According to a new American study, taking two half tablets instead of one whole tablet of the C/L medication reduces fluctuations in the active substances in the blood and thus the risk of movement disorders such as dyskinesia. A combination tablet typically works for two to four hours - for extended-release tablets, it can last four to six hours - causing the amount of active substance in the blood to fluctuate from high (immediately after intake) to low (just before the next dose), which some users recognize as "on-off periods" and can lead to symptoms. Therefore, the researchers studied the effect of taking two half tablets instead of one whole tablet. The study was a phase 1 trial using an immediate-release tablet containing 25 mg of carbidopa and 100 mg of levodopa. Participants received one whole tablet every four hours versus half a tablet every two hours. They consumed the same amount of active substance overall, but the levodopa levels in the plasma of those taking half tablets showed 44% fewer fluctuations. Signals indicating movement problems, such as dyskinesia, were found to be more than halved. Both tablet forms were equally safe and well-tolerated.
The disadvantage of more frequent administration is that it requires taking medication more often and adjusting your daily schedule accordingly. The total exposure (AUC) to levodopa did not significantly differ between fasting and fed states, but the exposure to carbidopa was significantly reduced after a high-fat, high-calorie meal. Neither the current results nor the literature provide insight into why there was an effect of food on carbidopa absorption but not levodopa absorption. It may indicate the involvement of different uptake mechanisms for the two molecules. In any case, the effect is small and likely not clinically relevant.
Tablets containing 12.5 mg of carbidopa and 50 mg of levodopa have been available in some countries for a long time, but not in France and apparently not in the US either?
Although this information is not entirely new and there is some conflict of interest, as the researchers work for Riverside Pharmaceuticals, a US manufacturer that produces the medication and funded the study, the scientific evidence is interesting!
Article: Thomas N. Chase et al., Reduced Plasma Levodopa Fluctuations with More Frequent Administration of a Novel Carbidopa/Levodopa Functionally Scored Tablet, doi.org/10.1002/cpdd.1360
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Thanks! I just realized I’ve been doing this and it works. My regular dosage was TWO 25/100 cl every four hours. I changed two weeks ago to just ONE pill every two hours. So no need to cut pills. I did experience a lesser reduction of certain symptoms but overall feel and function better. Also I often forget a dose with no ill effect so I’m using less cl overall Aldi, I practice intermittent fasting and plant based - 8 hour eating, 16 hours not eating so I just eat whenever with no problem.
That's great gallowglass that it works for you - really good. Especially with the food as its awful to read how many people cannot eat with meds... my husband luckily isn't one of them.
Amazing isn't it... very good you have a plan that works for you Gosh I don't think I could go without dairy - love it so much. My husband eats many eggs a day as well, as protein doesn't seem to affect him.
My dr, Jamiela Dulaney ( cardiologist ) Has lots of info about her version of the plant based diet available on her web site and YouTube. It is based on the eating plan explained in the video Forks over knives. Plus she requires one cup of blueberries and 4 cups of dark green leafies per day. In a nutshell i avoid meat, fish, eggs, dairy, seed oil, processed foods, sugar. I seek out organic fruits, veggies, dark green leafy veggies, beans, homemade tomato sauce w/o salt or sugar. A little whole grain is ok each day. This may sound undoable. But it’s very doable plus Dr Jamie provides dietician and how to cook videos. She got me off blood pressure meds, acid reflux meds, and painkillers. I lost 70 pounds without ever feeling hungry or deprived after the first 3 days. My skin looks good for my age (71). Sadly I still havePD. But it’s not as bad as it was! Hundreds of patients, including me, credited Jamie with saving their lives.
This is exactly what I do, and the on time I’m super charged, but the dyskinesia is awful when it wears off. I shall try your method this weekend and see if the dyskinesia gets any better. Thank you.
I don’t eat till 10 am and stop eating at 6 pm. Except coffee , tea, water . From 4 am to 10 am I work on exercises, Physical therapy , food prep and prayer ( i am a Carmelite).
