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Showing posts with label Bumetanide. Show all posts
Showing posts with label Bumetanide. Show all posts

Saturday, 29 February 2020

Clinical Trials – Bumetanide and Memantine & Making Sense of it all in a Single Book





This week I received a message: -

“Your Bumetanide treatment is on trial among 25 teenagers here and parents are loving it”

My reply, brief as usual (unlike my blog posts)

“Great!”

I did not mention that in the first phase of the trial 50% of the teenagers are going to be on the placebo.  It is Dr Ben-Ari’s treatment.

A clinician told me that all the parents of children, to whom she has prescribed bumetanide, think their children are responders and is wondering how to deal with the parental placebo effect.

I had another clinician telling me, “I guess from your experience with the blog, most people are not responders to Bumetanide”.  Then came an analysis of the recent tiny study in China that showed on average there was a measurable improvement on the CARS scale (Childhood Autism Rating Scale), but the question arose was “is this response large enough for parents to notice?”

Memantine (Namenda)

A few years ago, Memantine was also trialled at the University Hospital where we live, the same one that is part of the current Bumetanide study.

Memantine was subject to a rigorous multi-center study of nearly one thousand children a few years ago.  The FDA did not like all the off-label prescribing of Memantine for autism and asked the producer to carry out a serious clinical trial.

The first phase of the trial was to identify the responders, those responders then were to be enrolled to two follow-on trials to collect additional useful data.  The trial was terminated after the first phase was completed because in the subsequent trials the placebo produced as good results as Memantine.

So, we should assume memantine is no good for autism?

Or

In spite of spending millions of dollars and liaising with the FDA on the detailed structure of the trial, the producer did not know how to organize an autism trial properly?

I was just writing a part of my autism book that reviews all the drugs trialed to date in autism and I noted that Antonio Hardan (for me, Dr NAC from Stanford) has published a review of data from those expensive Memantine trials.


… the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

I think that is Hardan-speak for “I think Memantine can be a useful therapy, for some people”.  I am not totally sure and I can see why Barney Rubble might be left scratching his head. 

Hardan is about to become Stanford's Dr Nexium, as he runs a clinical trial of the acid lowering drug esomeprazole (Nexium).  I am not sure why he thinks this will improve autism.  I think it will make some people's autism worse, because over time it will cause intestinal dysbiosis.

https://stanfordhealthcare.org/trials/a/NCT03866668.html

Intestinal Dysbiosis Secondary to Proton-Pump Inhibitor Use



Autism for Dummies?

Writing a comprehensive book about autism is quite a task.  If it is too complicated nobody will read it, but if you do not go into the how and why of autism, you have not contributed very much.

My elder son has suggested calling it “Autism for Dummies”; but that was not helpful suggestion.  We probably all count as Dummies, when it comes to autism, even Dr Naviaux, who I think knows the most.

I like the book written by a US Academic who treated his "untreatable" brain cancer (Gioblastoma, life expectancy 14 months), by reading the research and applying off-label therapies, using cheap generic drugs.  He has lived long enough to publish a second edition.  The first edition has a cover that looks like a medical textbook; he learned his lesson and the second edition looks more like a cookery book.

Before using pharmaceuticals to treat autism, we used a Peter-created, ABA-inspired, home therapy program.  Amongst many resources, we had two old, but excellent books - they were published nearly 40 years ago.  One was blue and one was yellow (code named by me and therapists as the yellow and blue books), one was about increasing good behaviors and the other was about reducing bad behaviors.  I could not leave them lying around at home, because in the tittle of these use cute looking books was in large print “SEVERE RETARDATION”.  The books are great and of course they should have been combined into a single book. 




I am not a fan of giving a nice name to somethings that is bad.

To me, intellectual disability sounds like not being very good at playing chess.

Accept bad news and move on.


Peter’s Book

I decided to have three sections in my book and have a nice cookery book style cheerful cover, so nobody can be embarrassed.  I will not be citing endless complicated research papers. 

I start with all the general issues that are relevant to understanding autism, that do not relate to complicated science.  I finish with a section on how autism can be treated based on applying the research findings to date, what ideas I came up with myself and other people’s ideas shared on this blog. 

Sandwiched in between easy reading section 1 and practical section 3, is a more heavy-going section 2; it is a simplified review of the biology and chemistry that is relevant to autism.  These are things you need to know to make any sense of those tens of thousands of published autism papers, that most people do not know exist.

Section 2 is not going to be a favourite for Roger, but I think he will like sections 1 and 3.  To really judge what to do in the therapy part (section 3), understanding at least part of section 2 is advisable and that is why it has to be there.

It is just like fixing your car, it does help to know a little bit about how it works, before you start tinkering with it.  Even the mechanic at the dealership does not know everything about how it works, but hopefully he knows enough.

If the mechanic cannot fix your car, you just sell it. You may feel a pain in your wallet, but no long-term guilt.

The autism is equivalent is putting your child into an institution, or group home.  You either feel guilty at this point, or later on when something goes terribly wrong. 

