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==Overview==
==Overview==
Future investigational therapies of Lyme disease is directed towards decreasing the pro inflammatory immune process and decreasing the Th1 upregulation. Studies have also been conducted to test the role of neurohormones in neuropsychiatric complications of Lyme's disease.  
Future and investigational therapies of [[Lyme disease]] are directed towards decreasing the pro-inflammatory [[immune]] process and decreasing Th1 [[upregulation]]. Studies have also been conducted to test the role of [[Neurohormone|neurohormones]] in [[neuropsychiatric]] complications of [[Lyme disease]]. Other therapies including [[hyperbaric oxygen therapy]], [[Antifungal medication|antifungal medications]] and use of bee venom are also under investigation.
 
==Future or Investigational Therapies==
==Future or Investigational Therapies==
====Inflammation====
====Psycho-neuroimmunological therapies====
* Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct pro-[[inflammatory]] immune process. 
* A developing hypothesis is that the [[chronic]] secretion of [[Stress (medicine)|stress]] [[hormones]] (specifically [[glucocorticoids]] and [[catecholamines]]) as a result of ''[[Borrelia afzelii|Borrelia]]'' infection may reduce the effect of [[neurotransmitters]], or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones.<ref>{{cite journal |author=Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP |title=Cytokine dysregulation, inflammation and well-being |journal=Neuroimmunomodulation |volume=12 |issue=5 |pages=255-69 |year=2005 |pmid=16166805 |doi=10.1159/000087104}}</ref><ref>{{cite journal |author=Calcagni E, Elenkov I |title=Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases |journal=Ann. N. Y. Acad. Sci. |volume=1069 |issue= |pages=62-76 |year=2006 |pmid=16855135 |doi=10.1196/annals.1351.006}}</ref>
* This pro-inflammatory process is a [[cell-mediated immunity]] and results in Th1 upregulation. 
* This process is mediated via the [[hypothalamic-pituitary-adrenal axis]].  
* These studies have shown a significant decrease in [[cytokine]] output of (IL-10), an upregulation of [[Interleukin-6]] (IL-6), [[Interleukin-12]] (IL-12) and IFN-gamma and disregulation in [[TNF-alpha]] predominantly.<ref>{{cite journal |author=Shin JJ, Glickstein LJ, Steere AC |title=High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory lyme arthritis |journal=Arthritis Rheum. |volume=56 |issue=4 |pages=1325-35 |year=2007 |pmid=17393419 |doi=10.1002/art.22441}}</ref>
* Additionally, [[tryptophan]], a precursor to [[serotonin]], appears to be reduced within the [[CNS]] in a number of patients with [[Lyme disease]].<ref>{{cite journal |author=Gasse T, Murr C, Meyersbach P, ''et al'' |title=Neopterin production and tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme encephalopathy |journal=European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies |volume=32 |issue=9 |pages=685-9 |year=1994 |pmid=7865624}}</ref>  
* Host immune response to infection results in increased levels of IFN-gamma in the serum and lesions of Lyme disease patients that correlate with greater severity of disease.
* [[Antidepressants]] have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory [[cytokine]] processes, specifically on the regulation of Interferon gamma and [[IL-10]], as well as [[TNF-alpha]] and [[IL-6]] through a [[Psychoneuroimmunology|psycho-neuroimmunological]] process.<ref>{{cite journal |author=Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M |title=Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio |journal=Journal of clinical psychopharmacology |volume=21 |issue=2 |pages=199-206 |year=2001 |pmid=11270917}}</ref>
* IFN-gamma alters gene expression by [[endothelium|endothelia]] exposed to ''B. burgdorferi'' in a manner that promotes recruitment of [[T cells]] and suppresses that of [[neutrophils]].
* Antidepressants have also been shown to suppress Th1 upregulation.<ref>{{cite journal |author=Diamond M, Kelly JP, Connor TJ |title=Antidepressants suppress production of the Th1 [[cytokine]] interferon-gamma, independent of monoamine transporter blockade |journal=European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology |volume=16 |issue=7 |pages=481-90 |year=2006 |pmid=16388933 |doi=10.1016/j.euroneuro.2005.11.011}}</ref>
* Suppressors of cytokine signaling (SOCS) [[proteins]] are induced by cytokines, and T cell receptor can down-regulate cytokine and T cell signaling in [[macrophages]].
* These studies warrant investigation of antidepressants for use in a psycho-neuroimmunological approach for optimal [[pharmacotherapy]] of antibiotic refractory Lyme patients.
* It is hypothesized that SOCS are induced by IL-10 and ''B. burgdorferi'' and its [[lipoproteins]] in macrophages, and that SOCS may mediate the inhibition of IL-10 by concomitantly elicited cytokines. 
* IL-10 is generally regarded as an anti-inflammatory cytokine, since it acts on a variety of cell types to suppress production of proinflammatory mediators.
* Researchers are also beginning to identify [[microglia]] as a previously unappreciated source of inflammatory mediator production following infection with ''B. burgdorferi''.
* Such production may play an important role during the development of cognitive disorders in Lyme neuroborreliosis.
* This effect is associated with induction of [[NF-κB|nuclear factor-kappa B]] (NF-KB) by ''Borrelia''.<ref>{{cite journal |author=Rasley A, Anguita J, Marriott I |title=Borrelia burgdorferi induces inflammatory mediator production by murine microglia |journal=J. Neuroimmunol. |volume=130 |issue=1-2 |pages=22-31 |year=2002 |pmid=12225885}}</ref><ref>{{cite journal |author=Rasley A, Tranguch SL, Rati DM, Marriott I |title=Murine glia express the immunosuppressive cytokine, interleukin-10, following exposure to Borrelia burgdorferi or Neisseria meningitidis |journal=Glia |volume=53 |issue=6 |pages=583-92 |year=2006 |pmid=16419089 |doi=10.1002/glia.20314}}</ref>
* Deregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage in ''Borrelia'' infected patients.<ref>{{cite journal |author=Ramesh G, Philipp MT |title=Pathogenesis of Lyme neuroborreliosis: mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of astrocytes to Borrelia burgdorferi lipoproteins |journal=Neurosci. Lett. |volume=384 |issue=1-2 |pages=112-6 |year=2005 |pmid=15893422 |doi=10.1016/j.neulet.2005.04.069}}</ref>
* IL-6 and TNF-Alpha cytokines produce fatigue and malaise, two of the more prominent symptoms experienced by patients with chronic Lyme disease.<ref>{{cite web |url=http://www.columbia-lyme.org/flatp/treatment.html |title=Welcome to Lyme Disease Research Studies |accessdate=2007-08-23 |format= |work=}}</ref><ref>{{cite journal |author=Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP |title=The pathophysiologic roles of interleukin-6 in human disease |journal=Ann. Intern. Med. |volume=128 |issue=2 |pages=127-37 |year=1998 |pmid=9441573}}</ref>
* IL-6 is also significantly indicated in cognitive impairment.<ref>{{cite journal |author=Wright CB, Sacco RL, Rundek TR, ''et al'' |title=Interleukin-6 is associated with cognitive function: the Northern Manhattan Study |journal= |volume=15 |issue=1 |pages=34-38 |year=2006 |pmid=16501663 |doi=10.1016/j.jstrokecerebrovasdis.2005.08.009}}</ref>
 
