Local Anesthetics (Lidocaine, Novocaine, etc.)

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Local Anesthetics (Lidocaine, Novocaine, etc.)

Postby sixwings » Sun Aug 11, 2013 2:47 am

The evidence mounts that Lidocaine and Novocaine can have powerful therapeutic effects on ALS because they potentiate both the GABA-A and glycine effectors that are known to be deficient in ALS patients. They are especially good at activating the glycine receptors which would make them particular effective against limb-onset ALS. Both anesthetics also have powerful anti-inflammatory properties similar to sevoflurane.
Central effects of systemic lidocaine mediated by glycine spinal receptors: an iontophoretic study in the rat spinal cord
Gabriele Biellaa, Maria Luisa SotgiuCorresponding author contact information, Istituto di Fisiopatologia e Terapia del Dolore, Facolta' di Medicina, Universitàdi Milano, Milan Italy, Istituto di Neuroscienze e Bioimmagini, CNR, Milan Italy

Abstract

The objective of this investigation was to demonstrate the possible interactions of systemic lidocaine (lido) with inhibitory receptors in the spinal cord. In the lumbar dorsal horn of anesthetized and curarized rats, 60 physiologically identified, wide dynamic range (WDR) neurons, were recorded extracellularly. Glutamate, glycine and its selective antagonist, strychnine, were iontophoretically applied onto the neurons either singularly or concurrently. The effects of systemic lido on the drug-induced frequency changes and the interaction with the glycine receptors, using strychnine as a probe, were studied. It was consistently found that (i) lido (3–4 mg/kg) inhibited the excitatory responses to iontophoretic glutamate, (ii) this inhibition was significantly antagonized by concurrent iontophoretic strychnine, (iii) iontophoretic glycine induced comparable glutamate inhibition that was reversed by strychnine. In contrast, no effect on glutamate-induced excitations was observed when lido was applied by micropressure or a different local anesthetic was systemically administered. The results suggest that central inhibitory effects of lido could by mediated by spinal strychnine-sensitive glycine receptors, activated by lido itself or possibly by its glycine residue-bearing metabolites.

Source: ScienceDirect
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Re: Local Anesthetics (Lidocaine, Novocaine, etc.)

Postby sixwings » Sun Aug 11, 2013 2:57 am

Note that, in the study below, lidocaine = xylocaine and procaine = novocaine. I believe that lidocaine and novocaine will have a major beneficial impact on both bulbar and limb-onset ALS at low concentrations, possibly on a par with sevoflurane. Here is a something that some will find astonishing. I predict that direct local injections of either lidocaine or novocaine in the spinal column starting from the neck down will result in spectacular remissions of symptoms. The beauty of local anesthetics is that there is no need for general anesthesia.
The effects of the local anesthetics lidocaine and procaine on glycine and gamma-aminobutyric acid receptors expressed in Xenopus oocytes.
Hara K, Sata T.

Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, Yahatanishiku, Kitakyushu, Japan. kojihara@med.uoeh-u.ac.jp

Abstract
BACKGROUND:
The voltage-dependent sodium channel is the primary site of action for local anesthetics (LAs). Although systemically administered low-dose LAs have been shown to exert antihyperalgesic effects, the molecular targets responsible for these effects are not fully known and their functional effects on inhibitory neurotransmitter receptors associated with antinociception have not been sufficiently studied.

METHODS:
We examined the effects of lidocaine and procaine (0.1 microM to 3 or 10 mM) on recombinant human alpha1 glycine, alpha1beta2gamma2S gamma-aminobutyric acid type A (GABA(A)), and rho1 GABA(C) receptors expressed in Xenopus laevis oocytes, using a two-electrode voltage-clamp system. We also evaluated the effects of LAs on two mutant glycine receptors, alpha1(S267C) and alpha1(S267Q), in an effort to clarify the interaction between LAs and glycine receptors.

RESULTS:
Low concentrations of both lidocaine and procaine enhanced glycine receptor function, whereas high concentrations of lidocaine and procaine inhibited glycine receptor function. Lidocaine (10 microM) produced a significant leftward shift in the glycine concentration-response curve, indicating an increase in the apparent affinity for glycine. This enhancement was not altered in the mutant receptors. Both lidocaine and procaine at high concentrations inhibited GABA(A) receptor currents, whereas neither lidocaine nor procaine affected GABA(C) receptor function.

