钙离子阻断剂与降低PD风险有关

　　一篇大型案例控制研究的结果显示，目前所使用的钙离子阻断剂可显著降低巴金森氏症（Parkinson's disease，PD）风险。
　　
　　上述结果登载于2月6日的神经学(Neurology)期刊线上版。
　　
　　研究者之一、资深作者、Basel大学医院Basel药物流行病学组的Christoph R. Meier博士结论表示，目前长期使用的钙离子阻断剂可显著降低巴金森氏症的风险，至于血管收缩素转化酶抑制剂（angiotensin-converting-enzyme inhibitors）或者乙型阻断剂（beta blocker）则与此风险无关，而血管收缩素II拮抗剂（angiotensin II antagonists）则有些微的统计准度。
　　
　　【可能的神经保护？】
　　作者指出，在神经保护剂的研究中，最近在啮齿动物和非人类之灵长类动物的研究显示出ACE抑制剂和钙离子阻断剂的可能效果，包括减少实验引起的多巴胺细胞损失，以及增加基础神经节（striatal）多巴胺值；一篇针对7个中度PD病患的双盲安慰剂控制试验中，显示以ACE 抑制剂perindopril治疗4周后可以改善运动功能。
　　
　　这篇研究中，研究者使用综合实务研究资料库（General Practice Research Database）之资料，包括了超过5百万的英国开业医师所纪录的病患资讯，进行回溯案例控制分析，检视抗血压药物－包括了血管收缩素II拮抗剂、乙型阻断剂、ACE 抑制剂和钙离子阻断剂之间与初次诊断巴金森氏症的风险的可能关系。
　　
　　这些案例年纪在40岁以上，于1994至2005年之间偶发PD诊断；控制组的年纪、性别、综合实务、指标日期、资料库中的纪录期间和病患组相仿；总共鉴识了3,637件案例，控制组的人数也一样；其中有40% 是女性。
　　
　　以时间和暴露期间分析抗高血压药物，使用条件式逻辑回归（conditional logistic regression）计算风险比，校正身体质量指数、抽烟、心血管、代谢与精神疾病和失智症等因素。
　　
　　他们发现，和未使用抗高血压药物者相比，长期使用（30天以上的处方）钙离子阻断剂与降低发生PD风险有关，但是其他的抗高血压药物则无此一关联。
　　
　　现正使用抗高血压药物与未使用高血压药物者之自发PD 风险比较

制剂	校正风险比	95% CI
ACE 抑制剂	1.08	0.85 – 1.37
血管收缩素 II 拮抗剂	0.91	0.41 – 2.00
乙型阻断剂	1.16	0.95 – 1.41
钙离子阻断剂	0.77	0.63 – 0.95

　　钙离子阻断剂的效果，在校正其他抗高血压制剂的使用之后仍持续，女性使用者的风险降低略高于男性，不过使用未达30天者无此关联。
　　
　　他们指出，在80岁以上者效果最明显；此一发现相当引人注意，因为最近有报告指出多巴胺神经元依赖L-型Cav1.3-钙离子通道增加活性，使他们更容易受到神经损害，而年轻族群的神经元使用的是另外的机转；他们推测，如果这些钙离子通道被阻断，神经元再度使用比较没有伤害的机转，就可以减少细胞损伤。
　　
　　作者指出，PD通常合并自体缺损和低血压；与控制组相比，PD案例使用比较少的抗高血压药物，而导致不真实的低风险比；他们指出，控制组的高血压病患比案例组的人还多；控制组因而比较常接受抗高血压药物治疗，也可发现使用钙离子阻断剂者可以降低PD风险。
　　
　　他们也分析了使用钙离子阻断剂之案例组和无高血压之控制组的PD诊断风险，发现使用钙离子阻断剂治疗高血压以外之其他病症者的PD风险估计为0.60 (95% CI, 0.42 – 0.86)。
　　
　　Meier博士在美国神经医学会的一篇声明中表示，需要更多研究以确认何以钙离子阻断剂显示可以保护免于PD，这是否有因果关系，以及为何其他的抗高血压药物没有类似的降低风险效果。
　　
　　作者宣称无利益冲突。
　　
　　Neurology. 线上登载于2008年2月6日。

 

Calcium-Channel Blockers Linked to Reduced Risk for PD

By Susan Jeffrey
Medscape Medical News

February 6, 2008 — Results of a large case-control study suggest that current use of calcium-channel blockers, but not other antihypertensive agents, is associated with a significantly reduced risk for Parkinson's disease (PD).

