Patients and Medicine

They are currently 7-10 million people number of people living with Parkinson’s.o To get an accurate picture of our project and its prospects, we must consider the applications of our proposed solution in a real world context, taking into account existing treatments, economics and patient welfare. Parkinson’s is a disease caused by the death of dopaminergic neurons in the substantia nigra, leading to progressive deterioration of brain function that results in: involuntary shaking of particular parts of the body, slow movement, stiff and inflexible muscles as well as a whole host of other neurological symptoms. There is currently no cure, but there is medication available to help alleviate symptoms.

The standard treatments that are used to tackle Parkinson’s include: Levodopa, dopamine agonists (Pramipexole, ropinirole and rotigotine), monoamine-oxidase-B inhibitors (selegiline and rasagiline) and anticholinergics (apomorphine). For the purposes of comparison however we will focus on the first, as that treatment is what our proposed system aims to replace. Oral levodopa is prescribed to be taken 250 to 500 mg orally twice a day with meals, with a typical maintenance of 3000-6000 mg per day for an average patient.a Once ingested the L-DOPA makes its way through the gastrointestinal tract to be absorbed in the proximal part of the small intestine, where it is transported to the brain via the blood stream. This Absorption is dependent on a variety of factors including: rate of gastric emptying, the pH of gastric juice, the length of time of exposure of drug to degradative enzymes as well as a decreased rate of uptake in the case of hyperacidity, high protein consumption and/or the ingestion of drugs affecting rate of gastric emptying. Mean concentrations of L-DOPA in the blood stream are between 0.45-7.07 µg/ml with peak concentrations being between 0.95-13.75 µg/ml, only 1-5% of which gains entry into the brain facilitated by Lat1 transporters, with the remaining product being decarboxylated to dopamine in areas of extracerebral tissue (preventing any desired interactions).bc After staying in the plasma for 8 hours and with a half-life of 0.77-1.08 hours, the drug is subsequently metabolised in the liver, where it is then broken down into around 30 metabolites and excreted in urine.

A variety of side effects exist with L-DOPA treatment, including nausea (caused by the build-up of dopamine created from L-DOPAs decarboxylation), depression, pain, insomnia, hypertension, bowel and gastro-intestinal problems (constipation). Despite this, L-DOPA remains the most effective method of treating Parkinson’s symptoms, often being used in conjunction with Dopa decarboxylase inhibitors (Carbidopa) to prevent decarboxylation of levodopa to dopamine and increase L-DOPA uptake through the blood brain barrier whilst reducing side effects. However the most prevalent problem with oral dosages is the spikes in L-DOPA levels throughout the course of the day as medication is taken, resulting in diphasic dyskinesia as well as painful foot spasms.

Figure 1 Plasma levodopa concentrations after oral and continuous intra-intestinal levodopa administration. When levodopa was given orally patients experienced substantial motor complications but at 6 months, when levodopa was given by infusion, motor complications were much reduced. Note that infusion avoids the low trough concentrations seen with repeated oral doses of a standard levodopa formulation.

This results in ineffective and irregular suppression of symptoms, increasing in severity with age as the ability of dopamine neurons to retain some dopamine as a buffer is lost. To resolve this issue, as well as to avoid the many other side effects associated with oral L-DOPA, a treatment called Duodopa is used. This is a method by which L-DOPA gel is administered directly into the gastrointestinal tract via the jejunum using a gastrojejunostomy tube. It requires surgery and regular check-ups for maintenance and adjustments of the catheter.L

Unfortunately all the proposed solutions to the above problems have significant drawbacks, mainly concerning quality of life for the patient. Oral L-DOPA can be either administered in larger doses to maintain a sufficiently high plasma concentration to avoid diphasic dyskinesia, however side effects are greatly exacerbated. Smaller micro doses or “fractioning” can maintain therapeutic levels and avoid side effects, but put excessive demand on the patient, completely transforming their life to be about the “next pill”, as well as eventually resulting in the re-emergence of symptoms when levels are not consistent. Duodopa whilst addressing the problems found with oral L-DOPA, is invasive, costly and time consuming and much the same as fractioning, creates a patient preoccupied with treatment. Our project seemingly tackles these issues, producing a more pharmacologically available product, resulting in better action and reduced side effects, all whilst reducing stress and increasing quality of life for the patient.

Of course when it comes to new treatments and development, especially more delicate matters such as genetically modified organisms, assessment of biosafety and security must be made. The later is defined by WHO as containment principles, technologies and practices that are implemented to prevent unintentional exposure to pathogens and toxins, or their accidental release; as well as institutional and personal security measures designed to prevent the loss, theft, misuse, diversion or intentional release of pathogens and toxins. The former is following general good laboratory practice, making sure any potential contaminants are secure, keeping workspaces clean/clear, making sure there exist no potential risks regarding bacteria or infectious agents. Special attention is played due to the expression of DNA sequences derived from pathogenic organisms as well as the production of products that have potential for pharmacological activity.

