semagacestat fails to treat Alzheimer's

Yesterday, Gina Kolata in the NYT wrote that a large PHARMA is abandoning its drug semagacestat that decreases the production of amyloid in patients with Alzheimer's. IMHO I believe that this was a failed concept from the start.  Alll neurodegenerative diseases (multiple sclerosis, ALS, Huntington's, Parkinson's and many many more) occur when the central nervous system is stressed and reacts excessively. The answer for all these conditions is the same, rein in this excessive response. Treat these conditions at the source..I wrote this about Parkinson's years ago. I think PURSOR could work equally as well on other neurodegenerative disorders. It is at least worth a try.

Elsewhere, researchers at NIH have declared that mood altering drugs appear to partially protect the brain against neurodegenerative diseases  I am glad to see that mainstream medicine is coming around to this axiom.

All mood altering drugs influence the immune system (immunomodulate)

Sleep Apnea: An immune disorder

The conventional wisdom is that sleep apnea (SA), a condition that more than 5% of the American population and is associated with markedly increased risk of heart attacks and strokes, is a mechanical disease. Those with it are frequently overweight with short and thick necks. However, there is increasing evidence that SA is another immune disorder associated with inflammation. Inflammation and sleep apnea I strongly believe that PURSOR would remit SA. Do look at this review: serotonin rx of same

Severe allergies and celiac disease respond to treatment and didn't come back

This a recent review of celiac disease immunology. I have found that the combination of dopamine and serotonin precursors utilizing the PURSOR protocol has astounding therapeutic capabilities. Dopamine and 5-HT have reciprocal action, the former promotes Th1 and reigns in Th2 and the latter does the contrary. The PURSOR protocol seems to have the ability to restore Th1/Th2 balance. A patient with celiac disease did respond. Interestingly, she presented with life-threatening idiopathic anaphylaxis which not only also had total recovery but has been in remission for more than 10 years. Apparently, celiac and immediate hypersensitivity disorders do coexist.

In simpler words. Immune diseases are divided into allergies and autoimmune. Celiac disease is an autoimmune. Severe allergies lead to allergic disasters (anaphylaxis). This patient had both types of illness, responded to treatment and has never had a recurrence.

Could TH1 and TH2 diseases coexist? Evaluation of asthma incidence in children with coeliac disease, type 1 diabetes, or rheumatoid arthritis: a register study

Mechanisms of Glucocorticoid Receptor Action in Noninflammatory and Inflammatory Cells

Glucocorticoids differ from serotonin. The latter suppresses the inflammatory response (T_h1 driven) but augments T_h2. Glucocorticoids suppress either or both responses. Therefore, if you wish to manage an immune condition, the use of PURSOR^TM is far more specific than using the GLU sledgehammer. This is an extremely well-written article and, therefore, deserves a Frank McLynn award.

"Glucocorticoids exert profound and diverse physiological effects on a wide range of cell types. Produced and released from the adrenal cortex in response to stress, levels of glucocorticoids are under the control of the hypothalamic–pituitary–adrenal axis.

Glucocorticoids participate in numerous physiological processes such as glucose homeostasis; protein, lipid, and carbohydrate metabolism; development; neuorobiology; and programmed cell death. Glucocorticoids exert potent immunosuppressive and anti-inflammatory actions in a cell type–specific manner largely through the interruption of cytokine-mediated pathways. These anti-inflammatory actions are also complemented by the ability of glucocorticoids to induce apoptosis in many cells including thymocytes, blood monocytes, and peripheral T cells.

As a class of drugs, glucocorticoids are among the most widely prescribed in the world for the treatment of immune and inflammatory diseases, including asthma, rheumatoid arthritis, ulcerative colitis, and allergic rhinitis. They are also a component of many chemotherapy regimens for the treatment of leukemias, lymphomas, and myelomas because of their role in the induction of apoptosis. However, long-term use of glucocorticoids has been limited by adverse side effects ranging from suppression of the hypothalamic–pituitary axis and growth retardation to osteoporosis, in addition to the development of glucocorticoid resistance. These undesired side effects of glucocorticoids are hypothesized to occur mainly through activation of gene transcription, whereas the beneficial anti-inflammatory effects of glucocorticoids involve mainly mechanisms of gene repression.

