As the human population grows older, the challenge presented by disorders of the ageing body and brain, such as Parkinson’s disease, becomes ever greater. One in 37 people alive today in the UK will be diagnosed with Parkinson's in their lifetime. In 2023 in the UK, around 153,000 people were already living with the disease. In the years to come those numbers are expected to grow and reach 172,000 by 2030. Parkinson's UK describes it as "the fastest growing neurological condition in the world".
Researchers have now spent decades trying to alleviate suffering and distress caused by Parkinson’s – and have in some ways succeeded. But there is still a long road ahead. Recently, NHS England announced that it is to roll out a new treatment, Produodopa, which uses a pump to steadily release medicine into the bloodstream around the clock. As with nearly all drugs, Produodopa was tested in animals before being tested in humans to ensure its efficacy and safety in a controlled lab environment.
Understanding Parkinson’s disease
Parkinson’s disease is a disorder of the brain that leads to difficulties in movement. It causes tremors, shaking, stiffness, and difficulties with walking, balance and coordination that usually begin gradually and get worse over time. This is often accompanied by non-movement problems such as poor sleep quality, intestinal dysfunction and even a poor sense of smell, as well as changes in the way sufferers react to reward or motivation and sometimes a deterioration in their ability to understand complex ideas and to make plans.
Much of what we know about Parkinson's disease today comes from models of the disease in animals, usually mice. We now know that the root cause of these symptoms is the death of the brain cells that produce a neurotransmitter known as dopamine. As we age, we naturally lose a few of these dopamine-producing cells, but this loss somehow accelerates in patients with Parkinson’s and far exceeds what is normally expected.
Arvid Carlsson discovered dopamine in the 1950s using a variety of animal models, including mice, rabbits, sheep, and oxen. He showed that dopamine was involved in the nerve signals responsible for movement and that dopamine dysfunction could result in serious disorders such as Parkinson’s disease. He was awarded the 2000 Nobel Prize for Physiology or Medicine together with Paul Greengard who used animal models to investigate the mechanism of action of dopamine and other neurotransmitters, and Eric Kandel who used sea slugs to study the role of synaptic transmission in learning and memory.
Optimising treatment for Parkinson’s disease
Once the link between Parkinson’s disease and a lack of dopamine in the brain was made clear, scientists and clinicians worked on replacing the missing neurotransmitter in animals, including rodents and non-human primates, and then in humans. They found the first effective treatment for Parkinson's in a molecule often called L-dopa. This works brilliantly for some symptoms, but its benefits wear off over time.
The range of available drugs has broadened since then, but many patients still find them unsatisfactory and coping with the sheer quantity of medications used in combination can be taxing and demoralising. In the most severe cases, patients need to take more than 20 pills a day to control their symptoms – with inconsistent effects. Many patients currently taking a large number of tablets say their symptoms worsen later in the day and especially during the night, when they can’t take regular doses of medicine. Others have to be treated through a permanent feeding tube. It was to help these patients that researchers developed the new drug called Produodopa.
Produodopa is a combination of two drugs – foslevodopa and foscarbidopa. An infusion enters the patient's bloodstream through a cannula under the skin that is controlled by a small, automatic pump, releasing a steady flow of the treatment 24 hours a day to stay on top of symptoms. The treatment will soon be made available in the UK to around 1,000 people with advanced Parkinson’s disease.
Thorough testing in animals to ensure efficacy and safety
Produodopa was tested in rats, dogs, and monkeys before clinical trials were granted.
Proof of concept was established in rats that were given a continuous subcutaneous infusion, which was well tolerated throughout the study. Drug dosage studies in rats and pigs exploring a range of formulation ratios of foslevodopa to foscarbidopa established that a broad range of ratios from 4:1 to 15:1 were therapeutically relevant.
To estimate pharmacokinetic activity (how drugs reach their site of action and are eliminated by the body) in humans, the pharmacokinetic profiles of foscarbidopa, and foslevodopa – which make up Produodopa – were first characterised in animals, rats, Göttingen minipigs, dogs, and monkeys, both when they were delivered using an intravenous injection and a subcutaneous infusion. These profiles were then compared to that of a gold-standard drug against Parkinson’s in these animals.
This was a US study and animal welfare was protected under the guidelines provided in the NRC Guide for the Care and Use of Laboratory Animals (1996) and the Animal Welfare Act (National Research Council, 1986). The AbbVie Institutional Animal Care and Use Committee approved the animal work which was conducted in an Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC) accredited facility.
Animals are only allowed to be used in research when there is no other suitable non-animal alternative. Animal research is required by law for the development of almost all pharmaceutical products in order to minimise the possibility of unforeseen unwanted side effects, and we would not have life-changing therapies like Produodopa without it.
More information :
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251848/
https://docetp.mpa.se/LMF/Produodopa%20solution%20for%20infusion%20ENG%20PAR_09001bee830f19f6.pdf
Last edited: 22 January 2025 11:29