Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies. Methods: ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout. Results: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population. Conclusions: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population. Clinical Trial Identifier NCT00856544 and NCT00413699.
Administration, Oral ; Adult ; Aged ; Arthritis, Rheumatoid ; drug therapy ; Asian Continental Ancestry Group ; Female ; Humans ; Male ; Middle Aged ; Piperidines ; adverse effects ; therapeutic use ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Pyrimidines ; adverse effects ; therapeutic use ; Pyrroles ; adverse effects ; therapeutic use ; Surveys and Questionnaires ; Young Adult

Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides in Panax ginseng. However, the oral bioavailability of Rh2 is low, with P-glycoprotein (P-gp) and CYP3A4 being reported to be the main factors. The purpose of the present study was to determine the enhancing effect of piperine on the oral bioavailability as well as bioactivity of Rh2. The inhibitory effect of piperine on P-gp and CYP3A4 was determined using a Caco-2 monolayer model and a recombinant CYP3A4 metabolic system, respectively. The pharmacokinetics of oral Rh2 (10 mg·kg) administered alone or in combination with piperine (10 and 20 mg·kg) was performed in rats. The immune boosting effect of Rh2 was assessed in rats by measuring IL-12 level after treated by Rh2 alone or co-administered with piperine. The results indicated that piperine significantly increased the permeability of Rh2 and inhibited the metabolism of Rh2. The pharmacokinetic study results showed that the AUC of Rh2 was significantly increased in combination with piperine at high dose (20 mg·kg) when compared to the control group, with relative bioavailability of 196.8%. The increase of Rh2 exposure led to increased serum levels of IL-12. In conclusion, piperine may be used as a bioenhancer to improve pharmacological effect of Rh2 when given orally.
Administration, Oral ; Alkaloids ; administration & dosage ; Animals ; Benzodioxoles ; administration & dosage ; Biological Availability ; Caco-2 Cells ; Cytochrome P-450 CYP3A ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; Ginsenosides ; administration & dosage ; pharmacokinetics ; Humans ; Interleukin-2 ; metabolism ; Panax ; chemistry ; Piperidines ; administration & dosage ; Polyunsaturated Alkamides ; administration & dosage ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the effect of a single dose of ropivacaine combined with sufentanilfor thoracic paravertebral block (TPVB) on pain and enhanced recovery after surgery (ERAS) in patients undergoing video-assisted thoracosopic surgery.

METHODSSixty patients undergoing video-assisted thoracosopic surgery were randomly divided into three groups to receive intravenous combined general anesthesia (group C), a single dose of ropivacainefor thoracic paravertebral block before surgery combined with intravenous and general anesthesia(group T), or a single dose of ropivacaineand sufentanilfor thoracic paravertebral blockcombined with intravenous and general anesthesia (group T). None of the patients used postoperative analgesia pump, and tramadol hydrochoride injection (100 mg) was given in cases with NRS scores > 4 after the surgery. The data were recorded including analgesics used for nerve block before the operation, intravenous dosage of sufentanilduring operation, total dose of sufentanilused (intravenous+nerve block), intravenous remifentanil dose during operation, NRS scores at 4, 6, 24, 48 h after the surgery, rescue analgesia in the first postoperative 24 h after surgery, ICU stay and hospital stay after the surgery.

RESULTSCompared with those in group C, the intravenous sufentanildose, total sufentanildose, intravenous remifentanildose during operation, NRS scores at 4 and 6, 24 h, and ICU stay and hospital stay after the surgery were significantly decreased in groups Tand T(P<0.05). The total dose of opioids during the operation and NRS scores at 4 and 6 h were significantly lower in group Tthan in group T(P<0.05), but the total dose of sufentanil, ICU stay and hospital stay were simialr between the two groups.

CONCLUSIONA single dose of ropivacaine combined with sufentanilfor thoracic paravertebral blockbefore surgery can reduce the total dose opioids, produce the optimal analgesic effect, and promote postoperative recovery of the patients.

Amides ; administration & dosage ; therapeutic use ; Analgesics, Opioid ; therapeutic use ; Anesthesia, General ; Anesthetics, Intravenous ; therapeutic use ; Humans ; Injections ; Nerve Block ; methods ; Pain Management ; Pain Measurement ; Pain, Postoperative ; Piperidines ; therapeutic use ; Postoperative Period ; Sufentanil ; therapeutic use ; Thoracic Surgery, Video-Assisted

BACKGROUNDIn this prospective randomized study, we compared the predicted blood and effect-site C 50 for propofol and remifentanil target-controlled infusion (TCI) and the bispectral index (BIS) values at loss of consciousness (LOC) and response to a standard noxious painful stimulus (LOS) in elderly and young patients, respectively. We hypothesized that the elderly patients will require lower target concentration of both propofol and remifentanil at above two clinical end-points.