Thanks, you are blessed. If it were me, I would be terribly nauseous from the 8am dose of C/L on an empty stomach. It appears that the coffee and tea covers for you. My husband does intermittent fasting very successfully, but he doesn't have PD like me.
i have tried, fractionating the dose, as suggested by a neurologist- taking levodopa 50 every 2hrs as opposed to 100 every 4hrs. I just found my symptoms weren’t controlled with the 50mg
In addition to providing a more consistent supply of levodopa, a more effective action is also achieved because the peaks and valleys are significantly reduced. This is the theory and probably also the practice if there is no food intake. So it should also have a very beneficial effect on your PD symptoms. Even with a combination with food, you should normally have enough time in the 2-hour interval between levodopa intake. Half an hour before the meal, half an hour to eat, and an hour after the meal. It's challenging but doable. The impact of food, however, is highly individual. On average may play a less significant role. This is also in the interest of the pharmaceutical company that develops this. However, in individual cases, this can indeed pose a problem. We do read about this regularly. They also state that food has little influence on levodopa, only on carbidopa. This seems difficult because you still need enough carbidopa for the proces of dopamine production.
Like the previous commenter, I have personally found there's a threshold effect - If I only take half tablets I never seem to get enough to get an effect.
The findings are about immediate release and not about controlled release carbidopa levodopa. I recall that you are a CR user?
According to the research and also based on logic, there should be a more effective action with IR when it is taken more often in smaller doses. Besides the influence of food, which is not a coincidence that they also investigated, are there any other reasons why it may not work as well for some people?
🤔 Do you have any evidence for the Threshold effect of C/L medication ? I have asked twice before at HU where the claim from Sinemet comes from that you need at least 70mg of carbidopa daily for optimal efficacy of C/L. I haven't seen any studies... It could be a clever trick to push doctors to prescribe higher medication, but they are not that bad…? 😉 My current average medication of half a Sinemet IR of 5/50 per day (5mg) works just as well as the 10x 10/100 (100mg) from 2 years ago... Let's (for now) agree that we simply have different experiences and that we cannot draw any conclusions from that. 🍀
“Understanding the relationship between pharmacokinetics and pharmacodynamics of levodopa has been at the center of the most discussion of effective management of Parkinson’s disease patients experiencing motor fluctuations. The degree of correlation between variations in plasma levodopa concentrations and motor performance has been described by four types of responses to levodopa: the early disease duration of response, late disease duration of response, negative response and dyskinesias. The early disease duration of response assessed by the response to a single dose of levodopa is characterized by: (i) a plasma compartment and central-effect compartment threshold concentration of levodopa required to obtain a clinical response, (ii) a lag-time between peak plasma levodopa concentration and clinical response, (iii) the magnitude of the clinical response follows a dichotomic response after the threshold concentration is reached"
Very interesting, but indeed, a threshold effect is not described in this text. A threshold effect refers to a situation where a certain threshold value must be exceeded before a particular effect occurs. However, in this text, there is no specific threshold value mentioned at which an effect takes place. It mainly focuses on characterizing the pharmacokinetics of levodopa and carbidopa after administration of microtablets and evaluating the influence of various covariates.
Eric ahlskog's 2 pen'th is " To recap, the carbidopa in carbidopa/levodopa prevents the premature conversion to levodopa to dopamine outside the brain. This prevents nausea and allows much lower doses of levodopa to be used...
If nausea is not experienced, then the amount of carbidopa (or benserazide) can be ignored; progressively higher doses of carbidopa do not increase potency. In fact, the potency of carbidopa/levodopa relates to levodopa and not to carbidopa. Carbidopa appears to have no side effects, even in very high doses."
Any thoughts on one IR followed by judiciously timed CR doses? Might get you over threshold then coasting back down? Is my preferred option but still trying to fathom out food timings.
During the period when I needed higher doses of C/L on a permanent basis, I applied this method. It worked excellently for me. However, it may not work for everyone because when using customized dosing, which can also be done during periods of stress and intense exercise, it is important to have an understanding of the impact of the different forms of C/L medication.
This is an excellent summation yes - it's great that works as you say anything can impact the meds - stress, exercise, working on anything mentally taxing.....