Regarding the misuse of L-DOPA or off label potential applications, it is included in the new wave of “smart-drugs” with the potential to improve concentration, alertness and/or memory; sold as the non persciptive Mucuna pruriensis extract. There is evidence that L-DOPA does to increase neuronal activity in the prefrontal cortex in primates boosting certain cognitive abilities, which naturally extends to our treatment, meaning the potential for misuse is possible, especially considering the comparative ease in which probiotics can be obtained as opposed to drugs in conventional therapeutic forms.e Likewise L-DOPA has been used for “fear extinction”, a way of desensitising a subject to a stimulus with the eventual result of removing a phobia.h Whilst these implementations have the potential to be used maliciously hypothetically, in say ‘enhancing’ persons serving in the military, it is important to note that evidence shows L-DOPA can have no direct effect on mood that in vivo dopamine demonstrates.fg Similarly, any threat of biological warfare, terrorism or weaponisation is unfounded, with L-DOPA and our system having no potential for these implementations.

Figure 2 Availability of anti-Parkinsonian drugs in Primary care across various world regions (taken from WHO Neurology Atlas, 2004) [5]

One must also consider the financial aspects of such treatments. The average UK cost of Parkinson’s per annum, per patient for the NHS is £2,291 using conventional L-DOPA supplements.i At this level we doubt that the costs for conventional versus our proposed treatment would be enough of a factor to cause a big shift in the way prescriptions are currently dispensed, however savings can be made in secondary care, with carers no longer having to spend man-hours on making sure regular doses of L-DOPA supplements are taken in excess of 3 times a day. The real economic insensitive however is the replacement of duodopa, a treatment fulfilling the exact same function whilst costing between £30,000 to £60,000 depending on dosage, not including man-hours for medical professionals administering and maintaining equipment as well as tube replacements.

This is much the same story for the rest of Europe with 79.1% of Parkinson’s patients having access to treatment in Europe. Australia are somewhat similar, although with an average cost of $12,000 annually per patient, there could be greater potential to generate savings.k Regarding the US, estimates place costs between $12,800-41,500 per person annually, with good access but a high cost barrier for treatment. In this regard a probiotic solution would be far cheaper and accessible – removing the barrier of entry as well as the ability to be sold as a commercial product sidestepping FDA drug regulations. China and other East Asian territories are similar to the US, with good availability but treatment being comparatively expensive in the context of the average wage, meaning again a cheaper probiotic solution could increase the amount of sufferers treated.

The continent that has the potentially biggest benefits (as well as the biggest problems) is Africa. The economic advantages are two-fold, having a solution that’s easy, cheap to develop, pack and transport allows care to reach patients who might normally do without, but also with our production method being fermentation and therefore cheap, sustainable and low maintenance, it has the potential to be developed in the continent, helping to boost Africa’s fledging pharmaceutical business.m There could be concerns regarding diet however, whilst on average African diets are lower in protein (which if present in high quantities prevents L-DOPA uptake), more research would need to be done in order to ascertain whether our probiotic strain could survive in more unstable conditions. There are other factors, such as mis-diagnosis, cultural acceptance, and the prevalence of other more deadly diseases that may make our proposal unrealistic. It is unlikely for example that the low amount of money spent on healthcare e.g. 4.3% of GDP in Tanzania would be focused on Parkinson’s when HIV/AIDS is far more prevalent and deadly.n

Patients

Julia

Julia was diagnosed with PD three years ago and is an unusual and an outstanding patient. She does not take any medication at all, but does lots of therapeutical exercises and is feeling very well at the moment. However, Julia highlighted that “I would not like to think that I was a typical spokesperson to the people with PD, and I do think that there is quite apatite between the tiny minority of people who did not take any medication and the vast majority who do.” We respect Julia’s concerns about this.

Julia introduced the practical side of PD treatment saying that a PD patient does not go straight on to levodopa, but goes through a series of other drugs before the levodopa therapy. “This is done in order to prevent dependency and tremor, since people don’t know whether the tremor is the tremor of Parkinson’s or whether it is a tremor resulting from the actions of the drugs.” This opinion helps the team to specifically target the age group of the majority of PD patients.

Julia’s attitude towards medication is that “once people are on medication then it becomes a major preoccupation because they are having to take drugs for this, drugs for that, drugs to offset the effects of whatever,” – this supports our theory that DopaDoser will improve the quality of life of PD patients

When interviewing Julia, we got patient’s point of view that supported and highlighted ideas of the academics. The team needs to research the market before the clinical trials as mentioned by Doug Kossar and Julia present her side of view on this saying that “So good consultants particularly in the UK, I think less so in the US where they tend to be a bit more drug-happy, that is the reputation anyway, I think it varies a lot from consultant to consultant, but actually they will put back the prescription of levodopa.”

