@Iritu1021
here a promising publication about agmatine:
Evidence for Dietary Agmatine Sulfate Effectiveness in Neuropathies Associated with Painful Small Fiber Neuropathy. A Pilot Open-Label Consecutive Case Series Study
by
Michael L. Rosenberg 1,*,
Vahid Tohidi 1,
Karna Sherwood 1,
Sujoy Gayen 1,
Rosina Medel 1 and
Gad M. Gilad 2,*
1
JFK Neuroscience Institute, JFK Medical Center, 65 James Street, Edison, NJ 08820, USA
2
Research, Gilad&Gilad LLC, Henderson, NV 89015, USA
*
Published: 23 February 2020
Abstract
:
Peripheral neuropathies associated with painful small fiber neuropathy (SFN) are complex conditions, resistant to treatment with conventional medications. Previous clinical studies strongly support the use of dietary agmatine as a safe and effective treatment for neuropathic pain. Based on this evidence, we conducted an open-label consecutive case series study to evaluate the effectiveness of agmatine in neuropathies associated with painful SFN (Study Registry:
ClinicalTrials.gov, System Identifier: NCT01524666).
Participants diagnosed with painful SFN and autonomic dysfunctions were treated with 2.67 g/day agmatine sulfate (AgmaSet® capsules containing G-Agmatine® brand of agmatine sulfate) for a period of 2 months.
Before the beginning (baseline) and at the end of the treatment period, participants answered the established 12-item neuropathic pain questionnaire specifically developed to distinguish symptoms associated with neuropathy and to quantify their severity.
Secondary outcomes included other treatment options and a safety assessment. Twelve patients were recruited, and 11 patients—8 diagnosed with diabetic neuropathy, two with idiopathic neuropathy and one with inflammatory neuropathy—completed the study.
All patients showed improvement in neuropathic pain to a varied extent. The average decrease in pain intensity was 26.0 rating points, corresponding to a 46.4% reduction in overall pain (p < 0.00001).
The results suggest that dietary agmatine sulfate has a significant effect in reducing neuropathic pain intensity associated with painful SFN resistant to treatment with conventional neuropathic pain medications.
Larger randomized placebo-controlled studies are expected to establish agmatine sulfate as a preferred treatment.
1. Introduction
Pain is a strikingly prevalent symptom in our society. It has been estimated that 20.4% of American adults have chronic pain of various etiologies [
1].
Approximately half of these people have neuropathic pain secondary to small fiber neuropathy (SFN) caused by damage of small diameter somatic nerve fibers, which carry pain and temperature information, and small autonomic fibers involved in regulating sympathetic and parasympathetic nervous system functions (e.g., cardiovascular and sweat functions) [
2].
This disorder is associated with many different types of neuropathy including metabolic, autoimmune, inflammatory, infectious and toxic etiologies, as well as with fibromyalgia [
3].
One of the most common causes of peripheral neuropathy associated with SFN is diabetes mellitus. About half of the patients with diabetes mellitus develop peripheral neuropathy, and about one in three of these patients experience neuropathic pain [
1,
2]. Diagnosis in these patients is often missed as the neuropathy may precede clinical evidence of diabetes [
4]. The mechanisms of diabetic neuropathic pain are still not fully clear, with both genetic and environmental factors involved [
5].
Painful SFN is difficult to treat. Currently, the first line of treatment for neuropathic pain involves antidepressants such as serotonin norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) and anticonvulsants (such as gabapentin and pregabalin) [
5,
6,
7,
8].
However, overall, only about 50% pain relief is achieved in less than half of the patients treated with one of these agents, and many discontinue treatment within a few months due to poor tolerability [
9,
10,
11,
12], indicating the need for more effective treatments.
Topical therapies have had mixed results, but lidocaine, capsaicin and amitriptyline show promise [
13]. Opioids have been used, but their use is controversial and may not be effective [
14].
Because monotherapy in general is unsatisfactory, attempts were made to utilize combination therapies. Treatment with an anticonvulsant combined with an antidepressant, both at lower doses, may be more efficacious than either alone [
15]. This also indicates that the combination treatment targets more mechanisms that may underlie the complex disease pathology [
16].
There clearly is an urgent unmet need to develop safer and more effective therapies for neuropathies and neuropathic pain. To this end, we sought to assess the effectiveness of the neuroprotective dietary ingredient agmatine [
17,
18,
19] in treating neuropathies associated with painful small fiber neuropathy.
Substantial preclinical evidence suggests the utility of agmatine in treating a wide spectrum of complex nervous system diseases [
20,
21]. Previous clinical trials showed that oral agmatine sulfate treatment is safe and effective in reducing neuropathic pain and improving health-related quality of life in lumbar disc-associated radiculopathy (sciatica) [
22,
23]. These clinical studies served as a proof-of-concept for using dietary agmatine as a nutraceutical for neuropathies.
Agmatine, decarboxylated arginine [(NH2(CH2)4NH2C(NH= )NH], is a ubiquitous molecule found in low amounts in a wide variety of plant-, fish- and animal-derived foodstuffs [
24].
Additionally, gastrointestinal (GI) bacteria produce agmatine and the significant concentrations of agmatine found in the GI tract implicate microbial production as the main source of systemic agmatine [
25,
26].
Animal studies demonstrated that exogenous agmatine sulfate, the commonly used salt form of agmatine, is absorbed in the GI tract and then rapidly (within minutes) distributed throughout the body, including the brain [
20]. In humans, ingested agmatine is readily absorbed and eliminated unmetabolized by the kidneys, with an apparent blood half-life of about 2 h [
27].
Agmatine is principally metabolized into urea and putrescine, the diamine precursor of polyamines, which are essential for the viability of nerve cells [
28]. Additionally, agmatine can also be oxidized, resulting in the formation of agmatine-aldehyde, which may be toxic and secreted by the kidneys [
29]. This latter route is tissue specific, being significant in some tissues [
26], but minor in others [
30,
31], and apparently negligible in the central nervous system [
25].
It is postulated that, like a ‘molecular shotgun’, agmatine exerts its salutary effects by modulating multiple molecular targets including: several neurotransmitter receptors and receptor ionophores; key ionic channels and membrane transporters; nitric oxide (NO) formation; polyamine metabolism; protein ADP-ribosylation and hence signaling pathways; matrix metalloproteases (MMPs); enzymes implicated in nerve cell death and neuropathic pain; and advanced glycation end (AGE)-product formation, a process involved in the pathology of diabetes and neurodegenerative diseases [
20].
Conceivably, agmatine may modulate its molecular targets both at the peripheral and the central nervous system levels.
A concerning caveat of the previous clinical trials was that after the short two-week treatment period, the effectiveness of agmatine treatment gradually dissipated [
23]. This suggested that treatment should continue for as long as symptoms persist.
Reports from hundreds of people who use agmatine sulfate treatment on their own cognizance (unpublished observations), support the implications of these clinical trials. Namely, the treatment is effective in alleviating symptoms in several types of neuropathy, including diabetic neuropathy and idiopathic neuropathy—which are known to involve small fiber pathology [
3]—and that in order to maintain effectiveness, agmatine treatment must continue for as long as symptoms persist.
Therefore, in the present study, we set up a study to assess the effectiveness of a two-month long oral agmatine sulfate treatment for patients diagnosed with neuropathies associated with painful SFN.
