Synergistic Benefit of Low Dose Dopamine (Greek Coffee) and Diuretics (Bumetanide/Furosemide); better than Bromocriptine?

I did think of highlighting this post to the Bumetanide researchers in France, but I do not think they would take it seriously.

Another one to mention would be this new study, funded by Rodakis, to look at why some antibiotics improve some autism.  Dr Luna at Baylor College is running the study.  Its basic assumption is that the effect must be to do with bacteria, but as our reader Agnieszka has highlighted, common penicillin type antibiotics increase expression of the gene GLT-1 which then reduces glutamate in the brain.  It has nothing to do with bacteria.  Maybe for other antibiotics the effect does relate to bacteria.

But if you tell Dr Luna about GLT-1, quite likely she will not be interested.  

Study to investigate connection between antibiotic use and autism symptoms

Researchers will compare the gut microbiome (bacteria, yeasts and fungi found in the gut) and metabolome (small biological molecules produced by the microbes) of those who experience a change in symptoms during antibiotic use to those who do not. The study may provide valuable insight into when and why these changes occur and how this information can be harnessed for future interventions.  

There is even a case study very well documented here:-

Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism, A Case Report and Review of Literature

Petra, our regular reader from Greece, has pointed out that Bumetanide has a greater effect in her adult son, with Asperger’s, when taken with Greek coffee and suggested why this might be. 

Her reference is this article:- 

Added to Diuretics, Low-Dose Dopamine Renoprotective in Small Acute-HF Trial

It shows that the diuretic effect of low dose furosemide, with dopamine, is greater than the effect of high dose furosemide.

The diuretic effect of Furosemide is via the transporter NKCC2, which is the same affected by Bumetanide. 

NKCC2 is found in your kidneys, while the very similar NKCC1 is found in your brain.  Furosemide and Bumetanide affect both NKCC1 and NKCC2.

The caffeine in coffee is known to indirectly produce dopamine in your body.

Greek coffee is nothing like your instant coffee or watery Starbucks coffee, it contains a serious amount of caffeine. 

The question is how does dopamine interact with furosemide/bumetanide and will the effect in the kidney (NKCC2) also affect the brain (NKCC1). 

By more effectively blocking NKCC1 in neurons you would further lower chloride levels and potentially further improve cognitive functioning.  

This would further validate Petra’s observation. 

Then we would consider if there is an alternative to Greek coffee, or just accept that caffeine is the simplest and safest method to enhance Bumetanide.    

In the then end my conclusion is that coffee, or just the caffeine, is a better option than a selective Dopamine D2 receptor agonist.  But there is an interesting drug called Bromocriptine that may be better in some cases. 

Not only is it a dopamine D2 receptor agonist, but Bromocriptine also “inhibits the release of glutamate, by reversing the GLT-1 (EAAT2) transporter”. 

We came across the GLT-1 (EAAT2) transporter when we found why some people with autism improve when on beta-lactam antibiotics (that include the penicillin ones).   

GLT-1/ EAAT2 is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. EAAT2 is responsible for over 90% of glutamate reuptake within the brain 

We saw that the drug riluzole approved for the treatment of ALS (Amyotrophic Lateral Sclerosis) upregulates EAAT2/GLT-1.

I suggested that people with autism who improve on penicillin types antibiotics should get a similar effect from riluzole.  But riluzole is one of those monstrously expensive drugs.  

Based on my logic, we would then think that bromocriptine should help treat ALS (Amyotrophic Lateral Sclerosis).  What did I find when I looked it up:- 

Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients. 

So then how much does Bromocriptine cost?  It is a cheap generic.  So a cost effective potential drug for ALS. 

Bromocriptine has two potentially useful functions (Dopamine D2 and GLT-1),but it has numerous other effects:- 

Bromocriptine blocks the release of a hormone called prolactin, but this should not be an issue for males. 

Risperidone, one of only two drugs approved for side effects of autism, can boost levels of prolactin.  Elevated prolactin levels are linked to a range of side effects, including gynecomastia, or growth of breasts, in men and boys.  This did not stop the drug being approved.