I am forever having to fix things - from cars to computers, to solar panels, air conditioners, blocked drains, a leaking swimming pool etc.  Once you realize the "experts" are often not so expert, you engage yourself to solve the problems; or at least tell the expert what you want him to do, like “I found the leak, here it is, now fix it like this”.

Don’t skip section 2, invest time to learn some biology.



Friday, 14 February 2020

Thirst – Too much or too little (Polydipsia and Hypodipsia) Vasopressin and Angiotensin

Today’s post is about both drinking too much water and drinking too little water.

Polydipsia (drinking too much water) is a known cause of death in autism and schizophrenia.  A big part of the reason we talk about autism being a spectrum, is the pioneering work of an English Psychiatrist called Dr Lorna Wing.  Wing outlived her daughter with severe autism, because her daughter Susie developed Polydipsia around the menopause and this caused the sodium level in her blood to fall to the point where her heart stopped beating and she died.  Even though Mum was a (retired) doctor, the condition was not resolved; but Susie’s death should have been avoidable.  Polydipsia is treatable and people should not be dying from it.

Hypodipsia (drinking too little water) can occur in older people, who are neglected in care homes and for a wide range of other reasons.  People with autism treated by the diuretic Bumetanide are at risk of Hypodipsia and indeed this accounts for some of the side effects some people experience.  The other possible side effects of Bumetanide are caused by low levels of potassium in blood. Hypodipsia is also called Adipsia.

Hypodipsia/Adipsia is treatable and much more easily so than Polydipsia; drink more water. Drugs are not used to treat Hypodipsia/Adipsia, therapy relies on modifying behavior.  Drinks can be made more available and more interesting, some kids love drinking from a water fountain or water dispenser. Use a large glass rather than a small glass.  Many people prefer cold water.

Cold water can increase interest in water, but in people who binge drink, cold water is likely to temper their thirst, through a mechanism explained in the paper below called "Thirst".


The Biology of Thirst

There are multiple pathways involved in thirst and so multiple therapies are needed to treat Polydipsia.  The most likely problem relates to Vasopressin, a hormone produced the hypothalamus, a tiny part in the middle of your brain. Vasopressin release is triggered by a hormone called Angiotensin II.

To understand how complex the biology is there are two excellent papers suggested below.


Our bodies are mostly water, and this water is constantly being lost through evaporative and other means. Thus the evolution of robust mechanisms for finding and consuming water has been critical for the survival of most animals. In this Primer, we discuss how the brain monitors the water content of the body and then transforms that physical information into the motivation to drink.


Angiotensin II, or ANG II, is the key hormone driving thirst because it triggers the release of the hormone Vasopressin.

ANP (Atrial natriuretic peptide) hormone should tell you to stop drinking, because your volume of blood is excessive.  This signal must be too weak in people with Polydipsia.

Polydipsia is also a tell-tale sign of the onset of diabetes. Blood sugar rises, your kidneys cannot process the glucose, so the glucose and fluids are excreted as urine making you dehydrated.  You then drink like a fish; hopefully someone notices, otherwise you lose weight, feel tired and finally end up in hospital.

You see in the chart below that eating should activate certain hormones to make you thirsty.







(A) The most potent hormonal stimulus for thirst is angiotensin II (AngII), which is generated when the rate-limiting enzyme renin is secreted by the kidneys in response to hypovolemia or hypotension. Other hormonal stimuli for thirst are secreted by the stomach and pancreas during eating, as well as by the ovaries during pregnancy. Atrial natriuretic peptide, a potent inhibitor of thirst, is secreted by the heart in response to hypertension.
(B) The physiological stimuli that induce secretion of thirst-related hormones include changes in plasma volume and pressure, as well as eating and pregnancy. Decreases in blood volume and pressure increase levels of the dipsogenic hormone AngII, whereas increases in blood volume increase levels of the thirst-inhibiting hormone ANP.

This paper is interesting for those who like details.



Plasma Osmolality

Plasma osmolality measures the body's electrolyte-water balance

Serious electrolyte disturbances, like dehydration (hypodipsia) and overhydration (polydipsia), may lead to cardiac and neurological complications and result in a medical emergency.

Sodium is the main electrolyte found in extracellular fluid and potassium is the main intracellular electrolyte; both are involved in fluid balance and blood pressure control.

The most serious risk to life is from Hyponatremia, low sodium concentration in the blood.

Hyponatremia is the most common type of electrolyte imbalance. It occurs in about 20% of those admitted to hospital and 10% of people during or after an endurance sporting event.

Hypokalemia is the risk to those with autism taking Bumetanide.  The level of potassium circulating in your blood falls below a safe level and blood pressure may rise and abnormal heart rhythm may be experienced. The person will feel lethargic and may experience constipation.






Vasopressin

The hormone Vasopressin has functions within the brain, mediated by 2 types of receptor (Vasopressin receptor 1A and 1B) which relate to behavior (social bonding, aggressive behavior etc).

