The Effects of Immediate vs Gradual Reduction in Nicotine Content of Cigarettes on Smoking Behavior: An Ecological Momentary Assessment Study.

Background: In recent years, much research has examined the effects of various interventions and treatments for smoking cessation. The results suggest that interventions targeting changes of nicotine content can help smokers reduce tobacco use or quit smoking. A number of clinical studies show that smokers who received an immediate reduction in nicotine content to very low levels have significantly greater reductions in the number of cigarettes smoked and toxic substance exposure compared to those with gradual reductions. However, from the perspective of smoking craving, whether the immediate and gradual reduction in nicotine content reduce smoking by reducing cravings needs further investigation. Methods: 74 eligible Participants were randomly allocated to one of the two experimental conditions: (1) immediate reduction to 0.1 mg of nicotine per cigarette (n = 40); (2) gradual reduction from 1.0 (0.8 g ~ 1.2 mg) to 0.1 mg of nicotine per cigarette (n = 34). All participants completed 1-week baseline period during which they smoked their usual cigarette, followed by 16-week of interventions. The primary outcomes included cigarette cravings and number of cigarettes smoked per day (CPD); secondary outcomes included the number of cigarette-free day and emotional states. Results: Among the 52 participants [51 (98.1%) men; mean (SD) age, 33.44 (6.71) years; mean (SD) CPD, 16.83 (9.94)] who completed the trial, significantly lower cravings for cigarettes were observed in the immediate (n = 25) vs. gradual nicotine reduction group (n = 27) in the morning (t = -2.072, p = 0.039) and after dinner (t = -2.056, p = 0.041). Compared with the baseline daily smoking, the number of cigarettes smoked per day was significantly reduced at the beginning of week 12 in the immediate nicotine reduction group (p = 0.001) and at week 16 in the gradual nicotine reduction group (p < 0.001). The number of participants with any cigarette-free day was not significantly different between the groups (p = 0.198). The number of cigarette-free days was significantly more in the immediate vs. gradual nicotine reduction group (p = 0.027). Conclusions: The significantly lower cravings were observed in the immediate vs. gradual nicotine reduction group, and led to faster reduction in the number of CPD, and a significant increase in the number of cigarette-free days. These findings add to the evidence base for reduced nicotine content in cigarettes. Clinical Trial Registration: ClinicalTrials.gov, identifier: ChiCTR2100048216.

The moderating role of regulatory emotional self-efficacy on smoking craving: An ecological momentary assessment study.

Emotion is presumed as a major reason for smoking, but this hypothesis needs support from data with high ecological validity. Regulatory emotional self-efficacy (RESE) is key for emotion regulation, therefore RESE is likely to moderate the relationship between emotional states and smoking. The present study used the ecological momentary assessment (EMA) to record the levels of pleasure, arousal, and smoking craving in 33 male current smokers' daily lives, and examined the moderating effect of RESE in the prediction relationship between emotion and craving. The results showed that either end of the pleasure dimension, namely the high positive or high negative affect, predicted higher smoking craving. A similar pattern was also discovered in the arousal dimension, in which either of the activation and deactivation ends predicted higher smoking craving. Moreover, the prediction of negative affect on smoking craving was weakened by higher RESE, especially by the higher self-efficacy in managing negative emotions. In conclusion, smoking craving is closely related with immediate emotional states, and RESE reveals promising value in the reduction of smoking behavior. We discuss the possibility of expanding the RESE frame.

A simple LC-MS/MS method for the simultaneous quantification of resveratrol and its major phase II metabolites: Assessment of their urinary and biliary excretions in rats.

Trans-resveratrol (Res) is rapidly metabolized, extensively distributed into various tissues and mainly excreted by urine. The present study aimed to establish a simple LC-MS/MS method to simultaneously quantify Res and its major phase II metabolites (Res-3-O-ß-d-glucuronide, R3G; Res-4'-O-ß-d-glucuronide, R4'G; Res-resveratrol 3-sulfate, R3S; and Res-4'-sulfate, R4'S), and apply this method to assess their urinary and biliary excretions in rats. A simplified salting-out assisted liquid-liquid extraction (SALLE) strategy was developed to prepare samples with acetonitrile-methanol mixture (8:2, v/v) as extractant and ammonium acetate solution (10M) as salting-out reagent. The method validation demonstrated an acceptable recovery (>80%), good accuracy (85-115%), low deviation of detection (<15%) and no obvious matrix effect (<20%). Then the validated method was successfully applied to analyze the excretion of Res and its metabolites after intragastric administration of Res at 50mg/kg in rats. Only a minor proportion of Res (0.51nmol) and its metabolites (R3S, 35.8nmol; R4S, 0.25nmol; R3G, 142.3nmol; R4'G, 0.19nmol) were eliminated via bile, while the majority of Res (1670.2nmol), R3G (14,089.0nmol) and R3S (2975.6nmol) were excreted through urine. The major forms found in feces were Res and R3S, which were accumulated up to 241.8 and 250.8nmol, respectively. In summary, the SALLE technique simplified the samples preparation and could be well popularized, especially for those highly polar compounds in biosamples like urine, bile and feces, where various endogenous substances could significantly affect the extraction recovery and detection response.

