Portal vein velocity predicts portal vein system thrombosis after splenectomy with esophagogastric devascularization.

BACKGROUND: Portal vein system thrombosis (PVST) is a potentially fatal complication after splenectomy with esophagogastric devascularization (SED) in cirrhotic patients with portal hypertension. However, the impact of portal vein velocity (PVV) on PVST after SED remains unclear. Therefore, this study aims to explore this issue. METHODS: Consecutive cirrhotic patients with portal hypertension who underwent SED at Tongji Hospital between January 2010 and June 2022 were enrolled. The patients were divided into two groups based on the presence or absence of PVST, which was assessed using ultrasound or computed tomography after the operation. PVV was measured by duplex Doppler ultrasound within one week before surgery. The independent risk factors for PVST were analyzed using univariate and multivariate logistic regression analysis. A nomogram based on these variables was developed and internally validated using 1000 bootstrap resamples. RESULTS: A total of 562 cirrhotic patients with portal hypertension who underwent SED were included, and PVST occurred in 185 patients (32.9%). Multivariate logistic regression analysis showed that PVV was the strongest independent risk factor for PVST. The incidence of PVST was significantly higher in patients with PVV ≤ 16.5 cm/s than in those with PVV > 16.5 cm/s (76.2% vs. 8.5%, p < 0.0001). The PVV-based nomogram was internally validated and showed good performance (optimism-corrected c-statistic = 0.907). Decision curve and clinical impact curve analyses indicated that the nomogram provided a high clinical benefit. CONCLUSION: A nomogram based on PVV provided an excellent preoperative prediction of PVST after splenectomy with esophagogastric devascularization.

HCC treated with immune checkpoint inhibitors: a hyper-enhanced rim on Sonazoid-CEUS Kupffer phase images is a predictor of tumor response.

OBJECTIVES: We aimed to evaluate the efficacy of anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody therapy by assessing the hyper-enhanced rim phenomenon of hepatocellular carcinoma (HCC) on Sonazoid-contrast-enhanced ultrasound (CEUS) Kupffer phase images. METHODS: This retrospective study included 61 patients with HCC who received anti-PD-1/PD-L1 antibody therapy from August 1, 2020, to January 31, 2022. We compared the progression-free survival (PFS) of patients with hyper-enhanced rim+ and hyper-enhanced rim-nodules and the time to nodule progression (TTnP) of hyper-enhanced rim+ and hyper-enhanced rim- nodules. RESULTS: Thirty-nine patients received postoperative therapy, and 22 patients had unresectable HCC. The mean PFS was 11.8 months (95% confidence interval [CI]: 8.7-14.9) for patients with hyper-enhanced rim+ HCC nodules and 16.5 months (95% CI: 14.9-18.1) for patients with hyper-enhanced rim- HCC nodules in the surgery group (p = 0.017). The mean PFS was 9.2 months (95% CI: 3.6-14.8) for patients with hyper-enhanced rim+ HCC nodules and 17.8 months (95% CI: 14.9-20.6) for patients with hyper-enhanced rim- HCC nodules in the non-surgery group (p = 0.015). For hyper-enhanced rim+ HCC nodules, TTnP for each nodule exceeding the specified threshold was 10.1 months, whereas that for hyper-enhanced rim- HCC nodules was 17.6 months (p = 0 .018). The disease control rate was 42.9% (3/7) for hyper-enhanced rim+ HCC nodules and 85.7% (21/24) for hyper-enhanced rim- HCC nodules (p = 0.013). CONCLUSIONS: The presence of hyper-enhanced rim on the Kupffer phase images obtained via the non-invasive Sonazoid-CEUS is a promising imaging biomarker for predicting unfavorable response with anti-PD-1/PD-L1 therapy in patients with HCC. KEY POINTS: • The mean progression-free survival was 11.8 months for patients with hyper-enhanced rim+ HCC nodules and 16.5 months for patients with hyper-enhanced rim- HCC nodules in the surgery group. • The mean progression-free survival was 9.2 months for patients with hyper-enhanced rim+ HCC nodules and 17.8 months for patients with hyper-enhanced rim- HCC nodules in the non-surgery group. • The disease control rate was 42.9% for hyper-enhanced rim+ HCC nodules and 85.7% for hyper-enhanced rim- HCC nodules (p = 0.013).

Pharmacokinetics of trazodone sustained-release tablets in healthy subjects: Three open-label, randomized crossover studies
.