====Neuroendocrine====
* A developing hypothesis is that the chronic secretion of [[Stress (medicine)|stress]] [[hormones]] as a result of ''Borrelia'' infection may reduce the effect of [[neurotransmitters]], or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones, specifically [[glucocorticoids]] and [[catecholamines]], the major stress hormones. <ref>{{cite journal |author=Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP |title=Cytokine dysregulation, inflammation and well-being |journal=Neuroimmunomodulation |volume=12 |issue=5 |pages=255-69 |year=2005 |pmid=16166805 |doi=10.1159/000087104}}</ref><ref>{{cite journal |author=Calcagni E, Elenkov I |title=Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases |journal=Ann. N. Y. Acad. Sci. |volume=1069 |issue= |pages=62-76 |year=2006 |pmid=16855135 |doi=10.1196/annals.1351.006}}</ref>
* This process is mediated via the [[Hypothalamic-pituitary-adrenal axis]].  
* Additionally [[Tryptophan]], a precursor to [[serotonin]] appears to be reduced within the CNS in a number of infectious diseases that affect the brain, including Lyme.<ref>{{cite journal |author=Gasse T, Murr C, Meyersbach P, ''et al'' |title=Neopterin production and tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme encephalopathy |journal=European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies |volume=32 |issue=9 |pages=685-9 |year=1994 |pmid=7865624}}</ref>
* Researchers are investigating if this neurohormone secretion is the cause of neuro-psychiatric disorders developing in some patients with borreliosis.<ref>{{cite journal |author=Zajkowska J, Grygorczuk S, Kondrusik M, Pancewicz S, Hermanowska-Szpakowicz T |title=New aspects of pathogenesis of Lyme borreliosis |language=Polish |journal=Przegla̧d epidemiologiczny |volume=60 Suppl 1 |issue= |pages=167-70 |year=2006 |pmid=16909797}}</ref>
* [[Antidepressants]] acting on serotonin, [[norepinephrine]] and [[dopamine]] receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of IFN-gamma and IL-10, as well as TNF-alpha and IL-6 through a [[Psychoneuroimmunology|psycho-neuroimmunological]] process.<ref>{{cite journal |author=Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M |title=Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio |journal=Journal of clinical psychopharmacology |volume=21 |issue=2 |pages=199-206 |year=2001 |pmid=11270917}}</ref>
* Antidepressants have also been shown to suppress Th1 upregulation.<ref>{{cite journal |author=Diamond M, Kelly JP, Connor TJ |title=Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade |journal=European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology |volume=16 |issue=7 |pages=481-90 |year=2006 |pmid=16388933 |doi=10.1016/j.euroneuro.2005.11.011}}</ref>
* These studies warrant investigation for antidepressants for use in a psycho-neuroimmunological approach for optimal [[pharmacotherapy]] of antibiotic refractory Lyme patients.
 