When speaking about dosage of levodopa to be released, the team could clearly see the concern on the regulatory system: “The other school of thought is that it isn’t that the dopamine producing cells die, it’s that they seize to, they become dormant because for reasons not understood the body doesn’t draw down the dopamine. So it’s not actually absence of dopamine in the system, it’s the inability of the brain to process the dopamine that’s there. So that the effects of L-DOPA and the drug treatment is really very clued because it just zaps this enormous quantity of dopamine into the system. Which is what produced the parkinsonism, because the body can’t process it. So it’s like you know unlike insulin there is no system for calibrating what the levels of dopamine are so you can’t just get to that subtle little trigger point which the properly functioning body does for itself.” The solution to this is a muli-dimentional system based on quorum sensing or a suggestion by Dr Silverdale of a dopamine receptor.

Professor Angela Tod’s idea on patients welcoming the treatment by GMO also was reflected in Julia’s answer: “…And I have a lot of respect for him, so although I have an emotional reaction to the idea of genetically modified anything, I can also stand aside from that and see that all advances in science involve the engagement of the clever scientists with real problem solving issues. I mean penicillin is a modification of a bacteria, I mean whatever you are doing you are modifying all sorts of things. So I don’t have an intrinsic objection to genetic modification with the right checks and balances in place and a proper code of ethics in place. That sounds completely wonderful. And I mean I don’t know very much about chemistry but from what I do know, artificially manufactured chemicals are never as sympathetic as more naturally occurring chemicals. So I feel quite happy about that idea. If it improves the overall functioning of things. I mean, there are some obvious difficulties with that if you have an upset stomach or people’s digestive systems work in different ways but imagining that all of those things could be taken into account that’s just a minor detail then really. The gut makes perfect sense”

The team was happy to get first-hand knowledge from a patient about more rare dosage being beneficial because PD patients concern about medication less time. Julia’s comment on this was that “… as I get further along, weaker, and les able to do things, which I am, it does take more and more resolve to do what I am doing. That is sort of a trade-off: if you have only got so much energy you do not really want to spend it in a gym… it does not really make sense…because you do not want you to turn your life into a therapeutic exercise.” Moreover, Julia said that “Most people I [physiotheraist] give exercises to and they do not do that.”

Indirect information of tremor and placebo received form Julia moved the team to the following ideas: the therapeutic strain can be sweet, because “The good side of the tremors is it is terribly slimming”, have fragrance, colour, flavor and packaging that induce positive emotions “my body was just tremoring, you know, it just has this capacity to engage with the emotional content of thing… Having said that, it [doing therapeutic exercises] is not that easy, because PD does have huge depressive component and it is hard work to keep the psychological upper hand… it is not like having a stroke… it is a downhill path really. It does not matter how much you put into it, you are not going into reverse,” and placebo effect in PD can be influential “it has a high level of placebo effect benefit, which is really weird I think. So even though cognitively I can know that, if I am talking about the Parkinson’s I tremor more than if I am thinking about something else… it is a very odd condition, because it is highly suggestible” and “There is very intimate correlation that is not understood between the physical manifestation of PD and the psychological components. Particularly about PD,” - so even if the strain becomes outcompeted by other gut microflora, it is possible that placebo effect will start bringing its benefits.

Julia welcomed the idea of DopaDoser saying that “The idea of actually having dopamine gently fizzing away in the gut to feed the brain seems to me rather splendid.”

An interview with Julia gave the team the patient-side of a PD story. We were very impressed by how strong Julia is and wish her good luck and even more courage to tackle PD.

Walter

Talking to experts about Parkinson’s disease, doing our own research in that field and concentrating on our L-Dopa regulatory system does not tell you about the burdens of Parkinson’s disease as much as visiting a person that is actually affected by it. Walter was tested positive for Parkinson’s disease five years ago. For four years he rejects the oral L-Dopa therapy because of suffering from massive gastro intestinal side effects of the therapy. Talking to him it seamed that so far he is better off without L-Dopa. “Of course, “ he said, “you can see I’m shaking. But I can cope with it especially when I’m at home. I sometimes do not shake at all. I can control it with sports, nutrition and meditation a few times a day.” As he started with the oral L-Dopa therapy five years ago, the adaption to the medication went very fast so that L-Dopa concentration had to be increased quite fast. Considering the side effects of the therapy he decided to try it without L-Dopa. Still, he said he is not ruling out to try therapy methods from general medicine again. In the mean time he is open for every kind of new therapeutic approach against Parkinson’s disease as well.

Talking about our project, Walter mentioned that although, he was not a friend of genetic engineering he would not mind having genetically engineered gut bacteria integrated in his jejunum if they would do decent work and are approved by the health system. This was surprising for us, especially as we know that public opinion on genetically modified organisms in general is quiet bad in Austria.