SAN ANTONIO (EGMN) – While obstructive sleep apnea is closely associated with obesity, not all the drugs being developed for the treatment of OSA are based upon weight loss as their mechanism of benefit.
For example, acetazolamide addresses ventilatory instability, which has emerged as a potential novel therapeutic target in OSA. Another early study suggests the sedative eszopiclone (Lunesta) reduces sleep apnea severity and increases sleep duration by raising the respiratory arousal threshold, investigators reported at the annual meeting of the Associated Professional Sleep Societies.
Still, weight loss is the classic source of pharmacologic improvement in OSA. The first drug shown to be of benefit in patients with OSA was sibutramine (Meridia), a serotonin and noradrenaline reuptake inhibitor, noted Dr. Ronald R. Grunstein, professor of sleep medicine at the University of Sydney.
He was lead investigator in a study that showed 6 months of sibutramine plus a 600-kcal-deficit diet and exercise not only resulted in significant weight loss, it also brought marked improvement in OSA, reduced insulin resistance, a rise in high-density lipoprotein cholesterol, and decreased visceral, subcutaneous, and hepatic fat, with no change in blood pressure (J. Clin. Sleep Med. 2009;5:416-21).
At the sleep disorders meeting, audiences learned of another weight-loss drug with evidence of efficacy for OSA: Qnexa, an investigational once-daily proprietary combination of phentermine and controlled-release topiramate.
Dr. David H. Winslow presented a double-blind, single-center trial in which 45 obese patients with OSA were randomized to once-daily Qnexa at 15-mg phentermine/92-mg topiramate CR or to placebo for 28 weeks. All participants were either noncompliant with or disinterested in continuous positive airway pressure (CPAP) therapy, and all were provided with a structured lifestyle modification program.
At week 8, the mean apnea-hypopnea index (AHI) in the Qnexa group had dropped from a baseline of 45.5 to 19.1 events per hour. By week 28, their mean AHI had fallen to 13.5, as compared with 27.2 in the placebo arm, reported Dr. Winslow, a chest physician and president of the Kentucky Research Group, Lexington.
The Qnexa group experienced a mean 11% reduction in body weight over the 28 weeks, twice that of the placebo group. Other statistically significant and clinically meaningful changes in the Qnexa group included a mean 15 mm Hg drop in systolic blood pressure from a baseline of 138 mm Hg, as compared with a 7.3 mm Hg drop in controls, along with polysomnographic improvements in arousal index and mean and minimum overnight oxygen saturation.
The most common adverse events were mild to moderate dry mouth and altered taste. There were no serious adverse events in the study.
“I think we may be looking at a new paradigm in the treatment of OSA,” Dr. Winslow said in an interview.
Qnexa is under U.S. Food and Drug Administration review for a proposed indication as a treatment for obesity; a regulatory decision is expected later this year. While the results in the 45-patient OSA study are quite encouraging, getting an additional indication as a therapy for OSA will require much larger clinical trials, he noted.
Danny J. Eckert, Ph.D., of Brigham and Women’s Hospital, Boston, presented a double-blind, randomized crossover trial in which 17 untreated OSA patients received 3 mg of eszopiclone or placebo immediately prior to going to sleep during overnight polysomnography on two occasions in the sleep lab.
The patients’ mean AHI was 24 events per hour on eszopiclone, compared with 31 per hour with placebo. The seven patients with a low baseline respiratory arousal threshold, defined as less than 15 cm H2O, had a mean 42% improvement in AHI on active therapy, and all seven of them had at least a 20% improvement.
Patients on eszopiclone also had a marked increase in total sleep time, from 5.3 hours on placebo to 6.8 hours, along with fewer arousals per hour and improved sleep quality, he reported.
Dr. Bradley A. Edwards, also of Brigham and Women’s Hospital, presented a preliminary physiologic study in which six CPAP-treated patients with OSA underwent 2 nights of baseline polysomnography, and then took acetazolamide SR 500 mg twice daily for a week. This was followed by another 2 nights of polysomnography in which CPAP was intermittently turned down to subtherapeutic levels in order to see whether acetazolamide reduced ventilatory control instability. This indeed proved to be the case in all six patients. Moreover, five of the six patients experienced an associated reduction in AHI.
Dr. Grunstein said other drugs being explored as possible OSA therapies include lorcaserin, now under FDA review as a potential antiobesity drug, and testosterone.
