https://www.pharmacytimes.com/news/...aytime-sleepiness-in-patients-with-narcolepsy
Maybe this could help with fatigue in MECFS?
Maybe this could help with fatigue in MECFS?
FDA Approves Pitolisant for Daytime Sleepiness in Patients with Narcolepsy
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pattismith
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"Pitolisant, a first-in-class medication, is a selective histamine 3 (H₃) receptor antagonist/inverse agonist that increases the synthesis and release of histamine, a wake-promoting neurotransmitter in the brain. Pitolisant is administered orally once daily in the morning when a patient wakes up."
pattismith
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Histamine: neural circuits and new medications
Thomas E Scammell, Alexander C Jackson, Nicholas P Franks, William Wisden, Yves Dauvilliers
Sleep, Volume 42, Issue 1, January 2019, zsy183, https://doi.org/10.1093/sleep/zsy183
Abstract
Histamine was first identified in the brain about 50 years ago, but only in the last few years have researchers gained an understanding of how it regulates sleep/wake behavior.
We provide a translational overview of the histamine system, from basic research to new clinical trials demonstrating the usefulness of drugs that enhance histamine signaling.
The tuberomammillary nucleus is the sole neuronal source of histamine in the brain, and like many of the arousal systems, histamine neurons diffusely innervate the cortex, thalamus, and other wake-promoting brain regions.
Histamine has generally excitatory effects on target neurons, but paradoxically, histamine neurons may also release the inhibitory neurotransmitter GABA.
New research demonstrates that activity in histamine neurons is essential for normal wakefulness, especially at specific circadian phases, and reducing activity in these neurons can produce sedation.
The number of histamine neurons is increased in narcolepsy, but whether this affects brain levels of histamine is controversial. Of clinical importance, new compounds are becoming available that enhance histamine signaling, and clinical trials show that these medications reduce sleepiness and cataplexy in narcolepsy.
Statement of Significance
Histamine is a key wake-promoting neurotransmitter, and new medications that modulate histamine signaling are now under development. This paper reviews new research, ranging from basic science to recent clinical trials that highlight the normal functions of histamine neurons and how drugs that enhance histamine signaling may improve the symptoms of a variety of sleep disorders, including narcolepsy with cataplexy.
Introduction
Towards the end of World War 1, an epidemic of encephalitis lethargica spread across Europe, and the Viennese neurologist Constantin von Economo observed that most patients with severe sleepiness had inflammation and lesions in the posterior hypothalamus (PH) [1].
He proposed that the PH contains wake-promoting neurons, and in the last decades, researchers have identified several, specific neuronal populations in the PH that are crucial for wake, including neurons producing histamine, orexin (hypocretin), GABA, and glutamate.
The histaminergic system is now receiving increased attention as much has been learned in the last few years about the normal functions of this system and how its dysfunction may contribute to clinical sleep disorders [2, 3].
This article summarizes a symposium presented at the Sleep 2018 meeting focusing on the normal functions of the histamine system, how daily variations in activity of the histaminergic neurons help drive circadian rhythms of sleep and wake, and how new compounds that enhance histamine signaling improve wake and cataplexy in narcolepsy.
Overview of Histamine Signaling
Histamine is a small, monoamine signaling molecule.
Most clinicians are familiar with the functions of histamine in the periphery where it regulates immune responses and itch when released by mast cells and basophils, and how it regulates acid secretion when released by enterochromaffin-like cells of the stomach.
However, in the brain, histamine mainly functions as a wake-promoting and rapid eye movement (REM) sleep–suppressing neurotransmitter, with additional effects on feeding and endocrine function [4].
In the brain, the tuberomammillary nucleus (TMN) is the sole neuronal source of histamine.
The TMN is a loose constellation of 75–120000 neurons (in humans) scattered around the third ventricle and mammillary body in the ventral PH [5, 6].
The TMN neurons project widely throughout the brain, innervating and generally exciting neurons from the cortex to the brainstem.
Histidine decarboxylase (HDC) converts the amino acid histidine to histamine which is then packaged into synaptic vesicles by the vesicular monoamine transporter (VMAT2) [7] (Figure 1).
When nerve terminals are depolarized, histamine is released into the synaptic cleft and binds to histamine receptors which are located presynaptically or postsynaptically.
In contrast to other monoaminergic neurotransmitters such as serotonin and dopamine, there appears to be no high-affinity reuptake system for histamine, but some histamine may be taken up by the low-affinity organic cation transporter 3 which is expressed by astrocytes [8].