There is another type of receptor (Vasopressin receptor 2) which is in your kidneys and relates to diuresis and thirst.

The vasopressin system is well known to be dysfunctional in schizophrenia, so we should expect behavioral effects and effects relating to thirst.   There are even measurable irregularities in vasopressin levels in people with schizophrenia.

“It has been found that 69 – 83% of psychiatric polydipsic patients have a diagnosis of schizophrenia, and that 6 –17% of chronic psychiatric patients are polydipsic”

Vasopressin is released within the brain by the action of the hormone Angiotensin II.
Angiotensin II has multiple physiologic effects, including acting in the brain to promote drinking and salt consumption and acting in the periphery to constrict blood vessels and promote water reuptake by the kidneys.

Angiotensin II plays a key role in blood pressure and so there are numerous drugs that reduce Angiotensin II levels.  They are called ACE inhibitors and ARBs.

I did suggest a few years ago that Angiotensin could be an interesting target to treat schizophrenia and some autism.  The reason I was initially interested was the potential immuno-modulatory effect, but Telmisartan in particular has numerous potentially useful effects in autism. 

There are those two old posts:-

Targeting Angiotensin in Schizophrenia and Some Autism


I think it is likely that some sub-types of autism would likely benefit from an ACE inhibitor. As a secondary benefit, it will also reduce any troubling high levels of leptin.

There are other ways to modulate Th1, Th2 and Th17, but if you have elevated Angiotensin Converting Enzyme (ACE), then an ACE inhibitor would appear the logical choice.

How about a clinical trial in adults with Asperger's?


Angiotensin II in the Brain & Therapeutic Considerations


Telmisartan seems to have numerous potentially useful additional effects:


·        Acts as a PPAR gamma agonist, like the glitazone drugs shown effective in autism trials


·        Acts as a PPAR delta agonist, which should activate the impaired PPARδ  PGC-1α signaling pathway, and enhance mitochondrial biogenesis. This should help people with mitochondrial disease and should be evident by increased exercise endurance and, in theory, improved cognitive function.

·        Telmisartan regulates the Bcl-2 cancer gene, implicated in autism


While the effect in autism is complex, Telmisartan is already seen as a potent target for prevention and treatment in human prostate cancer


·        Telmisartan and other ARBs appear to give protection from Alzheimer’s Disease (suggested to be via its effect on PPAR gamma). Perhaps useful for young adults with Down Syndrome, where early onset Alzheimer’s is expected?

·       Telmisartan and other ARBs have a tendency to increase the level of potassium in blood. Up to 10% of people would experience mild hyperkalemia.  For people with autism taking bumetanide, this effect on potassium might actually be helpful. They would need to reduce their potassium supplementation, or might need none at all.


Vasopressin as a behavioral Therapy?

Vasopressin is a target of therapy in both autism and schizophrenia.

The vasopressin system is thought to be dysfunctional in schizophrenia and indeed that life-threatening water intoxication in schizophrenic patients only occurs if it is associated with a concurrent increase in vasopressin secretion.

It is bizarre that the same hormone that controls diuresis also influences social bonding and impulsive and aggressive behavior.  It does explain why in some people all these processes are all disrupted.

It looks like some people need less vasopressin and that can be achieved with an ACE inhibitor. Some people need to tamp down just Vasopressin receptor 1A, encoded by a gene known as the "daring/ruthlessness gene" AVPR1A, which you can with a new drug called Balovaptan.  Some people might want to tamp down just Vasopressin receptor 1B, which may reduce aggressive behaviors.

The research shows that another group of people actually respond to more Vasopressin, this can be achieved with a vasopressin nasal spray.

In the case of our reader Tanya’s son with Polydipsia, I would think an ACE inhibitor may help not only with reducing thirst, but give the Balovaptan effect to his behavior.  My guess is the vasopressin nasal spray from Stanford would have a negative effect on him.

ACE inhibitors are cheap generics with very known safety profiles.  You can achieve the same effect with another class of drugs called angiotensin receptor blockers (ARBs).  It is more a question of which drug produces the least side effects in the specific person. ACE inhibitor and ARBs are use to lower blood pressure.

We will see later that bother ARBs and ACE inhibitors are used in clinical practise to treat Polydipsia.

The recent Vasopressin trials in autism:-

Can manipulating a ‘social’ hormone’s activity treat autism?

Many people with autism have trouble making eye contact, reading the emotions in other faces, and sharing affection. And no drugs are approved to treat such social impairments. Now, results from a small academic clinical trial suggest boosting levels of vasopressin—a hormone active in the brain that’s known to promote bonding in many animals—can improve social deficits in children with autism. But in a confusing twist, a larger, company-sponsored trial that took the reverse approach, tamping down vasopressin’s effects, also found some improvements in adults with autism.
                                                                                                                               
Oxytocin is very similar to Vasopressin, in modifying behavior.



