Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil

BACKGROUND: Despite widespread use, little is known about the comparative pharmacokinetics of intrathecally administered opioids. The present study was designed to characterize the rate and extent of opioid distribution within cerebrospinal fluid, spinal cord, epidural space, and systemic circulation after intrathecal injection. METHODS: Equal doses of morphine and alfentanil, fentanyl, or sufentanil were administered intrathecally (L3) to anesthetized pigs. Microdialysis probes were used to sample cerebrospinal fluid at L2, T11, T7, T3, and the epidural space at L2 every 5-10 min for 4 h. At the end of the experiment, spinal cord and epidural fat tissue were sampled, and each probe's recovery was determined in vitro. Using SAAM II pharmacokinetic modeling software (SAAM Institute, University of Washington, Seattle, WA), the data were fit to a 16-compartment model that was divided into four spinal levels, each of which consisted of a caternary arrangement of four compartments representing the spinal cord, cerebrospinal fluid, epidural space, and epidural fat. RESULTS: Model simulations revealed that the integral exposure (area under the curve divided by dose) of the spinal cord (i.e., effect compartment) to the opioids was highest for morphine because of its low spinal cord distribution volume and slow clearance into plasma The integral exposure of the spinal cord to the other opioids was relatively low, but for different reasons: alfentanil has a high clearance from spinal cord into plasma, fentanyl distributes rapidly into the epidural space and fat, and sufentanil has a high spinal cord volume of distribution. CONCLUSIONS: The four opioids studied demonstrate markedly different pharmacokinetic behavior, which correlates well with their pharmacodynamic behavior.     

细菌对MLS类和糖肽类抗生素产生耐药性的作用机制

MLS类和糖肽类抗生素在人类与细菌感染性疾病的对抗中发挥着重要作用.与其他抗生素一样,随着这些抗生素的临床使用,细菌耐药性的出现和不断发展给人们带来新的挑战.本综述对这两类抗生素的细菌耐药性产生机制进行了剖析,并就已开发的若干个新型MLS类和糖肽类抗生素作了介绍.     

我国“审方药师”的现状分析与建议

目的:培养合格的审方药师,确保患者合理用药。方法:分析我国审方药师的现状,提出培养合格审方药师的具体建议。结果:目前,我国审方药师队伍普遍存在学历、职称偏低,专业知识、医学知识不足,成员匮乏等现象。结论:必须充分认识审方药师的重要性,提高审方药师的准入条件,制订审方药师的业务标准,明确审方药师的责任,加大审方药师的培养力度及增加审方药师的数量,方可确保患者合理用药。     

重组人白介素-2吸入给药对小鼠克雷伯肺炎感染的影响

目的研究重组人白介素-2吸入给药对小鼠克雷伯肺炎感染的保护作用。方法小鼠以滴鼻感染法进行感染。感染过程中,以鼻腔插管注入法和皮下注射给予小鼠重组人白介素-2。同时另设正常组、阴性对照组、模型组和阳性对照组(庆大霉素组)。观察各组动物肺病理变化,比较平均死亡时间和一周内死亡率,测定支气管肺泡洗涤液中总蛋白、白蛋白含量,碱性磷酸酶、乳酸脱氢酶活力。结果重组人白介素-2给药组肺病理变化与模型组和阴性对照组相比显著减轻,支气管肺泡洗涤液中总蛋白、白蛋白含量和碱性磷酸酶活力降低。结论吸入重组人白介素-2缓解感染后肺部病理变化, 为研发重组人白介素-2吸入剂提供了依据。     

Differential enantioselectivity and product-dependent activation and inhibition in metabolism of verapamil by human CYP3As.