Instead, most histamine is cleared from the extracellular space by conversion to the inactive tele-methylhistamine (tmHA) by histamine N-methyltransferase (HNMT) [4]
Histamine can act through four distinct G protein-coupled histamine receptors (H1-H4), and the H1, H2, and H3 receptors are all expressed in brain [4].
The H1 receptor depolarizes postsynaptic neurons and is crucial for the wake-promoting effects of histamine. In fact, over half of all over-the-counter sleep aids contain H1 receptor antagonists such as diphenhydramine or doxylamine.
The H2 receptor may mediate aggression as mice with high histamine levels due to a lack of HNMT show more aggressive behaviors such as chasing and biting another male mouse, and these behaviors are strongly suppressed by a H2 receptor antagonist [9].
The H3 receptor is an inhibitory autoreceptor akin to 5HT1a or D2 receptors on serotonin- and dopamine-synthesizing neurons, respectively; when histamine tone is high, histamine can bind to the H3 receptor on TMN neurons, hyperpolarizing and reducing the activity of these cells [10].
The H3 receptor is also expressed as a heteroreceptor on a variety of neurons, including cells that make dopamine, serotonin, norepinephrine, acetylcholine, GABA, and glutamate.
Thus, drugs that interfere with H3 receptor signaling such as pitolisant can block its inhibitory effects, increasing brain levels of histamine, as well as levels of serotonin, norepinephrine, dopamine, and possibly other neurotransmitters [11].
Strictly speaking, most H1 and H3 receptor “antagonists” are actually inverse agonists; H1 and H3 receptors are constitutively active, even in the absence of histamine, and drugs such as diphenhydramine and pitolisant reduce this constitutive activity
Thomas E Scammell, Alexander C Jackson, Nicholas P Franks, William Wisden, Yves Dauvilliers
Sleep, Volume 42, Issue 1, January 2019, zsy183, https://doi.org/10.1093/sleep/zsy183
Abstract
Histamine was first identified in the brain about 50 years ago, but only in the last few years have researchers gained an understanding of how it regulates sleep/wake behavior.
We provide a translational overview of the histamine system, from basic research to new clinical trials demonstrating the usefulness of drugs that enhance histamine signaling.
The tuberomammillary nucleus is the sole neuronal source of histamine in the brain, and like many of the arousal systems, histamine neurons diffusely innervate the cortex, thalamus, and other wake-promoting brain regions.
Histamine has generally excitatory effects on target neurons, but paradoxically, histamine neurons may also release the inhibitory neurotransmitter GABA.
New research demonstrates that activity in histamine neurons is essential for normal wakefulness, especially at specific circadian phases, and reducing activity in these neurons can produce sedation.
The number of histamine neurons is increased in narcolepsy, but whether this affects brain levels of histamine is controversial. Of clinical importance, new compounds are becoming available that enhance histamine signaling, and clinical trials show that these medications reduce sleepiness and cataplexy in narcolepsy.
Statement of Significance
Histamine is a key wake-promoting neurotransmitter, and new medications that modulate histamine signaling are now under development. This paper reviews new research, ranging from basic science to recent clinical trials that highlight the normal functions of histamine neurons and how drugs that enhance histamine signaling may improve the symptoms of a variety of sleep disorders, including narcolepsy with cataplexy.
Introduction
Towards the end of World War 1, an epidemic of encephalitis lethargica spread across Europe, and the Viennese neurologist Constantin von Economo observed that most patients with severe sleepiness had inflammation and lesions in the posterior hypothalamus (PH) [1].
He proposed that the PH contains wake-promoting neurons, and in the last decades, researchers have identified several, specific neuronal populations in the PH that are crucial for wake, including neurons producing histamine, orexin (hypocretin), GABA, and glutamate.
The histaminergic system is now receiving increased attention as much has been learned in the last few years about the normal functions of this system and how its dysfunction may contribute to clinical sleep disorders [2, 3].
This article summarizes a symposium presented at the Sleep 2018 meeting focusing on the normal functions of the histamine system, how daily variations in activity of the histaminergic neurons help drive circadian rhythms of sleep and wake, and how new compounds that enhance histamine signaling improve wake and cataplexy in narcolepsy.
Overview of Histamine Signaling
Histamine is a small, monoamine signaling molecule.
Most clinicians are familiar with the functions of histamine in the periphery where it regulates immune responses and itch when released by mast cells and basophils, and how it regulates acid secretion when released by enterochromaffin-like cells of the stomach.
However, in the brain, histamine mainly functions as a wake-promoting and rapid eye movement (REM) sleep–suppressing neurotransmitter, with additional effects on feeding and endocrine function [4].
In the brain, the tuberomammillary nucleus (TMN) is the sole neuronal source of histamine.
