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    Reyes-Garciaetal2006 Analgesic Effects of Vitamines B

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    Jonathan Olmos

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    \Nasibnal, Mexico, DF, Mexico. nsituto Nacion tor de Medicina del Instat Pliteniea de Eafe Respirators, Sansa de Sle, ‘Mévleo, DF, Meteo ‘Deparamento de Frmeccbie ogi, Centro de Invetiaciny de Estos Avnizados, Sede Sur, Clana Teorios 238, Col. Grnjs Cosa, 14330 México, DF Menor ABSTRACT However, more recent has been eisimed that, have. nown that ‘anlenfammaixy efect has age been reported Using the carragsenin dculopatny, neurlis associated wth pain aresthesis, and Glabete peripheral neutopathy. This use has bean Supported teeehty by precinial studies showing the cffcacy of hese viamins in wel established models of ouropattic pain in tals. The scapeponting sor ‘ered ne neurophysological mechanisms inuced by B Viamins are st unknown, However, KEYWORDS: 8 Vtarins, Thiamine, Pyridoxine, Cyanocobelamin, Viamins 6 complax. Neuto- pathic pair Intammatory pain TRoDUCTION Pain i a sensory and emational experience intinsealy unpleasant ssorated mith huring and soreness. Even though pain is essential a sensation, thas song cognitive ‘ng emotional co a have. been Patially defined by proving insight into how the diatnt ypes of pain are generated by ‘several eloiogte factors, Inflammatory pain appears. after noxious stimulation of bones, connective. tesue, musculoskeletal or visceral structures. and leads to an appropriate pysilogte response (irfanmaton,exravasaton ard vasosaton) by the nacicepive syst Despite advances in the patophysiclogy of neuropathic pain {1-2 relieving ehronie bain associated with injury of peripheral or canal Nervous eystem remains a dot treatment Challange. So far four medicaon calogoros have eon used to teat neuropathic: pin, antidepressants, niconvsanis, opioids and topical agents. A have lntatons and none provide more than 60% of moderate. to omplete alr role in patents. Conrarvse. current ‘anaigest" therapeute rating Strategies for chronic back, nec or arm pain ‘ely on non-steroidal antfamatory drugs (NSAIDs) "thet are known to releve Intammetory pain but not neuropathic pain NSAIDs also have Sie offocis whieh liste their prolonged use. Than, new Veatment ‘plons. are needed. ‘Adminievation, of 6 \amins alone ah combination with efectve analgesic agents could be ‘ane. promsing option to treat both Inlammatary and neuropathic pan ‘The introduction of new chemical entities in the analgesia arena has teen somewhat \Ssappolning over the last two decades and consequent, attenton has been ghen to combinations’ of varous analgesic agent, The use of a combination of anagesies may fer potentsl benefts. The combination tay fesult ina doce redicton of each drug Bn therefore should minimize the cccurence of side eflects.Diferent rugs may target afferent receptor cr cellular” mechanisms, which may lead to 2 synerisc ratner nan Just an adktive efeet Final, combinations ‘may rte diferent pan stats Gerardo Reye-Gatit ta B vitaning area group of water-soluble vitamins that are stored toon a ited extant. Then, Frequent consumption ie mandatary to mania appropriate levels in ‘sues, The funcion of B viamins & tact a8 cotactors for specie enzymes At physicogiel amounts © Vitamins are devoid of pharmscological actions. However, aciminisaton of pharma ological doses of 8 viaming has! several fetlect. One of he pharmacological effects of 5 viarins is rotted with pain. vamins Started to be use fo pain treatment n eases of ebvious vitamin defences Later they were errpiicaly used t eat savers nds of pain based on the assumption that hese \wtamins play 2 major role in ntton, axonal transpar, exctabuly ano synthesis of neuro transmits inthe nervous system 2]. The reported information about the eficacy of B vitamins “was scant and’ controversial. However, in the last years several stuies reach suflent statistical power and standard ‘ually in clinical va ‘Mechanism of action of vitamin By Pioxne supplementation nas been found benefida mn prevertng dabet neuiopaty and. renopaiy, andthe lysoyiaton of Bates [si Sines oggen radial and ‘vide Gamage have boon mpicaed inte ellaraystuncion and. compleatons of diabetes tte Mey ‘Wat pyridoxine may {uneton as an antontant