Bromocriptine agonizes the following monoamine receptors

• Dopamine D₁ family
• D₁ (K_i=682 nM)
• D₅ (K_i=496 nM)
• Dopamine D₂ family
• D₂ (K_i=2.96 nM)
• D₃ (K_i=5.42 nM)
• D₄ (K_i=328 nM)
• Serotonin 5-HT
• 5-HT_1A (K_i=12.9 nM)
• 5-HT_1B (K_i=355 nM)
• 5-HT_1D (K_i=10.7 nM)
• 5-HT_2A (K_i=107 nM)
• 5-HT_2B (K_i=56.2 nM)
• 5-HT_2C (K_i=741 nM)
• 5-HT₆ (K_i=33 nM)
• Adrenergic α family
• α_1A (K_i=4.17 nM)
• α_1B (K_i=1.38 nM)
• α_1D (K_i=1.12 nM)
• α_2A (K_i=11.0 nM)
• α_2B (K_i=34.7 nM)
• α_2C (K_i=28.2 nM)
• Adrenergic β family
• β₁ (K_i=589 nM)
• β₂ (K_i=741 nM)

  

This is why drugs have side effects. 

But for people with ALS who cannot afford riluzole, the cheap generic bromocriptine might be a good choice.

How about bromocriptine for autism? 

Well there was a trial in Italy a long time ago on girls with Rett syndrome 

Bromocriptine in the Rett syndrome

Twelve typical cases of the Rett syndrome and one forme fruste were treated with bromocriptine for six months and then had a washout for two months followed by resumption of the bromocriptine treatment. During the first bromocriptine treatment there were improvements in communication and relaxation in some of the girls: a more regular sleep pattern was observed in 4 and a more varied facial expression in 8, and 4 girls began to utter a few words. The bouts of hyperpnea disappeared in 5 and grinding of the teeth in 3. There was also a reduction in stereotypic hand activities in 5 girls and signs of improved motor abilities in 3. The washout caused a general decrease in the positive effects of the previously administered bromocriptine and resumption of the treatment with this drug led to less marked improvement. Metoclopramide was tested in all the girls before the treatment, and it was noted that, while endorphins were hyporesponsive, prolactin was hyperresponsive. This test was repeated two months after the bromocriptine treatment had been performed and, while beta-lipotropin remained unchanged, beta-endorphin showed increased responsiveness.

Current use of Dopamine with Lower Dose Diuretics 

There is extensive knowledge of the effect of taking dopamine with a bumetanide type diuretic. 

Bumetanide by itself has a plateau above which a higher dose causes no further diuresis, but when combined with dopamine there is more diuresis.  Alternatively you can use a lower dose of bumetanide and get the same amount of diuresis by adding dopamine. 

Of interest to people with autism, it is found that you can reduce the amount of potassium lost for the same amount of diuresis.

    

Added to Diuretics, Low-Dose Dopamine Renoprotective in SmallAcute-HF Trial

Synergetic Effects of Dopamine and High－Dose Bumetanide in Patients with oliguria

The effects of a combination of dopamine and bumetanide were studied in eight patients with oliguria not responsive to conventional treatment. Dopamine was infused at a rate of 3 чg/kg/min and bumetanide was given as a 0.05-0.1 mg/kg bolus every 2 hours intravenously. Administration continued for 3 to 15 days. Urine output, blood urea nitrogen, serum creatinine, the ratio of urine to plasma osmolarity, free water clearance, and serum electrolytes were measured before, during, and after the administration period. Six of the eight patients responded with an increase in urine output and improvement of the other variables ; the other two did not. We conclude that the combination of dopamine and high-dose bumetanide is effective in increasing diuresis in critically ill patients in the early stages of oliguria

How does dopamine interact with NKCC1/2?

This is a very logical question, but there is something in the literature on this subject.  It does come from frogs, but it was all I could find.

Functional expression of the murine D₂, D₃ and D₄ dopamine receptors in Xenopus laevis oocytes

The different murine D2-type dopamine receptors (D_2L, D_2S, D_3L, D_3S, and D₄) were expressed in Xenopus laevis oocytes. The D2-type receptors were all similarly and efficiently expressed in Xenopus oocytes and were shown to bind the D2 antagonist [¹²⁵I]sulpride. They were all shown to activate Cl⁻ influx upon agonist stimulation. Using the diagnostic inhibitor bumetanide, we were able to separate the Na⁺/K⁺/2Cl⁻ cotransporter component of the Cl⁻ influx from the total unidirectional Cl⁻ influx. The D_3L subtype was found to operate exclusively through the bumetanide-insensitive Cl⁻ influx whereas the other D2-type receptors acted on the Na⁺/K⁺/2Cl⁻ cotransporter as well. The pertussis toxin sensitivity of the receptor-activated chloride influx via the Na⁺/K⁺/2Cl⁻ cotransporter varied between the various D2-type receptors showing that they may couple to different G proteins, and activate different second messenger systems.

