Safety, tolerability, pharmacokinetics, and antiviral activity of the novel core protein allosteric modulator ZM-H1505R (Canocapavir) in chronic hepatitis B patients: a randomized multiple-dose escalation trial.

BACKGROUND: Hepatitis B virus (HBV) core protein-targeting antivirals (CpTAs) are promising therapeutic agents for treating chronic hepatitis B (CHB). In this study, the antiviral activity, pharmacokinetics (PK), and tolerability of ZM-H1505R (Canocapavir), a chemically unique HBV CpTA, were evaluated in patients with CHB. METHODS: This study was a double-blind, randomized, placebo-controlled phase 1b trial in Chinese CHB patients. Noncirrhotic and treatment-naive CHB patients were divided into three cohorts (10 patients per cohort) and randomized within each cohort in a ratio of 4:1 to receive a single dose of 50, 100, or 200 mg of Canocapavir or placebo once a day for 28 consecutive days. RESULTS: Canocapavir was well tolerated, with the majority of adverse reactions being grade I or II in severity. There were no serious adverse events, and no patients withdrew from the study. Corresponding to 50, 100, and 200 mg doses of Canocapavir, the mean plasma trough concentrations of the drug were 2.7-, 7.0-, and 14.6-fold of its protein-binding adjusted HBV DNA EC50 (135 ng/mL), respectively, with linear PK and a low-to-mild accumulation rate (1.26-1.99). After 28 days of treatment, the mean maximum HBV DNA declines from baseline were -1.54, -2.50, -2.75, and -0.47 log10 IU/mL for the 50, 100, and 200 mg of Canocapavir or placebo groups, respectively; and the mean maximum pregenomic RNA declines from baseline were -1.53, -2.35, -2.34, and -0.17 log10 copies/mL, respectively. CONCLUSIONS: Canocapavir treatment is tolerated with efficacious antiviral activity in CHB patients, supporting its further development in treating HBV infection. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT05470829).

[Application of dexmedetomidine combined with ropivacaine in the cesarean section under epidural anesthesia].

OBJECTIVE: To explore the anesthetic effect and neonatal effects of dexmedetomidine combined with ropivacaine in the cesarean section under epidural anesthesia. METHODS: Between January 2012 and March 2013 at the First Affiliated Hospital with Nanjing Medical University, sixty parturients with a single baby at full term in vertex presentation scheduled for caesarean section under epidural anesthesia, were randomly divided into 3 groups (n = 20 each) according to the random digits table: dexmedetomidine + ropivacaine (RD), fentanyl + ropivacaine (RF) and normal saline + ropivacaine (RN). After identification of the epidural space and a negative aspiration test for blood or cerebrospinal fluid, 15 ml of 0.75% ropivacaine, was administered epidurally in three the groups with addition of 1 µg/kg of dexmedetomidine in RD group, 1 µg/kg of fentanyl in RF group and 2 ml of normal saline in RN group. Recording the mean arterial pressure (MAP) and heat rate (HR) before anesthesia (T(0)), at 10 min (T(1)) and 30 min (T(2)) after the end of epidural administration, and at end of operation (T(3)). Recording the onset time, maximum sensory analgesic level, time to maximum sensory analgesic level, time to two segmental dermatomal regressions, and time to chief complaint of postoperative pain. The modified bromage degrees, sedation scores and traction reaction were also assessed. The Apgar scores at 1 and 5 min were also recorded after delivery, and the blood samples were drawn from umbilical vein for gas analysis. RESULTS: MAP, HR and the motor block (Bromage scale) were no statistics differences among the three groups (P > 0.05) . Compared with RN group, the onset time and the time to maximum sensory analgesic level were significantly earlier [(6.3 ± 2.4), (8.7 ± 2.3) min vs (10.9 ± 2.7) min; (11.5 ± 3.9), (16.2 ± 4.6) min vs(19.8 ± 5.2) min, P < 0.05], the time to two segmental dermatomal regressions and the time to chief complaint of postoperative pain were prolonged significantly[(22.5 ± 4.6), (18.5 ± 3.9) min vs (13.5 ± 3.8) min; (415 ± 92), (355 ± 86) min vs( 273 ± 68) min, P < 0.05], level of sedation and degree of traction reaction were better in RD group and in RF group, and the incidence of shivering was lower in RD group (5% vs 40%, P < 0.05), the incidence of dizziness was higher in RF group (20% vs 0, P < 0.05). Compared with RF group, the same results were also seen about the onset time, the time to maximum sensory analgesic level, the time to two segmental dermatomal regressions and the time to chief complaint of postoperative pain, and the level of sedation was better, the incidence of drowsiness was lower in RD group. There were no statistics differences about both the blood gas analysis of umbilical vein and the Apgar scores at 1 and 5 min after delivery. CONCLUSION: Administration of dexmedetomidine combined with ropivacaine can provide early onset, establishment of sensory anesthesia, much better sedation levels, decrease the degree of traction reaction and the incidence of shivering, and without adverse neonatal effects.