CONCLUSIONS:
Lidocaine and procaine enhanced glycine receptor function at low concentrations and inhibited the functions of glycine and GABA(A) receptors at high concentrations. The mechanism of the LA-induced enhancement of glycine receptor function probably differs from that of general anesthetics. These findings may explain the pharmacological effects of LAs, such as antinociception and convulsion.

Source:http://www.ncbi.nlm.nih.gov/pubmed/17513637
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Re: Local Anesthetics (Lidocaine, Novocaine, etc.)

Postby sixwings » Sun Aug 11, 2013 3:39 am

Lidocaine, like propofol and sevoflurane, also has very strong anti-inflammatory properties as seen in the following study from the Shanghai Jiaotong University School of Medicine. Immune system modulation is an absolute must in ALS.

Lidocaine attenuates proinflammatory cytokine production induced by extracellular adenosine triphosphate in cultured rat microglia.
Su D, Gu Y, Wang Z, Wang X.

Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dong Fang Road, Shanghai, 200127, China.

Abstract
BACKGROUND:
Our previous studies demonstrated that intrathecal lidocaine treatment could produce prolonged reversal of established hyperalgesia or allodynia, both induced by chronic constriction injury. Indeed, intrathecal lidocaine treatment remarkably suppressed the activation of p38 mitogen-activated protein kinase (MAPK) in hyperactive microglia. In the present study we suggest that lidocaine may act directly on the microglia and attenuate the release of cytokines.

METHODS:
We assessed the influence of lidocaine on the levels of phospho-p38 MAPK, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and intracellular calcium triggered by extracellular adenosine triphosphate (ATP) in cultured rat microglia. Our experimental methods included Western blot, real-time reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and calcium imaging.

RESULTS:
We found that lidocaine (in a dose-dependent manner) significantly attenuated p38 MAPK activation triggered by 1 mM ATP, by inhibiting the transcription of 3 cytokine messenger RNAs and causing a decrease in their respective protein concentrations (TNF-alpha, IL-1beta, and IL-6, P < 0.05, vs. the ATP group). SB203580, an antagonist of P38, attenuated ATP-activated elevation in protein levels of TNF-alpha, IL-1beta, and IL-6 in the microglia. The high level of intracellular calcium ([Ca(2+)]i) that is induced by ATP was decreased by the addition of 10 mM lidocaine (P < 0.05 vs. the ATP group).

CONCLUSIONS:
These findings indicate that lidocaine can directly act on microglia. Lidocaine, by inhibiting the increase of intracellular calcium, also inhibited p38 MAPK activation and attenuated the production of proinflammatory cytokines (including TNF-alpha, IL-1beta, and IL-6), which were triggered by extracellular ATP in cultured rat microglia.

Source: http://www.ncbi.nlm.nih.gov/pubmed/20686009
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Re: Local Anesthetics (Lidocaine, Novocaine, etc.)

Postby sixwings » Mon Aug 12, 2013 1:07 pm

The more I think about it and the more I research it, the more I am convinced that general anesthesia for ALS is neither needed nor desirable, given the alternatives. For one, general anesthesia is expensive because it requires the involvement of a qualified (read, highly paid) anesthesiologist and a visit to an adequately equipped hospital or clinic. Second, each visit can cost several thousand dollars. This is, of course, out of the question for most patients. I am currently researching an inexpensive method that will allow ALS patients to use local anesthetics in their own home without the help of paid professionals. My wife and I are experimenting with some exciting stuff but I cannot reveal what it is at this time. Coming soon.
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Re: Local Anesthetics (Lidocaine, Novocaine, etc.)

Postby sixwings » Mon Aug 19, 2013 12:47 pm

Here is more evidence of lidocaine's anti-inflammatory properties.
Lidocaine inhibits secretion of IL-8 and IL-1beta and stimulates secretion of IL-1 receptor antagonist by epithelial cells.
Lahav M, Levite M, Bassani L, Lang A, Fidder H, Tal R, Bar-Meir S, Mayer L, Chowers Y.

Department of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Israel.