ASZorangy hag been damsiated thet pyeaosie Brrcoarne Soran "werd ie Ferodaton end gated rerrogobifomatos Inigh gesso-emosed ree ood cele Thus Byrcoune or pyrdovamine can weit oxlgon fates! posicen, which intam events the ie_peroialon” and. pete” Sycooyaton ‘aices by te hyperahcera (8) Moser Pyrdonne, pyridoxal phosphate "and yt Soramine: can prevent the ong rate gererton and ip perodaton cuss by Fyerogenperoxdein U827 moneyts (0) Otver studies have reported that vain By ‘aso. shows @ proteeive efect against the ‘oxide sess inised in. hyparhom ‘steiner (a mode! of oxidaive’ ses in fais by 8 ‘ole. acid caficant det ad ‘methionine inte (70), Taken tgethe Wee Sluts suggest hl pyicosne. ands Gevates pyridoxal phosphate and pyro. xamine. may ncton 03. onioxan and ‘coud have an important place inthe retrent 10 Gea Reyes Gara ea of dabetesreiated pain. Mereover, cer stutes have ‘shown that pyridoxine: sgnficanty attenuated domoie aiccnduced Increase levels of glutamate, increase in levels of calcium inf, decrease in levels ‘of garima- ‘aminobutyric acid and incease in levels of the protocncogenes cs, ja-8 and jun-D in tiferent calls c the central nervous system, thus suggesting = neuroprotective effect for thi vitamin (7 ‘CYANOGOBALAMIN (VITAMIN B,:) ‘The structural frmua of vitamin Bs fs shown ln Fig. 6. Preparaions of lamin Biz for Uerapeutc use contain ether eyenocobalamin or hydroxycobalamin, This vamin functions in the "body as. a ‘coenzyme. named Imetnyebalamin or 5.2 ‘These coenzymes have an important role fn cel growth and repaton. Viamin By 880 Paticlpates in the fermaton of methionine Sand ts derivative S-adenosimethionine. Deficiency of eyanocotalamin leads t0 the Impairment of two enzymes, methionine synthase and matiymalanyl‘CoA mutase and ‘Morelos (othe accumulation of homaoysteine ‘and. metiyimalonic acd (72) Deflieney of Gyanacobatamin hax facts on hematopoietic snd cena! nervous etm [73°7].On nervous system, progressive sweling of mieinates neurons, demyelination (75-76) and neuronal ‘all death are obsewed in spinal cord and Fig. 6. Chemical structure of eyanccobalain, ‘erbralconox77-7], This causes poresthesios Of hand and fest, reduction of vibration and positon senses and decreased daep-tendon ‘efleres, The principal use of vitamin Bis is in the therapeutic or prophyictic treatment of ts defciency In addon, ths vitamin has been Used in the therapy of trigeminal neuralgia, utile sclerosis and ather neuropathies [79], Preclinical studies with vitamin Bas The group of Eschaler and coworkers [80] assessed the possible antnecceptve effect Cf veamin By in acute and intammatory pain ‘models in rats and mice, Cyanacabalamin ‘acute (100-800 igikg, 30 min) or chronic (100-960 ugtegitay for 7 days) acranisvation ‘was notable to reduce overall sponse seore Inthe elacrc shock testi als, At the same doses, cyanocobalamin faled to rodity the ‘eacon tne (king of forepaus) In the hot- Plate test in mice. Neier cyanocobalarin har hyérexyecbaiamin showed any significant aninociceptve effect on p-benzecuinone- indeed number of abdominal wrhes In mice ster acute of chron tatment. Actual at tha grainet ose (000 upikaisay) eheonia treatment wi cyenocobalamin, but not bnydroxyconiamin, significantly" inereased pain in tis mode, ‘The effect of cysnocobatamin in neuropathic pain models Is contoversil. Fst isu at 4 [81] reported that arin was rot able to modily nerve fiber conduction velooly and motor distal latency of the tl nerve In 2.5 hexanodione-indueed neuropathy in ral. NO behavioral measures of hyperalgesia or alodynia were cared out In the. made. Eased on This dala, authors suggested that tain Bis at able to reduce nevropathic pain In animale. More recently "our group ffemonsiated that this vara (075-12 mg, 2) dose-dependenty reduces tcl atocyns in spinal nerve igated rais (62) (Fi 3) I a well established neuropathic pain model in the rat (83) Therefore, futher studios are edad in oxder to fly eetabish the rola ‘fanocobatrsn in neurgpte pani arenas Citnical studies wth vitamin Biz Prolonged vitamin Bs deficiency may lead to nerve degeneration “and ieversise neuro logical camage possbiy relatos to dabete ‘neuropathy (64). Then this warn has been Pidpased asa possbie therapecte tool in tis Calidon (reviewed by [85). First, n 2 cout: bie cial Wal the eect of melnycebalamin on) patients wth slabetic