The TMN is a loose constellation of 75–120000 neurons (in humans) scattered around the third ventricle and mammillary body in the ventral PH [5, 6].
The TMN neurons project widely throughout the brain, innervating and generally exciting neurons from the cortex to the brainstem.
Histidine decarboxylase (HDC) converts the amino acid histidine to histamine which is then packaged into synaptic vesicles by the vesicular monoamine transporter (VMAT2) [7] (Figure 1).
When nerve terminals are depolarized, histamine is released into the synaptic cleft and binds to histamine receptors which are located presynaptically or postsynaptically.
In contrast to other monoaminergic neurotransmitters such as serotonin and dopamine, there appears to be no high-affinity reuptake system for histamine, but some histamine may be taken up by the low-affinity organic cation transporter 3 which is expressed by astrocytes [8].
Instead, most histamine is cleared from the extracellular space by conversion to the inactive tele-methylhistamine (tmHA) by histamine N-methyltransferase (HNMT) [4]
Histamine can act through four distinct G protein-coupled histamine receptors (H1-H4), and the H1, H2, and H3 receptors are all expressed in brain [4].
The H1 receptor depolarizes postsynaptic neurons and is crucial for the wake-promoting effects of histamine. In fact, over half of all over-the-counter sleep aids contain H1 receptor antagonists such as diphenhydramine or doxylamine.
The H2 receptor may mediate aggression as mice with high histamine levels due to a lack of HNMT show more aggressive behaviors such as chasing and biting another male mouse, and these behaviors are strongly suppressed by a H2 receptor antagonist [9].
The H3 receptor is an inhibitory autoreceptor akin to 5HT1a or D2 receptors on serotonin- and dopamine-synthesizing neurons, respectively; when histamine tone is high, histamine can bind to the H3 receptor on TMN neurons, hyperpolarizing and reducing the activity of these cells [10].
The H3 receptor is also expressed as a heteroreceptor on a variety of neurons, including cells that make dopamine, serotonin, norepinephrine, acetylcholine, GABA, and glutamate.
Thus, drugs that interfere with H3 receptor signaling such as pitolisant can block its inhibitory effects, increasing brain levels of histamine, as well as levels of serotonin, norepinephrine, dopamine, and possibly other neurotransmitters [11].
Strictly speaking, most H1 and H3 receptor “antagonists” are actually inverse agonists; H1 and H3 receptors are constitutively active, even in the absence of histamine, and drugs such as diphenhydramine and pitolisant reduce this constitutive activity
Histamine's role in wakefulness has been known for a long time (and how antihistamine allergy medications cause drowsiness).
So this drug is not surprising. But i doubt it will do much for ME patients.
Narcolepsy is caused because Orexin is not being produced. Orexin is like a conductor in an orchestra, it modulates wakefulness by modulating virtually all the common neurochemicals (serotonin, dopamine, acetylcholine, histamine and many more).
So if antihistamines make you drowsy a drug that activates them would be useless because you obviously don't need it.
That said many drugs affect more then their intended target so if someone with ME tries it and it helps them i would be glad to be pleasantly surprised.
So this drug is not surprising. But i doubt it will do much for ME patients.
Narcolepsy is caused because Orexin is not being produced. Orexin is like a conductor in an orchestra, it modulates wakefulness by modulating virtually all the common neurochemicals (serotonin, dopamine, acetylcholine, histamine and many more).
So if antihistamines make you drowsy a drug that activates them would be useless because you obviously don't need it.
That said many drugs affect more then their intended target so if someone with ME tries it and it helps them i would be glad to be pleasantly surprised.
Rufous McKinney
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What would it mean to have more histimine in the body if one is dealing with issues like MCAS and/or mast cell issues....?
So Provigil is the current drug for narcolepsy....it works thru some other mechanism but they don't really know what...possibly the dopamine pathway.
It takes me a very long time to wake up...I must not be producing...much histamine in the morning.
There have been various theories and most somehow involve Dopamine but its not really understood conclusively.
More likely your brain is not producing Orexin yet. Without it you can be awake but you typically feel groggy or brain fogged or like you could fall asleep again.
Rufous McKinney
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.... I can often just keep going back to sleep in the mornings...almost indefinately. I rarely ever want to get up. If I'm a bit PEM, its even more intense. I sleep 9-10 hours. Of course, whatever this sleep is, is non-refreshing. After around 2 pm, incredibly sleepy again...often sets in.
Its really hard to say what is causing it, tiredness can come from low cortisol or high GABA or hypothyroid or dozens of other possibilities.
pattismith
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I may not try this drug if I was suffering from MCAS.
Are you sure low Orexin isn't involved in ME/CFS or even in a subset?
