Synthesis of 14C‐labeled piperidines and application to synthesis of [14C]SCH 351125, a CCR5 receptor antagonist

1‐Benzyl‐4‐hydroxy[2‐¹⁴C]piperidine, a useful intermediate in labeled compound synthesis, was prepared from [¹⁴C]formaldehyde in high yield. The distribution pattern of ¹⁴C in the product is consistent with a mechanism involving reversible iminium ion formation and rapid equilibration of the iminium ion through a cationic aza‐Cope rearrangement. These steps precede the rate‐determining intramolecular cyclization step. SCH 351125 is a potent, selective CCR5 receptor antagonist with potential as a treatment for HIV infection. [¹⁴C]SCH 351125, required for metabolism studies, was prepared from 1‐benzyl‐4‐hydroxy[2‐¹⁴C]piperidine in six steps. [¹⁴C]SCH 351125 is a mixture of four atropisomers. Preparation of [¹⁴C]SCH 351125 besylate salt of the desired atropisomer pair is also described. Copyright © 2007 John Wiley & Sons, Ltd.     

A stereotactic approach to deep-seated central nervous system neoplasms using the carbon dioxide laser

This report describes a technique in which deep-seated CNS neoplasms, the volume and shape of which had been determined and stereotactically localized by computer reconstruction of CT data, were vaporized with a carbon dioxide laser attached to a stereotactic frame. The clinical results with 6 patients treated by this technique are presented.     

Effects of zymosan-activated plasma and phorbol myristate acetate on isolated, perfused rabbit lungs

The effects of complement activation on pulmonary vascular permeability are disputed. In rabbit lungs perfused with autologous blood, zymosan activated plasma (ZAP) induced a moderate increase in pulmonary vascular resistance (PVR), but did not detectably change the vascular permeability within 2 h. The stronger neutrophil granulocyte (PMN) activator, phorbol myristate acetate (PMA), usually gave larger PVR increases and also increased pulmonary vascular permeability. Lungs from neutropenic animals, similarly perfused and given PMA, showed unchanged PVR reactions but had no apparent increase in vascular permeability. Lungs perfused with cell-free medium and given PMA displayed modest PVR increases, and no measurable permeability change. The lung preparatory procedure itself markedly influenced leukocyte circulation. Exsanguination of lung donors decreased the concentration of circulating PMN significantly, and they virtually disappeared from the perfusate within minutes after start of lung perfusion. PMN-mediated effects must therefore have been caused by cells already sequestered in the lungs. We conclude that ZAP does not induce an increased pulmonary vascular permeability in isolated, perfused rabbit lungs, in contrast to PMA. The permeability effects of PMA appear to be PMN dependent.     

End-tidal Carbon Dioxide Monitoring during Procedural Sedation

OBJECTIVE: To prospectively determine whether end-tidal carbon dioxide (ETCO2) monitors can detect respiratory depression (RD) and the level of sedation in emergency department (ED) patients undergoing procedural sedation (PS). METHODS: This was a prospective observational study conducted in an urban county hospital of adult patients undergoing PS. Patients were monitored for vital signs, depth of sedation per the physician by the Observer's Assessment of Alertness/Sedation scale (OAA/S), pulse oximetry, and nasal-sample ETCO2 during PS. Respiratory depression was defined as an oxygen saturation <90%, an ETCO2 >50 mm Hg, or an absent ETCO2 waveform at any time during the procedure. The physician also determined whether protective airway reflexes were lost during the procedure and assisted ventilation was required, or whether there were any other complications. Rates of RD were compared with the physician assessment of airway loss and between agents using chi-square statistics. Spearman's rho analysis was used to determine whether there was a correlation between ETCO2 and the OAA/S score. RESULTS: Seventy-four patients were enrolled in the study. Forty (54.1%) received methohexital, 21 (28.4%) received propofol, ten (13.5%) received fentanyl and midazolam, and three (4.1%) received etomidate. Respiratory depression was seen in 33 (44.6%) patients, including 47.5% of patients receiving methohexital, 19% receiving propofol (p = 0.008), 80% receiving fentanyl and midazolam, and 66.6% receiving etomidate. No correlation between OAA/S and ETCO2 was detected. Eleven (14.9%) patients required assisted ventilation at some point during the procedure, all of whom met the criteria for RD. Pulse oximetry detected 11 of the 33 patients with RD. Post-hoc analysis revealed that all patients with RD had an ETCO2 >50 mm Hg, an absent waveform, or an absolute change from baseline in ETCO2 >10 mm Hg. CONCLUSIONS: There was no correlation between ETCO2 and the OAA/S score. Using the criteria of an ETCO2 >50 mm Hg, an absolute change >10 mm Hg, or an absent waveform may detect subclinical RD not detected by pulse oximetry alone. The ETCO2 may add to the safety of PS by quickly detecting hypoventilation during PS in the ED.     

