Patent Application: US-201414167028-A

Abstract:
l - lactate is required as a fuel for the continuous firing of nociceptors that produce many of the manifestations of chronic pain . polymer d - lactic acid forms a spontaneous non - enzymatic , thermodynamically favored stereocomplex with sequestration of l - lactate or “ trapping ” of l - lactate . injection or topical application of pdla can reduce pain by decreasing the l - lactate available to activated nociceptors without sequestering lactate in non - disrupted nerves . c fibers and unmyelinated visceral afferents are most sensitive to the analgesia produced by pdla . pdla can be used to ameliorate pain from a wide variety of medical conditions including skin ulcers , wounds and burns ; causalgia , radiculopathy , neuropathy ; arthritis ; and cancer . pdla oligomers can be inexpensively produced from d - lactic acid in a home microwave . the predicted toxicity of pdla is low and topical application or injection into perineural tissues for relief of pain may be very safe .

Description:
select oligomers of pdla are known to complex lactate , the reaction of which is spontaneous , thermodynamically favored and non - enzymatic . lactate is an essential agent that provides for continuous long term transmission of a nerve and more specifically nociceptors . ( feng , 1932 ; immke & amp ; mccleskey , 2001 ; stahl & amp ; longhurst , 1992 ) continuous transmission of a nociceptor is a hallmark of chronic pain . oligomers of pdla exist as hydrogels of low toxicity that can be injected or applied topically near sites of nociceptive or neuropathic pain . some of these sites that are commonly associated with inflammation include skin ulcers , joints , tendons and muscles or sites of nerve injury . another important site includes areas that contain neural tissue within the vicinity of malignant tumors . injections and topical application of steroids , local anesthetic and viscous agents are common techniques utilized in the field of pain management . often these injections are performed with fluoroscopic , ultrasound or nerve stimulation guidance however because pdla is water soluble and of predicted low toxicity , injections without imaging may be possible at a substantially reduced cost . at room and body temperature pdla exists as a hydrogel that slowly hydrolyzes and therefore pdla injections or topical applications provide pain relief for periods of time , much greater than the present agents in prior art including steroids , local anesthetics or viscous agents . prior art has largely recognized the significance of stereocomplex reactions to form new materials in the field of polymer chemistry . however , pdla also serves as a template for binding l - lactate . the dramatic change in melting point ( approximately 60 c .°) when pdla is mixed with plla to form a stereocomplex and the formation of a stereocomplex when l - lactate reacts with pdla suggests that a strong chiral attractive force which is a component of van der waals forces exists between these enantiomers . in racemic mixtures these chiral forces between enantiomers may not normally be observed because charge forces or hydrogen bonding predominate . however , when negatively charged pdla reacts with negatively charged l - lactate the chiral force overcomes the repelling charge and hydrogen bond forces ; thus a stereocomplex is formed . the formation of this stereocomplex can occur if charge and hydrogen bond forces are decreased over distance along the polymer units such that the hydrophobic “ tail ” of pdla can template molecules of l - lactate . since most organisms have evolved with l enantiomers of amino acids and d enantiomers of glucose , chiral polymers could be future drug targets . goldberg and weinberg have provided enzyme and hplc evidence that a stereocomplex is formed when oligomers of pdla are combined with l - lactate and described this reaction as sequestering or “ trapping ” lactate . ( goldberg , 2011 ; “ use of polymer d - lactic acid ( pdla ) or equivalents thereof to inhibit growth of cancer cells and diagnose cancers ,” 2012 ) lactate serves many functions in addition to being a waste product of glycolysis . lactate shuttling occurs between cancer cells and between astrocytes and neurons in the central nervous system . ( schousboe , et al ., 1997 ) parasites such as plasmodium produce large quantities of lactate . trapping lactate with pdla is an extraordinary versatile chemical reaction that may have medical uses in the treatment of cancer , malaria and in this invention , pain and also non - medical uses . in this invention , lactate trapping produces analgesia by disrupting the energy source required by nociceptors to continuously transmit information via action potentials to the brain . normally nociceptors exist nascent in equilibrium with their environment such that resting membrane potentials are maintained without generation of an action potential . when the environment changes , the equilibrium is disrupted , and membrane permeability changes produce an action potential . the information within the action potential is transmitted to the spinal cord ( where modulation occurs ) and to higher center in the brain and perceived as pain . the generation of an action potential requires energy initially supplied by glucose but repetitive stimulation requires that the nerve shift energy substrates to lactate . this shift in energy substrate is well established in the central nervous system where astrocytes shuttle lactate to neurons . ( schousboe , et al ., 1997 ) lactate then becomes the preferred energy substrate for nociceptors . lactate can be converted to pyruvate within the nerve by lactate dehydrogenase 1 ( ldh1 ). ldh1 is the predominant ldh isoform within nerves and unlike ldh5 it preferentially converts lactate to pyruvate . ( bittar , charnay , pellerin , bouras , & amp ; magistretti , 1996 ) pyruvate can be converted to acetyl - coa that the nerve can utilize to produce atp . this mechanisms explains the results of feng reported 82 yrs ago . ( feng , 1932 ) stereocomplexes of pdla with l - lactate is a thermodynamically favored , non - enzymatic reaction that traps l - lactate . when lactate is not available as a fuel to maintain continuous generation of action potentials the nociceptors cannot effectively transmit information and pain is reduced . the various oligomers of pdla have a pka that closely approximates 3 . 