Dr. Winslow disclosed that he serves as a consultant to Vivus Inc., which is developing Qnexa. Dr. Eckert’s study was partially funded by a research grant from Sepracor Inc. Dr. Grunstein’s sibutramine study was supported by Abbott Laboratories. Dr. Edwards reported no financial conflicts.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
圣安东尼奥(EGMN)——尽管阻塞性睡眠呼吸暂停综合征(OSA)与肥胖紧密相关，但并非所有用于OSA治疗的药物均基于减重这一效益机制。
研究者们在联合专业睡眠协会年会上报告说，例如，乙酰唑胺可用于治疗患者呼吸功能不稳，该药已经成为一种针对OSA的潜在新型靶向疗法。另一项早期研究显示，镇静类药物左旋佐匹克隆 (Lunesta)通过提高呼吸道唤醒阈值进而降低了睡眠呼吸暂停综合征患者的病情严重程度，并延长了其睡眠持续时间。
悉尼大学睡眠医学教授Ronald R. Grunstein博士指出，尽管如此，减重类药物仍然是OSA治疗药物改进的传统源头。最早发现对OSA患者存在益处的药物是西布曲明(Meridia)，该药是一种5羟色胺和去甲肾上腺素再摄取抑制剂。
据一项研究显示，对患者应用6个月的西布曲明+消耗600 kcal的饮食和运动不仅显著降低了患者的体重，还使患者的OSA病情得到显著改善，胰岛素抵抗程度下降，高密度脂蛋白胆固醇浓度增加，及内脏、皮下和肝脏脂肪减少，但其血压则未发生任何变化。
在本次睡眠障碍会议上，听众们得知，有证据表明，另一种减肥药对OSA同样有效：Qnexa，该药是一种目前仍处于研发中的专利药物，其同时含有芬特明和控释型(CR)托吡酯，用药频率为每日1次。
据David H. Winslow博士提交的一项双盲、单中心临床试验，该研究将纳入的45例肥胖患者进行了随机分配，一部分每日服用1次Qnexa，其中包含15 mg芬特明/92 mg CR型托吡酯，另一部分则接受安慰剂治疗。所有受试者对接受持续正压气道通气(CPAP)治疗或缺乏依从性或不感兴趣，该试验还为所有受试者提供了结构化的生活方式改进方案。
列克星敦市肯塔基研究机构的主席、胸科医师Winslow博士报告说，在第8周，Qnexa组患者的呼吸暂停低通气指数(AHI)均值已经从基线时的45.5次事件/h减少至19.1次事件/h。在第28周，这些患者的AHI均值已降低至13.5，与之相比，安慰剂组的患者的这一数值则为27.2.。
Qnexa组的患者在28周时间内体重平均降低了11%，这一数值是安慰剂组患者的两倍。Qnexa组患者具有统计学意义和临床意义的其他改变还包括收缩压平均降低15 mmHg(相对于基线时的138 mmHg)，而对照组患者的这一数值为7.3 mmHg，此外，对患者行多导睡眠图检查显示，其唤醒指数及夜间氧饱和度的均值和最小值均有所提高。
最常见的不良事件是轻至中度的口干和味觉改变。在该研究中未发现任何严重不良事件。
Winslow 博士在一次采访中说：“我认为，我们可能发现了一种新的OSA治疗模式。”
美国食品药品管理局目前正在就将肥胖治疗纳入Qnexa适应证的这一建议进行评审；相关的监管法规预计将于今年晚些时间出台。他指出，尽管这项纳入45例患者的OSA研究的结果令人倍受鼓舞，但将用于OSA治疗作为其新增适应证则还需要进行更大规模的临床试验。
据波士顿市布里格姆妇女医院的Danny J. Eckert博士提交的一项双盲、随机交叉临床试验，17例未经治疗的OSA患者在睡前服用3 mg左旋佐匹克隆或安慰剂，研究者对其进行整夜多导睡眠图监测，试验地点是睡眠实验室的2个不同场合。
服用左旋佐匹克隆的患者的AHI均值为24次事件/h，与之相比服用安慰剂的患者的这一数值为31次事件/h。在接受积极治疗后，7例伴有基线呼吸道唤醒阈值低下的患者(定义为<15 cmH2O) 的AHI值平均增加了42%，且全部7例患者的这一数值至少增加了20%。
他报告说，服用左旋佐匹克隆还显著增加了患者的总睡眠时间，从服用安慰剂的5.3 h增至6.8 h，此外该药还使患者的每小时唤醒次数减少，且使其睡眠质量提高。
布里格姆妇女医院的Bradley A. Edwards博士提交了一项生理学初步研究，在该研究中6例已进行CPAP治疗的OSA患者接受了2夜的基线多导睡眠图监测，然后每天服用2次缓释型(SR)乙酰唑胺，每次500 mg，用药持续1周。此后患者又接受了另外2夜的多导睡眠图监测，在此期间研究者将CPAP治疗间歇性地调整至治疗水平之下，以评估乙酰唑胺是否可以降低患者的呼吸控制方面的不稳定性。该研究最终在全部6例患者中得出了肯定结论。此外，6例患者中有5人还出现了与该治疗相关的AHI值降低。
Grunstein博士说，作为OSA的可能治疗方案予以检测的其他药物还包括氯卡色林(目前正作为一种潜在的抗肥胖药物接受FDA评估)和睾酮。
Winslow博士披露说，其目前正担任Vivus公司的顾问，该公司正对Qnexa进行研发。Eckert博士的研究部分由来自Sepracor公司的研究经费资助。Grunstein博士就西布曲明所进行的研究由雅培制药赞助。Edwards博士报告说无任何经济利益冲突。
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