Modern drug-based treatment for Parkinson's disease

Were one to ask a random passerby to name the most influential books in history, it is unlikely (particularly if your victim was under the age of 60) that they would mention Command of the Air by Giulio Douhet, yet it was every bit a significant influence on both military and political thinking as had been Mahan’s The Influence of Seapower upon History in the previous century.

Douhet argued that the vastness of the sky made effective defence against attack from the air extremely difficult. Bear in mind that he was writing in an era before radar, of primitive radio transmission, and where fighter planes were open cockpit biplanes with a top speed of only just over 100 mph. Be that as it may, his ideas were eagerly adopted by air staffs around the world, and nowhere more so (as we will shortly see) than in the United States. Central to his view was the principle was the phrase (not his exact words, but he never disclaimed them) “The Bomber Will Always Get Through”.

The image was a powerful one. On his way to Munich in 1938, Neville Chamberlain, making his first ever flight, looked down on the suburbs of London stretching from one horizon to the other, and, imagining them in flames and being bombed, was greatly affected. It resonated too with the British Air Staff. Their regularly revised and published War Plans envisaged small groups of twin engine bombers being able effectively to carry the offence to the enemy by roaming freely across continental Europe, bombing strategic targets with clinical precision. For the defence, they were actively considering what became known as a ‘heavy fighter’ which could stand off from any bomber formation and fire into it. The Defiant and the Whirlwind were two examples of this soon to be discredited concept.

In America, protected as they were by the vastness around them, the idea of strategic bombing offered an exciting vision of the future. They therefore pressed ahead with the development of a fleet of heavy four-engined bombers such as the B17 (Flying Fortress) and the B24 (Liberator). These machines bristled with heavy machine guns and it was assumed that if they could fly in suitably close formation then they would provide their own impenetrable defensive barrage.

While the Americans did not entirely neglect the development of a long-range fighter, the P38 (Lightning) was not envisaged as a bomber escort. If you have ever wondered why American fighters at this time had a ‘P’ prefix, it is because they were called pursuit aircraft, ‘pursuit’ in the sense of pursuing enemy aircraft which entered your own airspace, and shooting them down.

Thus, when the Americans deployed their bombers in Britain in 1943, it was still their belief that ‘the bomber would always get through’. Yes, the RAF had tried this in 1939 with catastrophic results, but these must have been due to British bombers being armed only with a small number of light machine guns, or perhaps not flying in sufficiently close formation.

Reality was to prove the Americans tragically wrong. Against modern fighters armed with cannon and primitive air to air missiles, they had no effective defence. In an act of bravado, soon to be revealed as hubris, they launched what were scheduled to be simultaneous bomber raids on two vital strategic targets deep inside Germany: the ball bearing plant at Schweinfurt, and the Me109 factory at Regensburg. The results were horrific. Of the 232 bombers which set out, 60 were destroyed and up to 95 so badly damaged that many of them never flew again.

Clearly what was needed was what the RAF high command stoutly maintained was impossible: a long range fighter escort, a plane with the range of a bomber, but the manoeuvrability and gun power of a fighter. As we all know, the Americans countered this ‘can’t be done’ attitude with a ‘must be done’ mentality and the result would be the amazing P51 Mustang.

What has all this to do with Parkinson's? Well, it neatly exemplifies the problems which befell those researching an effective Parkinson's treatment.

In my first article we left Dr Parkinson in the early 19th century hoping for a cure ‘ere long’. In this he would have been disappointed. As we now know, the most effective traditional treatment for Parkinson's symptoms is Levodopa, but this was to prove a very long path indeed. Levodopa was first synthesised by Funk in 1911, using plant extract from the humble broad bean (vicis farba) and then isolated by Guggenheim in 1913. This was a major step forward, but only a first step. Even today our understanding of all the different chemicals which are active within the brain, what they are, what they do, how they do it, and how each interacts with the others is imperfect. Back in 1913 it was non-existent.

In 1938 Levodopa Decarboxylase, the enzyme which converts Levodopa to Dopamine, was discovered. This was to prove in retrospect a vital step in the road, but at the time was in the nature of being given a shiny new toy but not being able find any batteries to fit it.

Not until 1957 was Dopamine was discovered to exist in the brain, but there was still no certain explanation of what it did. However, there were certain scientists with very strong hunches, and two different lines of research were shortly to lead to the same conclusion. In 1959 a study showed that the basal ganglia were definitely involved, and a study of postmortem brains from humans who had died with Parkinson’s showed consistent Dopamine deficiency within the basal ganglia. At much the same time, rats which had been injected with reserpine to induce Parkinsonism showed significant improvement in their symptoms when then exposed to Dopamine. The pieces were falling into place.