Optimal dosing regimen of biapenem in Chinese patients with lower respiratory tract infections based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation.

In this study, a population pharmacokinetic (PPK) model of biapenem in Chinese patients with lower respiratory tract infections (LRTIs) was developed and optimal dosage regimens based on Monte Carlo simulation were proposed. A total of 297 plasma samples from 124 Chinese patients were assayed chromatographically in a prospective, single-centre, open-label study, and pharmacokinetic parameters were analysed using NONMEN. Creatinine clearance (CLCr) was found to be the most significant covariate affecting drug clearance. The final PPK model was: CL (L/h)=9.89+(CLCr-66.56)×0.049; Vc (L)=13; Q (L/h)=8.74; and Vp (L)=4.09. Monte Carlo simulation indicated that for a target of ≥40% T>MIC (duration that the plasma level exceeds the causative pathogen's MIC), the biapenem pharmacokinetic/pharmacodynamic (PK/PD) breakpoint was 4µg/mL for doses of 0.3g every 6h (3-h infusion) and 1.2g (24-h continuous infusion). For a target of ≥80% T>MIC, the PK/PD breakpoint was 4µg/mL for a dose of 1.2g (24-h continuous infusion). The probability of target attainment (PTA) could not achieve ≥90% at the usual biapenem dosage regimen (0.3g every 12h, 0.5-h infusion) when the MIC of the pathogenic bacteria was 4µg/mL, which most likely resulted in unsatisfactory clinical outcomes in Chinese patients with LRTIs. Higher doses and longer infusion time would be appropriate for empirical therapy. When the patient's symptoms indicated a strong suspicion of Pseudomonas aeruginosa or Acinetobacter baumannii infection, it may be more appropriate for combination therapy with other antibacterial agents.

Efficacy and safety of biapenem against lower respiratory tract infections in elderly Chinese patients and optimal dosing regimen based on pharmacokinetic/pharmacodynamic analysis.

The present study evaluated the efficacy and safety of biapenem in elderly Chinese patients with lower respiratory tract infections (LRTIs) and proposed optimal dosage regimen on the basis of pharmacokinetic/pharmacodynamic (PK/PD) analysis. The clinical efficacy, bacterial eradication and comprehensive therapeutic effect rates of biapenem were 70.3 (78/111), 68.5 (37/54) and 61.1% (33/54), respectively. Drug-related adverse reactions were seen in 12.6% of patients (14/111). The total protein level, Acute Physiology and Chronic Health Evaluation (APACHE) II score, %fT>MIC, fAUC24/MIC and fCmax/MIC values of patients had significant impacts (P < 0.05) on clinical and bacteriological efficacy. However, logistic regression analysis showed that only %fT>MIC independently influenced comprehensive therapeutic effect (P < 0.01, odds ratio = 1.064). The cut-off value for predicting comprehensive therapeutic effect using %fT>MIC was 75.0%; the sensitivity and specificity were 87.9 and 85.7%, respectively. Monte Carlo simulations revealed that the usual dosage regimen (300 mg every 12 hours, 0.5 hour infusion) was considered to be insufficient to obtain satisfactory therapeutic outcomes against low susceptible pathogens for elderly Chinese patients with LRTIs (CLcr = 70 ml/min).

Assessment of UDP-glucuronosyltransferase catalyzed formation of Picroside II glucuronide in microsomes of different species and recombinant UGTs.

This study compared the hepatic glucuronidation of Picroside II in different species and characterized the glucuronidation activities of human intestinal microsomes (HIMs) and recombinant human UDP-glucuronosyltransferases (UGTs) for Picroside II. The rank order of hepatic microsomal glucuronidation activity of Picroside II was rat > mouse > human > dog. The intrinsic clearance of Picroside II hepatic glucuronidation in rat, mouse and dog was about 10.6-, 6.0- and 2.3-fold of that in human, respectively. Among the 12 recombinant human UGTs, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 catalyzed the glucuronidation. UGT1A10, which are expressed in extrahepatic tissues, showed the highest activity of Picroside II glucuronidation (K(m) = 45.1 µM, V(max) = 831.9 pmol/min/mg protein). UGT1A9 played a primary role in glucuronidation in human liver microsomes (HLM; K(m) = 81.3 µM, V(max) = 242.2 pmol/min/mg protein). In addition, both mycophenolic acid (substrate of UGT1A9) and emodin (substrate of UGT1A8 and UGT1A10) could inhibit the glucuronidation of Picroside II with the half maximal inhibitory concentration (IC(50)) values of 173.6 and 76.2 µM, respectively. Enzyme kinetics was also performed in HIMs. The K(m) value of Picroside II glucuronidation was close to that in recombinant human UGT1A10 (K(m) = 58.6 µM, V(max) = 721.4 pmol/min/mg protein). The intrinsic clearance was 5.4-fold of HLMs. Intestinal UGT enzymes play an important role in Picroside II glucuronidation in human.