Eden Oration 2018

Traditionally the Eden Orator talks about what they do. However, I thought a talk about shuffling paper across my desk would be rather boring, so let’s talk about drugs.

As Paracelcelsus said, “All things are poison, and nothing is without poison, the dosage alone makes it so a thing is not a poison.” That is still true today.

Warfarin will be known to many of you as rat poison, and it’s still commonly used as an anticoagulant, but get the dose wrong and you can get life threatening haemorrhage. One in 25 people given Warfarin will bleed, and 1 in 400 will have a life threatening bleed.

Botulinium toxin – death from paralysis if you eat John West salmon in a tin that’s not been properly prepared, but small doses are used for face-lifts or indeed actual medical problems like bladder instability or excess sweating.

Curare, an extract from the Chondrodendron plant which will be more familiar to you as the poison arrows of South Americans Indians used to kill prey and each other, but it is also used as a muscle relaxant in surgery. It’s also available from homeopathy stores on the web if you would like to purchase some.

However, some drugs we give with the best intent are simply poisons, mercury baths for syphilis prevalent at the time of Shakespeare or tobacco encouraged by GPs to help expectoration (coughing up phlegm) in the 1920s and 30s we now know is just a good way of killing you.

But I might add to Paracelesus it also depends on the indication – by which I mean the reason you are giving it. Fowlers ‘sunshine tonic’ was widely given ad nauseam to children by well–meaning mothers in the 1930’s. It contained arsenic that resulted in something called Bowen’s disease a form of a skin cancer many years later. But arsenic trioxide is used to treat acute myeloid leukaemia today. Thalidomide widely prescribed in the 1950’s for morning sickness became infamous because of the limb abnormalities it caused, but has been rehabilitated as a derivative called Lenlidomide which is now widely used for Myeloma and that’s one of the top 10 selling drugs worldwide.

So drugs are important to us all and we have all taken them – from the Vitamin K injected into us shortly after birth, to routine childhood vaccinations MMR and polio. The humble paracetamol, or if you prefer it ibuprofen, for a headache, and, alcohol, probably the most commonly taken drug in the UK.  It also does have medicinal uses, it is used to treat ethylene glycol or methanol poisoning by intravenous infusion. It is estimated that the NHS spends about £18 billion a year on drugs and that continues to grow. The average 60 year old will get 41 items prescribed for them each year. The most common are Simvastatin, Aspirin, Thoroxin and drugs to treat hypertension. So three of the four are used to treat cardiovascular disease or prevent it, reflecting the fact that a third of you in this room will die from cardiovascular disease. In comparison the people of the UK spend £6.7 billion on illegal drugs, some of which although we consider illegal are actually legal. The recent debates about the medicalisation of cannabis, but heroin is widely used in hospitals. We call it diamorphine and use it to treat heart failure and for pain relief. In Victorian times it was actually given as a cough syrup for children.

Cocaine – if you go to ENT department with a nose bleed it’s more than likely they will spray cocaine up your nose as it’s a very good vasoconstrictor which stops the nose bleed, and it is also an anaesthetic.

But where do drugs come from? So plants are an obvious source for some drugs. Cocaine, morphine, digoxin, penicillin. Others are less well known. Aspirin from the bark of the willow tree, Quinine from a South American Chinchona tree and even today plants continue to provide. Taxol comes from the Pacific yew tree (Taxu brevi folia) it is used for breast cancer.

Animals give us drugs. Premarin used as an HRT for post -menopausal women comes from the urine of pregnant mares, hence its name. Pigs and cows have for many years provided insulin before we had bacterial forms.

Perhaps surprising to many of you in the room is crude oil. It’s now the source of most drugs, even ones that originally came from plants, like aspirin and penicillin. Oestrogen and the oral contraceptive pill comes from crude oil ‘synthetic opiates like tramadol’, and also surfactants given to help the lungs of new born babies.

Antibodies have been historically used, Diphtheria and tetanus antitoxins came from horse antibodies. Now we have fully humanized antibodies, developed from the pioneering work of Cezar Milstein in Cambridge, for which he received the Nobel Prize in 1984. These are used for a wide range of diseases, breast cancer, rheumatoid arthritis, MS even high cholesterol and they account for more than 50% of all new drug registrations. The top selling agent in the world Humira, or Adalimumab, netted 19 billion dollars in 2017 and six of the best 10 selling drugs world-wide are biological agents based on antibodies. In the future we will see gene editing, stem cells (already used for cartilage) interfering mRNA to treat cholesterol, and many other drugs.