Understanding the molecular basis of glucocorticoid-induced side effects requires an understanding of their actions on homeostatic signaling processes in all cell types. In this review, we discuss the basic cellular and molecular signaling mechanisms of glucocorticoid action during noninflammatory and inflammatory situations."

Mechanisms of Glucocorticoid Receptor Action in Noninflammatory and Inflammatory Cells -- Necela and Cidlowski 1 (3): 239 -- Proceedings of the American Thoracic Society:

Neuroinflammation and Neurodegenerative Diseases: One Condition One Therapy

Does neuroinflammation fan the flame in neurodegenerative diseases?:

Microglial activation is the response to multiple traumatic insults whether triggered by infection, trauma or hypoxia. This common stress response can become self-feeding and can become chronic. The authors postulate that the particular presentation (PD, ALS, Huntingtons, etc) depends on genetic variation of environmental variability.

I believe and have so believed for more than a decade that all these conditions can be remitted by blocking the perpetuation of microglial activation by the use of dopamine and seotonin precursor therapy (PURSOR).

Summary

It is becoming increasingly evident that neuroinflammation plays a crucial role in the development and progression of many neurodegenerative diseases. Glia and in particular microglia are central to mediating the effects of neuroinflammation. While neuroinflammation and microglia provide an attractive therapeutic target in the treatment and prevention of neurodegenerative diseases investigators face several challenges ahead (Appendix 2) which must be overcome before one can advocate in favor of large-scale anti-inflammatory trials in the clinic. Some of these include developing approaches to improve the access of drugs to CNS tissue as well as developing therapies that maintain or optimize the beneficial effects of neuroinflammation while eliminating or minimizing its detrimental effects.

Key Observations

1. Neurodegenerative diseases are associated with signs of chronic neuroinflammation
2. A variety of initiating triggers (some as yet unknown) associated with the different neurodegenerative disorders converge at a common intersection point - activation of microglia.
3. While the initial neuroimmune response may be aimed at limiting the disease process, chronic neuroinflammation driven by persistent microglia activation is likely to aid in the progression of the disease and the hastening of neuronal demise.
4. How the inflammatory response affects specific neuronal and glial populations and contributes to specific neurodegenerative diseases remains a critical and unanswered question

Critical challenges involved in developing neuroprotective anti-inflammatory therapeutic strategies

1. Identify internal and external factors that trigger chronic neuroinflammatory responses, with a focus on how acute immune responses become chronic.
2. Identify inflammatory mediators that compromise survival of specific neuronal populations.
3. Develop therapeutic compounds that cross the blood brain barrier (BBB)
4. Selectively target destructive inflammatory mediators without compromising beneficial survival-promoting effects and overall immune function.
5. Develop inclusion and exclusion criteria for human subjects to be enrolled in clinical trials taking into account their immune status."

A cute introduction to the immune system from Vimeo

Lyme Arthritis: Current Concepts and a Change in Paradigm

The ability of B. burgdorferi, the spirochete responsible for Lyme Arthritis, to avoid clearance by the immune system may be attributed in part to an inadequate innate immune response upon infection. However, innate cells such as monocytes, macrophages, and dendritic cells display a vigorous response against borrelial infection and play a major role in the activation of the adaptive immune response against the spirochete. Despite these efforts, though, arthritis still develops in a significant number of patients infected with B. burgdorferi. It appears that the robust response elicited by monocytes, macrophages, and dendritic cells against the spirochete may be viewed as insufficient in early infection but excessive in the later stages. Paradoxically, in mounting such a strong defense against the organism, these cells may inadvertently be contributing to the induction of Lyme arthritis.

Lyme disease is associated with a chronic inflammatory bias with excessive T helper 1 cytokines. This condition has responded to PURSOR therapy in a Rhode Island lady who had not responded to antibiotic treatment at Yale under the care of my medical school classmate Allen Steere who has deservedly earned a reputation in this field.

