Q: When and where did the world’s first controlled clinical trial take place?

A: In 1754 248 years ago aboard a British man-of-war, HMS Salisbury.

Naval surgeon James Lind (1716-1794), who designed and conducted the study, selected 12 seamen suffering from scurvy and divided them into six two-man cohorts. They swallowed daily either cider; oil of vitriol; vinegar; sea-water; a mixture of garlic, radish, Peru balsam and myrrh; or oranges and lemons. The pair on citrus fruit were fit for duty in six days, and assigned to nurse the other 10, who remained very sick.

It took the British Admiralty another 41 years before it decreed mandatory issue of citrus on long voyages. Meanwhile, in 1740, Commodore Sir George Anson set sail with six poorly manned vessels, mustering 1,955 men, to hunt Spanish treasure ships in the Pacific. When his little fleet, reduced to a single ship, limped home four years later in 1744, only 638 of the original 1,955 remained alive. Fever and dysentery had felled 320 people and scurvy, 997.

Fast forward to 1932 when the anti-scorbutic vitamin C in lemons became the first vitamin to be synthesized in a laboratory. A year later its name was changed to ascorbic acid.

Is Scurvy A Long-Extinct Malady On Earth?

“There are current situations where people are severely malnourished, and develop scurvy,” observed molecular geneticist Robert Nussbaum, chief of the Genetic Diseases Research Branch at the National Human Genome Research Institute in Bethesda, Md. “But it’s really under conditions where they’re also deficient for a lot of other nutrients as well,” he added, “calorie and protein malnutrition as well as scurvy’s vitamin C.

“The peculiar thing about scurvy,” Nussbaum continued, “is that there were individual sailors on long ocean voyages centuries ago who were getting at least reasonable calorie, and some protein, intake. But they were very deficient in ascorbic acid.”

Nussbaum is senior author of an article in the May 2002 issue of Nature Medicine. It’s titled: “Ascorbic acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival.”

“The overall finding of our paper,” he told BioWorld Today, “is that in mice vitamin C ascorbic acid appears to be an absolutely essential compound for normal postnatal survival. The level of vitamin C in various murine tissues is strikingly high. In the brain for example, its level is 50 to 100 times higher than it is in the blood.

“Vitamin C,” Nussbaum pointed out, “is synthesized in the liver of mice, but not anywhere in the human body. In rodents, vitamin C synthesis comes on just before birth, and shoots up markedly at birth. It uncovers an unexpected role for vitamin C in normal birth, and in preparing a fetus for extrauterine life.

“The complications that we see in these mice,” he pointed out, “are very reminiscent of those one finds in a severely premature human infant bleeding in the brain, and also respiratory problems of the lungs. This raises the interesting question and it’s just a hypothesis, not something we’ve demonstrated at all as to whether the vitamin C status of mothers and infants at and before birth perhaps play a role in the severity and complications of prematurity.

“Just as an infant is predicted to be born prematurely, its mother is treated prenatally with steroid hormones to help induce maturation of the lung. And it’s possible that vitamin C could be an important component of treating pregnant women who are threatened with carrying a premature birth. So it might contribute to maturing the brain and lungs of preemie infants.”

Nussbaum remarked, “Possibly cigarette smoke which destroys ascorbic acid because of its oxidative action might play a role here. Cigarette smoke can have a very potent effect on cerebral circulation and on blood-vessel tone. So one could imagine that maternal smoking, which has been implicated in the cause of prematurity, perhaps also gets involved here.”

The endogenous ascorbic acid synthesized by mice is trafficked throughout its body by a transporter protein called SVCT2. This is encoded by the Slc23a1 gene, which the journal co-authors knocked out functionally in their experimental mice.

“Those vitamin C-lacking mice,” Nussbaum recounted, “suffered immediate postnatal death within minutes of being born. This result was serendipitous not what I predicted it would be. I did not expect these mice to die in the immediate postnatal period with intracerebral bleeding and respiratory failure. I thought I would see some kind of ongoing damage due to ROS reactive oxygen species inability to compensate for oxidative stress because,” he concluded, “ascorbic acid, missing in the KO mice, acts as an antioxidant.”

C’ Word: Drug Target For Ischemic Stroke?

Harvard University biochemist and cell membrane biologist Matthias Hediger reported identifying the SVCT2 rat vitamin C transporter in 1999. He contributed a News & Views commentary — titled “New view of C” to Nussbaum’s paper. In it, he described a commonality between human ischemic stroke and the common pond turtle.

“After an ischemic stroke, when oxygen comes back,” Hediger observed, “it’s similar to pond turtles. When they are diving, they are lacking oxygen. Then, after the dive, oxygen comes back. So this poses an oxidative stress to neurons.” Hediger continued: “The turtles show that, thanks to the high level of vitamin C in their brain, they can survive this exposure to oxygen after their dive, when they had no oxygen. So it is likely that the high level of vitamin C accounts for this ability to remove the free radicals produced when oxygen comes back after the dive. That’s similar to stroke when the oxygen comes back in the brain after the event. And vitamin C comes and scavenges the free radicals. So I think this analogy is real.

“A little vitamin C administered to a patient after a stroke might make the ascorbic acid transporter SVCT2 look as if it could be a therapeutic target,” Hediger suggested. “Originally I identified SVCT2 in 1999, and we have filed a patent application which is now pending. It would be interesting,” he concluded, “if I could find a commercial partner to work with me in developing this invention.”

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