neuropathy was astessed. Treatment wit) the vitamin ‘Significant improved the somato and tulonomic symptoms with regrestion of signe Of diabetic neuronathy. Motor and sensory ane conduction stiles showed no stata! improvement afer 4 monthe, The drug wa abi tolerated by the paberts ‘and no sie ‘efits were reported bythe sua (85) Inlother study caried out in patients with fabetc nowepsshy, reatment with 1800 yglday ff oral methyl viamin Bi Yor four weeks resulted less ofectve than prostaglandin €. to feduce symptom scores Compared! to the trebiment wit no drugs [87] Mote teconty the effect of metyleobelamin on 108 diabetic palonts has been assessed. Sat) two cases Were tated wth mebyt-ctalamin 800 ig Intiamusculary tives times @ weak for fout weeks then folowed by 500 pg oraly thee Times a day for adottonal eight eck. Forty she cases wore treated with vitamin ys ine sme way and served a¢ controls Treatment viy-methyleobaamin signieanty reduced spontaneous pain ana rumeness of lbs by 72% and 75%, espocivey. Ober symone uth as hypoestresia, hoboss, coldness, ofl Ayres ane ysura showed batter response in the ‘methyecbalamin group than tn the controls. In acition, metylecbalain’also improved nerve reflection and conduston vee ‘he effect of methylecbalamin on diabetic patients wih neuropathic pain has ‘boon Ssgossed after invenous, namvstu” ant intrathecal adminisvaton. In all cases Treatment with methyeotalamin signeanty reduced pin or patesiesa [8890 nravenous treatment also improved ewe conduction Vepaty (88). There are several oer studies aepessing the possible eect of vitamin Gyn neuropathic pain [81-93], however, since Viamin Big 8 combined with other vitamins such ae benfotamine or pyridoxine. the observed resus ae contoversial Taken {ogether it seers that teiment with vitamin Bs appears fo improve symptoms of abet neuropathy in human beings. However, more and high-quality “doube-bing stsias. are nigeded to confer the clinica eficacy ofthis viamin (85) ‘Mechanism of action of vitamin Bs Ithas been suggostod that Vian Bes produces is effets though the regulation of eyes and gene expression ‘of the phyeclageal neurotrophic agent eicarmal growth factor 4) ‘The stimulation ofthe synivess 0 epidermal grout factor, induced by. viamin By, Accompanied by''a decrease in the role damaging agent tumor necrosis factor-a production [6405] Thus cyancoabalarin pays 1 regulatory role inthe. mammalian “CNS regardless of ts coenzyme funcons, since the severe damage caused by ehonle amin By defency inthe rat oscure ag a reaut ofa shit in the. physclogial equlloium of cenal nervous stem cytes and grt factors favor ef tumor necreisfectora (ora review 20 4) B COMPLEX (THIAMINE, PYRIDOXINE, (CYANOCOBALAMIN) Proclinical studies with the mixture of vitamin By, By and By, ‘The mixtute of thiamine, pyridoxine and cyanocobalamin is known ag B complex Administration of the 8 viamine mistore Gepressed etl recorded rom single naurons inthe dorsomedial part of te vereal nucleus ot the thalamus. From 90 minules onwarcs, 2 roncunced,sigrifcant depression “occured Which reaches a maximum fram 400 to. 130 minutos ater te jection 08) In experiments carried out in single neurons inthe spinal coré dorsal hom in anestneted Cals, inathecal superfusion ofthe B complex vitamins produced a significant dose-dependent depression inthe responses. evoked. by dorsal horn neurons of eats (97. Ina smiae tay, he chronic treatment with 100 mpg for 7 days (6c) signitcaty increased afferent Inhibtony conto of noceaptve neurons atte Spinal cord doreal hom (98) Other experiments have shown that treatment ‘withthe miu of thamine, pyridoxine and tyanocabslemin (167-687 mgkg Ina 00-100:t proportion of thiamine, pyidoxne and cyanocobalamin,respectvaly, 6. 