METHODSThere were 80 American Society of Anesthesiologists (ASA) physical status I-II unpremedicated patients enrolled in this study, they were divided into elderly group (age ≥65 years, n = 40) and young group (aged 18-64 years, n = 40). Propofol was initially given to a predicted blood concentration of 1.2 μg/ml and thereafter increased by 0.3 μg/ml every 30 s until Observer's Assessment of Alertness and Sedation score was 1. The propofol level was kept constant, and remifentanil was given to provide a predict blood concentration of 2.0 ng/ml, and then increased by 0.3 ng/ml every 30 s until loss of response to a tetanic stimulus. BIS (version 3.22, BIS Quattro sensor) was also recorded.

RESULTSIn elderly group, the propofol effect-site C 50 at LOC of was 1.5 (1.4-1.6) μg/ml, was significantly lower than that of young group, which was 2.2 (2.1-2.3) μg/ml, the remifentanil effect-site C 50 at LOS was 3.5 (3.3-3.7) ng/ml in elderly patients, was similar with 3.7 (3.6-3.8) ng/ml in young patients. Fifty percent of patients lost consciousness at a BIS value of 57.3 (56.4-58.1), was similar with that of young group, which was 55.2 (54.0-56.3).

CONCLUSIONIn elderly patients, the predicted blood and effect-site concentrations of propofol at LOC were lower than that of young patients. At same sedation status, predicted blood and effect-site concentrations of remifentanil required at LOS were similar in elderly and young patients. BIS were not affected by age. Low-propofol/high-opioid may be optional TCI strategy for elderly patients.

Adolescent ; Adult ; Age Factors ; Aged ; Anesthetics, Intravenous ; administration & dosage ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Piperidines ; administration & dosage ; therapeutic use ; Propofol ; administration & dosage ; therapeutic use ; Prospective Studies ; Unconsciousness ; chemically induced ; Young Adult

OBJECTIVETo explore the impacts on EC50 in the remifentanil inhibition of tracheal intubation response by the transcutaneous electrical acupoint stimulation (TEAS) at Hegu (LI 4) and Neiguan (PC 6).

METHODSForty patients with selective surgery undergoing endotracheal intubation with intravenous general anesthesia were divided into I to II degree by the American Society of Anesthesiologists (ASA) and were randomized into an observation group and a control group, 20 cases in each one. Before general anesthesia induction, in the observation group, the transcutaneous electric stimulation was applied to bilateral Hegu (LI 4) and Neiguan (PC 6) for 30 min, with dense-disperse wave, 2 Hz/100 Hz in frequency; in the control group, the sham-stimulation was applied to the acupoints, with the lamp on, but without electric current output. Afterwards, the general anesthesia induction started. When the target concentration of propofol and remifentanil was stabilized at the preset value, the endotracheal intubation was conducted. Dixon sequential method was applied for the determination of ECs in remifentanil inhibition of tracheal intubation response.

RESULTSThe level of EC50 in remifentanil inhibition of tracheal intubation response was 3. 46 ng/mL, 95% confidence interval was 2. 80 ng/ml to 4. 27ng/mL in the observation group; those were 4. 18 ng/mL and 3. 30 ng/mL to 5. 29 ng/mL in the control group separately. The differences were significant in comparison of the two groups (P<0. 01).

CONCLUSIONTEAS apparently reduces EChe in the remifentanil inhibition of tracheal intubation response by around 17%as.