====New Developments====
* New research has also found that chronic Lyme patients have higher amounts of ''Borrelia''-specific [[FoxP3|forkhead box P3]] (FoxP3) than healthy controls, indicating that [[regulatory T cell]]s might also play a role, by [[immunosuppression]], in the development of chronic Lyme disease.
* FoxP3 are a specific marker of regulatory T cells.<ref>{{cite journal |author=Jarefors S, Janefjord CK, Forsberg P, Jenmalm MC, Ekerfelt C |title=Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic Borrelia-exposed individuals |journal=Clin. Exp. Immunol. |volume=147 |issue=1 |pages=18-27 |year=2007 |pmid=17177959 |doi=10.1111/j.1365-2249.2006.03245.x}}</ref>
* The signaling pathway [[P38 mitogen-activated protein kinases]] (p38 MAP kinase) has also been identified as promoting expression of pro-inflammatory cytokines from ''Borrelia''.<ref>{{cite journal |author=Ramesh G, Philipp MT |title=Pathogenesis of Lyme neuroborreliosis: mitogen-activated protein kinases Erk1, Erk2, and p38 in the response of astrocytes to Borrelia burgdorferi lipoproteins |journal=Neurosci. Lett. |volume=384 |issue=1-2 |pages=112-6 |year=2005 |pmid=15893422 |doi=10.1016/j.neulet.2005.04.069}}</ref>
* The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the ''Borrelia'' bacterium is still present in the host, or in the absence of the inciting pathogen in an [[autoimmune]] pattern.<ref>{{cite journal |author=Singh SK, Girschick HJ |title=Toll-like receptors in Borrelia burgdorferi-induced inflammation |journal=Clin. Microbiol. Infect. |volume=12 |issue=8 |pages=705-17 |year=2006 |pmid=16842565 |doi=10.1111/j.1469-0691.2006.01440.x}}</ref>
* Researchers hope that this new developing understanding of the [[biomolecular]] basis and [[pathology]] of cell-mediated signaling events caused by ''B. burgdorferi'' infection will lead to a greater understanding of immune response and inflammation caused by Lyme disease and, hopefully, new treatment strategies for chronic antibiotic-resistant disease.