Abstract

Lidocaine and related local anaesthetics have been shown to be effective in the treatment of ulcerative colitis (UC). However, the mechanisms underlying their therapeutic effect are poorly defined. Intestinal epithelial cells play an important role in the mucosal inflammatory response that leads to tissue damage in UC via the secretion of pro-inflammatory cytokines and chemokines. The aim of this study was to evaluate the direct immunoregulatory effect of lidocaine on pro-inflammatory cytokine and chemokine secretion from intestinal epithelial cells. HT-29 and Caco-2 cell lines were used as a model system and treated with lidocaine and related drugs. The expression of IL-8, IL-1beta and the IL-1 receptor antagonist (RA) were assessed by ELISA and quantification of mRNA. In further experiments, the effect of lidocaine on the secretion of IL-8 from freshly isolated epithelial cells stimulated with TNFalpha was tested. Lidocaine, in therapeutic concentrations, inhibited the spontaneous and TNFalpha-stimulated secretion of IL-8 and IL-1beta from HT-29 and Caco-2 cell lines in a dose-dependent manner. Similarly, suppression of IL-8 secretion was noted in the freshly isolated epithelial cells. Other local anaesthetics, bupivacaine and amethocaine, had comparable effects. Lidocaine stimulated the secretion of the anti-inflammatory molecule IL-1 RA. Both the inhibitory and the stimulatory effects of lidocaine involved regulation of transcription. The results imply that the therapeutic effect of lidocaine may be mediated, at least in part, by its direct effects on epithelial cells to inhibit the secretion of proinflammatory molecules on one hand while triggering the secretion of anti-inflammatory mediators on the other.

Source: http://www.ncbi.nlm.nih.gov/pubmed/11876744
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Re: Local Anesthetics (Lidocaine, Novocaine, etc.)

Postby sixwings » Mon Aug 19, 2013 4:24 pm

Lidocaine is such a powerful anti-inflammatory agent that 5 of 6 lidocaine-infused rabbits infected with peritonitis died because lidocaine suppressed their immune system's normal inflammatory response. This is the kind of drug that should work wonders in ALS patients. But don't take it if you have an infection. Question is, given lidocaine's powerful anti-inflammatory properties, why has it never been tried on ALS patients? Even a study of lidocaine's effect on ALS mice would have made sense. Why has it never been done? Because ALS researchers are either sleeping on the job or there is no money in it for them. That's why. Most patents on anesthetics have expired. This is why all ASL patients got from them is Rilutek (what a nasty joke that is) and they are still dying a slow agonizing death after all these years and all this money. We are dealing with heartless monsters. This sh!t must be cleaned up, folks. It's inhuman.
Lidocaine Inhibits Granulocyte Adherence and Prevents Granulocyte Delivery to Inflammatory Sites

By Rob Roy MacGregor, Richard E. Thorner, and David M. Wright

Abstract

Incubation of whole blood or PMNs in saline with 1O^2 or 1O^4 molar concentrations of lidocaine causes a reversible inhibition of granulocyte adherence. A single bolus dose of lidocaine, 2.5 mg/kg, given intravenously inhibits adherence in rabbits by 55.4% at 5 min, with return to normal by 15 min after dose. When the bolus dose is followed by an infusion of lidocaine. 0.3 mg/kg/min, adherence stays at less than 50% of control values for the duration of the infusion. Plasma from animals given lidocaine inhibits adherence of normal granulocytes. and the inhibiting factor is removed completely by dialysis of the plasma against modified Hanks’ solution for 24 hr. Lidocaine infusion prevents delivery of PMNs to sites of inflammation: normal rabbits given sterile peritonitis developed exudates in 6 hr containing a mean of 19.280 PMN/cu mm compared to 388/cu mm in lidocaine-infused rabbits (2% of control). By comparison. methylprednisolone-treated animals developed exudate PMN counts 40% of control. When peritonitis was induced by staphylococci, 5 of 6 lidocaine-infused animals died, whereas only 1 of 6 noninfused animals died. Pathologic examination of experimentally infected skin showed that control animals developed an inflammatory reaction characterized by edema and pronounced PMN infiltration 1 2 hr after intracutaneous injection of live staphylococci. In contrast, biopsies from lidocaine-infused animals showed only edema, with virtually no PMN infiltration. Thus, lidocaine inhibits granulocyte adherence in vitro and in vivo and markedly suppresses delivery of PMNs to sites of inflammation.