Whereas OT plays a key role both in prosocial behavior and in the central nervous control of stress and anxiety, AVP has primarily  been implicated in male-typical social behaviors, including aggression and pair-bond formation, and in stress-responsiveness.  Although most of the studies conducted thus far on human social behavior have focused on OT, few studies on AVP suggest behavioral effects similar to those found in animal research.  Coccaro and colleagues [33] examined the relationship between cerebrospinal fluid (CSF) AVP and indices of aggression in personality-disordered subjects. The authors found a positive correlation between levels of CSF AVP and life histories of general aggression and aggression against other persons, suggesting an enhancing effect of central AVP in individuals with impulsive aggressive  behavior. Two recent studies examined the effect of intranasal AVP administration on human facial responses related to social  communication. In a first study, Thompson and colleagues [144] examined the effects of 20 IU intranasal AVP on cognitive, autonomic, and somatic responses to emotionally expressive facial stimuli in healthy male students using a placebo-controlled, double-blind design. Whereas AVP did not affect attention toward, or autonomic arousal in response to, emotional facial expressions with different valence (neutral, happy, and angry), the authors did observe selective enhancements of the corrugator supercilii electromyogram (EMG) responses evoked by emotionally neutral facial expressions. Interestingly, subjects of the AVP group yielded magnitudes in response to neutral facial expressions that were similar to the magnitudes of placebo subjects in response to angry facial expressions [144]. In view to the crucial role of this muscle group for species specific agonistic social communication [86], these results suggest that AVP may influence aggression by biasing individuals to respond to emotionally ambiguous social stimuli as if they were threatening or aggressive.

Vasopressin receptor 1A  (encoded by the AVPR1A gene)

The genetic variants of the AVPR1A gene might be related to narcissism and gentle behavior. NatureNews has referred to AVPR1A as the "daring gene". The term "ruthlessness gene" has also been coined by Nature.com

Balovaptan  is a selective small molecule antagonist of the vasopressin receptor 1A, which is under development by Roche for the treatment of autism.  On 29 January 2018, Roche announced that the US Food and Drug Administration (FDA) had granted Breakthrough Therapy Designation for balovaptan in individuals with autism. The FDA granted this based on the results of the adult phase II clinical trial called VANILLA (Vasopressin ANtagonist to Improve sociaL communication in Autism) study.

So, Roche hope that blocking the rector encoded by the “ruthlessness gene” will improve social behavior.  This is reducing the effect of Vasopressin selectively, so not affecting diuresis.

I think you would expect the people who respond well to Balovaptan to also respond well to an ACE inhibitor or ARB, and vice versa.

In my son, an ARB made him want to sing, so I expect Balovaptan would likely have a similar effect.

In my son, increasing oxytocin in the blood, via increasing oxytocin produced in the gut, using the bacteria Lreuteri DSM 17938 did make him more emotional.

Neither of the above two effects were that significant to bother with.


Vasopressin V1b receptor 

 

“Inactivation of the Avpr1b gene in mice (knockout) produces mice with greatly reduced aggression and a reduced ability to recognize recently investigated mice.[13] Defensive behaviour and predatory behaviours appear normal in these knockout mice,[14] but there is evidence that social motivation or awareness is reduced.[15] The AVPR1B antagonist, SSR149415, has been shown to have anti-aggressive actions in hamsters[16] and anti-depressant- and anxiety (anxiolytic)-like behaviors in rats.[17] A single nucleotide polymorphism (SNP) has been associated with susceptibility to depression in humans.[6]

                              

Vasopressin, social cognition and schizophrenia

Introduction: vasopressin, also known as arginine-vasopressin (AVP) or antidiuretic hormone, is mainly synthesized on hypothalamus. It acts on three receptors, of which the centrally expressed V1A and V1B are known to mediate a variety of mental and behavioural effects. In recent years, research on social attachment and cognition in both animal models and humans has also revealed the involvement of vasopressin. Social dysfunction is a key feature of schizophrenia, and in the late 1970’s there were reports associating endogenous vasopressin and psychotic disorders. Indeed, studying the brains of untreated individuals with schizophrenia revealed heightened vasopressin levels, findings which were replicated in plasma levels; the latter were found to normalize after antipsychotic treatment. Methods: searches were undertaken in PubMed and other databases using keywords such as ‘vasopressin’, ‘social cognition’, ‘schizophrenia’ and ‘psychosis’. Results: recent data in human studies suggest that peripheral vasopressin relates to severity of acute psychosis in women with acutely-ill untreated first-episode psychosis, and that the administration of AVP may alter the valence of social stimuli in a sex-dependent manner. In fact, polymorphisms in genes in the AVP pathway have been associated with schizophrenia. The role of the V1A and V1B receptors in the neural regulation of social behaviour has also been studied with several genetic animal models of schizophrenia that reproduce certain aspects of the human disease phenotype. These findings add further evidence that the central vasopressin system may have therapeutics effects on positive and negative symptoms of schizophrenia, probably due to interactions with the glutamatergic and dopaminergic systems. Conclusions: vasopressin plays a significant role in the regulation of social recognition, social communication, and aggression, in integration with the “social behaviour” neural network. Vasopressin regulation is altered in schizophrenia and it has been hypothesized that this might relate to some clinical symptoms and cognition dysfunction. However, other putative factors (e.g., polydipsia, antipsychotics) could account for the results, and the published literature does not yet support a cohesive perspective regarding vasopressin and schizophrenia. Future studies should consider variations in AVP and its receptor genes as potential moderators of the relationship between hormone levels, clinical symptoms, and social cognition.