===Lyme Funding and Treatment Controversy===
====Hyperbaric oxygen therapy====
* Many of the scientists involved in formulating what have become controversial Lyme diagnostic tests and treatment guidelines have been heavily involved in both bioweapons research and commercial vaccine and diagnostic test development, which the Lyme patient community views  as a conflict of interest. <ref>Conflicts of Interest in Lyme Disease: Treatment, Laboratory Testing, and Vaccination, Lyme Disease Association Inc., 2001</ref>  
* The use of [[hyperbaric oxygen therapy]] (which is used conventionally to treat a number of other conditions), as an adjunct to antibiotics for Lyme has been discussed.<ref name="Taylor">{{cite journal|author=Taylor R, Simpson I|title=Review of treatment options for Lyme borreliosis.|journal=J Chemother|volume=17 Suppl 2|issue=|pages=3-16|year=2005|pmid=16315580}}</ref>  
* In response to these and other concerns expressed by the expanding national community of patients, Richard Blumenthal, the Attorney General of Connecticut has launched an investigation exploring possible corruption.
* Though there are no published data from clinical trials to support its use, preliminary results using a [[Murine|mouse]] model suggest its effectiveness against ''B. burgdorferi'' both [[in vitro]] and [[in vivo]].<ref name="Pavia">{{cite journal|year=2003|title=Current and novel therapies for Lyme disease.|journal=Expert Opin Investig Drugs|volume=12|issue=6|pages=1003-16|pmid=12783604|author=Pavia C}}</ref>


* To date, federal research aimed at developing treatments for chronic Lyme disease is roughly $30 million, as contrasted to a $22 billion budget for military biodefense. 
==== Antifungal medications ====
* Scientists setting Lyme treatment and diagnostic testing policy in the United States have a well publicized history in the biodefense field, and many have recently received lucrative biodefense grants for BSL-3 and BSL-4 Labs where, critics contend, Lyme treatment research lacks transparency, accountability and  focus on treatment research.<ref>Biocontainment lab planned at Primate Center,
* Some clinical research has shown potential for the antifungal [[azole]] medications such as [[fluconazole]] for the treatment of Lyme disease, but this has yet to be repeated in a controlled study or postulated a developed hypothetical model for its use.<ref>{{cite journal|author=Schardt FW|title=Clinical effects of fluconazole in patients with neuroborreliosis|journal=Eur. J. Med. Res.|volume=9|issue=7|pages=334-6|year=2004|pmid=15337633}}</ref>
PONTCHARTRAIN NEWSPAPERS COVINGTON, St.Tammany News, www.newsbanner.com Dec. 13, 2004</ref><ref>"Lyme Disease is  Biowarfare Issue" by Elena Cooke, published/discussed by Dave Emory, WFMU Talk Show Host, 2007 http://ftrsupplemental.blogspot.com/2007/02/history-of-lyme-disease-as-bioweapon.html</ref>


* In 2003, Lyme researcher Dr. Mark Klempner was appointed head of the new $1.6 billion biodefense top-security facility at [[Boston University]].<ref>[http://www.washingtonpost.com/wp-dyn/articles/A27646-2005Jan21.html Washington Post January 22, 2005]</ref>
==== Alternative medicine ====
* In 2004, Lyme researcher Dr. Jorge Benach,<ref>[http://www.nystar.state.ny.us/nl/archives2004/longislandA08-04.htm NYStar News Publication of the New York State Office of Science, Technology and Academic Research, August 2004]</ref> was reportedly chosen as a recipient for a $3 million biodefense research grant, and in 2005, Lyme researcher Dr. Alan Barbour was reportedly placed in charge of a $40 million dollar new biodefense complex based at UC Irvine. <ref>[http://www.ucihealth.com/News/Releases/06-05BiodefenseResearch.htm UCI Medical Centre, June 1, 2005]</ref>
* One approach in the field of [[alternative medicine]] is the use of bee venom to treat Lyme disease because it contains the peptide [[melittin]], which has been shown to exert inhibitory effects on Lyme bacteria [[in vitro]]; however, no clinical trials of this treatment have been carried out.<ref>{{cite journal|author=Lubke LL, Garon CF|title=The antimicrobial agent melittin exhibits powerful in vitro inhibitory effects on the Lyme disease spirochete|journal=Clin. Infect. Dis.|volume=25 Suppl 1|issue=|pages=S48-51|year=1997|pmid=9233664}}</ref>
* Former NIH [[Lyme disease]] program officer, Edward McSweegan has  published numerous articles and letters to editorial pages relating to biowarfare topics ranging from anthrax to plague.  
* Curiously, Mr. McSweegan's novel, Deliberate Release, is biowarfare thriller that describes the deliberate release of a germ weapon. <ref>McSweegan, Edward , "Deliberate Release", published September 20, 2002 by 1st Books Library, ISBN-10: 1403343535.</ref>