Lyme Arthritis: Current Concepts and a Change in Paradigm

Why 5-HTP and the PURSOR Protocol May Improve Parkinson's Disease Rx

Summary

The inevitable progression of Parkinson’s Disease (PD) is unresponsive to treatment. Dopamine (DA) agonists may promote the underlying neurodegenerative process. Combined 5‑hydroxytryoptophan (5-HTP), the immediate precursor of serotonin (5-HT), and levodopa therapy should block DA induced PD progression because DA and 5­­-HT have countervailing actions in the immune system. While DA promotes inflammatory Th1 cytokines, neurotoxicity and neural apoptosis (programmed cell death), 5-HT promotes anti-inflammatory Th2 cytokines, acts as a neuroprotectant, and is antiapoptotic. Combined DA and 5-HT precursor therapy (PURSOR) with levodopa and 5-HTP suspensions titrated by taste, already associated with unprecedented partial remissions in another neurodegenerative disorder, amyotrophic lateral sclerosis, should markedly improve symptomatic Parkinson’s treatment, decrease the incidence of levodopa toxicity, and, by restoring Th1/Th2 balance and putatively decreasing QUIN induced excitatory neurotoxicity, alleviate or even halt the progression of PD.

Seven Reasons:

A.      The buccal mucosal route permits both precursors to pass through the blood-brain barrier directly without first passing through the general circulation. Since this markedly diminishes the decarboxylation of either precursor prior to its entering the CNS, carbidopa is no longer necessary.
B.       Maximum therapeutic levodopa doses to assuage nigrostriatal DA deficiency should now be realized promptly and safely. Prior to the proprietary PURSOR protocol, the responsible clinician, concerned that increasing the levodopa dose could at any time induce severe adverse effects, knowing that the only clinical endpoints were the onset of levodopa toxicity or PD clinical improvement, recognizing there was no procedure to ameliorate levodopa toxicity except the passage of time, increased levodopa dosage slowly and gingerly. One can assume that many a PD patient never achieves maximal levodopa intervention because of this understandable concern. The PURSOR protocol permits one to increase levodopa more acutely since the administration of 5-HTP reverses the toxic symptoms of levodopa excess
C.      The neurotoxicity associated with PD and increased by levodopa administration presumptively can be reversed by the increase of 5-HT, a glutamate antagonist and a neuroprotectant with the ability to diminish excessive QUIN toxicity and cellular apoptosis associated with hyperstimulation.
D.      The PURSOR protocol, by promoting CNS 5-HT levels, should decrease or ablate the Th1>Th2 imbalances associated with autoimmune disorders and suppress or halt the underlying neurodegenerative PD process.
E.       The unprecedented and rapid partial remissions noted by patients with ALS treated with the PURSOR protocol strongly suggests that 5-HT is modulating the EAA-associated neurotoxicity endemic in neurodegenerative disorders.
F.      Approximately 15% of DA treated PD patients develop obsessive/compulsive disorders. The addition of 5-HT to the regimen potentially ablates this as a problem.
G.       PD destroys both dopaminergic and serotoninergic cells. If for no other reason, the joint administration of both 5-HT and DA precursors makes empiric sense.

(Full text) More Formal Presentation

Introduction to Immune disorders and their treatment with PURSOR

GLOSSARY

In my opinion, the neurotransmitters dopamine (DA) and serotonin (5-HT) are the primary regulators of life. These two similar substances control in a reciprocal fashion not only human beings but also all other animal species. More than two millennia ago both the Chinese and the Greeks recognized that "balance is health; imbalance is illness and pain." In summary, DA greatly resembles the Yang and 5-HT the Yin. Western medicine started to recognize this antipodal action in 1957.

Multiple articles in the current medical literature discuss imbalance in the T helper cells. T helper cells are simplistically divided into two major divisions, Th1 and Th2 cells. Harvard's Dr. Kimball summarizes this far better than I can. I would strongly recommend this link. Let's focus on the two major components.

