Phenotyping interindividual variability in obstructive sleep apnoea response to temazepam using ventilatory chemoreflexes during wakefulness

Centrally active agents have a variable impact in patients with obstructive sleep apnoea (OSA) that is unexplained. How to phenotype the individual OSA response is clinically important, as it may help to identify who will be at risk of respiratory depression and who will benefit from a centrally active agent. Based on loop gain theory, we hypothesized that OSA patients with higher central chemosensitivity have higher breathing instability following the use of a hypnosedative, temazepam. In 20 men with OSA in a double‐blind, placebo‐controlled cross‐over trial we tested the polysomnographically (PSG) measured effects of temazepam 10 mg versus placebo on sleep apnoea. Treatment nights were at least 1 week apart. Ventilatory chemoreflexes were also measured during wakefulness in each subject. The patients (mean ± standard deviation; 44 ± 12 years) had predominantly mild‐to‐moderate OSA [baseline apnoea–hypopnoea index (AHI) = 16.8 ± 14.1]. Patients’ baseline awake central chemosensitivity correlated significantly with both the change of SpO₂ nadir between temazepam and placebo (r = ?0.468, P = 0.038) and oxygen desaturation index (ODI; r = 0.485, P = 0.03), but not with the change of AHI (r = 0.18, P = 0.44). Peripheral chemosensitivity and ventilatory recruitment threshold were not correlated with the change of SpO₂ nadir, ODI or AHI (all P > 0.05). Mild–moderate OSA patients with higher awake central chemosensitivity had greater respiratory impairment during sleep with temazepam. Relatively simple daytime tests of respiratory control may provide a method of determining the effect of sedative–hypnotic medication on breathing during sleep in OSA patients.     

Effect of two durations of short-term intermittent hypoxia on ventilatory chemosensitivity in humans

The purpose of this study was to clarify the influence of duration of intermittent hypoxia per day on ventilatory chemosensitivity. Subjects were assigned to three different groups according to the duration of exposure to intermittent hypoxia (12.3 ± 0.2% O₂): a first group (H-1, n = 6) was exposed to hypoxia for 1 h per day, the second group (H-2, n = 6) was exposed for 3 h per day, and the third (C, n = 7) was used as control. Hypoxic and hypercapnic ventilatory responses (HVR and HCVR) were determined before and after 1 week of intermittent hypoxia. HVR was increased significantly (P < 0.05) after intermittent hypoxia in both the H-1 and H-2 groups. However, there was no significant difference in magnitude of increased HVR between H-1 and H-2 groups. HCVR did not show any changes in all groups after intermittent hypoxia. These results suggest that 1 h of daily exposure is as equally effective as 3 h of daily exposure to severe hypoxia for a short period for enhancing ventilatory chemosensitivity to hypoxia.     

Developments in autonomic research: a review of the latest literature

Congenital central hypoventilation syndrome (CCHS) is a developmental disorder of childhood, characterized by respiratory arrests during sleep. Initially referred to as Ondine’s Curse, children with CCHS show attenuated ventilatory responses to hypercapnia and hypoxia, develop life-threatening episodes of apnea with cyanosis, and require ventilatory support during sleep. In addition, there is evidence of other developmental disorders in these children. It is now widely accepted that the syndrome is due to a mutation in a single homeobox gene located on chromosome 4. PHOX2B is important for the normal development of the autonomic nervous system and is expressed in respiratory neurones in the parafacial region of the ventral medualla: mice with mutations in PHOX2B breathe irregularly, do not respond to hypercapnia and die shortly after birth from central apnea. Cardiovascular disturbances, including prolonged R-R intervals and sudden death, are directly related to the extent of the mutation in PHOX2B.     

Association of epidermal growth factor receptor mutations in lung cancer with chemosensitivity to gefitinib in isolated cancer cells from Japanese patients

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are reported to be associated with clinical responsiveness of lung cancer to gefitinib, an EGFR tyrosine kinase inhibitor. To elucidate the association between somatic mutations and the pharmacological actions of gefitinib, the chemosensitivity of isolated cancer cells from the lungs of Japanese patients to gefitinib was examined by the collagen gel-droplet embedded culture drug sensitivity test in vitro. In 30 specimens isolated from non-small-cell lung cancer patients, mutations were observed in eight tumour specimens (27%) and chemosensitivity to gefitinib was observed in seven specimens (23%). However, somatic mutations were not predominantly associated with chemosensitivity to gefitinib in vitro. Both mutation and chemosensitivity frequencies in this study were higher than those reported in studies from the United States, indicating a possible ethnic difference. Moreover, both frequencies were much higher in females than in males. Since a gender difference in chemosensitivity to gefitinib was observed in isolated cancer cells in vitro, this suggests that gefitinib works in part through the suppression of EGFR signalling, but that other factors, including sex-related factors, may participate in gefitinib action.     