2 6) Signiieanty reduced ‘bensoqunone indeed writing In rats [09] at the greatest coses (600-667 mg/kg). In adation, the ‘same auhors reported that hese doses Were a0 effective to reduce nactepton inte hokplate Hore recent, eur group hat reported that ‘fa, but nt local pera! (1-100 ug/paw in 12 100:1001 proportion, 10 mi), administration withthe B complex vtamins (30-17 ma/eg 2 100:100:1 proportion, = § min) sigcandy Teguced finching behavior nats injected win forraiin [100]. In. other study, the ‘Yoatmont wth the mature of B viamins @2-178. malta, po, -5 min) sigifeanty Foduced pase 2flaiad nociceptive behavior in he formals tect (1011, Prevatmant (11) vit either intrapertonest (20200 mgt) oF ‘al (§00-1000 maka) admnstration of this mixture in a 100-1008 proportion is abe to feuce the numberof absomnal cnstctions induced by acote acid. In addon, chronic (60-100 mgikg for 7 ‘days, but nol. acute 400-200" mgt, -1" f, inrapertoneal Droteatment withthe B complex significa {educed formaldehydeinduoed nosceptve behavior in’ mice [10]. Acta or chron preveatment wit the B compley vlamins (100-200 mgika) was. rot able to. modly latency in the hot plate tes! mice, Besies iis arthociceptna. effec, the. 8 viamins compex eignfeanty Tedced fermaldenyde- induced edema ater ror (100 malkg for Pe days) but not souta (200" gh), retreatment (10) Convarwise, acute (min ‘ral admnstation of tha & viemone mitre ‘Sgnifeanty reduced Ine dose" dependent ‘manner nacicemton induced by 1% formalin Inrats (Fi. 28). Gerard Reyes Garcia eral The possible antistodynic effect of the rite of B vitemine has been explore in neuropathic pan in rats. Acminsation of the mature of 8 vitamins (@,-Bs 10-33 mo/g, Brg 0.2.0.5 mafag, ip.) signfeanty produced 2 ong lastng reduction (2-24 ) of spinal gangla compressioninduced thermal hyper Sigecia in rte (12) In. acon, chronic treatment "or 7 and 14 days (83g 38 mghg, Bg 0.5 mag, Lp) rediced the seventy of hyperalgesia By 50%. The analgesic eft of the mite of vitamins wae stl present 310 7 waske afer treatment stopped (12). Oral adminisvation of vain B combination in inreasing doses (proporion 100:100:1 of vitamin Bi, Bg, By, respectively) induced 2 modest but” sigieant dose-dependent ‘eduction of tact afedynia in spinal nerve ligated rats. The maximal effect of the moxure of B vitamins was about 30% (EDae 3307 + 11282 mglkg) and higher doses were notable to further reduce taco sladynia in the rats {02} “Our group has. also found. tat subcutaneous administration ofthe mur af 1B viamins is able fo reduce neuropathic pain ina wall estabished mode of neuropathic ‘ain in rts [109]. Subcutaneous admiration fof B vtaming (75-600 mglk, sc) reduced {act aodynia ina dose-dependent manner being the maximal effet of about 50% of reduction in tactla allodynia. Taken together Gata seers to suggest that subcutaneous aminisvation preduced a greater antalooynlc {ect inthis mode, Contay tothe study of ‘Wang etal. [12, we found that atialodyne fect of vim laste only 4 hours. ‘Antinourtc effect of 8 vitamins Streptozotocn induced diabetes in rats shows 4 considerable deteriorating impact on the {uncione! properties of peripheral nerve Mars Ing the egevelated Increase of nerve ‘conduction velociy In the tat tall eve by about 20%, 8 weeks afer induction of labetes. An invapertoneal dally injection for 7 weeks wh a mitre of arin By (25 mat), amin. Be, (80 mgikg), and vitamin Bye (05 maka) increased nerve corcucton velosty Compared to fe untreated diabetic animsls Atlee fees of 8 ving —E—SESE—e “This occured without affecting bled glucose fovels or body weigh: Resuts suggest that iy. sdminttaton of the 8 vlamin ombnation would retard the process of Perpoersneuropatiy of dole. patents {tbe} Reeh [105] steeeeee. te neve fongucton loot ding. tow ‘ad high fFeavency”cleciea!‘stmvltion of rata neve. During high equeney_ station ‘uned depression of nerve conduction ‘osly was found in the plcabo bested abet group, wheres the arn feated GiouP shoves stately sgniicanty less need cepression of neve conduction Yelocty, mare closely Yesembing the surements in heathy contol “le worn 3 consnton (a 829 mg eid Ba 08 mg) was suded. OF nerve Eanaucton weoaly in_acryiamie induced neuropathy In tate maistnes on refed ‘emynthee complete wismn ond arin Bedotert diets in vie. Aey-omidesnduced nowepaty "was" clearer inthe. group Faintaned on vitamin 8-decien et tan those on a complete vlamin cat. The nerve enduston velodty tended to deweese by treatment wit acylase. The decrease of nerve conduction veosty "was paral Inntited ay utsmin 8 cominaon (10) {nan attempt to ent the rie of neurotropic B vitamins n peripers! nerve minerance and regeneraton,rateabeled choline wos inte ocaly ot ep cor of heay bits and of animals. sufeng rom imental allergic nevis, as a model for demyelnatng human neuropathies. Hal the ‘animals in each group received dally addons Inrapartoneatinjectons of tamine(& gic), pyfdexina (S mg ane eatin (60 ul) {erogartion neatly. 