OBJECTIVE: To characterize the pharmacokinetics of trazodone hydrochloride (HCl) sustained-release tablets (TSR) and trazodone immediate-release formulation (TIR) and investigate the effects of food on the pharmacokinetics of the drug in healthy subjects. MATERIALS AND METHODS: Three open-label, randomized crossover trials of single-dose, multiple-dose, and food-drug interaction testing were conducted. A validated high-performance liquid chromatography-fluorescence method was used to measure the plasma concentration of trazodone, and a non-compartment model was used to obtain the pharmacokinetic parameters. AUC and Cmax dose proportionality were analyzed using a power model. RESULTS: TSR lacked dose proportionality over a dose range of 25 - 150 mg. In the food-drug interaction study, no significant changes in the pharmacokinetic parameters of the drug under the fed conditions were observed. Multiple dosage of TSR and TIR reached steady state after 7 days, with no accumulation phenomenon observed. The peak time and peak concentrations of TSR were significantly longer and lower, respectively, than those of TIR. CONCLUSION: TSR showed clear sustained-release characteristics, and food exhibited no significant effects on the pharmacokinetic parameters of trazodone. TSR and TIR reached steady state levels after 7 consecutive days of administration, with no accumulation phenomenon observed.

CEUS in prediction of early recurrence of hepatocellular carcinoma after curative resection and to stratify the risk of early recurrence: a retrospective observational study.

PURPOSE: Early recurrence (ER) after surgery is related to early death in patients with hepatocellular carcinoma (HCC) after radical resection. To explore the role of preoperative contrast-enhanced ultrasound (CEUS) in predicting ER of HCC after curative resection and to stratify the risk of ER. MATERIALS AND METHODS: This study evaluated consecutive 556 patients with HCC who were examined by CEUS during the 2 weeks before curative resection between January 2011 and December 2018. ER was defined as intrahepatic and/or extrahepatic recurrence within 2 year after resection of HCC. Univariate and logistic regression analyses were performed to identify independent risk factors for ER after surgical resection of HCC. Recurrence-free time (RFS) rates were analyzed and compared by log-rank test. RESULTS: ER occurred in 307 (55.2%) of the 556 patients. Univariate and multivariate analyses revealed that a tumor size ≥ 30 mm and satellite nodules seen on CEUS, DL(deep learning) radiomics reoccurrence score based on the frame of image with the maximum intensity of CEUS and an elevated alpha-fetoprotein level were significantly associated with ER (P < .05). Based on the number of predictors present, patients with CEUS LR-5 HCC were stratified into three risk subgroups: risk group 3 (high-risk patients, 4 predictors), risk group 2 (medium-risk patients, 2-3 predictors), and risk group 1 (low-risk patients, 0-1 predictor). The 2-year RFS rate was 19.4% in risk group 3, 40.9% in risk group 2, and 48.1% in risk group 1; the corresponding mean RFS times were 14.0 ± 2.9 months, 43.7 ± 6.6 months, and 55.5 ± 2.8 months, respectively (P < .001). CONCLUSIONS: Tumor size ≥ 30 mm and satellite nodules seen on CEUS, DL radiomics reoccurrence score based on the frame of image with the maximum intensity of CEUS and an elevated alpha-fetoprotein level can predict ER of HCC.

Comparison of Sonazoid-Contrast­Enhanced Ultrasound and Gd­EOB­DTPA­Enhanced MRI for Predicting Microvascular Invasion in Hepatocellular Carcinoma.

OBJECTIVE: This study aims to evaluate and compare the predictive accuracy of Sonazoid-contrast-enhanced ultrasound (CEUS) and Gd-EOB-DTPA-enhanced MRI for detecting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). METHODS: In this single-center prospective study, we included 64 patients with histopathologically confirmed single HCC lesions. Based on post-operative pathologic data, patients were categorized into two groups: those with MVI (n = 21) and those without MVI (n = 43). The diagnostic efficacy of CEUS was compared with that of MRI in predicting MVI. RESULTS: Multifactorial analysis revealed that US features (tumor size > 4.35 cm, peritumoral enhancement, post-vascular ring enhancement, peak energy in the arterial phase of the difference between the margin area of HCC and distal liver parenchyma <-1.0 × 106 a.u), MRI features (rim enhancement, irregular tumor margin, and the halo sign) were all independent predictors of MVI (p < 0.05). The sensitivity and specificity of CEUS features in predicting MVI ranged from 61.9% to 86.4% and from 42.9% to 71.4%, respectively. For MRI features, the sensitivity and specificity ranged from 33.3% to 76.3% and from 54.7% to 90.5%, respectively. No statistically significant differences were observed in the area under the curve between CEUS and MRI (p > 0.05). Notably, peak energy of the difference showed the highest sensitivity at 86.4%, while the halo sign in MRI exhibited the highest specificity at 90.5%. CONCLUSION: Sonazoid-CEUS and Gd-EOB-DTPA-enhanced MRI demonstrate potential in predicting MVI in HCC lesions. Notably, CEUS showed higher sensitivity, whereas MRI displayed greater specificity in predicting MVI.