Acupuncture Points ; Adult ; Aged ; Anesthetics, Intravenous ; administration & dosage ; Female ; Humans ; Intubation, Intratracheal ; adverse effects ; Male ; Middle Aged ; Pain ; etiology ; Pain Management ; Piperidines ; administration & dosage ; Transcutaneous Electric Nerve Stimulation

PURPOSE: The purpose of this study was to determine the effect-site concentration (Ce) of remifentanil in 50% of patients (EC50) and 95% of patients (EC95) for smooth laryngeal mask airway (LMA) removal in adults under propofol and remifentanil anesthesia. MATERIALS AND METHODS: Twenty-five patients of ASA physical status I-II and ages 18-60 years who were to undergo minor gynecological or orthopedic surgery were assessed in this study. Anesthesia was induced and maintained with propofol and remifentanil target-controlled infusion (TCI). Remifentanil was maintained at a predetermined Ce during the emergence period. The modified Dixon's up-and-down method was used to determine the remifentanil concentration, starting from 1.0 ng/mL (step size of 0.2 ng/mL). Successful removal of the LMA was regarded as absence of coughing/gagging, clenched teeth, gross purposeful movements, breath holding, laryngospasm, or desaturation to SpO2<90%. RESULTS: The mean+/-SD Ce of remifentanil for smooth LMA removal after propofol anesthesia was 0.83+/-0.16 ng/mL. Using isotonic regression with a bootstrapping approach, the estimated EC50 and EC95 of remifentanil Ce were 0.91 ng/mL [95% confidence interval (CI), 0.77-1.07 ng/mL] and 1.35 ng/mL (95% CI, 1.16-1.38 ng/mL), respectively. CONCLUSION: Our results showed that remifentanil TCI at an established Ce is a reliable technique for achieving safe and smooth emergence without coughing, laryngospasm, or other airway reflexes.
Adolescent ; Adult ; Analgesics, Opioid/*administration & dosage ; Anesthetics, Inhalation/*administration & dosage ; Cough/prevention & control ; Device Removal ; Dose-Response Relationship, Drug ; Female ; Gynecologic Surgical Procedures ; Humans ; *Laryngeal Masks ; Male ; Middle Aged ; Orthopedic Procedures ; Piperidines/*administration & dosage ; Propofol/*administration & dosage ; Treatment Outcome ; Young Adult

PURPOSE: The aim of this study was to evaluate the effects of premedication with oral atenolol or enalapril, in combination with remifentanil under sevoflurane anesthesia, on intraoperative blood loss by achieving adequate deliberate hypotension (DH) during orthognathic surgery. Furthermore, we investigated the impact thereof on the amount of nitroglycerin (NTG) administered as an adjuvant agent. MATERIALS AND METHODS: Seventy-three patients undergoing orthognathic surgery were randomly allocated into one of three groups: an angiotensin converting enzyme inhibitor group (Group A, n=24) with enalapril 10 mg, a beta blocker group (Group B, n=24) with atenolol 25 mg, or a control group (Group C, n=25) with placebo. All patients were premedicated orally 1 h before the induction of anesthesia. NTG was the only adjuvant agent used to achieve DH when mean arterial blood pressure (MAP) was not controlled, despite the administration of the maximum remifentanil dose (0.3 microg kg-1min-1) with sevoflurane. RESULTS: Seventy-two patients completed the study. Blood loss was significantly reduced in Group A, compared to Group C (adjusted p=0.045). Over the target range of MAP percentage during DH was significantly higher in Group C than in Groups A and B (adjusted p-values=0.007 and 0.006, respectively). The total amount of NTG administered was significantly less in Group A than Group C (adjusted p=0.015). CONCLUSION: Premedication with enalapril (10 mg) combined with remifentanil under sevoflurane anesthesia attenuated blood loss and achieved satisfactory DH during orthognathic surgery. Furthermore, the amount of NTG was reduced during the surgery.
Administration, Oral ; Adrenergic beta-Antagonists/administration & dosage/*pharmacology ; Adult ; Aged ; *Anesthesia, Inhalation ; Atenolol/administration & dosage/*pharmacology ; Blood Loss, Surgical ; Blood Pressure/drug effects ; Cardiac Output/drug effects ; Double-Blind Method ; Enalapril/administration & dosage/*pharmacology ; Female ; Heart Rate/drug effects ; Humans ; Intraoperative Care ; Male ; Methyl Ethers/*administration & dosage ; Middle Aged ; *Orthognathic Surgical Procedures ; Piperidines/*administration & dosage ; *Premedication ; Treatment Outcome

