and lower-dose groups (p > 0.05). However, the lower-dose group had a significantly shorter closure time of 5 d compared with the higher-dose group (p < 0.05). In addition, although the lower-dose group showed shorter healing times (about 3 d) compared to the higher-dose group for large-sized perforations, the dosage of bFGF did not significantly affect the large-sized perforation closure rate (p > 0.05) or closure time (p > 0.05). Nine large-sized perforations with secondary purulent otorrhea achieved complete closure, with closure times of 7-25 (14.2 ± 5.8) d. CONCLUSION: This study suggested that continued daily application of a lower dose of bFGF not only shortens the closure time of human traumatic TMP but also avoids secondary purulent otorrhea.

Sensory Feedback and Central Neuronal Interactions in Mouse Locomotion.

Locomotion is a complex process involving specific interactions between the central neural controller and the mechanical components of the system. The basic rhythmic activity generated by locomotor circuits in the spinal cord defines rhythmic limb movements and their central coordination. The operation of these circuits is modulated by sensory feedback from the limbs providing information about the state of the limbs and the body. However, the specific role and contribution of central interactions and sensory feedback in the control of locomotor gait and posture remain poorly understood. We use biomechanical data on quadrupedal locomotion in mice and recent findings on the organization of neural interactions within the spinal locomotor circuitry to create and analyze a tractable mathematical model of mouse locomotion. The model includes a simplified mechanical model of the mouse body with four limbs and a central controller composed of four rhythm generators, each operating as a state machine controlling the state of one limb. Feedback signals characterize the load and extension of each limb as well as postural stability (balance). We systematically investigate and compare several model versions and compare their behavior to existing experimental data on mouse locomotion. Our results highlight the specific roles of sensory feedback and some central propriospinal interactions between circuits controlling fore and hind limbs for speed-dependent gait expression. Our models suggest that postural imbalance feedback may be critically involved in the control of swing-to-stance transitions in each limb and the stabilization of walking direction.

Association fiber tracts related to Broca's area: A comparative study based on diffusion spectrum imaging and fiber dissection.

Broca's area, made up of Brodmann areas (BA) 44 and 45 in the ventrolateral frontal region, is associated with language production and articulation. A comprehensive network analysis of Broca's area is necessary for understanding language function, which is still lacking. In this study, we attempted to investigate the association fiber tracts related to Broca's area using both diffusion spectrum imaging (DSI) and postmortem fiber dissection. DSI was performed on 10 healthy subjects and an atlas comprising the average data of 842 healthy subjects from the Human Connectome Project. Fiber dissection was implemented in 10 cerebral hemispheres of cadaver donors. The following five association fiber tracts related to Broca's area were identified: first, the distinct fasciculus of the inferior fronto-occipital fasciculus (IFOF), from Broca's area (BA44, BA45) and pars orbitalis (BA47) to the parietal and occipital lobes; second, the ventral superior longitudinal fasciculus (SLF-III), from the supramarginal gyrus (BA40) to the ventral precentral gyrus (PreG, BA6) and posterior Broca's area (BA44); third, the arcuate fascicle (AF), from the superior, middle, and inferior temporal gyrus (BA20, BA21, BA22) to Broca's area (BA44, BA45) and ventral PreG; fourth, the frontal aslant tract (FAT), from Broca's area (BA44, BA45) to the lateral superior frontal gyrus (SFG), medial SFG, and supplementary motor area (BA6, BA8, BA9); and fifth, the frontal longitudinal fasciculus (FLF), a novel intralobar frontal association fiber tract, from the anterior part of the middle frontal gyrus (MFG, BA46) and Broca's area (BA45) to the caudal MFG (BA8), caudal SFG, and dorsal PreG (BA6). Moreover, compared with the left FAT, the right FAT covered almost the entire inferior frontal gyrus (BA44, BA45, BA47). The cross validation between DSI and fiber dissection revealed a good consistence in the association fiber tracts of Broca's area. Combining DSI and fiber dissection, this study first identified five association fiber tracts related to Broca's area and characterized their structure and anatomy comprehensively. The frameworks provided key elements for functional research in Broca's area.

[Analysis of the effect of one-stage revascularization with internal carotid artery resection on cervical metastatic carcinoma in advanced head and neck carcinomas].

