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Old drug sheds new light

For a large part of my time at Univ I have enjoyed exploring the capacity of the lungs spontaneously to squeeze lung blood vessels in areas of the lungs that are not well ventilated with air so as to improve the flow of blood to those areas of lung that are well ventilated with air. The mechanisms involve responding to local concentrations in the lung of oxygen and carbon dioxide; they have the names “hypoxic pulmonary vasoconstriction” (HPV) and “hypercapnic pulmonary vasoconstriction” (HCPV). It turns out that Covid-19 is in a sense a disease of HPV, switching it off whilst also doing damage elsewhere to the heart and kidneys, possibly by stimulating inappropriate clotting of blood in small blood vessels.

For some decades the French have manufactured and used a drug that appears to have a beneficial effect in lung diseases by enlivening this HPV response. It is called almitrine. It was first shown in patients with chronic obstructive lung disease (COPD, which we think of mainly as the chronic bronchitis associated with smoking) to improve the HPV behaviour at lowish doses and actually stimulate breathing at higher doses as well. It found a clinical use but seems to have fallen out of favour because long-term use, over years, led to some unacceptable side effects: peripheral neuropathy and weight loss amongst them. New inhaled drugs came along which tended to render almitrine tablets obsolete.

However, in the last few years almitrine has been shown to improve the oxygenation of the blood (probably by enhancing our HPV) in patients with severe lung disease from all sorts of causes, including viral pneumonias. The group term for these conditions is Acute Respiratory Distress Syndrome (ARDS). The most recent study is from Marseille in 2019. There is some debate about whether this new Covid-19 disease leads to the same kind of ARDS as its other causes, but there is reason to believe that almitrine, given either as tablets or an intravenous infusion might prevent some patients from progressing to needing intubation and ventilation (a limited resource) or treatment with an artificial lung (termed “ECMO”), an even sparser resource.

And here starts the big problem. The company that makes it has little in stock and is obliged to offer it to French hospitals. It is not licensed in the UK. You can buy it by the kilogram from the sort of suppliers that keep academic chemists in business, but to turn a chemical into an “Active Pharmaceutical Ingredient” that satisfies “Good Manufacturing Practice” tends to require the expenditure of hundreds of thousands of pounds and take six to nine months. I have been involved with senior colleagues in Oxford in seeking funding and ethical permission to set up a trial of almitrine in Covid-19 patients, whilst facing what looks like an impossible obstacle to acquiring a form of the drug that would satisfy the Medicine and Healthcare Products Regulatory Agency (MHRA). Colleagues better connected (and much better at chemistry) than I are trying to find a way through the bureaucratic hurdles to obtaining something we can use, and quickly.

Dr Keith Dorrington, Tutorial Fellow in Physiology & Medicine

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If you are involved in research or frontline work relating to COVID-19 that you would like to bring to the attention of the Univ community worldwide, please email communications@univ.ox.ac.uk.

Published: 16 April 2020

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