• The cellular immune system (Th1 driven, Th2 opposes) (increased by DA, suppressed by 5-HT) goes to work when it senses a foreign cell threatening our well-being. These foreign cells can arise from the outside, from viruses and bacteria whose survival inside our body is at the expense of our health or even our survival. This cellular system can also be activated to fight our own cells that have mutated and threaten us with cancer and similar diseases.

• The humoral system (Th2 driven, Th1 opposes) (increased by 5-HT, suppressed by DA)   becomes activated when it senses that there are foreign proteins threatening to overwhelm us. The humoral system produce antibodies that can safely engulf these foreign chemicals and dispose of them safely.

Interestingly enough, each system controls the other. The cellular system reins in the humoral and the humoral keeps the cellular in control. Th1 suppresses Th2 and Th2 suppresses Th1

Unfortunately, when we are diseased, one or the other system can break out of control and start to overact. If the cellular system excessively dominates, doing its job too well, It starts to attack our own good cells and autoimmune diseases such as lupus, rheumatoid arthritis, psoriasis and Lyme disease ravage our bodies. In the brain, the cellular system running amok can cause neurodegenerative conditions such as Lou Gehrig/s disease or multiple sclerosis that rot our brain and spinal cord.. This is Th1 excess.

Th2 excess conditions, when the humoral system is too vigilant and the body reacts to unimportant levels of foreign protein, are allergic in nature. Asthma, allergic shock, hives and food allergies can cause us woe.Th2 excess.

By the year 2002 there had been already 200 patent applications to bring such imbalances under control. Those folks were looking to create a harmonious equality of the humoral and cellular immune systems or, in fancy terms, a Th1/Th2 balance. The treatments covered in these patent applications shared, in most cases, three qualities. They were toxic, expensive, and ineffectual.

Fortunately, It is apparent when one reads the medical literature that brain dopamine and serotonin controls the Th1/Th2 ratio and can restore it to balance.

• Dopamine increases TH1 and controls Th2 
• Serotonin increases Th2 and diminishes Th1. 

Why not, you may ask, don't we correct the Th1/Th2 imbalance and remit illness by increasing the brain levels of dopamine and serotonin?

The administration of the PURSOR protocol which permits our own brain to bring dopamine and serotonin into balance permits us to control either immune system that is overeager and bring us into balance. It is not surprising that when we bring the Th1 and Th2 under control that autoimmune, neurodegenerative, and allergic conditions can remit and stay away as long as the treatment is given.

Immunodeficient conditions are a bit, just a bit, more complicated. In such conditions both the cellular and humoral systems are damaged. I believe, however, with the restoration of proper dopamine and serotonin levels, these conditions  will also improve. I have seen a phenomenal success with an AIDS patient, but that is another story.

Technical section below. Click on title to get full text.

The Restoration of ImmuneTh1/Th2 Balance with Combined Dopamine and Serotonin Agonists

Pietr Hitzig, M.D.
phitz96@gmail.com 
443 231-6240

The YIN YANG (DA/5-HT) duality

the Monoamines Dopamine and Serotonin are Antipodal in Nature.

Yin (陰 or 阴 "shady place, north slope, south bank (river); cloudy, overcast"; Japanese: in or on; Korean: 음, Vietnamese: âm) qualities are characterized as soft, slow, substantial, water, cold, conserving, tranquil, gentle, and corresponds to the night.

Yang (陽 or 阳 "sunny place, south slope, north bank (river), sunshine"; Japanese: yō; Korean: 양, Vietnamese: dương) qualities are characterized as hot, fire, restless, hard, dry, excitement, non-substantial, rapidity, and corresponds to the day.

Dopamine is Yang while Serotonin is Yin

DA and 5-HT have been antipodal in their activities for more than a billion years. Here, for example, the prostostomes, who according to Dawkins, went their particular way and parted from us 500M years ago are using the monoamines to decide whether to move or not.