Liver resection versus microwave ablation for solitary and small (≤ 3 cm) HCC with early recurrence in different stages of liver cirrhosis: A propensity score matching study.

BACKGROUND: This study aimed to compare the effectiveness of liver resection (LR) and microwave ablation (MWA) in hepatocellular carcinoma (HCC) patients with early recurrence and varying stages of cirrhosis. METHOD: This study analyzed patients with HCC who underwent hepatectomy and experienced early tumor recurrence (≤3 cm) between December 2002 and December 2020 at the Tongji Hospital. Treatment effectiveness was assessed using a propensity score matching (PSM) analysis. RESULTS: This study included 295 patients (106, LR; 189, MWA), 86 patients in each of the 2 groups were chosen for further comparison, after PSM. After PSM, both LR and MWA demonstrated similar recurrence-free survival (RFS) and overall survival (OS) rates (p = 0.060 and p = 0.118, respectively). However, the LR group had more treatment-related complications. In patients with moderate or severe cirrhosis, no significant differences in RFS or OS rates were found between the LR and MWA groups (p = 0.779 and p = 0.772, respectively). In patients without cirrhosis or with mild cirrhosis, LR showed better RFS and OS rates than MWA (p = 0.024 and p = 0.047, respectively). Multivariate analysis after PSM identified moderate or severe cirrhosis and recurrence intervals ≤12 months as independent predictors of poor RFS and OS in patients with early recurrence of HCC. CONCLUSION: LR is more effective than MWA for early recurrence of HCC in patients without cirrhosis or with mild cirrhosis, showing improved RFS and OS rates. In patients with moderate or severe cirrhosis, the OS and RFS were statistically equal between the two therapies. However, MWA may be preferred owing to its low complication rate.

Postoperative adjuvant tyrosine kinase inhibitors combined with anti-PD-1 antibodies improves surgical outcomes for hepatocellular carcinoma with high-risk recurrent factors.

Background: The clinical value of postoperative adjuvant therapy (PAT) for hepatocellular carcinoma (HCC) remains unclear. This study aimed to explore the effect of PAT with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies on the surgical outcomes of HCC patients with high-risk recurrent factors (HRRFs). Methods: HCC patients who underwent radical hepatectomy at Tongji Hospital between January 2019 and December 2021 were retrospectively enrolled, and those with HRRFs were divided into PAT group and non-PAT group. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups after propensity score matching (PSM). Prognostic factors associated with RFS and OS were determined by Cox regression analysis, and subgroup analysis was also conducted. Results: A total of 250 HCC patients were enrolled, and 47 pairs of patients with HRRFs in the PAT and non-PAT groups were matched through PSM. After PSM, the 1- and 2-year RFS rates in the two groups were 82.1% vs. 40.0% (P < 0.001) and 54.2% vs. 25.1% (P = 0.012), respectively. The corresponding 1- and 2-year OS rates were 95.4% vs. 69.8% (P = 0.001) and 84.3% vs. 55.5% (P = 0.014), respectively. Multivariable analyses indicated that PAT was an independent factor related to improving RFS and OS. Subgroup analysis demonstrated that HCC patients with tumor diameter > 5 cm, satellite nodules, or vascular invasion could significantly benefit from PAT in RFS and OS. Common grade 1-3 toxicities, such as pruritus (44.7%), hypertension (42.6%), dermatitis (34.0%), and proteinuria (31.9%) were observed, and no grade 4/5 toxicities or serious adverse events occurred in patients receiving PAT. Conclusions: PAT with TKIs and anti-PD-1 antibodies could improve surgical outcomes for HCC patients with HRRFs.

Repeat hepatectomy versus microwave ablation for solitary and small (≤3 cm) recurrent hepatocellular carcinoma with early or late recurrence: A propensity score matched study.

