Department of Pharmaceutics, JSS College of Pharmacy, Ootacamund, India.
JSS Academy of Higher Education and Research, Mysuru, India.
J Clin Pharm Ther. 2019 Jun;44(3):337-348. doi: 10.1111/jcpt.12808. Epub 2019 Feb 9.
Alzheimer's disease (AD) is the most common cause of dementia among the elderly. The exact cause of the disease is not clearly known, and no existing therapies are able to prevent disease progression. Identification of the possible "impaired brain insulin signalling in AD" enriched the scope for "the repurposing of diabetic drugs in AD management." Among the different classes of diabetic drugs, pioglitazone (PIO), a PPARγ agonist classed as an insulin sensitizer, is of the highest interest for AD management. The drug is reported to have direct action on multiple targets involved in AD, independent of insulin signalling. Even though PIO has appeared to be a potent molecule in preclinical trials, limited success was observed in the clinical stage. The tentative reasons for the limited therapeutic success in the clinical stage are not clear. The main focus of the review is to discuss various factors that might limit the therapeutic success of PIO in clinical trials and possible approaches to overcome those limitations.
The research articles, review articles, and patents containing information regarding the clinical and preclinical trials of PIO in AD have been reviewed thoroughly using the keywords related to diabetic drugs in AD, PIO for AD management and mechanism of PIO in AD. Literature search was conducted on PubMed, SCOPUS and EMBASE.
Previous studies have indicated that the blood-brain barrier (BBB) is the biggest challenge to delivering PIO to the brain. Therefore, to attain a therapeutic concentration in the brain, a higher dose is needed, which is also supported by preclinical investigations in AD; however, in clinical studies, scientists have used the usual diabetic doses. This dose is inadequate to attain a therapeutic concentration in the brain and appears to be the primary reason for the limited success of PIO in clinical trials. The stage of drug intervention and the nature of the study population are also influential factors for the therapeutic response.
The insufficient concentration of the drug reaching the brain appears to be the crucial factor that limits the therapeutic success of PIO in AD management. Since the administration of higher doses cannot be recommended due to safety issues, the current situation demands the use of novel tools to ensure a therapeutic concentration reaches the brain.
阿尔茨海默病（AD）是老年人中最常见的痴呆症病因。该病的确切病因尚不清楚，也没有现有的疗法能够阻止疾病的进展。“AD 中可能存在的受损脑胰岛素信号”的发现拓宽了“重新利用糖尿病药物来管理 AD”的范围。在不同类别的糖尿病药物中，吡格列酮（PIO）作为胰岛素增敏剂的 PPARγ 激动剂，是 AD 管理中最受关注的药物。有报道称，该药物对 AD 相关的多个靶点具有直接作用，与胰岛素信号无关。尽管 PIO 在临床前试验中表现出强大的作用，但在临床阶段的效果有限。在临床阶段治疗效果有限的原因尚不清楚。本文的主要重点是讨论可能限制 PIO 在临床试验中治疗效果的各种因素以及克服这些限制的可能方法。
使用与 AD 中的糖尿病药物、PIO 用于 AD 管理以及 PIO 在 AD 中的作用机制相关的关键词，全面审查了关于 PIO 在 AD 中的临床和临床前试验的研究文章、综述文章和专利。在 PubMed、SCOPUS 和 EMBASE 上进行了文献检索。
先前的研究表明，血脑屏障（BBB）是将 PIO 递送到大脑的最大挑战。因此，为了在大脑中达到治疗浓度，需要更高的剂量，这也得到了 AD 中的临床前研究的支持；然而，在临床研究中，科学家们使用了通常的糖尿病剂量。这个剂量不足以在大脑中达到治疗浓度，这似乎是 PIO 在临床试验中效果有限的主要原因。药物干预的阶段和研究人群的性质也是影响治疗反应的因素。
到达大脑的药物浓度不足似乎是限制 PIO 在 AD 管理中治疗效果的关键因素。由于安全性问题不能推荐使用更高的剂量，因此当前情况需要使用新的工具来确保治疗浓度到达大脑。