[Effects of preloading epidural space with epinephrine (1:200 000) on the incidence of vascular injuries through the insertion of an epidural catheter during cesarean section].

OBJECTIVE: To evaluate the effects of preloading epidural space with epinephrine (1:200 000) on the incidence of vascular injuries through the insertion of an epidural catheter during cesarean section. METHODS: Between May 2011 and December 2011, upon obtaining institutional ethics approval and informed consent from the Human Ethics Committee of Nanjing Medical University, 100 laboring women with singleton cephalic presentation at term, ASA (American Society of Anesthesiologists) class I-II, undergoing caesarean section under continuous epidural analgesia were randomly divided into E and N groups according to a random digit table (n = 50 each). After an identification of epidural space, 5 ml of normal saline with epinephrine (1:200 000) was injected into epidural space in group E and 5 ml of normal saline in group N through an epidural needle. The syringe plunger was pressed firmly for 20 seconds to ensure a sufficient diffusion. For both groups, the levels of mean arterial pressure and heart rates were recorded prior to anesthesia (T1), 2 min after switching into a supine horizontal position after successful puncture (T2), the time of fetal delivery (T3) and when surgery was over (T4). The cases with bloody fluid in epidural puncture needle during puncture or epidural catheter during catheter placement, fresh blood in epidural catheter and bloody fluid in caudal end of epidural catheter during extubation were recorded. RESULTS: All hemodynamic changes were within the normal ranges. There were no obvious inter-group differences (P > 0.05). No significant difference existed in the cases with bloody fluid in epidural needle during catheter insertion (10% vs 12%) or epidural catheter during catheter placement (4% vs 6%), fresh blood in epidural catheter (0% vs 0%) or bloody fluid in caudal end of epidural catheter during extubation (26% vs 30%) between the groups (P > 0.05). CONCLUSION: Preloading epidural space with epinephrine (1:200 000) may not lower the incidence of vascular injuries through the insertion of an epidural catheter during cesarean section.

A novel balanced anesthesia shortens time to emergence in patients undergoing modified radical mastectomy: a randomized prospective trial.

BACKGROUND: In balanced anesthesia, protocol during the last 30 min is very important to guarantee rapid emergence and smooth extubation. In clinical practice, sevoflurane and propofol are often used in combination to achieve a better anesthetic effect and less adverse reaction. Approximately 30 min before surgical completion, sevoflurane inhalation is often discontinued and propofol is adjusted to keep sufficient depth of anesthesia. However, propofol-based anesthesia may delay time to emergence due to its unpredictable interindividual variability. In contrast, sevoflurane can be rapidly excreted unchanged from the respiratory tract, and more importantly, with minimal variability. This study aimed to investigate the effect of a novel balanced anesthesia protocol, that is propofol-based intravenous induction, propofol-sevoflurane combined maintenance, and total sevoflurane inhalation during the last 30 min of the surgery, on the time to emergence/extubation. METHODS: In our study, a total of 100 female patients undergoing modified radical mastectomy were enrolled. All patients received propofol-based intravenous anesthesia for induction followed by propofolsevoflurane combined maintenance. Approximately 30 min before the end of surgery, sevoflurane was continually inhaled without propofol infusion in group Sev (n=50), while propofol was only infused in group Pro (n=50). The primary outcome was the time to emergence/extubation. The second outcomes included time to respiratory recovery, and duration of post-anesthesia care unit (PACU) stay. The hemodynamic parameters and incidences of postoperative adverse events such as hypoxemia, nausea, vomiting, dizziness, and emergence agitation (EA) were also assessed. RESULTS: The time to emergence/extubation in group Sev was shorter than that in group Pro (12.74±4.31 vs. 17.74±4.27 min, P<0.0001). Similarly, time to respiratory recovery, and duration of PACU stay were significantly shortened in group Sev (all P<0.0001). Most of the patients in group Sev were extubated under a totally waking state of consciousness. The hemodynamic parameters and incidences of postoperative hypoxemia, nausea, vomiting, dizziness, and EA during the PACU stay were similar between the two groups. CONCLUSIONS: In patients undergoing modified radical mastectomy, this novel balanced anesthesia method could shorten the time to emergence/extubation and better waking state without increasing the incidence of adverse events.