BACKGROUND: Repeat hepatectomy (RH) and microwave ablation (MWA) are frequently used procedures for the treatment of recurrent hepatocellular carcinoma (HCC) after curative resection. This study aimed to compare the long-term outcomes of RH and MWA for solitary and small HCC with early or late recurrence. METHOD: This retrospective study enrolled patients who underwent RH or MWA for solitary and small (≤3 cm) recurrent HCC at Tongji hospital between April 2006 and December 2020. Propensity score matching (PSM) was further employed to analyze the prognosis of different treatment methods. RESULTS: A total of 256 patients were analyzed, of whom 94 and 162 underwent RH and MWA, respectively. The overall treatment-related complication rate was higher in the RH group. Both recurrence-free survival (RFS) and overall survival (OS) rates of RH were significantly better than those of MWA. Multivariate analysis showed that MWA, early recurrence (within 24 months after initial resection), cirrhosis, and AFP >400 ng/ml were independent risk factors for poor prognoses of recurrent HCC. The stratified analysis demonstrated that MWA and RH had similar long-term outcomes in patients with early recurrence. Nevertheless, MWA had worse RFS and OS than RH in patients with late recurrence. The same results were obtained in the PSM analysis. CONCLUSION: The long-term outcomes of HCC patients with late recurrence were significantly better than those with early recurrence. RH should be the first choice for solitary small recurrent HCC patients with late recurrence, while MWA should be selected for those with early recurrence.

Metabolomic analysis of biochemical changes in the plasma and urine of first-episode neuroleptic-naïve schizophrenia patients after treatment with risperidone.

Early findings propose that impaired neurotransmission in the brain plays a key role in the pathophysiology of schizophrenia. Recent advances in understanding its multiple etiologies and pathogenetic mechanisms provide more speculative hypotheses focused on even broader somatic systems. Using a targeted tandem mass spectrometry (MS/MS)-based metabolomic platform, we compared metabolic signatures consisting of monoamine and amino acid neurotransmitter (NT) metabolites in plasma/urine simultaneously between first-episode neuroleptic-naïve schizophrenia patients (FENNS) and healthy controls before and after a 6-week risperidone monotherapy, which suggest that the patient NT profiles are restoring during treatment. To detect and identify potential biomarkers associated with schizophrenia and risperidone treatment, we also performed a combined ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) and 1H nuclear magnetic resonance (NMR)-based metabolomic profiling of the same samples, indicating a further deviation of the patients' global metabolic profile from that of controls. The NTs and their metabolites together with the 32 identified biomarkers underpin that metabolic pathways including NT metabolism, amino acid metabolism, glucose metabolism, lipid metabolism, energy metabolism, antioxidant defense system, bowel microflora and endocrine system are disturbed in FENNS. Among them, pregnanediol, citrate and α-ketoglutarate (α-KG) were significantly associated with symptomatology of schizophrenia after Bonferroni correction and may be useful biomarkers for monitoring therapeutic efficacy. These findings promise to yield valuable insights into the pathophysiology of schizophrenia and may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

Machine learning predicts portal vein thrombosis after splenectomy in patients with portal hypertension: Comparative analysis of three practical models.

BACKGROUND: For patients with portal hypertension (PH), portal vein thrombosis (PVT) is a fatal complication after splenectomy. Postoperative platelet elevation is considered the foremost reason for PVT. However, the value of postoperative platelet elevation rate (PPER) in predicting PVT has never been studied. AIM: To investigate the predictive value of PPER for PVT and establish PPER-based prediction models to early identify individuals at high risk of PVT after splenectomy. METHODS: We retrospectively reviewed 483 patients with PH related to hepatitis B virus who underwent splenectomy between July 2011 and September 2018, and they were randomized into either a training (n = 338) or a validation (n = 145) cohort. The generalized linear (GL) method, least absolute shrinkage and selection operator (LASSO), and random forest (RF) were used to construct models. The receiver operating characteristic curves (ROC), calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were used to evaluate the robustness and clinical practicability of the GL model (GLM), LASSO model (LSM), and RF model (RFM). RESULTS: Multivariate analysis exhibited that the first and third days for PPER (PPER1, PPER3) were strongly associated with PVT [odds ratio (OR): 1.78, 95% confidence interval (CI): 1.24-2.62, P = 0.002; OR: 1.43, 95%CI: 1.16-1.77, P < 0.001, respectively]. The areas under the ROC curves of the GLM, LSM, and RFM in the training cohort were 0.83 (95%CI: 0.79-0.88), 0.84 (95%CI: 0.79-0.88), and 0.84 (95%CI: 0.79-0.88), respectively; and were 0.77 (95%CI: 0.69-0.85), 0.83 (95%CI: 0.76-0.90), and 0.78 (95%CI: 0.70-0.85) in the validation cohort, respectively. The calibration curves showed satisfactory agreement between prediction by models and actual observation. DCA and CIC indicated that all models conferred high clinical net benefits. CONCLUSION: PPER1 and PPER3 are effective indicators for postoperative prediction of PVT. We have successfully developed PPER-based practical models to accurately predict PVT, which would conveniently help clinicians rapidly differentiate individuals at high risk of PVT, and thus guide the adoption of timely interventions.