Objective:To analyze the therapeutic effect of internal carotid artery resection and one-stage revascularization in advanced cervical metastatic carcinoma. Method:Twenty-one patients with advanced head and neck malignant tumors who underwent internal carotid artery resection and one-stage revascularization were analyzed retrospectively. Among those, 11 patients suffered from hypo-pharyngeal carcinomas, 5 laryngeal carcinomas, 2 external auditory carcinomas, 1 middle ear carcinoma, and 2 parotid gland carcinomas. All patients received CT, MRI, DSA and other examinations before operation. It was found that all the internal carotid artery walls had been invaded by tumors, and there were different degrees of lumen stenosis. Autogenous saphenous vein grafts were used in 18 cases; artificial vessels were used in 3 cases. After revascularization, pedicled or free flaps were used to protect the anastomotic areas. All patients were treated with radiotherapy and chemotherapy according to different situations. Result:Among the 21 cases, 16 cases underwent reconstruction of cervical segment internal carotid and 5 cases were the skull base segment internal carotid. Twenty patients were successfully reconstructed in the first stage, and no vascular reconstruction-related nervous system complications occurred after operations. Postoperative imaging showed that the reconstructed blood vessels were well recanalized, with a success rate of 95.2%（20/21）. Only 1 case received ligation of internal carotid artery after the failure of vascular reconstruction. Among all the cases, the 1-year survival rate and 3-year survival rate were 90.5% and 40.4%, respectively. Conclusion:In patients with advanced head and neck malignant tumors with cervical metastatic cancer invading the internal carotid artery, one-stage revascularization after radical resection of the tumor and the internal carotid can achieve good therapeutic effect. Careful preoperative evaluation, proficient vascular anastomosis technology, adequate risk assessment and prevention are the key to the success of the operations.

In vivo corrosion behavior of Mg-Mn-Zn alloy for bone implant application.

Magnesium alloy has been implanted in rats to investigate the in vivo degradation behavior of magnesium for bone implant application. After 9 weeks postoperation, 100% implants were fixed and no inflammation was observed. Histological analysis showed new bone was formed around magnesium implant and no difference was found in the histological microstructure of the new bone and the cortical bone. A degradation or reaction layer, which was mainly composed of Ca, P, O, and Mg, was formed on the surface of magnesium alloy implants. High Ca content in the degradation layer displayed that magnesium could promote the deposition of Ca. Residual area calculation has showed that 10-17% magnesium alloy implant has been degraded in vivo. Compared with that of the controlled rats, no increase in serum magnesium and no disorder of kidney were observed after 15 weeks postoperation. After 18 weeks postoperation, 100% magnesium implants were fixed and no inflammation was observed. About 54% magnesium implant has degraded in vivo. Element analysis showed that Zn and Mn in Mg-Mn-Zn alloy distributed homogeneously in the residual magnesium implant, the degradation layer, and the surrounding bone tissue after 18 weeks implantation, indicating that Zn and Mn elements were easily absorbed by bioenvironment.

In vivo evaluation of biodegradable magnesium alloy bone implant in the first 6 months implantation.

In vivo degradation of magnesium alloy implant, the bone response to the magnesium, and the effect of the degradation of magnesium on the blood composition and organs were investigated by using light microscopy and scanning electronic microscopy with energy dispersive spectrum. Magnesium alloy showed different degradation rates in the marrow channel and the cortical bone. More degradation of magnesium implant was observed in the marrow channel than in the cortical bone. New bone tissue formed around the magnesium implants after 6 weeks implantation but no fibrous capsule was found. There existed two distinct layers separating the new bone tissue from the magnesium implant. On the magnesium implant side, crystalline magnesium calcium phosphate formed on the surface of the implant due to the reaction between the implant and blood or body fluid. On the new bone tissue side was a 10-30-microm membrane comprising two distinct layers with many fibroblasts in the layer close to the new bone tissue. The new bone was in tight contact with the implant through the membrane and phosphate layer due to the good osteoconductivity of the phosphate layer. After 10 and 26 weeks postimplantation, more new bone tissues as well as the membrane were found around the implant. However, no apparent increase in the thickness of the membrane was observed with the increasing of the implantation duration. Blood examination has shown that the degradation of the magnesium implant caused little change to blood composition but no disorder to liver or kidneys.

In vitro and in vivo evaluation of the surface bioactivity of a calcium phosphate coated magnesium alloy.

Magnesium has shown potential application as a bio-absorbable biomaterial, such as for bone screws and plates. In order to improve the surface bioactivity, a calcium phosphate was coated on a magnesium alloy by a phosphating process (Ca-P coating). The surface characterization showed that a porous and netlike CaHPO(4).2H(2)O layer with small amounts of Mg(2+) and Zn(2+) was formed on the surface of the Mg alloy. Cells L929 showed significantly good adherence and significantly high growth rate and proliferation characteristics on the Ca-P coated magnesium alloy (p<0.05) in in-vitro cell experiments, demonstrating that the surface cytocompatibility of magnesium was significantly improved by the Ca-P coating. In vivo implantations of the Ca-P coated and the naked alloy rods were carried out to investigate the bone response at the early stage. Both routine pathological examination and immunohistochemical analysis demonstrated that the Ca-P coating provided magnesium with a significantly good surface bioactivity (p<0.05) and promoted early bone growth at the implant/bone interface. It was suggested that the Ca-P coating might be an effective method to improve the surface bioactivity of magnesium alloy.