1001001) during 9" days Radiolabeled cheine racer incorporation wae ‘measured in the scaie nerves. Chane acura was, uated by mona Bitamins in the heathy. anima, but was signifeanty rgher in all neuropathic srimals, Feflesting ongoing mystin tumover during jeneraton. In rabbis win experiments) alergic neu teated wih viarin 8 complex, mean tracer noporson was thr sims b {o about 150% of the actvty found in lunveated animals wih expermontal als nour (107) Adminisvation of a combination of vitamins By, Be and Bis (proportion 700:100'1) In rabbits produced an increase inthe number of regenerating axors anda reducion In the degenerating axons compared to the contol ‘untreated rabbis [T08} Ia ada, tt rmoture of the vilamins By, Bp, and Bis induces @ faster regeneration “of nerves damaged under cold fasion by accelerating the processes of Valerian degenefaton and ‘axonal regeneration (108-110) Administration ‘of combination of wo vain (©; and) ‘also enhanced nerve regeneration [103], The ‘morphological analysis was performed in’ treatment’ groups of rabbits. After a standardized cold lesion of the saphenous nerve each gioup was parertealy Vented ‘over perods of 4,10 or 24 days wit thiamine (7 akg), pyrene (7 mak) or ‘yanceobalamin (70 ual) (100:100:1). The results showed no diferences regarding the regeneration nether between the. groupe thomselves ‘nor in. comparison to contol ‘groups. The anayss ofa group rested with 2 ‘combination of 8; and Bp demonstrates Sightly” proved | regenettionTherafor fesuts suggest that administration oF the combination of B vitamins is beter te increase "erveregeneraon than rsvidil components Ctinical studies with the mixture of vitamin In. double-bing placebo contoled randomized ‘study 120 ations with dlabetie oe aleohalc polyneuropathy wore vested wath the ‘combination of vitamins By, By, and Bx (N=60) with placebo (N=60) for'3) wets (111). Treament wit) te combination reduced sgnieanly pan corplants compared fo the Dlacebo group. In adtion, among. the Sabetes the exercise tlerancs rose n43 3% tthe patients treated compared to 73.3% In the placebo group. In other double-bind placeba controled study the effeacy ofa viamin 8 combination in 20, sabetle patients wih peripheral neuropathy 4 was investigated (1121, Ten pallonts were rested with the combinaton (220. mg Denfotarine, 720 mg pytdoxine and 2 mg ‘yanccobalarinlday) end 10 palents with Diacebo for 3 weeks. There was a sinially felevant and signfeant Improvement in subjective symptoms seoe (7/10 inthe combination group and 1/10 In the placobo {'0up). The vibrtory perceplon treshold Improved in the combination group (0.84 to 222) and. showed no. ference inthe Placebo group (1-48 to 1.42), averse effets were not reported, In a double-blind plecebo-convolles. study ‘al cally edrnistrston of B vain (200 mq By, 600 mg By and 06 mp 8) 99 patents for 18 wooks sigifeanty” improved the thermosonstviy of atectes hands in gabete patents (113). Consstont wih the Improved emperature sensitviy of the hands, Upper limb pai was. reduced “aswel, The temperature sansbty inthe fet could not be Sanficanty infuenced by B wlan therapy. “The neuropathy was lass inten nthe hands than inthe feat Glyceme canal a5 Setermined by HbA, was almost Mental between the ho groups throughout the sty. ‘There were no adverso effects dus te viamin therapy. In a double-blind, randomized, contoted Sudy, the ffectveness of treatment wih 2 Combination of bonfotamine (en analog. of thiamine), vitamin By and By, on objective Parameters of neuropaty was stucled over 3 eros of 12 weexs on 24 diabetic patents wih elabeto neuropathy. Treatment showed a siriflcant improvement of narva conduction \elat in the peroneal newe and astasteal trend toward improvement of the uibeaton perception tveshold. No sce sfiets were served [2]. The effect of the combination of viamin By, 8), and By, on nerve conduction vlocy fe: Biweeks' ‘veatment of 33. patents wih diabetic nevropathy was determnad! (114) Patents were auminstered ether one ampule ‘of the miture of B vilsmine ance aly oF placebo. Normalization of newe conduction Yelocty was observed in both inpatens and Gear Rayer Garin ff autpaents, but the pre post dierence was ester among inpatena Te over uty ‘eau shows Signa efcay beaten win the conbinaion, a5 oasis increased nave condocon tly expec