Anatomical liver resection improves surgical outcomes for combined hepatocellular-cholangiocarcinoma: A propensity score matched study.

Background: The efficacies of anatomical resection (AR) and non-anatomical resection (NAR) in the treatment of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remain unclear. This study aimed to compare the prognostic outcomes of AR with those of NAR for cHCC-CCA. Method: Patients diagnosed with pathology-confirmed cHCC-CCA, and who underwent curative resection at Tongji hospital between January 2010 and December 2019 were included in this retrospective study. A one-to-one propensity score matching (PSM) analysis was used to compare the long-term outcomes of AR to those of NAR. Results: A total of 105 patients were analyzed, of whom 48 (45.7%) and 57 (54.3%) underwent AR and NAR, respectively. There were no significant differences in short-term outcomes between the two groups, including duration of postoperative hospital stay, the incidence of perioperative complications, and incidence of 30-day mortality. However, both, the 5-year overall survival (OS) and recurrence-free survival (RFS) rates of AR were significantly better than those of NAR (40.5% vs. 22.4%, P=0.002; and 37.3% vs. 14.4%, P=0.002, respectively). Multivariate analysis showed that NAR, multiple tumors, larger-sized tumors (>5 cm), cirrhosis, lymph node metastasis, and vascular invasion were independent risk factors for poor prognoses. Stratified analysis demonstrated similar outcomes following AR versus NAR for patients with tumors > 5cm in diameter, while AR had better survival than NAR in patients with tumors ≤5 cm in diameter. After PSM, when 34 patients from each group were matched, the 5-year OS and RFS rates of AR were still better than those of NAR. Conclusion: Patients with cHCC-CCA who underwent AR had better long-term surgical outcomes than those who underwent NAR, especially for those with tumors ≤5 cm in diameter. However, no differences in the risk of surgical complications were detected between the two groups.

Deep learning-based radiomics based on contrast-enhanced ultrasound predicts early recurrence and survival outcome in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. AIM: To predict early recurrence (ER) and overall survival (OS) in patients with HCC after radical resection using deep learning-based radiomics (DLR). METHODS: A total of 414 consecutive patients with HCC who underwent surgical resection with available preoperative grayscale and contrast-enhanced ultrasound images were enrolled. The clinical, DLR, and clinical + DLR models were then designed to predict ER and OS. RESULTS: The DLR model for predicting ER showed satisfactory clinical benefits [area under the curve (AUC)] = 0.819 and 0.568 in the training and testing cohorts, respectively), similar to the clinical model (AUC = 0.580 and 0.520 in the training and testing cohorts, respectively; P > 0.05). The C-index of the clinical + DLR model in the prediction of OS in the training and testing cohorts was 0.800 and 0.759, respectively. The clinical + DLR model and the DLR model outperformed the clinical model in the training and testing cohorts (P < 0.001 for all). We divided patients into four categories by dichotomizing predicted ER and OS. For patients in class 1 (high ER rate and low risk of OS), retreatment (microwave ablation) after recurrence was associated with improved survival (hazard ratio = 7.895, P = 0.005). CONCLUSION: Compared to the clinical model, the clinical + DLR model significantly improves the accuracy of predicting OS in HCC patients after radical resection.

Determination of dansylated monoamine and amino acid neurotransmitters and their metabolites in human plasma by liquid chromatography-electrospray ionization tandem mass spectrometry.