In vitro studies of enantioselective metabolism of R-(+)- and S-(-)verapamil (VER) were conducted using human cDNA-expressed CYP3A isoforms, CYP3A4, CYP3A5, and CYP3A7. N-dealkylated products nor-VER [2,8-bis-(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile] and D617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile] were the major metabolites for all CYP3A isoforms regardless of enantiomer. Enantioselectivity of CYP3A4 and CYP3A7 was most similar among the three isoforms. This coincides with the degree of homology of amino acids at the active sites and in the total amino acid sequences of the enzymes. Biphasic substrate inhibition was observed for the formation of nor-VER and D617, whereas simple biphasic kinetics were observed for the formation of O-demethylated products for both enantiomers with CYP3A4. The biphasic substrate inhibition was observed only for nor-VER, and simple biphasic kinetics were observed for D617 and O-demethylated products for both enantiomers with CYP3A5. However, with CYP3A7, D617 and O-demethylated products showed typical Michaelis-Menten kinetics, and only nor-VER displayed substrate (monophasic) inhibition. When metabolic rates of VER were determined in the presence of three different effectors, midazolam, testosterone, and nifedipine, activation, inhibition, or activation and inhibition of VER metabolism was observed depending on the enantiomers, metabolites, effectors, and cytochrome P450 isoforms. Addition of anti-CYP3A4 antibody inhibited formation of all metabolites for both CYP3A4 and CYP3A5. The atypical phenomena (biphasic substrate inhibition, activation, and inhibition depending on product formation) of VER kinetics could be adequately explained by introducing the concept of steric interaction into a two binding-site model.     

Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes.

Oxycodone undergoes N-demethylation to noroxycodone and O-demethylation to oxymorphone. The cytochrome P450 (P450) isoforms capable of mediating the oxidation of oxycodone to oxymorphone and noroxycodone were identified using a panel of recombinant human P450s. CYP3A4 and CYP3A5 displayed the highest activity for oxycodone N-demethylation; intrinsic clearance for CYP3A5 was slightly higher than that for CYP3A4. CYP2D6 had the highest activity for O-demethylation. Multienzyme, Michaelis-Menten kinetics were observed for both oxidative reactions in microsomes prepared from five human livers. Inhibition with ketoconazole showed that CYP3A is the high affinity enzyme for oxycodone N-demethylation; ketoconazole inhibited >90% of noroxycodone formation at low substrate concentrations. CYP3A-mediated noroxycodone formation exhibited a mean K(m) of 600 +/- 119 microM and a V(max) that ranged from 716 to 14523 pmol/mg/min. Contribution from the low affinity enzyme(s) did not exceed 8% of total intrinsic clearance for N-demethylation. Quinidine inhibition showed that CYP2D6 is the high affinity enzyme for O-demethylation with a mean K(m) of 130 +/- 33 microM and a V(max) that ranged from 89 to 356 pmol/mg/min. Activity of the low affinity enzyme(s) accounted for 10 to 26% of total intrinsic clearance for O-demethylation. On average, the total intrinsic clearance for noroxycodone formation was 8 times greater than that for oxymorphone formation across the five liver microsomal preparations (10.5 microl/min/mg versus 1.5 microl/min/mg). Experiments with human intestinal mucosal microsomes indicated lower N-demethylation activity (20-50%) compared with liver microsomes and negligible O-demethylation activity, which predict a minimal contribution of intestinal mucosa in the first-pass oxidative metabolism of oxycodone.     

两种鼻黏膜切口在鼻内镜下鼻腔泪囊吻合术中的应用

目的：比较两种鼻黏膜切口在鼻内镜下鼻腔泪囊吻合术中出血情况和术后治疗效果。

方法：回顾性研究。收集2016-06/2018-05在我院眼科确诊为慢性泪囊炎并接受鼻内镜下鼻腔泪囊吻合手术治疗的患者63例66眼。根据鼻黏膜瓣基底部位的不同分组,A组以中鼻甲腋为基底的鼻腔黏膜切口行泪囊鼻腔吻合术,B组以上颌骨线为基底的鼻腔黏膜切口行泪囊鼻腔吻合术。随访至术后6mo,比较两组患者术中出血和术后疗效。

结果：两组患者术中出血情况有差异(χ²=11.803,P<0.05),术后有效率比较无差异(82% vs 73%,P>0.05)。

结论：以中鼻甲腋为基底部的鼻腔黏膜切口,术中并发出血较多; 而以上颌骨线为基底的鼻腔黏膜切口,术中出血较少。两组患者术后疗效无差异。     

Clinical Outcomes of Revision Total Knee Arthroplasty after High Tibial Osteotomy and Unicompartmental Knee Arthroplasty: A Systematic Review and Meta‐Analysis

