某些鈣離子阻斷劑可能預防巴金森氏症


  【24drs.com】January 29, 2010 — 一項以群眾為基礎的研究新結果,支持使用鈣離子阻斷劑(CCB),特別是dihydropyridines類藥物,這個藥物可能預防發生巴金森氏症(PD)。
  
  在第一項這類大型、群眾為基礎的研究中,洛杉磯加州大學公衛學院的流行病學教授Beate Ritz博士與丹麥癌症學會的研究者們合作,發現使用dihydropyridines類CCB藥物,例如nifedipine及nimodipine與PD風險下降26%~30%有關。
  
  這項發現於2009年12月7日線上發表,且將刊登於這期的神經學誌。
  
  【使用CCBs類藥物風險下降27%】
  這些結果是建築在黑質體多巴胺激性神經元有那些與心臟與平滑肌相同的L型鈣離子通道。Dihydropyridines類CCB也會通過血腦障壁,使得它們有作用在腦部的潛力。
  
  在這項研究中,研究者們想要看使用於治療高血壓的dihydropyridines類CCB藥物,是否也對於PD的發生有影響。
  
  Ritz博士與同事們使用丹麥的註冊試驗資料進行一項以群眾為基礎的病例控制研究,評估1931位PD病患與9651未受影響個體的醫療史及使用藥物情形,時間是診斷罹患PD之前12年。
  
  他們發現使用作用於中樞CCB類藥物的受試者,發生PD風險降低了27%。
  
  Ritz博士向Medscape神經學表示,這是個令人驚奇的數據,這是世界上最老的電子數據系統,且我們非常幸運,丹麥癌症機構讓我們使用這些數據,而國家相關機構提供我們經費進行這些研究。
  
  Ritz博士表示,這個資料庫的數量讓研究者們可以探討許多藥物的效果。我們的研究與過去的不同,因為我們有非常大的樣本數目,且可以區分不同鈣離子通道阻斷劑的效果。
  
  【Amlodipine,其他降血壓藥物並不具保護性】
  他們發現,只有中樞作用的L型CCB類藥物與發生PD風險顯著下降有關。週邊作用藥物amlodipine或是其他種類降血壓藥物並沒有這個作用。
  
  Ritz博士表示,關鍵在於這些藥物的作用模式,以及它們是否會通過血腦障壁。有些會、有些不會。我們發現這項研究受試者使用的所有降血壓藥物,僅有dihydropyridines類CCB藥物會通過進入腦部,在那裡他們可能有辦法作用在神經元的鈣離子通道,提供保護性作用。這支持了特定藥物的作用模式,以及是否進入腦部是神經保護作用的重要因子。
  
  研究者們懷疑,鈣離子通道作為腦部多巴胺神經元的節律器(就像它們在心臟的角色),但是對神經元的能量更高。阻斷這些通道可能促使這些細胞轉移到其他節律器,例如鈉離子通道,拯救其他耗盡或老化的神經元。
  
  【在使用CCB類藥物之前需要早期PD生物標記】
  然而,Ritz博士強調,流行病學發現在短暫時間內不太可能轉變成臨床用途。
  
  這種神經保護作用必須非常早期就開始使用,早到60%細胞死亡,以及病患開始有症狀之前。我們需要當細胞死亡30%或40%時可以顯現的生物標記,且這個時候是該做些事情的時候。
  
  不幸的,目前並沒有這樣的生物標記。
  
  研究作者們寫到,第二個問題是,具保護作用的中樞作用CCB類藥物也可能降低血壓。因為低血壓是個常見的特徵,且許多PD病患會有這樣的問題,在考慮使用這些降血壓藥物於PD治療用途之前,應該進一步地研究,以及更完整地了解它們的生物與潛在神經保護作用角色。
  
  Ritz博士表示,這仍然有「老藥」的問題,這些由美國食品藥物管理局核准的藥物都已經過了專利期,因此不太可能吸引臨床研究中大藥廠的經費贊助。
  
  在等待PD生物標記被發現的同時,Ritz博士與同事們正繼續分析丹麥資料庫。在一項正在進行,收納17,000位PD病患的研究將會評估室外與室內工作者(主要懷疑他們的低維生素D濃度),運動、暴露工業毒性物質、以及使用statins類藥物及非類固醇抗發炎藥物對於PD風險的影響。Ritz博士的團隊也正在進行2000位PD與2000位相對應健康控制組受試者們的DNA分析,以尋找與PD風險增加有關的基因檔案。
  
  這項研究由國家環境健康科學機構以及國家神經疾患與中風機構贊助。Ritz博士表示已無相關資金上的往來。

Some Calcium Channel Blockers May Protect Against Parkinson's Disease

By Janis C. Kelly
Medscape Medical News

January 29, 2010 — New results from a major population-based study support the hypothesis that use of calcium channel blockers (CCBs), specifically dihydropyridines, may protect against the development of Parkinson's disease (PD).

