This study investigates the pharmacokinetics and metabolic characteristics of three marine-derived piericidins as potential drug leads for kidney disease: piericidin A (PA) and its two glycosides (GPAs), glucopiericidin A (GPA) and 13-hydroxyglucopiericidin A (13-OH-GPA). The research aims to facilitate lead selection and optimization for developing a viable preclinical candidate. Rapid absorption of PA and GPAs in mice was observed, characterized by short half-lives and low bioavailability. Glycosides and hydroxyl groups significantly enhanced the absorption rate (13-OH-GPA > GPA > PA). PA and GPAs exhibited metabolic instability in liver microsomes due to Cytochrome P450 enzymes (CYPs) and uridine diphosphoglucuronosyl transferases (UGTs). Glucuronidation emerged as the primary metabolic pathway, with UGT1A7, UGT1A8, UGT1A9, and UGT1A10 demonstrating high elimination rates (30%-70%) for PA and GPAs. This rapid glucuronidation may contribute to the low bioavailability of GPAs. Despite its low bioavailability (2.69%), 13-OH-GPA showed higher kidney distribution (19.8%) compared to PA (10.0%) and GPA (7.3%), suggesting enhanced biological efficacy in kidney diseases. Modifying the C-13 hydroxyl group appears to be a promising approach to improve bioavailability. In conclusion, this study provides valuable metabolic insights for the development and optimization of marine-derived piericidins as potential drug leads for kidney disease.
Animals ; Male ; Mice ; Aquatic Organisms/chemistry* ; Biological Availability ; Cytochrome P-450 Enzyme System/metabolism* ; Glucuronosyltransferase/metabolism* ; Microsomes, Liver/metabolism* ; Molecular Structure ; Biological Products/pharmacokinetics* ; Pyridines/pharmacokinetics*

Objective To explore the value of procalcitonin(PCT)in diagnosis of early-onset stroke-associ-ated pneumonia and prognosis of patients with acute stroke.Methods 37 patients with acute stroke admitted to inten-sive care unit were enrolled in this study.The clinical data of patients were recorded and the maximum temperature, the serum levels of WBC,PCT and CRP were measured at 1,2,and 3 days respectively after admission.The follow up period was 28 days.Patients were divided into early-onset stroke-associated pneumonia (EOP)group and NEOP group by related examination results.According to the mean of serum PCT concentration,those patients were divided into high-PCT level(≥0.5μg/L)and low-PCT level group(<0.5μg/L).The difference of PCT level between EOP group and NEOP group was analyzed.SPSS13.0.Kaplan-Meier curves were used to analyze the survival at 28 days between the high and low PCT level group,and multivariate analysis of COX regression model was used to find the prognosis factors for survival.Results Statistically significant differences were observed for the comparison of PCT values at three days of admission between EOP and NEOP group [First day:(2.18 ±0.76 )μg/L vs (1.14 ± 0.64)μg/L.Second day:(2.10 ±0.79)μg/L vs (1.19 ±0.64)μg/L.Third day:(2.02 ±0.78)μg/L vs (1.17 ± 0.55)μg/L](t =4.250,3.625,3.573,all P <0.05).Kaplan-Meier survival analysis showed that there was signifi-cant difference in 28-day survival between the high and low PCT level group(mean survival time 21.8 vs 26.2 days,χ2 =4.659,P =0.031 ).Multivariate COX regression analysis revealed that PCT was independent risk factor of 28-day mortality(Wald =4.084,P =0.043).Conclusion The detection of PCT can be an effective parameter for diagnosis of EOP.High PCT levels indicate poor prognosis in patients with acute stroke.