So how do we get new drugs? Well historically serendipity played a very important part. You will all be familiar with the story of penicillin. Nitro-glycerine is used for cardiovascular disease, (angina) and that came about because munition factory workers, got a headache when they worked in the factory and nitroglycerines vasodilating property became apparent. And perhaps poignant  in this 100th anniversary of World War 1 ending are mustard gas derivatives, used to treat cancer to this day. It is estimated that 6% of drugs on the current market were accidental discoveries and serendipity continues to be important. Viagra originally synthesized for angina didn’t work, but all the volunteers complained of an interesting side effect and the fastest drug ever to market was born. Artemisinin an anti-malarial developed by Tu YouYou who went on to win the Nobel Prize in 2015 for its discovery. She had been instructed by the Chinese government to find a cure for Malaria to help the North Koreans during the war with South Korea because the Americans blocked the supply of chloroquine. She turned to a traditional Chinese herbal remedy that was widely used for malaria locally called sweet wormwood, and now we have a very effective and safe drug.

Designer drugs. These will become more and more important. They are designed by clever chemists and biologists to target a particular process, an enzyme or receptor. Perhaps the best example is Imatinib. When I trained chronic myeloma leukaemia was a death sentence. We knew it was genetic because if you looked down a microscope you could see a funny shaped chromosome called the Philadelphia chromosome. Clever molecular biologists worked out that it was a gene rearrangement which activated an enzyme and we developed a drug to inhibit that protein. Similarly anti HIV drugs are based on rational science.

So how do we know drugs work? Well historically we didn’t. I pointed out the example of Sunshine tonic and arsenic, but drugs are now rigorously tested in clinical trials before they are licenced. Perhaps the first recognised trial was by James Lind in 1747 he added acid to the diet of sailors who had scurvy after two months at sea and looked at its effect. He assigned groups to sulphuric acid, vinegar, oranges and lemons, spicy paste, cider or sea water. Most of those given the fruit, and actually some of those given the cider, recovered hence the change in diet for British sailors. Today the RCT, or randomised clinical trial, is considered the pinnacle of evidence. Often double-blind, and a comparison made against placebo or the best current alternative. But patient perception pseudoscience, misinformation, or, as people like to call it these days, ‘fake news’ are important drivers of patient compliance or adherence to treatment. Take statins for cholesterol. They are very effective and safe drugs and rarely do they cause side effects perhaps one in 10,000 to 100,000 but repeated scare stories in publications like the Daily Mail or even the British Medical Journal tell us that statins don’t work. They are dangerous and we should avoid them. The best proof that this is nonsense comes from a study done by one of our own alumni and honorary fellows Peter Sever. In the ASCOT study he gave half of the people fake statin and half real statin, but didn’t tell them what they were on.  The incidence of side effects in the two groups was identical. At the end of the trial when he told those people they were on the statin then of course the incidences of side effects went up. This is called the ‘nocebo’ effect. We are all familiar with the ‘placebo’ effect. The nocebo effect means that if you tell people something is going to be harmful for them then it will be.

Just finishing on my own therapeutic area hypertension. This will affect about a third of you in the room, and today it kills more people worldwide than anything else. However it is a therapeutic success story. Before we had any effective drugs 60% of people with severe hypertension were dead in 5 years.

It was treatable with a rice water diet, but who is going to live on a rice water diet. Sympathectomy does work as did early antimalarial agents like pentaquin. These were very effective in lowering your blood pressure, but you could not stand up because your blood pressure fell too much. The first really useful effective drugs were the Thiazides diuretics introduced in the 1950’s. Unfortunately that was too late for the 3 wartime leaders pictured at Yalta, who all died of the consequence of hypertension namely stroke. Each decade since the 1950s we have had a new class of drugs, and now we have four very effective class of drugs, with very few real side effects that are generally well tolerated.

But as I said hypertension will still kill more of you in the room than any other problem, why?   Because patients don’t take their tablets, and that is the real problem that we face today we can develop very clever drugs that work, but getting patients to take their tablets is something we are not very good at.

By Professor Ian Wilkinson, 30 November 2018