In the first large-scale, population-based study of its kind, Beate Ritz, MD, PhD, professor of epidemiology at the University of California, Los Angeles, School of Public Health, in collaboration with researchers from the Danish Cancer Society, found that use of dihydropyridine CCBs, such as nifedipine and nimodipine, was associated with a 26% to 30% decrease in the risk of PD.

The findings were published online December 7, 2009, and will appear in an upcoming issue of Annals of Neurology.

CCBs Cut Risk by 27%

Their results build on data showing that dopaminergic neurons of the substantia nigra that are affected in PD have L-type calcium channels similar to those specifically addressed by dihydropyridines in cardiac and smooth muscle. Dihydropyridine CCBs also cross the blood brain barrier, giving them the potential to act in the brain.

In this study, the researchers looked to see if they could find evidence that use of dihydropyridine CCBs in the treatment of hypertension might also have some effect on the development of PD.

Dr Ritz and her colleagues used Danish population registry data to conduct a population-based, case-control study evaluating medical histories and medication use for 1931 PD patients and 9651 unaffected subjects for a period up to 12 years before the diagnosis of PD.

They found a 27% reduction in PD risk in those who had taken centrally acting CCBs.

“This is an amazing dataset, the oldest data system in the world that is electronic, and we are very lucky that the Danish Cancer Institute gave us access to it and the National Institutes gave us funding for these studies,” Dr. Ritz told Medscape Neurology.

The size of the dataset enabled the researchers to tease apart the effects of a variety of drugs. “Our study differed from previous ones by having a huge population and the ability to distinguish between the calcium channel blockers,” Dr. Ritz said.

Amlodipine, Other Antihypertensives Not Protective

They found that only centrally acting L-type CCBs were associated with a significant decrease in the risk of developing PD. Neither the peripherally acting drug amlodipine nor other classes of antihypertensive medications had this effect.

"The key was to consider the mode of action of these drugs and whether or not they cross the blood-brain barrier," Dr. Ritz said. "Some do and some don't. We found that of all the hypertension medications taken by our study subjects, only the subset of dihydropyridine class drugs that cross into the brain, where they might be able to act on the calcium channels of neurons, provided a protective effect. This supports the idea that the mode of action of a given drug and whether it penetrates into the brain are important factors in neuroprotection."

The researchers suspect that calcium channels serve as pacemakers for dopamine neurons in the brain (as they do in the heart) but at a high energy price to the neurons. Blocking these channels might force the cells to shift to other pacemakers, such as sodium channels, saving neurons that might otherwise become exhausted and perish.

Early PD Biomarker Needed Before Using CCBs

However, Dr. Ritz emphasized that this epidemiologic finding is not likely to translate into clinical use any time soon.

“This type of neuroprotection would have to be used early, long before 60% of those cells die and the patient begins to show symptoms. We need a biomarker that will show when cell death is at 30% to 40% and it is time to do something,” Dr. Ritz said.

Unfortunately, no such biomarker yet exists.

A second problem is that the centrally acting CCBs that are likely to be protective also reduce blood pressure. “Given that hypotension is a common feature and manifests preclinically in many PD patients, further investigation and a more complete understanding of their biological and potential neuroprotective role are essential before considering these antihypertensive medications for therapeutic use in PD,” the study authors write.

There is also the “old drug” problem: Dr. Ritz noted that all of these US Food and Drug Administration–approved drugs are off patent and thus unlikely to attract funding from major pharmaceutical companies for clinical trials.

While waiting for PD biomarkers to be discovered, Dr. Ritz and colleagues are continuing to mine the Danish data. An ongoing study of 17,000 PD patients will assess the impact on PD risk of outdoor vs indoor workers (in whom low vitamin D level is a prime suspect), physical activity, exposure to industrial toxins, and use of statins and nonsteroidal anti-inflammatory drugs. Dr. Ritz's group is also in the midst of DNA analyses of 2000 PD and 2000 matched healthy controls to search for genetic profiles linked to increased PD risk.

The study was supported by the National Institute of Environmental Health Sciences and the National Institute of Neurological Disorders and Stroke. Dr. Ritz has disclosed no relevant financial relationships.

Ann Neurol. Published online December 7, 2010.

    
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