I think as always that different things work for different people. IR and CR work well at 4.5 hrs for my husband so cutting it to every 2 hrs for him isn't necessary, but for others it may be great. Food intake makes no diff at all to him either..
By the way, the Sinemet IR immediate release pills can be easily divided, so I don't see that as an advantage of a new pill. It is beneficial if you want to be even more precise and break the 12.5/50 into 6.25/25.
Since the controlled release version cannot be split without losing the CR effect, it would be a real breakthrough if a 12.5/50 CR version becomes available. For many, the 25/100 CR dosage is too much, and the jump to 50/200 CR is too large. You don't even need an expensive study to understand the usefulness of that. The choices made by pharmaceutical companies are unfathomable, or perhaps it would be commercially more interesting to promote these excessively high dosages? They can't be that bad, right?
The 200/50 CR are perfect though for some people, my husband included. I'm just wondering why you come to the conclusion that 200/50 CR is an excessively high dose. Is that what you have used up to now and its not effective for you?
That's a misunderstanding. I didn't mean a specific dosage, but rather the situation where high dosages have to be chosen out of necessity because there is no alternative suitable medication available.
Because my therapeutic dose is 125 mg L-dopa, I take 1 and a 1/4 25/100 C/L pills in each dose. So I have successfully been using a pill cutter to cut the pills into quarters. My doctor, however, prescribed some extra pills in case some pills crumble when cut. It sometimes happens, but not too often.
Because I'm only taking what I need to get above the threshold where my symptoms are relieved, I may need to take my next dose in 2 or 2.5 hours to remain symptom free. For me, normally when I feel myself starting to lose finger dexterity then I know it's time for my next dose.
My generic C/L ER pills can be split without losing the time release effect. The instructions say not to crush or chew but no prohibition on splitting.
If a pill has a score line, you can assume that it can be broken. Otherwise, I would only do it if explicitly stated in the package insert. Even pills of the same brand, such as Sinemet, can have different manufacturers worldwide. Extended-release (ER) pills can have different mechanisms to achieve their time-release effect. In some cases, it may involve a specialized coating, while in others, it may involve multiple layers within the pill or a matrix structure. Splitting ER pills can potentially damage these mechanisms, affecting the medication's intended release profile.
In the case of my Sinemet CR and Teva CR pills in France, they do not have a score line, and breaking them is not recommended in the package insert:
"SINEMET CR should be administered as a whole tablet. To maintain the controlled-release properties of the product, the tablets should not be chewed, crushed, or broken."
Rather than take 150mg every 4 hours as neurologist suggested, have been alternating every two hours between 100mg and 50mg Madopar for some time. It definitely does smooth out the response and I avoid the big peaks and troughs and I generally feel well on it. Eating is a bit more tricky but not impossible. The main problem as mentioned previously, is that the 50 mg is not often enough to get me moving well, but is successful at removing pain and discomfort
If you use IR, you might be able to achieve better spacing by dividing the 50mg dose into two and taking 75mg twice, instead of 100mg and 50mg.
Another option is to take the next 50mg dose after a 2.5-hour interval following the 100mg dose, and then wait 1.5 hours before taking the next 100mg dose. This way, you can also create slightly longer intervals for your meals.
My husband has experimented with the levadopa 12.5 50 mgs taking half doses throughout the day and he also found it wasn’t symptom controlling after a few days.
He now takes 2 x 100 mgs twice a day with. 12.5 50 mgs in between that dose as 3 full doses of 100 mgs a day put him into dyskinesia quite quickly.
Just resorted to cut his Rasagaline into half and take a split dose or the dykenesia lasts most of the day. It is still a work in progress, he doesn’t have defined on and off times in the day just more dyskinesia or not so much. Think the fish oils and citicholine have helped him somewhat as the dyskinesia is less but still very unpredictable.
I’ve been experimenting with a hybrid of this by taking a smaller regular dose and then taking the maximum I can bare before meals. It works out for me at 1.5 45-mins before breakfast, lunch and dinner and 1 mid-morning and mid-pm. It gives me the boost to get me on then the maximum time for food to pass.