Early-stage clinical trials of Levodopa began in 1961. In 1963 the susbtantia nigra of human Parkinsonian brains was seen to exhibit severe dopamine deficiency, allowing scientists to posit the existence of a Dopamine pathway, a hypothesis then proved correct by animal experimentation.

In 1967, the first trial of oral Levodopa on human patients began.

It is December 1943, and the men clustered in the briefing room are grateful for their heavy sheepskin flying jackets, since the dark, clammy chill of an East Anglian winter buffets the corrugated iron walls and sneaks insidiously around the ill-fitting windows.

A shouted command from the adjutant brings the room to its feet, and the Group Commander, a tall, lanky man with a shy boyish smile, bounds up onstage. For every man in the room there is a strange feeling of instant recognition, which transcends even the normal intense familiarity of a wartime combat unit.

“At ease, please, gentlemen,” he says in that calm drawl they know so well, and nods to the adjutant to pull the cover away from the mission map, showing their path to the target, and the interception points to rendezvous with different groups of escorting fighters. Colonel Jimmy Stewart would end the war with a clutch of decorations, and 20 combat missions flown during the darkest days of the war as the 8^th Air Force struggled to maintain crew morale following the Schweinfurt / Regensburg raid.

A couple of hundred yards away, Sergeant Walther Matthau is supervising a bombing-up squad, chain smoking, and complaining without pause about the goddam English weather. A few miles up the road, Captain Clarke Gable, officially restricted to filming duties, is preparing to stowaway on a B-17 to fly one of his several combat missions as a waist gunner. Away across the Atlantic, a newly qualified Joseph P. Kennedy Jnr awaits his posting as a pilot to a B-24 Group. He will not survive the war.

Both before and after the introduction of the Mustang, fighter escort tactics were fairly straightforward. Relatively short range fighters, such as Spitfires, would cover the bombers to the enemy coast, hang on with them as long as their fuel supplies permitted, and then turn for home. In the meantime, medium range fighters, such as Thunderbolts, would have taken off later but could use their superior speed to catch up with the bomber formation and escort them towards the target. As they in turn started to run short of fuel and turn for home, the long range fighters, the Mustangs and Lightnings, would have taken off later still and now take over escort duty as the bombers neared their target. For the return journey, the process would be reversed, with the short range Spitfires, having refuelled in the meantime, picking the bombers up for the last leg of their journey.

It may not be immediately obvious, but something very similar happens in the case of Parkinson's medications. Think of Levodopa as the bomber formation, and the various enzyme inhibitors as the different types of escort fighter, each with their own dedicated role to play in the mission.

Just like the American bombers, Levodopa comes under attack from the moment it enters the body. Before it has even got anywhere near the brain, for example, it is acted upon by Levodopa Decarboxylase, the enzyme which converts Levodopa to Dopamine. You may be wondering why this should be thought of as undesirable. Isn’t that exactly what we want to happen? To which the answer is ‘yes, but not yet.’

Levodopa can pass across the blood / brain barrier (BBB). Dopamine cannot. Thus, any part of the Levodopa which turns into Dopamine too early is the equivalent of that part of the bomber force which never reaches the target. This is where the fighter escort comes into play.

You will have noticed that the various Levodopa brands have two dosage measures (such as 25/100) rather than just one. That is because each pill contains two different drugs: Levodopa, the bomber force (which is the second dosage number), and Carbidopa, its close escort. It is specifically designed to attack the Decarboxylase enzyme (the enemy fighters which swarm up to attack). The more Decarboxylase they can destroy, the less remains to neutralise the Levodopa, and the more Levodopa which manages to reach the target, the greater its efficacy.

The next nasty trick the enemy has up his sleeve is something with the catchy title of Monoamine oxidase-B, known as MAO-B for short. MAO-B attacks Dopamine within the brain, once it has crossed the BBB. As it breaks it down, we obviously end up with less and less. Cue Rasagiline, which now arrives to take up its share of escort duty. By attacking the MAO-B, it ensures that less Dopamine is broken down, leaving more available for use.

Finally, there is an enemy fighter (enzyme) whose name is abbreviated to COMT. Here our escorts take the form of COMT inhibitors, such as the Capone brothers, Entacapone or Opicapone. NHS practice is to begin with the former (because it’s cheaper), only progressing to Opicapone in case of a bad reaction to Entacapone’s dreaded side effect, which can result in many hours spent striking a Rodinesque pose in the smallest room.

This summarises the various drug treatment regimes practised today. In the background hover exciting prospects such as DBS and the Duopa pump, which I will comment upon in a later article.