Remifentanil injected during analepsia shortens length of postanesthesia care unit stay in patients undergoing laparoscopic surgery for endometrial cancer: a randomized controlled trial.

BACKGROUND: To guarantee efficient operating room (OR) activity, tracheal extubation is often performed in the postanesthesia care unit (PACU). Therefore, the ability of PACU to accommodate postoperative patients is crucial. Optimizing extubation management may speed up the turnover of PACU beds. The aim of the present study was to investigate the effect of remifentanil, which is used during analepsia, on the length of PACU stay in patients undergoing laparoscopic surgery for endometrial cancer. METHODS: In this prospective trial, we recruited a total of 99 patients, who were scheduled for laparoscopic surgery for endometrial cancer. At the end of the surgery, all patients were immediately transferred to the PACU and continued mechanical ventilation. Upon PACU admission, sputum aspiration was routinely performed. If the hemodynamic parameters fluctuated >30% of the baseline level, or patients moved unconsciously without reaching the criteria of extubation, a bolus injection of either 1 µg/kg remifentanil (Rem group, n=51) or propofol 1.0 mg/kg (Pro group, n=48) was randomly administered. The primary outcome was the duration of PACU stay. The secondary outcomes included time to respiratory breath recovery and time to extubation, along with bispectral index (BIS) values and hemodynamic status after remifentanil or propofol intervention. Times of repeated intervention, rescue administration of vasoactive drugs, and the incidence of adverse events were recorded. Visual analog scale and satisfaction scores at the time of PACU discharge were also evaluated. RESULTS: The duration of PACU stay was shorter in the Rem group than in the Pro group [49 (46.47-51.06 minutes) vs. 62 minutes (60.75-69.29 minutes), P<0.0001]. Compared with the Pro group, the time to spontaneous breathing recovery, the time to extubation, and the incidence of hypoxemia after extubation were reduced in the Rem group (P<0.0001, P<0.0001, P=0.03, respectively). After anesthetic administration, the BIS value decreased less in the Rem group (P<0.0001); blood pressure and heart rate (HR) declined, but were comparable in both groups. CONCLUSIONS: Remifentanil, which is injected during analepsia, significantly shortens the duration of PACU stay without increasing adverse events in the peri-extubation period.

Rapid change of methicillin-resistant Staphylococcus aureus clones in a Chinese tertiary care hospital over a 15-year period.

The incidence of methicillin-resistant Staphylococcus aureus (MRSA) has been increasing yearly at Peking Union Medical College Hospital (PUMCH). In order to understand the molecular evolution of MRSA at PUMCH, a total of 466 nonduplicate S. aureus isolates, including 302 MRSA and 164 methicillin-susceptible (MSSA) isolates recovered from 1994 to 2008 were characterized by staphylococcal cassette chromosome mec (SCCmec) typing, spa typing, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST). The 302 MRSA isolates were classified into 12 spa types and 9 sequence types (STs). During the years from 1994 to 2000, the most predominant MRSA clone was ST239-MRSA-III-spa t037. Since 2000, ST239-MRSA-III-spa t030 has rapidly replaced t037 and become the major clone. Another clone, ST5-MRSA-II-spa t002 emerged in 2002 and constantly existed at a low prevalence rate. The 164 MSSA isolates were classified into 62 spa types and 40 STs. ST398 was the most common MLST type for MSSA, followed by ST59, ST7, ST15, and ST1. Several MSSA genotypes, including ST398, ST1, ST121, and ST59, were identical to well-known epidemic community-acquired MRSA (CA-MRSA) isolates. MLST eBURST analysis revealed that the ST5, ST59, and ST965 clones coexisted in both MRSA and MSSA, which suggested that these MRSA clones might have evolved from MSSA by the acquisition of SCCmec. Two pvl-positive ST59-MRSA-IV isolates were identified as CA-MRSA according to the clinical data. Overall, our data showed that the ST239-MRSA-III-spa t037 clone was replaced by the emerging ST239-MRSA-III-spa t030 clone, indicating a rapid change of MRSA at a tertiary care hospital in China over a 15-year period.