In contrast to the D2 and D3 receptor subtypes, D4 receptor activity was not significantly altered by the presence of PTX, suggesting that in Xenopus oocytes it may couple with one or more PTX-insensitive G proteins to cause changes in Cl3 influx. By contrast, in the case of the D2 receptor, PTX reduced the total Cl3 influx mediated by the D2S isoform by approximately 67%, and that mediated by the D2L isoform by approximately 40% (Fig. 2A). However, the activities of the two components of this ion influx, namely the bumetanide sensitive Na/K/2Cl- cotransporter and the bumetanide-insensitive Cl- influx, differed between these two isoforms. While the bumetanide-insensitive Cl3 influx was reduced by approximately 60% by PTX for the D2L isoform, it was only slightly reduced for the D2S isoform (Fig. 2C). Thus, the majority of the inhibitory effect of PTX on the D2S-induced influx was caused by uncoupling from the signalling cascade that activates the Na/K/2Cl- cotransporter. On the other hand, the signal transduction pathway that activates the cotransporter after stimulation of the D2L receptor remained relatively unaffected by PTX (Fig. 2B), indicating that D2S and D2L couple to different G proteins when expressed in Xenopus oocytes. For the D3 receptor, both long and short isoforms showed a reduction (50^60%) in the presence of PTX, at the bumetanide-insensitive Cl- influx (Fig. 2C), whereas for both D3 receptor isoforms, PTX had little or no effect on the Na/K/2Cl- cotransporter, indicated by the bumetanide-sensitive component of the Cl3 influx (Fig. 2B).  

PTX = pertussis toxin

  

Caffeine among its many effects is effectively a dopamine D2/3 receptor agonist.

Caffeine mimics the effect of a dopamine D2/3 receptor agonist onthe expression of immediate early genes in globus pallidus.

Conclusion

As I understand from the large scale trial use of bumetanide use in autism, there is indeed an issue with hypokalemia (loss of potassium).  

I would think that this should be solvable using a supplement and dietary potassium.  Agnieszka pointed out that kiwis have the advantage of potassium with little carbohydrate, as do avocados. Bananas and orange juice are the traditional potassium-rich foods for people on diuretics. 

This is a case where the care giver has to play an active role, it is not just about the doctor prescribing a pill.  The care giver has to manage the process to minimize the side effects.  So potassium needs to be managed, as does fluid intake. 

For people who struggle with hypokalemia, the idea of a lower dose of bumetanide, but with dopamine, could be interesting.  The other method is to add a potassium sparing diuretic like spironolactone. 

For my son, the dietary option, plus 250mg of potassium twice a day, is very effective.  Now I just have to persuade him to take a Greek coffee with his breakfast. 

For people whose autism responds to penicillin type antibiotics and who take bumetanide then Bromocriptine might be interesting as a caffeine alternative.

A Hypothesis: Vitamin D, Calcium, Milk, and the Autism Epidemic

by Seth Bittker

My name is Seth Bittker, and I am the father of a boy with ASD.  My son’s development was slow up until about 2 1/2 years of age.  Around this time, his milk consumption increased, and it began crowding out other sources of sustenance.  Within a few months he regressed, and we received an autism diagnosis soon after this.  Stopping his milk consumption was the first step in helping him get better.

Like some other parents of those with ASD children, I noticed that his behavior varies significantly with what he eats.  When he consumes large amounts of calcium fortified foods or beverages, his behavior gets worse: he becomes more autistic in a behavioral sense.  Since milk has a lot of calcium, and calcium fortified foods do as well, it seemed like there might be some connection to calcium and his symptoms.  Later based on a doctor’s recommendation we gave him supplemental vitamin D.  We did not notice much initially, but a few weeks later he developed hives, and he regressed.  Since supplementation with vitamin D increases absorption of calcium, it appeared that the bad reaction to calcium and vitamin D might be connected.  Based on these experiences and others, I eventually inferred that we should keep him on a relatively low-calcium diet and avoid vitamin D supplementation or fortification (milk as well as many other foods in the US are fortified with vitamin D).