Certainly there is a ME/CFS subset with subclinical seronegative neurosjogren (possibly associated with low Mannose Binding lectin), and in a study on fatigue in SS patients:
"The main findings of this study indicate a functional network in which several IL-1β-related molecules in CSF influence fatigue in addition to the classical clinical factors of depression and pain.
The neuropeptide Hcrt1 seems to participate in fatigue generation, but likely not through the IL-1 pathway. "
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pattismith
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@Alvin2
Another paper from Bardsen published september 2020 (maybe from the same study)
Interleukin-1β, heat shock protein 90α, and hypocretin-1 in chronic fatigue
Methods:
To explore mechanism of fatigue, a cohort of 71 patients with primary Sjögren’s syndrome were investigated.
CSF samples where available from 49 patients.
A method based on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was developed for measurements of Hcrt1.
Hcrt1 was measured in CSF samples from 22 healthy subjects and 9 patients with narcolepsy type 1.
Results: Measures of HSP32, -60, -72, and -90α in plasma revealed that the concentrations of HSP90α were significantly higher in pSS patients with high fatigue versus low fatigue. A tendency toward higher concentrations of HSP72 was observed in patients with high fatigue compared to patients with low fatigue.
....
Analysis of IL-1β related proteins (IL-1Ra, IL-1RII, and S100B), IL-6, and Hcrt1 in CSF demonstrated that IL-1Ra showed significant association with fVAS scores together with the clinical variables BDI scores and pain scores. The relationship of the biochemical variables was explored in PCA, and two significant components appeared: Variables related to IL-1β activity dominated the first component while in the second component there was a negative association between IL-6 and Hcrt1. Fatigue was introduced as an additional variable in a second model. In this PCA, fVAS scores were associated with the first component as was the IL-1β related variables. In addition, the second PCA model revealed a third component that showed a negative relationship between Hcrt1 and fatigue.
Conclusions:
I) HSP90α and to a lesser degree HSP72 in blood may possibly be parts of a fatigue inducing mechanism.
II) The LC-MS/MS method with high selectivity and accuracy revealed considerably lower levels of Hcrt1 in CSF than previously reported.
III) IL-1β signaling is a primary driver in fatigue. Several other proteins and molecules interact with IL-1β in a complex network, in which several cell types (neurons, microglia, and astrocytes) probably participate.
IV) Hcrt1 also influences fatigue, but probably through another pathway than the IL-1 route.
Another paper from Bardsen published september 2020 (maybe from the same study)
Interleukin-1β, heat shock protein 90α, and hypocretin-1 in chronic fatigue
Methods:
To explore mechanism of fatigue, a cohort of 71 patients with primary Sjögren’s syndrome were investigated.
CSF samples where available from 49 patients.
A method based on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was developed for measurements of Hcrt1.
Hcrt1 was measured in CSF samples from 22 healthy subjects and 9 patients with narcolepsy type 1.
Results: Measures of HSP32, -60, -72, and -90α in plasma revealed that the concentrations of HSP90α were significantly higher in pSS patients with high fatigue versus low fatigue. A tendency toward higher concentrations of HSP72 was observed in patients with high fatigue compared to patients with low fatigue.
....
Analysis of IL-1β related proteins (IL-1Ra, IL-1RII, and S100B), IL-6, and Hcrt1 in CSF demonstrated that IL-1Ra showed significant association with fVAS scores together with the clinical variables BDI scores and pain scores. The relationship of the biochemical variables was explored in PCA, and two significant components appeared: Variables related to IL-1β activity dominated the first component while in the second component there was a negative association between IL-6 and Hcrt1. Fatigue was introduced as an additional variable in a second model. In this PCA, fVAS scores were associated with the first component as was the IL-1β related variables. In addition, the second PCA model revealed a third component that showed a negative relationship between Hcrt1 and fatigue.
Conclusions:
I) HSP90α and to a lesser degree HSP72 in blood may possibly be parts of a fatigue inducing mechanism.
II) The LC-MS/MS method with high selectivity and accuracy revealed considerably lower levels of Hcrt1 in CSF than previously reported.
III) IL-1β signaling is a primary driver in fatigue. Several other proteins and molecules interact with IL-1β in a complex network, in which several cell types (neurons, microglia, and astrocytes) probably participate.
IV) Hcrt1 also influences fatigue, but probably through another pathway than the IL-1 route.
If it is involved then we would have symptoms of narcolepsy.
That said we have no disease mechanism for ME nor do we even have a definitive test for ME so we can't even be sure we all have the same disease.
pattismith
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I don't, but I tryed Betahistine, an old H3R antagonist. It fixed my headache and I felt less sleepy