Psychogenic Polydipsia (PPD) and Hyponatremia in the research

The first thing to note is that the same condition gets called different things.  The fanciest sounding term is Psychogenic polydipsia (PPD), the simplest is Excessive water drinking behavior.  Take your pick, but Google them all.  The best research is the schizophrenia research, as is often the case.


The aim of this study was to determine the incidence of polydipsia in 49 autistic children, and also the influence of psychotropic drugs and residential factors on water drinking behavior, as compared with in 89 mentally retarded children, in schools for mentally handicapped children in Fukui prefecture. Questionnaires were used to detect polydipsia and to assess the severity of the water drinking behavior in the autistic children and mentally retarded children. The incidence of polydipsia in the autistic children tended to be higher (P = 0.074) than that in the retarded children. The severity of water drinking behavior was significantly higher in autism (P = 0.022) than in mental retardation. The majority of the autistic children with polydipsia had been taking no psychotropic drugs. The incidence of polydipsia showed no significant difference between two residential situations, i.e. 'not at home' and 'at home'. The present study suggests that polydipsia or excessive water drinking behavior occurs more often in autism than in mental retardation, possibly due to some intrinsic factor in autism itself.

The present study indicates that polydipsia tends to occur somewhat more often in autism than in mental retardation, and is significantly more severe in autism. Bremner et al. studied 877 mentally handicapped inpatients. In their study, the prevalence of polydipsia in autism was 27.2% (six of 22 cases), compared with 16.3% in the present study. Furthermore, they described a case of autism with fatal water intoxication, who was taking fluvoxamine and chlorpromazine, but did not discuss the role of the drugs as a cause of polydipsia. Autism has been stated to be associated with a hypothalamic-pituitary dysfunction indicated by a blunted-plasma growth-hormone response following the oral administration of l-dopa, an abnormal plasma growth hormone response to insulin-induced hypoglycemia, and a premature or delayed response of growth hormone to clonidine and l-dopa. The blunted growth hormone response exhibited by at least 30% of autistic children to a provocative challenge with l-dopa suggests an alternation of hypothalamic dopamine receptor sensitivity (subsensitivity) in autistic children. The premature response of growth hormone to clonidine and delayed response to l-dopa suggest possible abnormalities of both dopaminergic and noradrenergic neurotransmission in subjects with autism. Furthermore, Hiratani et al. described a case of autism with water intoxication and the episodic release of antidiuretic hormone. The thirst center is said to be located in the hypothalamus. Therefore, a possible factor causing polydipsia in autism may be a hypothalamic–pituitary dysfunction. In 1988, the male case described by Hiratani et al. , who was 19-years old at that time, exhibited a remarkable daily body weight change that was probably due to excessive water drinking. After mild water restriction and intermittent forced water restriction according to the setting of a body weight limit, the daily change became smaller in 1994. We have often observed that autistic children sometimes fiddle with water, or only drink from a single faucet, presumably one manifestation of the restricted interest characteristic of autism. Therefore, preservative tendencies may contribute to compulsive water drinking. In conclusion, in view of the present results, it is possible that the principal cause of polydipsia is some intrinsic factor in autism itself (e.g. a hypothalamic–pituitary dysfunction, restricted interest and activity)


Note in this paper,   Vasopressin  = ADH (antidiuretic hormone)

Psychogenic polydipsia (PPD), a clinical disorder characterized by polyuria and polydipsia, is a common occurrence in inpatients with psychiatric disorders. The underlying pathophysiology of this syndrome is unclear, and multiple factors have been implicated, including a hypothalamic defect and adverse medication effects. Hyponatremia in PPD can progress to water intoxication and is characterized by symptoms of confusion, lethargy, and psychosis, and seizures or death. Evaluation of psychiatric patients with polydipsia warrants a comprehensive evaluation for other medical causes of polydipsia, polyuria, hyponatremia, and the syndrome of inappropriate secretion of antidiuretic hormone. The management strategy in psychiatric patients should include fluid restriction and behavioral and pharmacologic modalities.

In addition to high water intake, risk of hyponatremia is further compounded by impaired water excretion. Impairment in excretion can be due to coexisting ADH increases secondary to stress, nausea, or a syndrome of inappropriate secretion of ADH (SIADH)


Most psychiatric patients with hyponatremia will fit into the final category and will have low plasma osmolality. They will have normovolemia and will lack clinical indicators of altered volume status. PPD and SIADH fit into this category. Most cases of PPD severe enough to cause hyponatremia have a very high volume of intake. These cases have very low levels of ADH and have urine osmolality that is very low (< 100). SIADH by definition has high ADH levels and high urine osmolality (> 500). SIADH, as opposed to the other conditions listed (except salt wasting), has high urine sodium (> 20). High urine sodium occurs in SIADH due to low activation of the RAA system.