After reading an article on "less pulsatile dosing " I tried this and it worked for me. Instead of madopar 100mg every 4 hours I take 50mg every 2 hours, and find the wear off is far less intense and reduces dyskinesia. My consultant complied with my wish when she saw the effect after spending a day in the clinic for observation. I find it worth the inconvenience.
good grief, finally . Have been saying that for a few years now!
And start the day with a couple of stronger doses 2 hours apart to boost up levels and take smaller doses later in the day as you have multiple doses tails overlaying by that stage.
Interesting. I had a theory that this would work and I'm just starting out the day today with one and a half tabs. I'm thinking of taking a whole one in 2 hours and then back to 4 hours apart. Is that similar to what you do?
Yes agree on this starting the day with enough boost to get the flight (you) off the ground and then enough juice to keep the plane flying...... it's something that seems to be necessary to keep the day even from the beginning. A friend of mine has no trouble taking off, but he cannot keep himself airborne as he doesn't have enough fuel.
Thank you for that. That's how I view it as well. The only problem I've had with these experiments is if I take too much I tend to get light-headed and have some racing heart. Of course, my MDS said those symptoms were not from the C/L even though when I cut down the symptoms went away. I'm looking for a new doctor.
Isn't it crazy though. How can PD be SO different for every person. My husband then is opposite to you. He gets racing heart, breathlessness when he is nearly 'off'. Little meds in the system and until he takes his next dose, it doesn't calm down, the breathlessness anyway. It can never hurt to get second opinions.
After reading an article on "less pulsatile dosing " I tried this and it worked for me. Instead of madopar 100mg every 4 hours I take 50mg every 2 hours, and find the wear off is far less intense and reduces dyskinesia. My consultant complied with my wish when she saw the effect after spending a day in the clinic for observation. I find it worth the inconvenience.
I fully agree. Smaller doses at regular intervals certainly reduces dyskenisia. One has to find the right dosage. If splitting the tablet is difficult, one can always dissolve the tablet in known or measured quantity of water and take take it in required quantity . C/L tablet though not dissolve fully, one can always prepare a homogeneous solution. This method is basically titration and requires patience and careful monitoring . For sure with effort it is possible to find the right dosage with minimum dyskenisia.
My husband has a genetic test that says his dopamine betahydoxylase is fast so he chews through dopamine fast so I think that’s why this works for him. Maybe if people don’t have a fast DBH the 4 hourly is fine.
I wish it was a requirement for all these studies to take dna samples . If they did that and everyone cooperated into collecting results of studies and dna results we could start to see patterns. At least when an AI model can be built to churn through the data we would have a head start if samples are collected now. They can be anonymous. Then it would be much easier to decide what drug regime is most likely to work for someone.
That would be convenient, but even AI cannot solve this for you. In addition to DNA, there are also supplements and various lifestyle factors such as stress, diet, and exercise, which vary for each individual. For now, all that remains is a good dose of common sense.
Interesting in some ways, but surprised this wasn't already known as I read this thinking it made basic sense that taking halves every 2 hrs versus a full pill every 4 hours would keep things more level for some people. Half pills have always been part of my husbands pill regime for many years eg: taking a half pill IR for exercise days. Or at night if he has woken up. 1/2's can work really well but we have noticed that sometimes taking the extra 1/2 is enough to bring dyskinesia on, other times not. As always trial and error. We've never had any issues splitting Sinemet 200/50 or 100/25 pills.
My dyskinesia started 8 months into starting Madopar. It began with my left toes twitching when upped to 50 mg 5 x times daily from 4 x : 1 at 8:am, 4 & 8 pm, 2 at noon. The double dose started it, so I then fractionated the dose. It was during lockdown and the clinic could only do phone appointments, so both parkinson's nurse and consultant said that it couldn't be dyskinesia, must be tremour, until they saw it ! I now take 50 mg 9 times spread out the day . Timing depends on activity. Dyskinesia now spread up my left leg at peak dose and can make me clumsy, but I aim to keep it minimal, and hoping B1 will help as I' m taking 1, and occasionally 2 less doses.