wit 2 cuttlety ong ond nee hel ‘orertera weston ose tn oer open and. cbseraional_ sy invaing 230 doctors in privat racic, the tvohton of eynptars andthe Werabshy af ‘amin 8 preparaton used seamen ‘148 patents th polmewropety. neva ‘adedopaty and neue asadated wih fain and” paecinesia wero stserved restrent with the combination ‘markedly improved these symploms, a pose eft tn pain was chsored i 6OX ef the cases ing In an opon study assessed the eect of therapetie™ domes ofa" sonbinston, of ‘iam (25 ry) and piso (0 may) in 100 cadet pants [110] Four weeks Stor lating Veatment tha grate of abeoe. Tested pal symplome was tse than on the fest itn 868 82. and 897% of pa, hubeess and paesbesia, respecte) The overly of aghe of gerber neutathy Seoreted 40.0% of pens Inger 8 fempaed wh 1.4% m lesbo grup. The veatment wih te combhaton of B vitamin (y 40 mg. Be40\m9, Be 8 mg. ip 30'mg, nachamde 200 rg’ zie cughale 2472 mg) n 18 dete pats with pat pecphesl polyneuropathy dung 3 rents ‘Te sensory symptoms tmproverent od he changesin the raton peeaton tiesholds ere ro nica (9) Ina Sveck open cic al 36 patents were treated win fe contnton of benotarine {520° mgéayh pyonne’ (720mg) and tyanocobasin {2 mgfeay\ of tonxerane (20 rglayy, pyionne (270 mele) end ‘Sjanccatalarin (07s mg/day wae corpared tnncterory wih erftonins 150 ety) tn davose patents autenng om panel Ppnerl dbete neuropaty in an open incl sy (23 Parameters were reper the beginning ofthe stay andthe end of Analgesic eet of B vitamins wet 9 ty 8 pe Se as come Gok ies, ar hao Garey aren sea a eae ad ice Thon gee ao ot a ae eas ie cane hemes Stayt ana Seth cewmer tote aete ses eee as eae aerate russia ot Mchanism of action of the mixture of vitamin By, Bs and By. 8 vitamins have. diferent eects, Previous stucies showed that te B wtamin complex Was able fo increase the cycle GMP levels in ‘he rat va the setvation ot guanyyt cyclase (197) Later it was proposed that 8 vitamins ‘ould produce thelr antinoceaptve ‘effects trough the increase in imnbory conto at Ue spinal cord [87] or an increase. of ‘serotonin content in soverl bln areas (118 In sciion, experiments from our laboratory Suggest that Bias ‘could produce Bitnociception in format test by ‘indirect [ctvaion of opiold receptors ae naloncne ‘Was ble to duce 6 viamins-induced ant ‘ociceoton. In the same ‘stvoy. the. anti oclceptve efect of te mire of 8 vitamins Was Docked by LNAME (2 nie oxide Synthesis inhibitor, Gut nat by metianepin (a Nenvselectva sereionn receptor aniagons} née gibenciamiae (an ATP senetive channel Dlockes) thus suggesting te partkipaton ot ‘ve oxide release, bl nat the aciation of Serotonin receptors or K" channels (118) Other studies have suggested tat 8 vitamins may fureton, as requstrs_ of too-adical reations. reducing the formation of fe ‘ical 120), COMBINATIONS OF & VITAMINS AND OTHER DRUGS Prectincal studies with combinations The combination of vitamins with non- Stefoidal ant-lammatery drugs (NSAIDS) is began withthe study of Staisavcruk ef a 1121} where repeated adminstraton of Ihiamine diphosphate (10 mala, Lp. once daly for 1 weak) was able to metease the ‘nthinfammatory and antnecceptve effec of SSeotenac (4 mak, io. once daly for 1 Week) in rals wih chronic adjuvant afin. afer that twas shown thatthe vitamin moure (B: and Be 10 mgikg and By: 0.05 mafeg of Bg. 100 ‘mghg, By 200. tgkg” and. By 0.02 mglkg) did not reduce noscepion however they produced 2 weak polonation (20% of increase) of ccetenec (5 maka, po) or metamae! (30 mei, po.binduced antinocicepive effets (122) in the withing {set in mice. In ection, oral administration of 1B vitamins (B, and 8 100-200 mole, pos Bast 1-25 mgt, po) was notable to induce fan ant-hyperalgesc effect. but signifcanty Increased that Induced by oral diotenae In ‘the tapressurecarrageanin test in ra (123), Etfectve dose. to produce a. half of the maximum effect (ED) of diclofenac alone Was 5:1 mglkg whoress that was reduced to 3 |t has been shown that the mixture of inefecive doses of 8 vitamins (1858 alka) in. a proporion 100:100 4 amine, pyrdoxna. and cyanocobalamin, espectvey) signifeanty increased the nthyperalgesic effet of dtictonac (18 mala) In @ model of carageenin-nduced thermal ‘nyperalgesia in the rat (101). Moreover, the imiure of 8 vitamins (100'100-1 maka. of thiamire, pyidorine and cyanocobeamin, Fespectvey) increased