Investigation

A comprehensive work-up needs to include a thorough history, physical examination, and routine laboratory tests. Low-cost and high-yield tests for determining diagnosis include the plasma and urine osmolality and plasma and urine sodium. Other tests that may be of benefit include a complete metabolic panel, urinalysis, urea, chest x-ray, and CT head.

Whereas history, serum sodium, and osmolality produce some diagnostic certainty, a water restriction test is the gold standard for diagnosis. A valid test achieves plasma osmolarity greater than 295 mOsm/kg, producing a maximal renal response of ADH in normal individuals. Plasma ADH can be drawn before and after water restriction and then sent if other results are equivocal. With the diagnosis of PPD alone, urine is very dilute prior to water restriction (< 100 mOsm/kg), and plasma ADH is low. The picture can be clouded if there is a corresponding central defect of SIADH and PPD. Then ADH will be elevated (due to SIADH), and the urine will not be maximally dilute. If the defect is renal hypersensitivity to ADH and PPD, the urine still will not be maximally dilute. However, in this setting, ADH could be low or normal (but its increased effect on the kidney would produce an SIADH-like picture). With both comorbid conditions, the added problem of increased renal retention of water will produce hyponatremia more often than the increased intake of PPD alone. In DI, as with PPD, urine would be dilute prior to a water restriction test. ADH levels would depend on whether the defect is central DI (low ADH secretion) or renal DI (low renal response to ADH). Hence, prior to a water restriction test, central DI and PPD can appear similar (low ADH and dilute urine). Although PPD can have low sodium, whereas DI can have high sodium, both can coexist, as exemplified in a case study. After water restriction, PPD alone shows very concentrated urine (> 600 mOsm/L) and high ADH. On the other hand, DI shows urine concentration that rises little even after fluid restriction (< 600 mOsm/L). (Urine concentration can rise somewhat if DI is only a partial defect.) As with PPD, ADH will be elevated in renal DI, but ADH will be low in the case of central DI. Exogenous ADH can be administered immediately following a nondiagnostic water restriction test. In PPD, no increase in urinary concentration occurs after exogenous ADH is administered. Yet in central DI, in which this hormone is lacking, a dramatic increase in urinary concentration will occur. Some impairment in concentrating ability often is present in chronic PPD due to medullary gradient washout and down-regulation of ADH release. These factors can cloud the picture even more. Chronic PPD patients can have maximal urine concentrations closer to 600 mOsm/L instead of the normal range, greater than 800 mOsm/L. (Note: Raising osmolarity with hypertonic saline is best completed by nephrology [0.5 mL/kg for up to 2 hours] if needed due to poor compliance. Raising plasma osmolarity should be avoided in patients strongly suspected of having nephrogenic DI, as it could induce hypernatremia [eg, long-term lithium use]. Drugs listed under “Contributing factors” could interfere with an accurate test.)

Treatment for hyponatremia

See the full paper


Treatment for PPD

Behavioral treatments

Therapeutic fluid restriction is an inexpensive form of treatment; given the higher rates of noncompliance, it may take several days for an effect to be seen in patients with mental illness. Patient weights often are used to determine water intake diurnally. Differences in weight in PPD patients (2.2%) can be much greater than in controls (0.6%) [33]. Reinforcement schedules using tokens to get rewards, as well as removal of these tokens for nonadherence have been used with some success. Most behavioral intervention studies are in inpatients, as they often require close monitoring and substantial time commitment from staff. In extreme cases of nonadherence, patients may require a locked unit away from all water sources. Another novel behavioral outpatient treatment that may suit higher-functioning patients addresses several areas of behavioral change. Therapists used cognitive techniques to address thoughts leading to drinking behavior and then implemented a behavioral program to restrict water intake. They implemented a stimulus control device that included positive reinforcement and coping skills. They followed the patient with weekly visits for 12 weeks and addressed delusions and fears related to drinking excessively. The patient used a record book for time, fluid amount, and situation for each beverage consumed. The patient was given a 500-mL water jug as a stimulus control device and instructed to fill it only six times daily to achieve a goal of less than 3 L for water restriction. The patient used coping skills (substituting ice cubes for drinks, taking small sips, distracting activities). Positive feedback from the therapist and improvement of urinary frequency reinforced fluid restriction.