Objective To assess the role of stroke volume variation (SVV) in predicting the volume responsiveness of mechanically ventilated patients with severe sepsis and septic shock. Method A total of 28 mechanically ventilated patients with severe sepsis and septic shock were admitted from January 2009 to March 2010. Every patient was treated with volume loading test. Cardiac index (CI), stroke volume index (SVI), systemic vascular resistance (SVR) and SVV were measured non-invasively by Ultrasonic Cardiac Output Monitor (USCOM) device.Patients with an increase in CI ＞ 12% and ＜ 12% after volume loading test were classified as responders and nonresponders, respectively. The comparisons between these two sorts of patients were assessed by using two sample Student' s t -test, and comparisons between changes before and after volume loading test were assessed by using a paired Student's t -test. The roles of SVV, central venous pressure (CVP) and the changes of CVP (△CVP) after fluid administration in predicting volume responsiveness were evaluated by receiver operating characteristic (ROC) curves. Results Before volume loading test, the SVV was higher in responders in comparison with non-responders [(18.2 ± 4.7)% vs. (12.7 ± 4.2)%, P = 0.003] and the CVP was not significantly different between two groups [(10.2±4.0) cmH2O vs. (10.8±4.8) cmH2O, P ＞0.05]. After volume loading test,the CVP was lower in responders [(2.9 ± 3.1 ) cmH2O vs. (5.3 ± 2.7) cmH2O, P = 0.003]. The areas under the ROC curves (AUC) were 0.836 (95% CI:0.680 ～ 0.992,P = 0.003),0.549 (95% CI:0.329 ～ 0.768,P = 0.662)and 0.762 (95% CI:0.570 ～ 0.953,P = 0.019)for SVV, CVP and △CVP, respectively. The 15.5% of SVV value had the 84.6% of sensitivity and 80% of specificity for prediction of volume responsiveness. Conclusions SVV can serve as a valid indicator of predicting volume responsiveness in mechanically ventilated patients with severe sepsis and septic shock and it is more reliable than conventional indicators such as CVP and/△CVP.

Objective To assess the value of procalcitonin(PCT) in diagnosis and treatment of ventilator associated pneumonia(VAP). Methods 60 patients on ventilators were divided into VAP group and non-VAP group depending on whether the patients developed VAP in 7 days or not. The VAP group again was divided into PCT group and the control group. Data of PCT, C-reactive protein (CRP) and WBC were assessed at baseline, in 6 hours when VAP was suspected, and every two days after mechanical ventilation. The control group received antibiotics according to usual practice and stopped when CPIS≤6 scores. Antibiotic treatment of the PCT group was based on serum PCT concentrations. Results The CRP and WBC showed no obvious difference between the VAP and non-VAP group before mechanical ventilation ( all P ＞ 0. 05 ), after ventilation both mean values increased, with the P 0. 046 and 0. 822,respectively;Taking CRP≥28mg/L and WBC≥ 10×109/L as the cutoff value,the diagnostic sensitivity of CRP and WBC for VAP were 73.3% and 66.7% respectively,their specificity was 50% and 43.3 % ,respectively.Taking PCT ≥0.40μg/L as the cutoff value, the PCT positive percentage did not show difference between VAP group and non-VAP group before mechanical ventilation( P ＞ 0. 05 ). However, it was much higher in the VAP group than that of non-VAP group after mechanical ventilation( P ＜ 0. 01 ). The PCT level of 0.40 ug/l yielded a 93.3% sensitivity and a 73.3 % specificity for VAP in the study cohort ( AUROCC = 0. 823; 95 % CI,0.71-0. 94; P ＜ 0. 01 ). The antibiotic duration of the PCT group was( 12. 6 ± 5.6) days compared with( 15. 1 ± 9.1 ) days for the control group (P ＜ 0. 05). Patients assigned to the PCT group had 2.5 days shorter mean duration of antibiotic therapy for the first episode of infection than the control group ( P ＜ 0. 05 ). Conclusion PCT had high sensitivity in the diagnosis of VAP. CPIS ≥6 combined with serum levels of PCT ≥0. 40μg/L markedly improved the specificity( 100% ). PCT guidance substantially reduced antibiotic use in VAP, so that timely surveillance of serum PCT was necessary for patients on ventilator.

