糟糕的药物如何使可治疗的疾病致命

在世界各地，十分之一的药物是不合格或假冒的，这可能导致耐药细菌的增加。Here, fake boxes of amoxicillin, a commonly used antibiotic, are seized from a store in Côte d’Ivoire. Photo by Issouf Sanogo/AFP/Getty Images

Muhammad Zaman learned at an early age that one did not shop for medicine at the convenient neighborhood pharmacy. In Pakistan, where he grew up, the safer thing to do was walk the extra mile to a pharmacy whose drugs were known to be high quality.

Four decades later as a Boston University professor of biomedical engineering and materials science and engineering, Zaman was reminded of the dangers of low-quality drugs in his native country when he learned that more than 200 people in the city of Lahore died after being treated with an adulterated version of a hypertension drug.

2012年的那次事件改变了扎曼的新濠影汇线上赌场研究进程。Now, he focuses on the global problem of “substandard drugs,” poorly made medicines containing ingredients that are either ineffective or toxic. 他最近的发现对我们对耐药性的理解有着惊人的影响：利福平是一种广谱抗生素，通常被用作治疗结核病的第一道防线，它的低质量版本可能极大地促进了耐药性感染的发展。

发表在《抗微生物药物和化疗》杂志上的这些发现特别紧迫，因为耐药结核病在世界范围内是一个日益严重的问题。Of the 10 million new cases of tuberculosis in 2016, about 600,000 were rifampin resistant, requiring second-line treatments which come with increased toxicity.

“没有明确的新濠影汇线上赌场研究表明缺乏[抗生素]质量导致耐药性，”Zaman说，他也是霍华德休斯医学新濠影汇线上赌场研究所生物医学工程和国际卫生教授。“Now we are sure that it does, and it does with TB, a global problem that has become stubbornly hard to resolve.”

“We had always thought of this a scientific issue, but now it is also an ethical issue.”穆罕默德扎曼

扎曼说，不合格药品以及故意制造假药在发展中国家太常见了。A recent survey by the World Health Organization found that in low- and middle-income countries, one in ten medicines is substandard or falsified. 原因之一可能是,政府实施安全生产规范是虚弱的或不存在的。例如，在巴基斯坦这个拥有近2亿人口的国家，只有少数新濠影汇赌场检查员监督药品生产的质量。

在撒哈拉以南非洲，情况也好不到哪里去。A recent World Health Organization (WHO) study written in part by Paul Newton, an adjunct professor at BU School of Public Health, found that substandard antimalarials killed more than 120,000 children under the age of five in 2013. Another WHO study, conducted in 2008, found that 64 percent of antimalarial drugs tested in Nigeria were substandard. When the same study looked at antimalarials in Cameroon, Ethiopia, Ghana, Kenya, Nigeria, and Tanzania, it found that 28 percent of 267 samples were substandard.

扎曼说，不可能知道全球有多少人死于不合格药物，因为人们通常不会立即死亡。他们可能会像拉合尔的受害者一样，死于毒性反应，也可能死于这种药物本应治愈的疾病。

Or, says Zaman, he and other scientists have long speculated that they could die for a third reason: adulterated medicines could encourage the development of drug resistance, rendering the disease incurable with standard treatments. Although that possibility had been considered for years, Zaman and Zohar Weinstein teamed up to finally put the hunch to the test.

在实验室里，Zaman和即将完成医学学位的生物分子药理学博士后新濠影汇线上赌场研究员Weinstein用利福平进行了几次测试，以了解一种降解形式的结核病药物是否会在细菌中产生耐药性。

他们首先在体外进行了一系列利福平对抗大肠杆菌的试验，大肠杆菌有时被称为实验室的主力细菌，因为它的快速倍增时间使其成为此类新濠影汇线上赌场研究的理想选择。新濠影汇线上赌场研究人员将细菌暴露在逐渐增加剂量的利福平中，利福平抑制细菌的RNA转录，导致细胞死亡。然后他们用利福平醌进行了同样的测试，这是最常见的利福平降解形式。在一周内，他们观察到细菌对药物的抵抗力明显增强。

接下来，新濠影汇线上赌场研究人员重复了这个实验，把大肠杆菌换成了一种叫做耻垢分枝杆菌的结核病菌株，选择它是因为它的倍增时间很短，只有两个小时，而更常见的结核病菌株的倍增时间大约是一天。两周后，耻垢分枝杆菌也开始表现出抵抗的迹象。

“We found that over five days, E. coli exposed to [rifampin quinone] became up to 64 times more resistant to rifampin,” says Weinstein. “在22天的时间里，耻垢分枝杆菌对利福平的耐药性提高了100倍。”

“你可能是一个好病人，但仍然会感染耐药细菌，因为你服用的药物会导致你产生耐药性。”穆罕默德扎曼

扎曼和温斯坦预料到了这样的反应，但他们没有料到会遇到如此强大的阻力。事实上，一旦细菌产生耐药性，再多的标准利福平也无法杀死它们。

新濠影汇线上赌场研究人员还寻找了利福平耐药性的另一个指标：一种名为rpoB的基因突变。他们的发现令人震惊。

温斯坦说：“我们发现，暴露于[利福平醌]的大多数细菌也有这种基因突变，即使它们从未暴露于标准药物。”

In other words, the degraded drug wasn’t just failing to cure the disease, it was cultivating cross-resistance to the high-quality, standard product. In that sense, says Zaman, bad drugs can become doubly dangerous.

“That [observation] was very revealing,” says Zaman. “It changed the equation, because we had always thought of this a scientific issue, but now it is also an ethical issue. 我们通常从两方面考虑耐药结核病的传播。我们说你得了肺结核是因为你接触了耐药结核病，也许你和耐药结核病患者住在一起。第二种可能是因为你本该服药而你却没有坚持服药。但这项新濠影汇线上赌场研究表明，你可能是一个好病人，但仍然会感染耐药细菌，因为你服用的药物会导致你对[治疗]产生耐药性。”

“虽然亚治疗剂量的药物在抗菌素耐药性中发挥了作用，但据我所知，这是第一次证明不合格药物如何直接推动病原体中耐药基因的出现，”美国药监局质量新濠影汇线上赌场研究所副所长Michael Levy说，该新濠影汇线上赌场研究所新濠影汇线上赌场研究不合格药物对健康结果的影响。USP是一个非营利性组织，其制定的药品质量标准在美国得到法律认可，并在其他140多个国家使用。

扎曼接下来要做的是三件事。首先，他计划测试几个低收入国家社区医院提供的药物的质量，特别寻找利福平醌（利福平的降解形式）的存在。其次，他计划与国家新兴传染病实验室（NEIDL）的新濠影汇线上赌场研究人员合作，建立小鼠模型，新濠影汇线上赌场研究体内的耐药性机制。Third, he says he hopes to expand his work to investigate adulterated forms of other commonly used, high-impact antibiotics.

与此同时，世界各地的患者每天仍在服用不合格的抗生素。

“The patient may be doing everything he or she is supposed to do and still become resistant [to treatment],” Zaman says.

这项工作得到了国家普通医学科学新濠影汇线上赌场研究所和USP的支持。