PURPOSE: This randomized, controlled, double-blind study was designed to determine the optimal dose of remifentanil for preventing complications associated with the removal of a laryngeal mask airway (LMA) without delaying emergence. MATERIALS AND METHODS: This study randomly assigned 128 patients to remifentanil effect-site concentrations (Ce) of 0 ng/mL (group R0), 0.5 ng/mL (group R0.5), 1.0 ng/mL (group R1.0), and 1.5 ng/mL (group R1.5) during emergence. The emergence and recovery profiles were recorded. Adverse events such as coughing, airway obstruction, breath-holding, agitation, desaturation, nausea, and vomiting were also evaluated. RESULTS: The number of patients with respiratory complications such as coughing and breath-holding was significantly lower in the R1.0 and R1.5 groups than in the R0 group (p<0.05). Emergence agitation also decreased in the R1.0 and R1.5 groups (p<0.0083). The time to LMA removal was significantly longer in the R1.5 group than in the other groups (p<0.05). CONCLUSION: Maintaining a remifentanil Ce of 1.0 ng/mL during emergence may suppress adverse events such as coughing, breath-holding, and agitation following the removal of LMA without delayed awakening.
Adult ; Airway Management/*methods ; Anesthesia Recovery Period ; Anesthetics, Intravenous/*administration & dosage ; Cough/prevention & control ; Device Removal ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Humans ; Infusions, Intravenous ; Laryngeal Masks/*adverse effects ; Male ; Middle Aged ; Piperidines/*administration & dosage ; Postoperative Complications/prevention & control ; Psychomotor Agitation ; Vomiting/prevention & control

PURPOSE: This randomized, controlled, double-blind study was designed to determine the optimal dose of remifentanil for preventing complications associated with the removal of a laryngeal mask airway (LMA) without delaying emergence. MATERIALS AND METHODS: This study randomly assigned 128 patients to remifentanil effect-site concentrations (Ce) of 0 ng/mL (group R0), 0.5 ng/mL (group R0.5), 1.0 ng/mL (group R1.0), and 1.5 ng/mL (group R1.5) during emergence. The emergence and recovery profiles were recorded. Adverse events such as coughing, airway obstruction, breath-holding, agitation, desaturation, nausea, and vomiting were also evaluated. RESULTS: The number of patients with respiratory complications such as coughing and breath-holding was significantly lower in the R1.0 and R1.5 groups than in the R0 group (p<0.05). Emergence agitation also decreased in the R1.0 and R1.5 groups (p<0.0083). The time to LMA removal was significantly longer in the R1.5 group than in the other groups (p<0.05). CONCLUSION: Maintaining a remifentanil Ce of 1.0 ng/mL during emergence may suppress adverse events such as coughing, breath-holding, and agitation following the removal of LMA without delayed awakening.
Adult ; Airway Management/*methods ; Anesthesia Recovery Period ; Anesthetics, Intravenous/*administration & dosage ; Cough/prevention & control ; Device Removal ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Humans ; Infusions, Intravenous ; Laryngeal Masks/*adverse effects ; Male ; Middle Aged ; Piperidines/*administration & dosage ; Postoperative Complications/prevention & control ; Psychomotor Agitation ; Vomiting/prevention & control

The study aims to establish a method for simultaneous determination of repaglinide and pravastatin sodium in rat plasma by LC-MS/MS and to study its pharmacokinetic interactions. Eighteen male SD rats were divided into repaglinide group, pravastatin sodium group and co-administration group. Blood samples were collected at different times after oral administration. Repaglinide and pravastatin sodium in rat plasma were separated by Agilent HC-C18 with the mobile phase consisting of methanol-0.1% formic acid (80 : 20). Detection and quantification were performed by using ESI-MS. The detector was operated in selected Reaction-monitoring mode at m/z 453.3-->230.1 for repaglinide, m/z 447.2-->327.4 for pravastatin sodium and m/z 285.1-->192.9 for diazepam as the internal standard. The calibration curve obtained was linear (R2>0.99) over the concentration range of 9.77-10,000 ng.mL-1 for repaglinide and 4.88-625 ng.mL-1 for pravastatin sodium. Compared with the single administration group, Cmax and AUC0-6h of repaglinide increased significantly (P<0.05) and tmax of pravastatin sodium prolonged (P<0.05) in co-administration group. The method is found to be simple, sensitive and accurate for determining the concentration of repaglinide and pravastatin sodium in rat plasma. There exists pharmacokinetic interactions in the co-administration of repaglinide and pravastatin sodium.
Administration, Oral ; Animals ; Carbamates ; administration & dosage ; blood ; pharmacokinetics ; Chromatography, High Pressure Liquid ; Drug Interactions ; Male ; Piperidines ; administration & dosage ; blood ; pharmacokinetics ; Pravastatin ; administration & dosage ; blood ; pharmacokinetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Sensitivity and Specificity ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry