ObjectivesNalbuphine is as effective as morphine as a perioperative analgesic but has not been compared directly with sufentanil in clinical trials. The aims of this study were to compare the efficacy and safety of nalbuphine with that of sufentanil in patients undergoing colonoscopy and to determine the optimal doses of nalbuphine in this indication.MethodsTwo hundred and forty consecutive eligible patients aged 18–65 years with an American Society of Anesthesiologists classification of I–II and scheduled for colonoscopy were randomly allocated to receive sufentanil 0.1 μg/kg (group S), nalbuphine 0.1 mg/kg (group N1), nalbuphine 0.15 mg/kg (group N2), or nalbuphine 0.2 mg/kg (group N3). Baseline vital signs were recorded before the procedure. The four groups were monitored for propofol sedation using the bispectral index, and pain relief was assessed using the Visual Analog Scale and the modified Behavioral Pain Scale for non-intubated patients. The incidences of respiratory depression during endoscopy, nausea, vomiting, drowsiness, and abdominal distention were recorded in the post anesthesia care unit and in the first and second 24-hour periods after colonoscopy.ResultsThere was no significant difference in analgesia between the sufentanil group and the nalbuphine groups (p>0.05). Respiratory depression was significantly more common in group S than in groups N1 and N2 (p<0.05). The incidence of nausea was significantly higher in the nalbuphine groups than in the sufentanil group in the first 24 hours after colonoscopy (p<0.05).ConclusionsNalbuphine can be considered as a reasonable alternative to sufentanil in patients undergoing colonoscopy. Doses in the range of 0.1–0.2 mg/kg are recommended. The decreased risks of respiratory depression and apnea make nalbuphine suitable for patients with respiratory problems.
ET-26 hydrochloride (ET-26HCl) is a novel etomidate analogue, approved for clinical trials, which has an effective sedative-hypnotic effect, a stable myocardial performance, and milder adrenocortical suppression than etomidate in rats and beagle dogs. Additionally, ET-26HCl showed similar hemodynamic stability as etomidate in the rat uncontrolled hemorrhagic shock model. Furthermore, ET-26HCl, in the rat lipopolysaccharide-induced sepsis model, was found to have a higher survival rate, a lower inflammatory reaction, and less organ injury. In the present study, we measured the potential adverse effects of ET-26HCl in beagle dogs in accordance with the Guidance on single-and repeated-dose toxicity published by the China Food and Drug Administration. In toxicity studies, single and repeated (14 days) intravenous doses of up to 16 mg/kg were well tolerated, with only pharmacologically related clinical signs seen in both studies. Thus, the no-observed-adverse-effect level (NOAEL) of ET-26HCl was found at 16 mg/kg/day. Toxicokinetic examination demonstrated that ET-26HCl showed a dose-dependent increase to exposure, no gender difference, and no evidence of accumulation. These results provide useful information for guiding a phase I clinical trial of ET-26HCl in healthy volunteers. K E Y W O R D SET-26 hydrochloride, general anesthesia, intravenous anesthetic agent, preclinical toxicology, repeated dose toxicity, single dose toxicity, toxicokinetic
Among the advancements in drug structural modifications, the increased focus on drug metabolic and pharmacokinetic properties in the anesthetic drug design process has led to significant developments. Drug metabolism also plays a key role in optimizing the pharmacokinetics, pharmacodynamics, and safety of drug molecules. Thus, in the field of anesthesiology, the applications of pharmacokinetic strategies are discussed in the context of sedatives, analgesics, and muscle relaxants. In this review, we summarize two approaches for structural optimization to develop anesthetic drugs, by designing prodrugs and soft drugs. Drugs that both failed and succeeded during the developmental stage are highlighted to illustrate how drug metabolism and pharmacokinetic optimization strategies may help improve their physical and chemical properties.
ET‐26 hydrochloride (ET‐26HCl), a novel analog of etomidate, induces as effective sedation, with good cardiac and respiratory stability, as etomidate but with mild adrenocortical suppression. The objective of this study was to evaluate the potential adverse effects of ET‐26HCl in rats. In a single‐dose toxicity study, abnormal urine color (red) was observed in all groups: control (100%), 8 mg/kg (10%), 16 mg/kg (50%), and 20 mg/kg (70%) ET‐26HCl, which returned to normal on the day of dosing. There were no mortalities or serious toxicological signs; the maximum tolerable dose of ET‐26HCl was 20 mg/kg. In the repeated‐dose toxicity study, deaths occurred in the 12‐ (13.33% of males) and 16‐mg/kg/day (20% of males and 3.33% of females) groups. Abnormal urine color (red or brown) was detected in the control group (10%) and all treatment groups (30%, 46.67%, and 40% at 8, 12 and 16 mg/kg/day, respectively), at a frequency of 1.43% in the control group, 4.76% in 8 mg/kg/day, 7.62% in 12 mg/kg/day, and 4.29% in 16 mg/kg/day. Increases in neutrophils and plasma fibrinogen were temporary and recoverable effects. Macroscopic and histopathologic changes were found only at the injection sites: abnormal skin color, scabbing, thrombus, ulceration, and inflammation. During the recovery period, there was evidence of reversibility, including fibroblast proliferation and vessel recanalization. The no‐observed‐adverse‐effect level of ET‐26HCl was 8 mg/kg/day. Toxicokinetic variables of ET‐26HCl, except the calculated initial concentration in females on Day 1, showed a dose‐dependent increase to exposure, with no gender difference and no evidence of accumulation.
Background: ET-26 hydrochloride is a novel intravenous anesthetic, approved for clinical trials, that produces a desirable sedative-hypnotic effect with stable myocardial performance and mild adrenocortical suppression in rats and beagle dogs. The objective of this study was to assess the absorption, distribution, metabolism, and excretion of ET-26 hydrochloride. Methods: Hepatocytes from human, monkey, dog, rat, and mouse were used to determine the metabolites of ET-26 hydrochloride. Distribution and excretion were assessed in rats and pharmacokinetic studies were performed in beagle dogs. Results: The metabolic pathway and proposed structure of metabolites were fully assessed resulting from the biotransformation reactions of hydrolysis, dehydrogenation, demethylation and glucuronic acid conjugation. The main distribution of the drug was in fat (15067 ± 801 ng/ml) and liver (13647 ± 1126 ng/ml), and the kidney was the primary excretion route (4.47%-11.94%). The Cmax after injection with 1.045 mg/kg, 2.09 mg/kg, and 4.18 mg/kg was 1476.5 ± 138.9 ng/ml, 2846.1 ± 223.3 ng/ml, and 6233.3 ± 238.9 ng/ml, respectively. The t1/2 of the drug was similar across dose groups at 74.8 ± 10.8 min to 81.4 ± 4.2 min. The AUC0-t values were 30208.1 ± 2026.5 min*ng/ml, 62712.8 ± 1808.3 min*ng/ml, and 130465.2 ± 7457.4 min*ng/ml, respectively. Conclusion: The metabolic pathway and the proposed structure of metabolites for ET-26 hydrochloride were fully assessed. The majority of distribution for ET-26 hydrochloride occurs in the fat and liver, while the primary route of excretion for ET-26 hydrochloride is through the kidney. In dogs, pharmacokinetic features of ET-26 hydrochloride had a linear relationship with dosage.
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