The determination of neurotransmitters (NTs) and their metabolites facilitates better understanding of complex neurobiology in the central nervous system disorders and has expanding uses in many other fields. We present a liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI/MS/MS) method for the quantification of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), vanillymandelic acid (VMA), 3-methoxy-4-hydroxy phenylglycol (MHPG), 5-hydroxytryptamine (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA), glutamate (Glu), and gamma-aminobutyric acid (GABA). The NTs and their metabolites were dansylated and analyzed by an LC gradient on a C18 column on-line with a tandem mass spectrometer. This method exhibited excellent linearity for all of the analytes with regression coefficients higher than 0.99. The lower limit of quantification (LLOQ) values for DA, DOPAC, HVA, NE, VMA, MHPG, 5-HT, 5-HIAA, Glu, and GABA were 0.57, 0.37, 0.35, 0.40, 0.35, 0.91, 0.27, 0.43, 0.65, and 1.62 pmol/ml, respectively. The precision results were expressed as coefficients of variation (CVs), ranging from 1.5% to 13.6% for intraassay and from 2.9% to 13.7% for the interassay. This novel LC-ESI/MS/MS approach is precise, highly sensitive, specific, and sufficiently simple. It can provide an alternative method for the quantification of the NTs and their metabolites in human plasma.

Effect of Fluconazole on the Pharmacokinetic Properties of Imrecoxib, a Novel NSAID: A Single-center, Open-label, Self-controlled Study in Healthy Chinese Male Volunteers.

PURPOSE: Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co-administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib's pharmacokinetic (PK) parameters. METHODS: In this single-center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22.6 [2.43] years) received the following 2 treatments separated by a washout period of 8 days under a fasting state: (1) a single oral dose of imrecoxib 100 mg; and (2) fluconazole 200 mg/d over 6 days followed by concurrent dosing of imrecoxib 100 mg and fluconazole 200 mg. Plasma concentrations of imrecoxib (M0) and its metabolites (4'-hydroxymethyl metabolite [M1] and 4'-carboxylic acid metabolite [M2]) for PK analysis were obtained at 0 (baseline) and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, and 72 hours after imrecoxib dosing. Safety and tolerability assessments were performed throughout the study. FINDINGS: All subjects completed the study. There was 1 adverse event; drug-induced liver damage in 1 subject occurred after he received imrecoxib plus fluconazole, and the subject recovered without any sequelae. Coadministration with fluconazole resulted in much higher plasma imrecoxib concentrations, with an increase of 88% in Cmax and 72% in AUC0-t compared with only imrecoxib treatment, which showed that fluconazole may increase plasma exposure to imrecoxib. Fluconazole also caused a small, but not clinically relevant, decrease in M1 and M2 mean Cmax (13% and 14%, respectively), but there was minimal change in M1 and M2 mean AUC0-t (3% and 2%). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or adverse events between treatments. IMPLICATIONS: Concurrent administration of imrecoxib and fluconazole did not seem to change imrecoxib's safety profile. The ratio (imrecoxib + fluconazole/imrecoxib) for AUC0-t was 1.72 (90% CI, 1.41-2.11) and for Cmax it was 1.88 (90% CI, 1.59-2.21). Hence, it is necessary to adjust the imrecoxib dose when it is concurrently used with other CYP2C9 inhibitors.

[Treatment of Stroke Patients with Shoulder-wrist Syndrome by Acupoint Catgut Embedding and Surface Electromyogram Biofeedback Therapy].

OBJECTIVE: To observe the clinical effectiveness of acupoint catgut embedding and surface electromyogram biofeedback therapy (sEMGBF) in the treatment of stroke patients complicated with shoulder-hand syndrome (SHS). METHODS: A total of 90 stroke patients with SHS were randomly divided into acupoint catgut embedment (ACE), sEMGBF and ACE+sEMGBF (combined treatment) groups (n=30 cases/group). The catgut embedment was performed at Jianliao (LI 14), Jianyu (LI 15), Quchi (LI 11), Waiguan (TE 5) on the affected side, once every 3 weeks, twice altogether. The electromyographic biofeedback therapy (30-50 Hz, pulse duration 200 µs, 6 s-on and 10 s-off, appropriate strength) was applied to the skin area co-vering the deltoid muscle, flexor muscle of wrist and wrist extensor for 20 min, once per day, 5 times/week, for 6 weeks. The total effective rate was assessed by using Liao's and Zhu's methods (1996), the pain severity assessed using visual analogue scale (VAS), and Fugl-Meyer assessment (FMA, 66-points) scale and the patients' activities of daily living function (ADL, 100-points) were also scored. RESULTS: Before treatment, the VAS, FMA and ADL points of the three groups were not significantly different (P>0.05). After the treatment, the total effective rate (93.33%), FMA and ADL scores of the combined treatment group were significantly higher than those of the ACE and sEMGBF groups (P<0.05), while the VAS score of the combined treatment group was significantly lower than those of the ACE and sEMGBF groups (P<0.05). The total effective rates, FMA and ADL scores of the ACE and sEMGBF groups were comparable (P>0.05). The VAS score of the ACE group was markedly lower than that of the sEMGBF group (P<0.05). CONCLUSION: The combined administration of ACE and sEMGBF has a better therapeutic effect for stroke patients complicated with SHS relevant to simple ACE and simple sEMGBF therapy in improving the upper limb function, relieving pain, and enhancing the daily life quality.