The effect of dopamine on [snail] command neurons is significantly reduced in the presence of serotonin. In the presence of dopamine, the efficacy of serotonin action on the size of the response elicited in command neurons is reduced. Based on the data obtained, it was concluded that the interrelation of dopamine and serotonin concentrations could be the basis for the formation of behavioral choice in snails

Dopamine is the Reward Neurotransmitter

When the cortex has received and processed a sensory stimulus indicating a reward, it sends a signal announcing this reward to a particular part of the midbrain–the ventral tegmental area (VTA)–whose activity then increases. The VTA then releases dopamine not only into the nucleus accumbens, but also into the septum, the amygdala, and the prefrontal cortex.The nucleus accumbens then activates the individual’s motor functions, while the prefrontal cortex focuses his or her attention.
These regions are connected by what is called the pleasure or reward bundle. In neuroanatomical terms, this bundle is part of the medial forebrain bundle (MFB), whose activation leads to the repetition of the gratifying action to strengthen the associated pathways in the brain.
First described by James Olds and Peter Milner in the early 1960s, the MFB is a bundle of axons that originates in the reticular formation, crosses the ventral tegmental area, passes through the lateral hypothalamus, and continues into the nucleus accumbens as well as the amygdala, the septum, and the prefrontal cortex.
The MFB is composed of ascending and descending pathways, including most of the pathways that use monoamines as a neurotransmitter. The mesocorticolimbic dopaminergic system is one of its main components.

But Serotonin inhibits Reward and Stops Excessive Behavior

Serotonin plays a major role in the behavioural inhibition system (BIS).

This system was identified by Henri Laborit in the early 1970s. It is associated with the septo-hippocampal system, the amygdala, and the basal nuclei. It receives inputs from the prefrontal cortex and transmits its outputs via the noradrenergic fibres of the locus coeruleus and the serotininergic fibres of the medial Raphe nuclei.
The BIS is activated when both fight and flight seem impossible and the only remaining behavioural option is to submit passively. The pathological consequences of this behavioural inhibition have provided an understanding of how destructive chronic stress can be to people’s health.

Substantial evidence suggests that the functional status of the mesocorticolimbic dopamine (DA) system originating in the ventral tegmental area is under a phasic and tonic inhibitory control by the 5-HT system that acts by stimulating 5-HT(2C) receptor subtypes. Serotonin within the nucleus accumbens may play an important role in mediating incentive motivation by modulating dopaminergic neurotransmission.

Several hypotheses regarding physiopathology of major psychiatric diseases exist. Attention has been focused on cerebral monoaminergic systems, the dysfunction of which is thought to underlie various aspects of their symptomatology. There are reports describing the involvement of serotonergic and dopaminergic systems in the mechanism of action of psychotropic drugs. This article reviews current knowledge on interaction between 5-hydroxytryptamine (5-HT), acting at 5-HT2C receptors in the central dopamine (DA) systems. Since 90s, a growing body of behavioural, neurochemical and electrophysiological evidence from animal studies have demonstrated a clear role for 5-HT2C receptors in modulation of activity of dopamine neurones.

The blockade of serotonin receptors potentiates behavioral effects of dopamine agonists. It is concluded that central serotonin may play an inhibitory role, antagonistic to that of catecholamines

Increasing 5-HT activity in the nucleus accumbens inhibits dopamine-dependent behaviour, and further indicate that activation of 5-HT(1B) receptors is particularly important in this regard

T helper cell I and II Duality of the Immune System are under the Control of Dopamine and Serotonin

Devoino wrote seminal articles in the early 1980s that dealt with the monoamines regulation of the immune system. She wrote prior to the discovery of the T helper cell and its differentiation into Th1 and Th2 subsets. However, interpolating her articles forward she was clearly stating that DA promotes Th1 and suppresses Th2 cytokines and serotonin does the converse. She wrote in 1984:

The monoamine systems take part in the mechanisms of immunomodulation: the dopaminergic one accelerates and the serotoninergic system inhibits the development of immune response, the final result being determined by their interaction.

The combined use of a combined dopamine and serotonin agonist protocol (CODAS) such as PURSOR can titrate DA and serotonin into sufficiency and balance and remit addictive craving and immune disorders.