86 that of lactic acid . at ph 7 . 4 the microspecies of oligomers are predominantly in the charged form : for oligomers of low molecular weight , such as n = 2 units , charge predominates over chiral forces inhibiting stereocomplex formation . however as the size of the oligomers increase charge considerations become less important and the “ tail ” of the pdla molecule approaches neutral to allow pdla to sequester lactate . for topical or local injection therapy in the vicinity of a nerve , oligomer size is less important than for systemic injection . systemic administration of pdla requires that pdla diffuse across vascular endothelium to reach nociceptors and molecular weight impedes this diffusion . in this invention , pdla is applied topically or injected in the vicinity of nerves . when applied topically such as for the treatment of pain from skin ulcers , wounds or burns , pdla immediately contacts nociceptors . when injected into the vicinity of a disrupted nerve , pdla can diffuse through the disrupted perineural tissues , epineurium , perineurium , endoneurium and reach the axons of nociceptors that can be c fibers , visceral afferents or aδ fibers . pdla can then complex lactate in the vicinity these nociceptors . examples of use would be for relief of pain from causalgia , radiculopathy , arthritis and cancer . in non - disrupted nerves , it would be unlikely that pdla could cross the various tissues to trap lactate . ( fig3 ) therefore , pdla would not trap lactate in the vicinity of normal nerves and not impair normal nerve function . oligomers of pdla likely to have drug like properties according to lipinski &# 39 ; s criteria and diffuse from vasa nervorum to axons are listed in table 1 . the bioavailability and effectiveness of systemic administration of pdla for the treatment of pain is not known . pdla and pdla — lactate stereocomplexes are expected to slowly dissolve in the body through ester hydrolysis in a similar manner as stereocomplexes of plla - pdla ( polylactides ). polylactides are used in the manufacture of cardiac stents , drug delivery systems , prosthetic devices and wound dressings and are degraded into d and l lactate . l - lactate is a natural product of glycolysis and can be metabolized or converted into glycogen in the liver . d - lactate can be excreted in the urine or sweat . the toxicity of pdla in humans or animal has not been reported but the stereocomplex formed by pdla and plla ( pdll or polylactide ) is found in prosthetic devices , cardiac stents , biodelivery systems and wound coverings . ( panyam & amp ; labhasetwar , 2004 ; tamai et al ., 2000 ) a metabolite of pdla , d - lactic acid , is neurotoxic at average plasma concentrations of 7 . 98 mm with reversible symptoms of altered mental status , dysarthria , and ataxia . ( uribarri , oh , & amp ; carroll , 1998 ) measurement of plasma d - lactate in asymptomatic exercising subjects has been reported as 12 mm . ( kondoh , kawase , & amp ; ohmori , 1992 ) these seemingly high plasma concentrations of d - lactate are possible because the overwhelmingly predominant microspecies of pdla is charged and unlikely to cross the blood - brain - barrier at ph of 7 . 4 . d - lactic acid , pdla and possible synthetic precursers are moderately expensive reagents . table 2 list some known suppliers with costs : synthesis of specific molecular weight oligomers requires the expertise of an experienced organic chemist . however , mixed oligomers of pdla that have demonstrated analgesic activity can be prepared from d - lactic acid in a home microwave oven . ( pandey & amp ; aswath , 2009 ) chronic pain precipitated by age , trauma , malignant or non - malignant disease usurps quality of life . the famous quote by albert schweitzer “ pain is a more terrible lord of mankind than even death itself ” succinctly summarizes the plight of humans unfortunate to suffer chronic pain . chronic pain is more complex than a nociceptive disturbance , but of all the causes and possible treatments of chronic pain , interrupting the firing of nociceptors either through medications , injections , stimulation or behavioral therapies has shown promise in ameliorating the symptoms . by formation of stereocomplexes , lactate , a known , but not well recognized substrate essential for repetitive neural transmission , can be trapped by pdla . pdla can be prepared in a home microwave . if toxicity studies support the use of pdla , pdla has the potential to improve the lives of millions suffering chronic pain at a price society should be able to afford . a 0 . 5 × 1 . 5 cm skin lesion of approximate depth of 1 . 5 mm was made in the left index finger of a subject ( jsg ) with 60 grit sandpaper . the lesion produced vigorous bleeding and pain . application of approximately 10 mg of pdla in the form of a hydrogel to the lesion produced an intense burning lasting approximately 30 seconds after which there was complete analgesia without loss of sensation ( numbness ). the analgesia lasted 24 hours until the lesion was exposed to water . additional pdla was applied and analgesia continued thereafter until the lesion completely healed in 10 days . bittar , p . g ., charnay , y ., pellerin , l ., bouras , c ., & amp ; magistretti , p . j . 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