Determination of duloxetine in human plasma via LC/MS and subsequent application to a pharmacokinetic study in healthy Chinese volunteers.

BACKGROUND: The pharmacokinetics of duloxetine hydrochloride have been well studied after its approval for clinical use. However, few such data have been reported in the English language literature. We developed a method to determine the pharmacokinetics of duloxetine enteric-coated capsules in healthy Chinese volunteers. METHODS: A rapid and sensitive liquid chromatography-mass spectrometric (LC/MS) method for the determination of duloxetine in human plasma using flupentixol as the internal standard (I.S.) was developed and validated. Sample preparation of the plasma involved deproteination with acetonitrile twice, repeatedly. Samples were then analyzed by HPLC on a Thermo Hypersil-Hypurity C18 column (150 x 2.1 mm, 5 microm). A single-quadrupole mass spectrometer with an electrospray interface was operated in the selected-ion monitoring mode to detect the [M+H](+) ions at 298 m/z for duloxetine and at 435 m/z for the internal standard. RESULTS: Pharmacokinetics were measured in 12 healthy Chinese male volunteers (6 males and 6 females) who received a single regimen with 3 different dosages at 22.4, 44.8 and 67.2 mg of duloxetine enteric-coated capsules. CONCLUSION: A sensitive and specific method for quantifying duloxetine levels in human plasma has been devised and successfully applied to a clinic pharmacokinetic study of an enteric-coated capsule of duloxetine hydrochloride administered as a single oral dose.

Determination of perospirone by liquid chromatography/electrospray mass spectrometry: application to a pharmacokinetic study in healthy Chinese volunteers.

Perospirone is a novel atypical antipsychotic with a unique combination of 5-HT(1A) receptor agonism as well as 5-HT(2A) and D(2) receptor antagonism. A simple rapid and selective LC-MS method utilizing a single quadrupole mass spectrometer was developed and validated for the determination of perospirone hydrochloride in human plasma. N-hexane was used to extract perospirone hydrochloride and amlodipine benzenesulfonate (internal standard (IS)) from an alkaline plasma sample. LC separation was performed on a XTerra MS C(18) column (100mmx2.1mm, i.d. 3.5microm) using methanol -10mM ammonium acetate (84:16, v/v) as a mobile phase. The quantification of target compounds was obtained by using a selected ion monitoring (SIM) at m/z 427.5 [M+H](+) for perospirone hydrochloride, and at m/z 431.4 [M+Na](+) for IS (amlodipine benzenesulfonate). Perospirone and IS eluted as sharp, symmetrical peaks with retention times of 3.11+/-0.01min and 4.15+/-0.2min, respectively. Calibration curves of perospirone hydrochloride in human plasma at concentrations ranging from 0.10 to 21.1ng/mL exhibited excellent linearity (r(2)=0.9997). The mean absolute recovery of the drug from plasma was more than 85%. Intra- and inter-day relative standard deviations were less than 6.43% and 11.9% for perospirone hydrochloride at the range from 0.32 to 10.6ng/mL. Stability characteristics of the drug-containing plasma were thoroughly evaluated to establish appropriate conditions to process, store and prepare for chromatographic analysis without inducing significant chemical degradation. The following pharmacokinetic parameters were elucidated after administering a single dose of 8mg perospirone hydrochloride. The area under the plasma concentration versus time curve from time 0 to 24h (AUC(0-24)) was 15.48+/-4.23microg/Lh; peak plasma concentration (C(max)) was 2.79+/-0.78microg/L; time to C(max) (T(max)) was 1.79+/-0.45h; and elimination half-life (t(1/2)) 6.78+/-1.38h. The described assay method showed acceptable precision, accuracy, linearity, stability, and specificity and can be used for pharmacokinetic studies, therapeutic drug monitoring, and drug abuse screening.