The results are published online February 6 in Neurology.

"Current long-term use of calcium-channel blockers was associated with a significantly reduced risk of a Parkinson disease diagnosis, while the risk was not materially altered for users of angiotensin-converting-enzyme inhibitors or beta blockers and, with less statistical precision, for users of angiotensin II antagonists," the researchers, with senior author Christoph R. Meier, PhD, from the Basel Pharmacoepidemiology Unit, University Hospital Basel, Switzerland, conclude.

Possible Neuroprotection?

In the search for neuroprotective agents, the authors note, recent studies in rodent and nonhuman primates have shown "promising" results with ACE inhibitors and calcium-channel blockers, including a reduction of experimentally induced dopaminergic cell loss and an increase in striatal dopamine levels. One double-blind, placebo-controlled trial in 7 patients with moderately severe PD showed an improvement in motor function after 4 weeks of treatment with the ACE inhibitor perindopril.

In this study, the researchers used data from the General Practice Research Database, containing information on more than 5 million people registered with general practitioners in the United Kingdom, to carry out a retrospective case-control analysis examining the possible association between the use of antihypertensive drugs, including in this case also angiotensin II antagonists and beta-blockers as well as ACE inhibitors and calcium-channel blockers, on the risk of developing a first-time diagnosis of Parkinson's disease.

Cases were 40 years of age or older, with an incident PD diagnosis between 1994 and 2005. Controls were matched with PD cases on age, sex, general practice, index date, and duration of previous history in the database. A total of 3637 cases were identified and compared with an equal number of controls; 40% of these were women.

Antihypertensive use was assessed by timing and exposure duration. Odds ratios were calculated using conditional logistic regression, with adjustment for body-mass index, smoking, and a number of cardiovascular, metabolic, and psychiatric diseases and dementia.

They found that current long-term exposure, defined as 30 or greater prescriptions, to calcium-channel blockers was associated with a reduced risk of developing PD compared with no antihypertensive use, while no association was seen with the other antihypertensive agents assessed.

Risk for Idiopathic PD with Current Use of Antihypertensive Agents vs Nonuse of Antihypertensive Drugs

Agent	Adjusted Odds Ratio	95% CI
ACE inhibitors	1.08	0.85 – 1.37
Angiotensin II antagonists	0.91	0.41 – 2.00
Beta blockers	1.16	0.95 – 1.41
Calcium-channel blockers	0.77	0.63 – 0.95

The effect of calcium-channel blockers persisted in the model when adjusted for the use of other antihypertensive agents. The risk reduction was slightly stronger in women with long-term use than in men, although not in those with less than 30 prescriptions.

The effect was strongest in those 80 years of age and older, they note. This finding is interesting given recently reported findings that dopaminergic neurons rely increasingly on L-type Ca_v1.3-calcium channels for their activity, making them more vulnerable to neurologic damage, while neurons in younger people use different mechanisms, the authors write. "If these calcium channels are blocked, neurons again make use of the less harmful mechanisms, and cell damage may be decreased," they speculate.

PD is often associated with autonomic insufficiency and hypotension, the authors note. PD cases, then, may receive fewer antihypertensive drugs than controls that may potentially lead to a spurious low odds ratio. They did find in this cohort that hypertension was significantly more common in controls than cases. While controls therefore would be expected to be treated more often with antihypertensives, they still saw a decreased PD risk only with calcium-channel blockers and not the other antihypertensives.

"We also analyzed the risk of a PD diagnosis in association with the use of calcium-channel blockers in a subgroup of cases and controls without hypertension," they add. In this subgroup that received calcium-channel blockers for indications other than hypertension, the risk estimate for PD was 0.60 (95% CI, 0.42 – 0.86).

More research is needed to determine why calcium-channel blockers appear to protect against PD, whether this is in fact a causal association, and why other antihypertensives do not appear to afford a similar reduced risk, Dr. Meier said in a statement from the American Academy of Neurology.
 

The authors declare no conflicts of interest.

Neurology. Published online February 6, 2008.