I also concluded that my son was different from most others affected with autism as some have suggested that vitamin D deficiency is involved in inducing autism,[1] and he evidently did not have a deficiency based on the vitamin D trial even though vitamin D levels in his blood were relatively low.

But is he really different than others with autism?  If one examines the evidence from a number of genetic syndromes that are comorbid with autism, in many cases the cause is over-active calcium channels (effectively too much intra-cellular calcium).[2]  You can see this by looking at syndromes such as Timothy syndrome, Williams syndrome, and Sotos syndrome, which have high comorbidity with autism and seem to be caused by too much intra-cellular calcium.  In Williams syndrome the connection is through a gene which upregulates vitamin D.[3]  In some of these syndromes is it well known that supplementation with calcium and vitamin D are contraindicated.[4]

In addition there are certain biochemical markers that are typical in autism, and my son seems to have this same biochemical gestalt.  For example two types of immune system cells released by the thymus are called “Th1” cells and “Th2” cells, and Th2 cell levels relative to Th1 cells are much higher in the blood of those with autism than in controls.[5]  As Th2 is associated with extra-cellular immunity, this suggests that those with autism will be prone to allergies,[6] which fits with anecdotal observation.  In addition with autism we see elevated markers for oxidative stress and endothelial damage.[7]  Also those with autism typically have functional deficiencies of magnesium[8] and potassium.  By functional we mean the levels may not be low in the blood relative to controls, but there is a biochemical need for greater consumption.  To see the latter you can give somebody with autism a small dose of supplemental potassium, and the result is generally a reduction in autistic symptoms.  For more on this, see Peter’s work: http://epiphanyasd.blogspot.com/2013/08/potassium-may-play-important-role-in.html.

It turns out that vitamin D skews the immune system to produce elevated levels of Th2 cells.[9]  One can infer that it also produces functional deficiencies of potassium and magnesium as these minerals offset the effect of calcium on calcium channels and vitamin D increases the absorption of calcium.  In addition in high doses vitamin D causes oxidative stress and endothelial damage as we see in autism.[10]

Oral supplementation with vitamin D can cause other consequences as well.  Supplementation with significant doses of vitamin D early in life, results in more cases of allergies, asthma, and dermatitis later.[11]  Asthma, allergies, and dermatitis all feature high levels of Th2 cells like autism.[12]  Is it too much of a stretch to suggest that supplementation with vitamin D early in life, might result in more cases of autism later as well?

On looking at the data we can see that my son as well as most other babies in much of the civilized world received, and in many cases continue to receive, large oral doses of vitamin D starting from birth.  As a baby we gave him vitamin D drops, and he also occasionally received some formula.  Starting at one year of age he consumed increasing amounts of milk (fortified with vitamin D in many countries) as well as children’s multivitamins, which also contained vitamin D.   Here is a graph showing vitamin D content of various beverages:

 

We are giving babies today much more oral vitamin D than they would consume from human milk alone and also much more than they would have consumed in past decades through formula and food sources when vitamin D fortification was more restrained.  In fact based on nutrition data and caloric intake, a baby just out of the womb consuming Similac baby formula today will receive approximately 855 IU per day of vitamin D.[13]  I am 190 pounds.  If we assume that dose should be proportional to weight, which is a good baseline assumption for most vitamins, I should consume 16,245 IU per day of vitamin D.  This is a huge dose, and based on past experience I know it would have a devastating effect on my health.  Why should it not be the same for some subset of babies?

When and where vitamin D consumption by the young is high, is where autism rates are high.  For example, in the United States autism rates are high relative to much of the rest of the world and they rose gradually starting around 1980 as much of the population transitioned to lower fat milks, which increased consumption of vitamin D.[14]  Later rates rose again in the early 1990s as the amount of vitamin D in milk was increased significantly with no change in the label.[15]  Rates continued rising with the popularization of the Sippy Cup starting in the 1995.[16]  They rose further during the 2000s as the Institute of Medicine increased the supplementation recommendations for babies in 2003 and again in 2008.[17]