the anlhyperaigesl ‘and anteinfammatory effect of Ketoprofen (+ malig) in rats (124) These resuts have been confmed using is2bolographic ‘anayses, Oral aciminisvaton ‘of dlelotonac ‘and B viarins show ‘dose ‘dependent ‘eduction of finching behavior inthe. rat formain test ang this entnocieepive effect an be reached wih Tower cases when ‘ilotenac and 8 viamins are glen together 1125) (Fig. 7) Shee. te isabolographic ‘analysis Is a formal way to demonstrate a possible synergism botwaen two anvgs (126), ‘ur resus leery deat hat co-administaon| Gera Reyes-Garla Punters) Fig. 7. lscbolograms showing the synergistic interaction between dclfonac and B vitamins ‘iter at a 0.505 (A) and 028-075 (B) combinations on the 1% formalin tet In rls, Fotizontal and vertical bars indicate S.E.M. The oblique ine between the x axis andy aus ‘he theoretical adaive ine. The pant in tia mide ofthis ine is tie reoreteal adie point (1) calculated from te separate ED values In bon cases, the experimental pant (©) fos far below the adatve tn, inleting a significant synergism (P < 0.05 by stuart), Reprinted by permission, Westom Pharmacology Society. of ‘diclofenac. and 8 vitamins produce Sntinociesption, nthe formalin tes, using lower doses. As stated above, 3 dose reduction could have an Important impact the siloefects profle of te. sdrinstred [127] acetaminophen or metarizol (Te Rossies et sl, 2008) and the modure of B iamins in the rat fermatn test. “The possible synergistic Interaction between Bvtamins and gabapentin has been assessed ‘nthe spinal neve figation model of neuro- pathic pain in the rat [83] Inthe fist study of {fis combination, was observed tht oral administration of gabapentin (30-200 mak) Jwas able to completely radvee spinal nerve ligaon-induceé tact aedyra nthe rats. In cenvast, te al aamiistraion ofthe matte (of B vitaming (76-800 mgixg In a 100:100:4 Proportion) Induces @ maximal reduction of factlealodynia of "about 30%. Co ‘éminisvation of gabapentin and & vitamins ‘dose-dependently reduced tactle allodynia in smergisic interacon between gabapentin ‘dB vias to reduced neuropathic pain I rats (Fig 8). Using the same model of neuropathy, our group has shown that the Subcutaneous adminstraton of "ether B vwtemins (75-600 mata, 10100: preporten) fr dexamethasone are able ta reduce tate ‘ledyria in spinal nerve. gated rats In [bddton, iscbolographic analyses showed that B viamins signifearty increased the ant aledjic ettect induced by dexamethasone 1 ‘ha rts (103) Our result with dexaratnasone {sin ine wis those reported by Dever of al [125] showing that dexamethasone was able fo reduce ectopic activity in neuromas. In addition, our study agrees with observations ‘neuropathic hens in which tye combination of prednisolone (2 mgfeody) and 8 vitamins {28 malbody) Is mare efectve in aleiaing ‘ewopathy than admbistrton of ether of the ‘wo agants alone [130 Clinical studios with combinations ‘The combination of metamizal and 8 ising (By, By and By.) was assessed in patents ‘complaining of acute pain in the lumbosacral ‘Aralgsic eect of B vitamins 7 —_Ae i oe ee wm | topuntn gts 0) Fig. 8. Isoboiogram showing the syneriste ineracton of {gabapentin and 8 viamins ina newepathe pain model ithe ‘at, Horzenal and vertical bas indeate SEM. The colique. line Between the x axis and y aide isthe thoorelel eve line, The point in the middle of tht tne ts the thooratial ‘alive point (1) calculated tom the separate EDs. voles, ‘The exporimental point (E) lies far betow the adatve ine, | Indieatng 3 elgnitcant synergism (F< 008 by student test, atta [131] o* rasicular compression [132]. measure of pain reel indcated superior ‘The combination raleves pain in 77% of ta resus with tha” wtanin aepplonertcy tents with alow incidence of side effec. therapy when compared with results obained Moreover thes been show that B vitamins win dielolense.