Objective To evaluate, the safety of keeping watching central venous catheter and whether it decreased unnecessary catheter removal in unexplained fever patients. Methods Eighty-two unexplained fever patients with suspected catheter-related infection whose clinical conditions were relatively stable were retrospectively analyzed and divided into keep watching group (31 patients) and immediate removal group (51 patients). ICU mortality, sequential organ failure assessment (SOFA) score, temperature, the rate of catheter-related infection, and the rate of central venous catheter removal were compared. Results There was no significant difference in ICU mortality, SOFA score, temperature and the rate of catheter-related infection between two groups (P > 0.05). Eleven of 31 (35.5%) were removed central venous catheter at last, versus all patients (100.0%) in the immediate removal group (P < 0.05). Conclusion Keep watching central venous catheter will decrease a substantial unnecessary catheter removal without increased morbidity in unexplained fever patients with suspected catheter-related infection if their clinical conditions are relatively stable.

Objective To study the diagnostic and prognostic value of procalcitonin (PCT)in patients with sepsis in early stage. Methods In the perspective study, 168 patients enrolled were classified into three groups,ncluding 31 cases in control group,37 cases in SIRS group and 100 cases in general sepsis group. The latter were com-posed of moderate sepsis sub-group with 36 cases, severe sepsis sub-group with 40 cases and septic shock sub-group with 24 cases. Indexes of inflammation, SOFA and concentration of PCT in all patients were determined and their cor-relation with sepsis prognosis was analyzed. Results The level of PCT and CRP is 3.1 ± 2.3 μg/L and 34.7 ± 28.0 mg/L in SIRS group,is 10.8 ± 8.1 μg/L and 106.8 ± 69.3 mg/L in general sepsis group respectively. Which are higher than the level of PCT (0.3 ± 0.2 μg/L )and CRP (4.1 ± 2.9 mg/L)in control group (P < 0.01 ). Higher con-centration of PCT and CRP were found in general sepsis groups than these in SIRS group. The difference is prominem.Moreover,an increasing trend of PCT with the more serious of illness was found in subgroup analysis ,but not in CRP.According to the receiver operating characteristic curves( ROC curves) ,The best cutoff values in the diagnosis of sep-sis were >4.395 μg/L for PCT,>51.8 mg/L for CRP and >4.0 for SOFA score. Condusion PCT and CRP are useful diagnostic parameters with high specificity in early sepsis. PCT combining with SOFA score can be used as ide-al quantitative index to estimate the severity of sepsis and prognosis in patients with sepsis.

Objective To evaluate the influence of glutamine(Gln)-enriched total parenteral nutrition on nutritional status,suppression of excessive systematic inflammatory responses and immunological competence on critical patients in ICU.Methods Sixty critical patients were included in a randomized controlled clinical trial and divided into Gln group and control group,with 30 case for each group.Both groups received isocaloric and isonitrogenous nutritional formulas on everyday.In addition,Gln was added to Gln group from day 1 to day 8.On day 1 and 8 after treatment,serum albumin,proalbumin,transferin,IgA,IgG and IgM were determined respectively.The plasma level of CPR,IL-6,TNF-?,blood suger,liver function were also monitored.Results (1)The level of serum albumin,proalbumin,transferin,IgA,IgG,and IgM decreased in all patients.Albumin,proalbumin,transferin,IgA,IgG,and IgM were significantly improved in Gln group on day 8 compared with control group and before treatment(P

Objective To investigate the influences of hypothermia on hemodynamics and hemorrheology .Methods The body temperature of 10 mongrel dogs decreased at 35℃ ,and was kept for 30 min, and then warmed to normal degree with physical methods. The parameters of hemodynamics and hemorrheology were measured with the polygraph system (RM 6000, Nihon Kohden).Results Compared with the baselines, 30 min following hypothermia heart rate, mean arterial pressure, cardiac output, maximum rate of rise and decline of pressure(?dp/dtmax),cardiac index, left ventricular stroke work index were significantly reduced, while systemic peripheral resistance , blood viscosity were higher than those under normal body temperature (P