[...]

The profound antiinflammatory effect of lidocaine that we have shown raises several questions. First, are patients who are receiving lidocaine infusions for arrhythmias at increased risk of developing and being unable to control bacterial infections? A brief retrospective review of such patients in our medical intensive care unit did not demonstrate an unanticipated frequency of infection, but most patients were infused for only 12-36 hr, perhaps insufficient time for the development of a spontaneous infection. Second, in addition to the known antiarrhythmic effects of lidocaine, could the drug’s inhibition of inflammation around areas of myocardial infarction contribute to its effectiveness in controlling arrhythmias in this disease? Finally, could the antiinflammatory properties of lidocaine infusion be used in some of the inflammatory reactions that cause destruction rather than protection in the host’s tissues, such as vasculitis, arthritis, and other autoimmune reactions? A therapeutic trial of lidocaine infusion in these conditions when other antiinflammatory therapy is failing would seem rational on the basis of our findings.

Source: http://bloodjournal.hematologylibrary.org/content/562/203.full.pdf

Emphasis mine. Note that PMN stands for polymorphonuclear leukocytes, which are abnormally elevated in the brains and spinal cords of ALS patients.
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Re: Local Anesthetics (Lidocaine, Novocaine, etc.)

Postby sixwings » Mon Aug 19, 2013 4:52 pm

As seen below, monocyte chemoattractant protein-1 (MCP-1) is a known biomarker in the cerebrospinal fluid of ALS patients.
Production of monocyte chemoattractant protein-1 in amyotrophic lateral sclerosis.
Baron P, Bussini S, Cardin V, Corbo M, Conti G, Galimberti D, Scarpini E, Bresolin N, Wharton SB, Shaw PJ, Silani V.

Department of Neurological Sciences, Dino Ferrari Center, University of Milan Medical School, IRCCS Ospedale Maggiore Policlinico, Via S. Sforza 35, 20122 Milan, Italy. pierluigi.baron@unimi.it

Abstract

The presence of activated microglia in the spinal cord of amyotrophic lateral sclerosis (ALS) patients is usually accompanied by inflammatory biochemical changes, but these are largely unexplored. Monocyte chemoattractant protein-1 (MCP-1) is critical for recruitment of inflammatory cells of monocytic lineage after inflammation or injury to the central nervous system. MCP-1 concentrations were measured by an enzyme-linked immunosorbent assay in the cerebrospinal fluid (CSF) and the serum of 27 patients with ALS and 30 patients with noninflammatory neurological diseases. In ALS, circulating MCP-1 levels were significantly increased in the serum and particularly in the CSF. Immunoreactivity for MCP-1 in ALS spinal cord was detected mostly in astrocytes but also in microglia, neurons, and within the vasculature of the cord. Our findings suggest a role for MCP-1 as an important molecular mediator of the injury response in ALS.

Source: http://www.ncbi.nlm.nih.gov/pubmed/15962273

Unsurprisingly, lidocaine inhibits the production of MCP-1, as seen in this study:
Lidocaine Attenuates Monocyte Chemoattractant Protein-1 Production and Chemotaxis in Human Monocytes: Possible Mechanisms for Its Effect on Inflammation

Abstract

The recruitment and activation of peripheral bloodmonocytes are potentially critical regulatory events for the control of inflammation. Increased levels of monocyte chemoattractant protein (MCP)-1 have been reported in several inflammatory disorders. In this study, we examined the effect of lidocaine on lipopolysaccharidestimulated MCP-1 secretion and MCP-1 induced chemotaxis in a human monocytic cell line, THP-1. Lidocaine inhibited lipopolysaccharide-induced MCP-1 production as well as messenger RNA expression in a dosedependent manner. Furthermore, we demonstrated that lidocaine suppressed MCP-1-induced chemotaxis and peak cytosolic-free calcium in THP-1 cells. These results suggest that lidocaine may modulate MCP-1 production and MCP-1-induced activation in inflammatory cells.

Source: http://www.anesthesia-analgesia.org/content/97/5/1312.full.pdf
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