When looking internationally, the evidence also points to a role for oral consumption of vitamin D in inducing autism.  Cuba for example has extraordinarily low rates of autism.[18]  The Cuban Health Service does not supply vitamin D drops to babies.  Nor do they fortify milk or other foods with vitamin D in Cuba.[19]  The Amish also have very low rates of autism as well.  They do not provide vitamin D drops to babies, and the milk they consume comes straight from cows: no vitamin D is added.[20]  In the United Kingdom rates of autism are lower than in the United States.[21]  Fortification and supplementation are common in the United Kingdom, but at somewhat lower levels than in the United States.[22]

Vitamin D is also used as a rodenticide, and experiments in rats show that it is more deadly to male rats than female rats.[23]  Is it any coincidence that autism strikes many more males than females?  Babies who get most of their sustenance from formula also receive more vitamin D than those who receive vitamin D from human milk.  Not surprisingly autism rates are higher among those who are formula fed.[24]

Vitamin D’s involvement also explains why some with autism benefit from a “casein” free diet as such diets avoid milk, which has high calcium content and is fortified with vitamin D in many countries.  It also explains why low-oxalate diets are beneficial as well as ketogenic diets.  Oxalates cause excess calcium salts to precipitate in the body and ketones effectively remove excess calcium due to acidity.[25]  Both lower the calcium load.  Oral supplementation with vitamin D also explains why some with autism have a favorable reaction to chelation.  Chelation agents remove excess calcium at the same time as they remove other metals.[26]  So they also lower the calcium load.

So the evidence suggests that over-consumption of vitamin D by babies and toddlers may induce autism in a genetically susceptible subset of the population.  This explains the biochemistry of autism as well as the nature of the autism epidemic.  There are a number of other data points that fit with this hypothesis.  If you are interested in this topic, here is an ebook with a lot more detail: http://www.amazon.com/dp/B00GVB46ES.

I want to thank Peter for allowing me to be a guest blogger here, and I also want to thank you for reading this. How do you view this hypothesis?  Do you have observations that are relevant to it?  Are you aware of existing data that would help confirm it or refute it?

---

[1] http://www.medical-hypotheses.com/article/S0306-9877(07)00537-3/abstract

[2] For more on calcium channels and autism, please see http://www.autismcalciumchannelopathy.com/Genetic_Factors.html.

[3] http://www.ncbi.nlm.nih.gov/pubmed/6977721

[4]  http://www.fpnotebook.com/pharm/Vitamins/VtmnD.htm

 

[5] http://www.ncbi.nlm.nih.gov/pubmed/9627004

[6] http://www.sciencedirect.com/science/article/pii/S1380293397100057

[7] http://www.ncbi.nlm.nih.gov/pubmed/21651783 and http://www.ncbi.nlm.nih.gov/pubmed/16908745.

[8] http://mdheal.org/magnesiu1.htm

[9] http://www.jneuroinflammation.com/content/8/1/56

[10] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052582/ and Gross, David Ross, Animal Models in Cardiovascular Research, p. 316.

[11] http://www.direct-ms.org/sites/default/files/Hypponen%20Vit%20D%20allergy%2006.pdf

[12]http://www.nature.com/jid/journal/v133/n10/full/jid2013148a.html and http://www.ncbi.nlm.nih.gov/pubmed/10919498.

[13] http://nutritiondata.self.com/facts and www.nal.usda.gov/fnic/DRI/DRI_Energy/energy_full_report.pdf.

[14] http://future.aae.wisc.edu/

[15] FDA, M-I-92-13.

[16] http://www.nytimes.com/2013/08/11/magazine/

[17] http://www.ncbi.nlm.nih.gov/pubmed/12671133 and http://pediatrics.aappublications.org/content/122/5/1142.

[18] http://healthimpactnews.com/2013/study-evidence-that-acetaminophen-especially-in-conjunction-with-vaccines-is-a-major-cause-of-autism-and-asthma/

[19] http://www.ncbi.nlm.nih.gov/pubmed/12947458

[20] http://www.ncbi.nlm.nih.gov/pubmed/22513133

[21] http://www.bmjopen.bmj.com/content/3/10/e003219.full

[22] http://mpkb.org/home/food/vitamind/vitamin_d_supplementation_policy

[23] http://www.toxicologyinternational.com/article.asp?issn=0971-6580;year=2008;volume=15;issue=2;spage=143;epage=144;aulast=Kaur

[24] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1578554/

[25] http://www.news-medical.net/health/Ketogenic-Diet-Side-Effects.aspx

[26] http://link.springer.com/article/10.1385/BTER:83:3:207#