Distribution of acquired AmpC ß-lactamase genes in Sydney, Australia.

Investigation of plasmid-borne AmpC ß-lactamase genes in Escherichia coli and Klebsiella spp. revealed blaCMY-2-like genes predominantly in E. coli and blaDHA genes equally distributed between both species. This distribution remained stable over time, but blaACT/MIR-like genes, initially common in Klebsiella spp., were not identified in more recent isolates.

Effect and Placental Transfer of Dexmedetomidine During Caesarean Section Under General Anaesthesia.

Many drugs can pass through the placenta and cause adverse effects on the foetus. Thus, during Caesarean section for puerperas who have contraindications for intravertebral anaesthesia, the use of proper drugs that have sedative, analgesic effects on the puerperas without adverse effects on the foetus is important. In this study, we investigated the effect and placental transfer of dexmedetomidine during Caesarean section under general anaesthesia. Thirty-eight puerperas were randomly divided to receive dexmedetomidine or saline before anaesthesia induction and during the operation. The dexmedetomidine-treated parturients had lower mean arterial pressure and heart rate at the delivery and at the end of the operation. The dexmedetomidine-treated parturients also needed 5.5% less propofol and 8.4% less fentanyl than the saline-treated ones. Between the dexmedetomidine-treated and saline-treated parturients, there was no difference in the maternal artery, umbilical vein, umbilical artery blood gas analysis results and the Apgar scores at 1 and 5 min. after delivery. The placental transfer rate of dexmedetomidine was 0.76. We concluded that dexmedetomidine was effective in maintaining the haemodynamic stability in the parturients during Caesarean section under general anaesthesia without adverse neonatal effects. Dexmedetomidine can pass through the placenta with a placental transfer rate of 0.76.

Paradoxical effect of Klebsiella pneumoniae OmpK36 porin deficiency.

AIM: To evaluate the effect of defined mutations in the major OmpK35 and OmpK36 porins in Klebsiella pneumoniae on the activity of two common plasmid-mediated AmpC enzymes. METHODS: Naturally occurring conjugative plasmids containing bla(DHA-1) and bla(CMY-2) were obtained from K. pneumoniae isolates in western Sydney. These were moved into K. pneumoniae ATCC13883 and isogenic porin knockouts Kp885 (DeltaompK35) and Kp886 (DeltaompK36), created by homologous recombination of kanamycin resistance cartridges into the specified genes, and their antimicrobial susceptibilities compared. RESULTS: beta-lactam resistance was greater in the presence of CMY-2-containing plasmids than DHA-1-containing plasmids, and higher in K. pneumoniae than Escherichia coli. Neither cefepime nor imipenem resistance was observed, and DHA-mediated cefotaxime and ticarcillin/clavulanate resistance was unexpectedly reduced from 8-24 (CTX) and >256 (TIM) mg/L in Kp13883 to 1-2 (CTX) and 32-48 mg/L (TIM) in the isogenic DeltaompK36 porin knockout Kp886. CONCLUSIONS: AmpC plasmids in particular are an important cause of transmissible resistance to ticarcillin/clavulanate in K. pneumoniae, but probably not in E. coli. Single knockouts of OmpK35 and OmpK36 porins in K. pneumoniae do not significantly increase antibiotic resistance in K. pneumoniae, and a paradoxical lowering of resistance to CTX and TIM is seen with deletion of ompK36. This has potentially important clinical implications.