Involvement of aminopeptidase N in enhanced chemosensitivity to paclitaxel in ovarian carcinoma in vitro and in vivo

Aminopeptidase N (APN/CD13), a 150-kDa metalloproteinase, is a multifunctional cell surface aminopeptidase with ubiquitous expression. Recent studies have suggested that APN/CD13 plays an important role in tumor progression in several human malignancies. In the current study, we investigated the role of APN/CD13 in paclitaxel (PAC)-resistance of ovarian carcinoma (OVCA) cells. We first examined the correlation between APN/CD13 expression and IC50 values of PAC in a variety of OVCA cell lines. Next we investigated whether suppression of APN/CD13 using bestatin, an inhibitor of APN/CD13 activity or the siRNA technique influenced PAC-sensitivity in ES-2 cells, which highly express APN/CD13. Moreover, we investigated the effect of bestatin on peritoneal metastasis using nude mice. We found a negative correlation between APN/CD13 expression and chemosensitivity to PAC in various carcinoma cell lines. Subsequently, we found a significant increase in PAC-sensitivity of APN/CD13 expressing OVCA cells by suppression of this enzyme, using the addition of bestatin or the siRNA technique. Furthermore, in a peritoneal metastasis model using nude mice, combination treatment with PAC and bestatin caused a synergistic increase of survival time compared with PAC alone treatment. (mean survival time: 37.7 +/- 7.0 s and 27.1 +/- 6.6 days, respectively). The present findings showed that APN/CD13 may be involved in decreased sensitivity to PAC in OVCA cells and that the mechanism of this effect involves its enzyme activity at least in part. APN/CD13 may be a therapeutic target for the treatment of OVCA in combination with chemotherapy.     

Subrenal capsule assay applied to examine the sensitivity of allogenic mouse fibrosarcoma to hyperthermia,chemotherapeutic drugs or combined treatment

The thermosensitivity and chemosensitivity of fibrosarcomas of C3H/He mouse were investigated using the subrenal capsule assay with female ICR mice as host. Five typical chemotherapeutic drugs (mitomycin C, adriamycin, 5-fluorouracil, cis-DDplatinum and cyclophosphamide) tested were effective in suppressing tumour growth. Total-body hyperthermia given at 41.5°C for 30 min twice during the 6-day period exerted little effect. However, an interactive effect was found with the combination of hyperthermia and mitomycin C. The combination of hyperthermia with other drugs failed to exhibit an interactive effect, since the effects of the drugs alone were considerable. The potential clinical applicability of this test is discussed.     

体外药敏试验ATP-TCA与流式细胞仪在肝癌化疗中的应用

目的 探讨体外化疗药敏试验系统（ATP-TCA系统）联合流式细胞仪（FCM）在肝癌化疗中的应用及其结果之间的关系。方法 取24例肝癌切除，活检或穿刺组织行体外药敏试验和流式细胞仪P170检测，并分析二者间的关系。结果 ATP-TCA的可评估率为91.67%;10种化疗药物的敏感率分别为：氟尿嘧啶5.00%，诺消灵5.00%，顺铂14.26%，足叶乙甙19.05%，草酸铂19.05%,丝裂霉素23.81%，表阿霉素28.57%，开普拓45.46%，健择47.62%，泰素63.64%；P170检测阳性率为57.14%；丝裂霉素，表阿霉素的敏感率在P170阴性表达时高，开普拓健择，泰素的敏感率高且在P170阳性表达和阴性表达时无显著差异。结论 ATP-TCA法联合FCM可较好用于肝癌化疗药物的筛选；丝裂霉素，表阿霉素可用于P170阴性表达的病人，开普拓，健择，泰素可用于P170阳性表达的病人。     

MTT比色分析法检测卵巢癌药物敏感性

目的:探讨四氮唑蓝比色分析法(MTT法)用于指导临床个体化化疗药物选择的实用性,为卵巢癌临床化疗用药提供参考.方法:采用常用的12种化疗药物对65例卵巢癌进行MTT法药物敏感试验.结果:不同类型的卵巢癌及同一类型的不同个体对化疗药物的敏感性差异较大.卵巢癌对紫杉醇、表阿霉素、卡铂和顺铂中度敏感,平均抑制率分别为(67.3±4.6)%、(54.5±4.8)%、(52.0±4.3)%和(50.8±4.5)%;对鬼臼乙叉甙、烃基喜树碱和长春地新低度敏感,平均抑制率分别为(39.6±3.8)%、(39.3±4.3)%和(30.7±2.6)%;而对丝裂霉素C、噻替哌、5氟尿嘧啶、长春新碱和氨甲喋呤则耐药,平均抑制率均小于30%.结论:卵巢癌化疗敏感性个体差异较大.MTT法是一种简便而快速的肿瘤体外药物敏感实验方法,可为卵巢癌临床个体化化疗方案的选择提供客观依据.     

用MTT法预测胃癌化疗药物敏感性试验研究

用ＭＴＴ法测定７２例新鲜人胃癌组织对１０种常用化疗药物的敏感性，试图选出针对性较强的化疗药。结果表明对胃癌较敏感的药物依次是：５－ＦＵ、ＡＤＭ、ＰＹＭ等，并发现不同病理类型间敏感性有差异，各个体间对抗癌药的反应性亦不同。由此进一步说明，同一类型肿瘤的不同个体其临床化疗效果有较大差异。ＭＴＴ法具有快速、简便、经济、重复性好等优点。本试验结果与实际疗效的相关性有待临床进一步观察。