Drug treatments

Atypical antipsychotic agents have been shown in case reports to have some success in alleviating symptoms of PPD. Clozapine has had effects in the literature in management of PPD but remains unproven in large trials. Low-dose risperidone and olanzapine improved polydipsia in a case report. Their effect potentially stemmed from dopamine receptor regeneration after chronic, typical neuroleptic administration. Kruse et al.  theorized that this reduction in dopamine supersensitivity decreased thirst stimulation. Beta blockers such as propranolol have been found to be effective. Another method of treatment for patients with chronic hyponatremia is demeclocycline, 600 to 1200 mg/d, which directly inhibits ADH action at the level of the distal renal tubules and reduces urine concentration. Demeclocycline is expensive and is associated with nephrotoxicity [15], and it has not been found to be efficacious in double-blind, placebo-controlled trials. Lithium, which works as a direct competitive antagonist of ADH action by inducing nephrogenic DI, is rarely used because its own adverse effects are potentially nephrotoxic and thyrotoxic. A double-blind, placebo-controlled pharmacologic study (crossover design) looked at the use of clonidine, an B-adrenergic blocking agent, and enalapril, an ACE inhibitor, in 14 chronically psychotic, institutionalized patients who suffered from PPD. These medications were administered separately and individually at a dose of clonidine, 0.2 mg orally twice daily, and enalapril, 10 mg orally twice daily. The study found improvement in fluid consumption (determined by calculated urine output and urine osmolality) in approximately 60% of the test subjects who were on either drug, although no behavioral improvement was demonstrated. The study concluded that medications known to affect body water balance might decrease excess fluid intake in some patients with histories of water abuse. ACE inhibitors in other trials as PPD treatment have produced equivocal results. Irbesartan, an angiotensin receptor blocker, was found to be an effective adjunct in the treatment of PPD in a case report of a schizophrenic patient due to a proposed effect of blocking the thirstinducing effect of angiotensin. Recently, newer agents called “aquaretics” that antagonize ADH receptors were developed. These agents have been found to increase free water clearance without directly affecting the handling of tubular sodium. Conivaptan is an aquaretic that recently has been approved by the US Food and Drug Administration for the treatment of euvolemic hyponatremia in hospitalized patients.


Conclusion

I have rather gone into the details in today’s post, because for some people with autism, and more with schizophrenia, it will literally be a matter of life or death.

People do not usually die the first time they binge drink water.

The first medical emergency should set alarm bells ringing, because drinking water to excess is known to be habit forming.  One day your luck may run out.

In today’s post there were a whole range of therapies (ACE Inhibitor, ARB, Propranolol, Clozapine etc) and a list of medical investigations that can be carried out. 



As Agnieszka pointed out to Tanya in the comments recently, a treatable tumor of the Pituitary gland was the cause of death for a well-known Greek girl with autism; the symptom she presented with was Polydipsia. Had the patient had a CT scan of the head, as suggested in the above paper by Dundas, Harris and Narasimhanm, she might be alive today. A tumor there is likely going to affect function of the hypothalamus, where Vasopressin is produced.

I do wonder whether, somewhat paradoxically, treating a person with Polydispsia, with a diuretic might not be a very clever solution.

If you take Bumetanide (or a non-sulfonamide diuretic, for those, like Tanya’s son, with an allergy), you actually get to drink a lot of water, without a problem with low sodium levels (hyponatremia); you just need to eat bananas to maintain potassium levels.  You also might be so preoccupied about dashing urgently for the toilet, you lose all interest in binge drinking water.











Thursday, 22 August 2019

Bumetanide 5mg for Parkinson’s Disease?



I have been asked twice about off-label therapies for Parkinson’s, both times I mentioned Bumetanide, but having rechecked the literature, there is now plenty of supporting data, enough that a clinical trial has now been put in motion in France.

Parkinson’s disease is all about a lack of dopamine and bumetanide is all about making GABA work as inhibitory. You might wonder why is Peter suggesting people to talk to their doctor about giving their elderly parents a diuretic. Well the lack of dopamine goes on to cause a GABA dysfunction, which is treatable and does improve the symptoms of Parkinson’s.

So, Bumetanide will not cure Parkinson’s, but may reduce its severity.

In the case of the last person who asked me, her mother already takes a diuretic for other reasons, so all she would have to do is to switch drugs to Bumetanide. The doctor was only too happy, when given the evidence, to switch her to Bumetanide - a rare victory for common sense. 

What caught my attention was the dosage of Bumetanide used in the published case histories and the concern about polyuria. Polyuria is too much urination. The dose used was 5mg taken all in one go and that is a lot; you would have to run to the bathroom, which might cause falls in people with poor balance.

Since we recently discovered that Azosemide has the same effect on GABA as Bumetanide, but can have a less urgent effect as a diuretic, it may be that Azosemide is a better choice for Grandma with Parkinson’s.  Incontinence can be a feature of Parkinson’s disease.  The ideal drug will be the new one being developed by Neurochloré for autism.


Standard Parkinson’s Drugs

Since most symptoms of Parkinson’s disease (PD) are caused by a lack of dopamine in the brain, many PD drugs are aimed at either temporarily replenishing dopamine or mimicking the action of dopamine. These types of drugs are called dopaminergic medications. They generally help reduce muscle rigidity, improve speed and coordination of movement and lessen tremor.

L-DOPA, the standard treatment for Parkinson’s is actually also used in some people with autism, in particular people with Angelman Syndrome, although it failed in a clinical trial.