RP-HPLC study of resveratrol derivative (BTM-0512) in rat plasma and tissue distribution.

This paper described a rapid and sensitive HPLC method to analyze (E)-3,5,4'-trimethoxystilbene (BTM-0512) in rat plasma and tissues. The analysis used a BDS Hypersil C18 analytical column (250 mm x 4.6 mm ID, 5 microm) and acetonitrile/water as the mobile phase. The UV detection wavelength was 319 nm. Proteins were precipitated with acetonitrile and diethylstilbestrol as internal standard. The method was validated according to State Food and Drug Administration of China and ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines. The limit of detection (S/N: 3/1) for BTM-0512 was 0.005 microg x mL(-1) for plasma. The method performances were shown to be selective for BTM-0512 and the linearity of the assay method was up to 10.0 microg x mL(-1) and 40.0 microg x g(-1) for plasma and tissues, respectively. At 0.1, 1 and 5 microg x mL(-1) (n=5), intraday and interday precision values (% RSD) were in the range of 2.6% - 5.1% and 2.4% - 4.8%, respectively. Mean accuracy and absolute recoveries of BTM-0512 ranged from 95.3% - 100.1% and 95.9% - 100.9% for plasma and tissues, respectively. This method can be quite useful for BTM-0512 pharmacokinetic and tissue distribution studies, for purpose which multiple plasma and tissue samples can be analyzed quickly with high reproducibility.

Bis(2-amino-pyridine-κN)bis-(benzoato-κO)cobalt(II).

In the title compound, [Co(C(7)H(5)O(2))(2)(C(5)H(6)N(2))(2)], the Co(II) atom is hexa-coordinated by four O atoms from two benzoate anions, and two N atoms from two 2-amino-pyridine mol-ecules, resulting in a distorted octa-hedral geometry. Both benzoate anions act as bidentate ligands and both 2-amino-pyridine mol-ecules are coordinated to the metal through their pyridyl N atoms. The crystal packing is stabilized by inter-molecular N-H⋯O hydrogen bonds, C-H⋯π, and π-π stacking inter-actions involving benzoate anions and 2-amino-pyridine mol-ecules.

The differential effects of steady-state fluvoxamine on the pharmacokinetics of olanzapine and clozapine in healthy volunteers.

The combination of atypical antipsychotics and selective serotonin reuptake inhibitors is an effective strategy in the treatment of certain psychiatric disorders. However, pharmacokinetic interactions between the two classes of drugs remain to be explored. The present study was designed to determine whether there were different effects of steady-state fluvoxamine on the pharmacokinetics of a single dose of olanzapine and clozapine in healthy male volunteers. One single dose of 10 mg olanzapine (n = 12) or clozapine (n = 9) was administered orally. Following a drug washout of at least 4 weeks, all subjects received fluvoxamine (100 mg/day) for 9 days, and one single dose of 10 mg olanzapine or clozapine was added on day 4. Plasma concentrations of olanzapine, clozapine, and N-desmethylclozapine were assayed at serial time points after the antipsychotics were given alone and when added to fluvoxamine. No bioequivalence was found in olanzapine alone and cotreatment with fluvoxamine for the mean peak plasma concentration (C(max)), the area under the concentration-time curve from time 0 to last sampling time point (AUC(0-t)), and from time 0 to infinity (AUC(0- infinity )). Under the cotreatment, C(max) of olanzapine was significantly elevated by 49%, with a 32% reduced time (t(max)) to C(max), whereas the C(max) and t(max) of clozapine were unaltered. The cotreatment increased the AUC(0-t) and AUC(0- infinity ) of olanzapine by 68% and 76%, respectively, greater than those of clozapine (40% and 41%). The presence of fluvoxamine also prolonged the elimination half-life (t(1/2)) of olanzapine by 40% and, to a much greater extent, clozapine by 370% but reduced the total body clearance (CL/F) of clozapine (78%) more significantly than it did for olanzapine (42%). The apparent volume of distribution (V(d)) was suppressed by 31% in olanzapine combined with fluvoxamine but was unaltered in the clozapine regimen. A significant reduction in the N-desmethylclozapine to clozapine ratio was present in the clozapine with fluvoxamine regimen. The effects of fluvoxamine on different aspects of pharmacokinetics of the two antipsychotics may have implications for clinical therapeutics.