Increased carbon monoxide levels in the nasal airways of subjects with a history of seasonal allergic rhinitis and in patients with upper respiratory tract infection

BACKGROUND: Carbon monoxide (CO) has emerged as an endogenously produced gaseous mediator known to be involved in bronchial smooth muscle regulation. Increased amounts of CO have been found in exhaled air during asthma and lower airway inflammation. Recently CO has been shown to be produced in the nasal airways, but there are no reports of altered CO levels in nasal airways during inflammation. OBJECTIVE: This study was designed to investigate if CO levels increase in the human nasal airways during inflammatory conditions, such as allergy and upper airway respiratory tract infection (URTI). METHODS: CO was sampled separately from the upper and lower airways of 13 healthy control subjects, six patients with a history of allergic rhinitis and six patients with URTI. RESULTS: Nasal CO levels were increased in subjects with allergic rhinitis, compared to healthy controls (2.07 +/- 0.15 ppm, n = 6 and 1.62 +/- 0.08 ppm, n = 13, respectively, P < 0.01). CO levels were also increased in patients with URTI, compared to the same controls (1.92 +/- 0.09 ppm, n = 6, P < 0.05). Normal levels of CO were found in air from the lower airways among subjects with allergic rhinitis, whereas corresponding levels in the URTI patients were increased. CONCLUSION: The present data demonstrates that upper airway CO levels increase in parallel with different inflammatory stimuli, such as allergy and infection, suggesting a role for CO as marker or mediator of nasal inflammation.     

Lymphokine activated killer cells in murine coxsackievirus B3 myocarditis

The purpose of the present study was to determine whether lymphokine activated killer (LAK) cells were involved in the development of coxsackievirus B3 (CB3) myocarditis in both the acute viremic (Experiment I) and the subacute aviremic (Experiment II) stages. To induce LAK cells, recombinant human interleukin-2 (IL-2) was administered to CB3-infected mice subcutaneously daily, starting on day 0 in Experiment I and on day 7 in Experiment II for 7 days, respectively. The treated groups were compared to infected controls. Splenic lymphocytes of IL-2 treated mice were further cultured in vitro in IL-2 containing medium for 7 days, and LAK cell activity, i.e., cytotoxic activity of the lymphocytes against EL-4 tumor cells and against cultured fetal myocytes, was assayed by⁵¹Cr-release method. In Experiment I, histologic scores, myocardial virus titers, and LAK cell activity did not differ significantly between IL-2 treated and untreated groups. In contrast, in Experiment II, there were more cellular infiltration associated with severe necrosis and higher LAK cell activity against EL-4 cells and cultured myocytes in IL-2 treated than in untreated groups. The presence of LAK cells was demonstrated in the subacute stage of murine CB3 myocarditis. Thus, the behavior of LAK cell activity may vary with the course of myocarditis, and enhanced LAK cell activity may be involved in the development of the disease.This work was supported by research grants from the Conference on Coronary Artery Disease, Japanese Education of Science and Walfare (Nos. 08877110 and 09470164), Kanae Shinyaku Foundation, and Japan Cardiovascular Research Foundation.     

二硫化碳对大鼠胚胎发育及血清锌和铜含量影响的研究

本文观察了CS_2对大鼠胚胎发育及血清锌、铜含量的影响。发现胚胎着床前死亡率升高,胎鼠皮下出血、心包淤血及骨骼骨化不金的发生率增高。但无明显的致畸效应。14.1及103.9ng/m~3的CS_2对妊娠大鼠的血清锌、铜含量无明显影响。说明CS_2对大鼠的胚胎毒性与其对妊娠大鼠血清锌、铜含量的影响之间没有关联。     

Activated prothrombin complex concentrate (FEIBA®) treatment during surgery in patients with inhibitors to FVIII/IX

Non-activated and activated prothrombin complex concentrates (PCC/aPCC) have been used successfully to treat bleeds in haemophilia patients with inhibitors, but most physicians do not consider these products as effective as factor VIII/IX (FVIII/IX) concentrates in non-inhibitor patients. Thus, surgical procedures in inhibitor patients have been performed reluctantly. We have performed 14 minor and five major surgical and invasive diagnostic procedures in eight patients with congenital haemophilia A and inhibitors and in two patients with acquired haemophilia. When a loading dose of 100 U kg-1 of FEIBA was given followed by 200 U kg-1 day-1 in three divided doses every 8 h for 3 days, and then, when the daily dose was tapered to 100-150 U kg-1, no severe or unexpected bleeding complications were observed. However, one adverse event was observed. A 69-year-old man who suffered a myocardial infarction the third postoperative day following sigmoidectomy was managed safely with opiate analgesia, nitrates and diuretics, and the continued use of FEIBA(R).     

二硫化碳对大鼠海马一氧化氮合酶活力和基因表达的影响

目的:探讨二硫化碳(CS2)对大鼠海马一氧化氮合酶(NOS)活力和基因表达的影响。方法:以吸入染毒法制作不同浓度CS2中毒大鼠模型:染毒2个月后,用Morris水迷宫法检测实验大鼠的学习记忆功能;以NOS测定试剂盒测定大鼠海马NOS活力;以半定量逆转录一聚合酶链式反应(RT-PCR)法测定神经元型一氧化氮合酶(nNOS)mRNA 含量的变化。结果:Morris水迷宫测试显示染毒后大鼠平均逃逸潜伏期较对照组延长,差异有显著性;各CS2染毒组大鼠海马NOS活性降低,与对照组比较差异有显著性,随CS2浓度的增加NOS活性降低,各染毒组间比较差异有显著性差异;染毒后海马nNOS mRNA含量比对照组显著减少,与CS2浓度呈剂量依赖关系,差异有显著性意义。结论:CS2致大鼠海马NOS活力降低及nNOS mRNA含量减少可能是CS2干扰学习记忆功能的机制之一。