I was getting severe dyskinesia when taking Madopar 100/25 for times a day.On changing to Madopar 50/12.5 I now take 7 a day at 2 hrly intervals( which has reduced my levedopa dose) am on for longer and much less dyskinesia. It’s not rocket science and don’t know why you can’t get 50/12.5 tabs in every country.In Spain at one time could only get 200/50 tabs! I use the alarm on my watch and have a pill box with an alarm as it is very important to take the meds on time every time to get the best control.
That's very interesting. I work with the half-life of carbidopa (or green tea) to keep the levodopa aloft in my brain for longer. The half-life of levodopa and also carbidopa is 1,5 hours, therefore after 1,5 hours with C/L in the system one can still benefit from a follow-up dose of mucuna.
I'm still researching and experimenting with substituting green tea for carbidopa. So far I have experienced green tea extending my ON time by 1 hour. MS Bing Copilot says: Dr. Rafael González Maldonado has discussed the use of Mucuna pruriens (a tropical bean that contains natural levodopa) and its interaction with green tea, particularly in relation to Parkinson’s disease treatment and the blood-brain barrier (BBB)1. He highlights that green tea enhances the effect of Mucuna pruriens, which can be significant for patients taking levodopa, as it may increase the potency of the treatment1. This interaction is due to certain components in green tea acting similarly to carbidopa, a medication used alongside levodopa to enhance its effect1
Interesting, thank you. Does it have a similar effect with levadopa? Daft question 😶🌫️ madopar is benserizide + levadopa . Possibly overdo things if combined with green tea ?
I'm investigating for the purpose of reducing my C/L meds and taking mucuna with green tea instead to some degree. Hoping for a way to reduce dyskinesia. The difficulty is I have to reduce C/L ever so gradually, so experimenting takes patient focus.
I have tried on accasion to reduce meds due to dyskinesia. I've reduced only by one 50 mg tablet ! It was difficult due to the extra muscle pain and sleeplessness, but sheer determination got me there in 8 weeks. I'm hoping b1 will help.
If you change back to the previous way of taking the medication your symptoms return very likely to their previous level, but it is not guaranteed for everyone. Preferably do these changes with your doctor, but not every neurologist likes to experiment...
I have found that a large finger nail cutter works very well for 100/25 sinimet. I only use it for those pills and have a cheap $10. cutter for everything else.
Park-bear is right "The threshold effect" most of the LD is removed from your body in your urine but must be taken to circulate in your bloodstream so some will get to your brain . I take two 100/25 eight times a day (every three hours ) it lasts 2.5 hours. So many things affect the the length of on-time. I take Amantadine to ward of Dyskinesia and I am looking into a pump you wear that continually delivers CD/LD medication in a gell to the intestines and a pump that delivers to just under the skin.
I'm less than 6 months into using levodopa meds. I'm still tailoring them to suit me. Initially the effect was all positive and I dutifully increased to the 'one size fits all' 100/25, 3 times per day. After 3 weeks I started feeling a need to stretch my toes and foot on my affected side 1 to 2 hours after taking the tablets. Almost a restless legs sensation. Not dyskinesia but I'm wondering if it's a very mild dystonia. I started halving the odd dose and things somewhat improved. I'm currently taking 4 doses of 50/12.5 to good effect.
Although we are all dealing with moving goal posts as the disease changes, it seems worthwhile taking time to get the optimal initial dose right.
Among the causes mentioned for why taking half doses of C/L more frequently does not work for some individuals, there may still be another phenomenon at play alongside the interaction with food. It is known as the "morning-off" phenomenon, in which PD symptoms worsen in the morning after a period of not taking C/L medication and/or experiencing a lower level of dopamine production during sleep.
The first doses of the day often need to be slightly higher or the second doses need to be taken slightly earlier. If you start with a half dose, this morning-off phenomenon may become noticeable earlier.
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Gosh I don't think I could go without dairy - love it so much. My husband eats many eggs a day as well, as protein doesn't seem to affect him.
Gap or Withdrawal? 
Parkinson's pill with the fastest onset of relief?