As more high tibial osteotomy (HTO) and unicompartmental knee arthroplasty (UKA) are performed, orthopaedic surgeons realize that more HTO and UKA failures will require revision to total knee arthroplasty (TKA) in the future. To systematically evaluate the clinical outcomes of TKA after HTO and TKA after UKA, the Embase, PubMed, Ovid, Web of Science, and Cochrane Library databases were searched for studies investigating revision TKA after HTO and UKA published up to June 2021. RevMan version 5.3 was used to perform the meta‐analysis. The revision TKA after HTO and revision TKA after UKA groups were compared in terms of operative time, range of motion (ROM), knee score, postoperative complications, postoperative infection, revision, and revision implants used. Nine studies were ultimately included in the meta‐analysis. Results revealed that the knee score for the revision TKA after HTO group was better than that of the revision TKA after UKA group (MD 4.50 [95% CI 0.80–8.20]; p = 0.02). The revision TKA after HTO group had a lower revision rate (OR 0.65 [95% CI 0.55–0.78]; p < 0.00001) and fewer revision implants used (OR 0.11 [95% CI 0.05–0.23]; p < 0.00001). There were no statistical differences in operation time (MD ‐2.00 [95% CI −11.22 to 7.21]; p = 0.67), ROM (MD ‐0.04 [95% CI ‐3.69–3.61]; p = 0.98), postoperative complications (OR 1.41 [95% CI 0.77–2.60]; p = 0.27), or postoperative infections (OR 0.89 [95% CI 0.61–1.29]; p = 0.53). To conclude, the revision rate of revision TKA after UKA was greater, and more revision implants were required. It is important for orthopaedic surgeons to preserve bone during primary UKA.     

Arthroscopic Management of Giant Meniscal Cysts Among Young Patients: An Average Three‐Year MRI Follow‐Up

ObjectiveTo describe an arthroscopic technique for giant meniscal cyst excision with preservation of the functional meniscus, report the short‐ and medium‐term outcomes, and assess magnetic resonance imaging (MRI) for follow‐up imaging evaluations.MethodsA total of 54 consecutive patients with symptomatic meniscal cysts were admitted to the Second Xiangya Hospital of Central South University between 2014 and 2019. Nine patients with giant meniscus cysts (six females and three males) were included in this study. The age range of the patients was 6–34 years. All patients underwent a complete physical examination, X‐ray, Doppler ultrasound, and MRI of the knee preoperatively. After an arthroscopic diagnosis of a meniscal rupture with a giant meniscal cyst, partial meniscectomy, ablation of the cyst, and suturing of the retainable meniscus were performed. Lysholm and International Knee Documentation Committee (IKDC) scores were used preoperatively and at the most recent follow‐up. Clinical outcomes were classified into four categories: excellent, good, fair, and poor. During the last visit, all patients underwent MRI to assess the recurrence of the cyst and meniscal suture healing.ResultsPreoperative MRI and arthroscopic examination revealed giant meniscal cysts combined with meniscal tears and congenital discoid meniscus, and all giant meniscal cysts occurred in the lateral meniscus. The main types of meniscal tears were horizontal and complex tears. The cysts were unicystic in one case and multicystic in eight cases. The mean size of the cysts on the MRI was 5.86 cm × 2.24 cm × 2.48 cm. The mean follow‐up periods were 37.5 (19–60) months. Clinical outcomes were excellent in six patients and good in three patients. The postoperative scores were significantly improved compared to the preoperative scores (Lysholm: 90.78 ± 4.60 vs. 54.56 ± 7.25; IKDC: 96.2 ± 3.46 vs. 61.69 ± 3.36; p <0.01). No recurrence of the cyst was indicated on the MRI, and there was good healing of the torn meniscus.ConclusionsArthroscopic cystectomy combined with the meniscus suture technique was effective to eradicate residual cyst cavities, and traffic orifices be highly recommended.