Bumetanide for Parkinson’s?

The clinical trial for Parkinson’s will use the standard rating scale (UPDRS) that is very much centered on motor skills. There is a tiny part on memory.

Cognition is affected in Parkinson’s and this might be another area that improves with Bumetanide; but someone has to bother to measure it.

Nobody has measured the effect of Bumetanide on IQ in those with autism, even though the effect can be substantial.

                                  


Four patients suffering from idiopathic PD at the stage of motor fluctuation were included. All of them gave their written informed consent to receive open-label bumetanide. Bumetanide was progressively titrated up to 3 mg/d (once daily) received for a month. After having verified the good tolerability of the treatment, bumetanide was increased to 5 mg/d (once daily) and received for another month. Bumetanide was added to the patient's usual antiparkinsonian treatment that was maintained stable the month before and unchanged during the study. The patients were assessed before and at 1 and 2 months after the initiation of bumetanide.
At each visit, the patient was asked about any side effects having occurred since the last visit. A Unified Parkinson's Disease Rating Scale (UPDRS)19 was performed before and after 2 months of treatment in a practical OFF stage (the patients came in the afternoon, having not taken antiparkinsonian drugs for 4 hours, and confirmed to be in an OFF stage). At the end of the study, the patient was also asked to give a global impression of change compared with baseline.

Case 3

The patient was a 58-year-old man with a 21-year history of
PD. After early development of disabling motor fluctuation and dyskinesia despite an optimized drug treatment, bilateral subthalamic electrodes were implanted 16 years ago for continuous deep brain stimulation (DBS). He got an excellent control of PD motor symptoms. However, after a year of DBS treatment, he started to develop freezing of gait and dysarthria. Despite many attempts of adjusting the treatment (DBS parameters, changes in drug treatment, and physiotherapy), these symptoms remained disabling and even slowly worsened with time. Motor fluctuation and dyskinesia were well controlled by both DBS (left side: case positive, electrode 2 negative, voltage 3.5 V; right side: case positive, electrode 1 negative, voltage 3 V; for both sides: pulse width 60 microseconds, frequency 100 Hz) and drug treatment. The latter consisted of L-DOPA, 1000 mg/d (5 intakes per day); ropinirole, 2 mg/d; and amantadine, 200 mg/d. The freezing of gait was highly disabling.

At home, the patient could walk a few steps alone with a high risk of falls. Most of the time, he was wheelchair bound. After a few days of bumetanide at a dosage of 5 mg/d, the gait dramatically improved. He was able to walk almost 1000 m without any help.

The voice was unchanged. The UPDRS III in the OFF stage was hardly changed (10% improvement), and the UPDRS II in the worst state improved by 15%. The UPDRS II in the best condition was unchanged (21 to 18). The patient and the caregiver assessed the general improvement at 50%. Despite the polyuria and the fatigue, he has decided to continue the bumetanide treatment.
After a few weeks, the improvement of gait was less dramatic but still noticeable.


GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease 

We report that half striatal cholinergic interneurons are dual transmitter cholinergic and GABAergic interneurons (CGINs) expressing ChAT, GAD65, Lhx7, and Lhx6 mRNAs, labeled with GAD and VGAT, generating monosynaptic dual cholinergic/GABAergic currents and an inhibitory pause response. Dopamine deprivation increases CGINs ongoing activity and abolishes GABAergic inhibition including the cortico-striatal pause because of high [Cl]i levels. Dopamine deprivation also dramatically increases CGINs dendritic arbors and monosynaptic interconnections probability, suggesting the formation of a dense CGINs network. The NKCC1 chloride importer antagonist bumetanide, which reduces [Cl]ilevels, restores GABAergic inhibition, the cortico-striatal pause-rebound response, and attenuates motor effects of dopamine deprivation. Therefore, most of the striatal cholinergic excitatory drive is balanced by a concomitant powerful GABAergic inhibition that is impaired by dopamine deprivation. The attenuation by bumetanide of cardinal features of Parkinson’s disease paves the way to a novel therapeutic strategy based on a restoration of low [Cl]i levels and GABAergic inhibition.



Official Title:
A Randomized Double-blind Placebo-controlled Multicenter Proof-of-concept Trial to Assess the Efficacy and Safety of Bumetanide in Parkinson's Disease
Actual Study Start Date  :
April 26, 2019
Estimated Primary Completion Date  :
September 2020
Estimated Study Completion Date  :
August 2021



Conclusion

There is now a long list of neurological conditions that may respond to bumetanide:-

·        Autism
·        Fragile-X Syndrome
·        Down Syndrome
·        Schizophrenia
·        Huntington’s Disease
·        Parkinson’s Disease

In addition, it is obvious that some epilepsy will respond to Bumetanide. The original epilepsy drug from 150 years ago, KBr, has the same mechanism of action, lowering chloride within neurons.

Perhaps higher doses of Bumetanide need to be trialled in autism, 5mg all at once is far higher than what has been used so far in studies.