==References==
==References==
{{reflist|2}}
{{reflist|2}}
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Overview

Future and investigational therapies of Lyme disease are directed towards decreasing the pro-inflammatory immune process and decreasing Th1 upregulation. Studies have also been conducted to test the role of neurohormones in neuropsychiatric complications of Lyme disease. Other therapies including hyperbaric oxygen therapy, antifungal medications and use of bee venom are also under investigation.

Future or Investigational Therapies

Psycho-neuroimmunological therapies

Hyperbaric oxygen therapy

  • The use of hyperbaric oxygen therapy (which is used conventionally to treat a number of other conditions), as an adjunct to antibiotics for Lyme has been discussed.[6]
  • Though there are no published data from clinical trials to support its use, preliminary results using a mouse model suggest its effectiveness against B. burgdorferi both in vitro and in vivo.[7]

Antifungal medications

  • Some clinical research has shown potential for the antifungal azole medications such as fluconazole for the treatment of Lyme disease, but this has yet to be repeated in a controlled study or postulated a developed hypothetical model for its use.[8]

Alternative medicine

  • One approach in the field of alternative medicine is the use of bee venom to treat Lyme disease because it contains the peptide melittin, which has been shown to exert inhibitory effects on Lyme bacteria in vitro; however, no clinical trials of this treatment have been carried out.[9]

References

  1. ↑ Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP (2005). "Cytokine dysregulation, inflammation and well-being". Neuroimmunomodulation. 12 (5): 255–69. doi:10.1159/000087104. PMID 16166805.
  2. ↑ Calcagni E, Elenkov I (2006). "Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases". Ann. N. Y. Acad. Sci. 1069: 62–76. doi:10.1196/annals.1351.006. PMID 16855135.
  3. ↑ Gasse T, Murr C, Meyersbach P; et al. (1994). "Neopterin production and tryptophan degradation in acute Lyme neuroborreliosis versus late Lyme encephalopathy". European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies. 32 (9): 685–9. PMID 7865624.
  4. ↑ Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M (2001). "Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio". Journal of clinical psychopharmacology. 21 (2): 199–206. PMID 11270917.
  5. ↑ Diamond M, Kelly JP, Connor TJ (2006). "Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade". European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 16 (7): 481–90. doi:10.1016/j.euroneuro.2005.11.011. PMID 16388933.
  6. ↑ Taylor R, Simpson I (2005). "Review of treatment options for Lyme borreliosis". J Chemother. 17 Suppl 2: 3–16. PMID 16315580.
  7. ↑ Pavia C (2003). "Current and novel therapies for Lyme disease". Expert Opin Investig Drugs. 12 (6): 1003–16. PMID 12783604.
  8. ↑ Schardt FW (2004). "Clinical effects of fluconazole in patients with neuroborreliosis". Eur. J. Med. Res. 9 (7): 334–6. PMID 15337633.
  9. ↑ Lubke LL, Garon CF (1997). "The antimicrobial agent melittin exhibits powerful in vitro inhibitory effects on the Lyme disease spirochete". Clin. Infect. Dis. 25 Suppl 1: S48–51. PMID 9233664.


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