‘sene. Undecrabe ate Pull relics the time of therapy of cofenac eects Were documented with 38 patent, tf 5 low back pain patents [133]. Two huncred of them having dacontnued tercey fe toe ang. fy si palistsparlkpated “In reason’ bu no satshcaly egret mulicenter controled, randomized and Gifrence ‘ould be detomaned wie ait e-bind tal which compared the clinical group wh regard to hep) faa cetaaton oF Sete mer Ee Omer clic ls were cared ttn oder to ombination of delofenac (180 mg) and 8 Stomine (B: an "By 50 mg, Sqr Soe ge, Setetmine whether these fess can se te Pants were eted day fr aximumai Sched. when a" Teduced”souage of {wo wks, having the Spon to emg daofonac (76 mg day) or an nereases dose Dartcaton n'a tt afer t week’ te of 8 amin ond be 100 ng Be Sg fart tll patel The Sin ‘of 258 tl) sued Ih fet eas ene untied fafnts were bie be iced n the twenty bee Paetswh' acu "pon Evauaton” "Twenty ine bates epee sytomes ef the bear apne wee web Sstontinue theary “ve Yo remiston’ on wi eter 8 vsmire: and acsense fapgtoms, Nncaon (880%) "ot hese Stra soe fr mann of? aye, babents otorged te he combined tetany ‘Tare waste ooton lence hese {yGup, the oer 10 (34.5%) having taken He ial ae’ 8 dye mie coca eed ean Glcoonae one. Al parameters used ana ell” ory We Paton ans a Pa eatment due to comission of symptoms. Thity patients belonged ta the combinstion therapy greup, the ober 15 took dlltenac sone. All parameters conceming pain rele! fd movement of te vrtabral cot snowed Btalsticalysignifeartdiferences in faver of ‘he B vitamins celfenac combination (134) In other sty, 418 patients received ‘teatment daly (era maximum of 2 waoks. ose of loll pai role, thvany should bo ‘scones ater one week. Data of 375 patents could be evauatoa Fity three ot of ‘4 patints receiving the comeinaion and 4 cut of 192 patents tated wit defense ‘alone could stop therapy due to sufictent pain felet ater one week. sta about pain Intensity revealed better resus forthe fombination. There were no. dferences in sieeffects (eympioms in’ 70 out of 418 stants) between the two mediealons [135 Centrarvise, the combination of 8 vismins (amine 100""mg, pyridoxine 200 mg. ‘yanecobalemin 20 pg, p.0,) and diclofenac (G0 mg, po) produced the same efecto 38 healthy’ volunteers with” nondofemmstory experimental pain (196). Diferences in resus auld bo atvbuted to dlerences in dorage fd kind ef pin In a doublowbind study cared out by our ‘foup to assoss the possise synerssic effect othe B viamine mature and dielofenae, ‘analgesia produced by defense alone of Combines ‘wth a8 viaming midire was ampsrec ‘in’ post-surgery patents alter {onslleciomy [137], Patents were divided in ‘wo groups: group one received an Infusion of 00°19 tiamine, 100 mq pyridoxine and 5 img oyanocobaiamin during 2 pared of 12 h before the tonsilectomy, while tho. cther oup received vehicle. Paints received & 5D mg Lv. dose eighth befere the surgery. “Two houts after tonsllectomy, the st grav recelves anotver B vtamine mixture infusion 2s slated. above and. subjects were asked ‘bout te pain intensity using a visvalanaiog Seale of 10cm (VAS). Then, doses. of Sebtenae (60mg, |v) ware administered ‘ander requirement by the patent without exceeding 180mg per day. Diclofenac consumption was recorded and. VAS was Gerard Reyes Garcia evaluated each 4 hunt §4 h. Group that was {rested withthe B vitamins mbture exhibieg 2 lowe: pan Itensy 2 hours afer tonsilectory ‘Then, both groups exited similar vals of anaigesa. However, 2 signifcant reducton in Sicferac consumption was observed, ndeatng that 8 viamins re sparing analgesic agents (Fa. ur group has also assessed the possible syneiglem between gabapentin and Vamins Byand By, in patents wih ciabete newropathy. ‘The’ study neluded 30" patente that wore assigned fo one of two groups. Group + (n= 18) feceived gabapentin, and group 2_(0=18) ‘ceived gabapentin and vitamins By ond Bx. Diabetic pains taking the combination had a ‘gnfcent improvement in he global cont of rewopatic pain compared to patents receiving onty gabapentin (Fg. 10). Threfore, results suggest hat hs combination could be fn allematve to teat neuropathic Fl labete patents Tota dicotenae administered (mg) Delotenae Dicolnae ‘Bviemine Fig. 8. Sparing effect of 8 vitamins en the analgesic activity of acloferac In postsurgical paints with fonsiectomy. Diclofenac wae administeres to patients fying the. 54 hours. flowing the tonsilecomy in the groups tested with fieiotenac alone er combined with B Wiarrins (6), Be 2nd Bp) Dsta are ‘expressed as mean + SEM. for 20 ballets per group.» Sgnfeanty ceront from cont group (P< 0.05), as etarmined bythe Sudants test Analgesic effets of B vitamins 2” Seeeten avane Fig. 10, Analgesic fect of gabapentin (blac ces) ad gabapentin + 8 vitamins (G; end Bi.) (white cles) inpatients with iabetc neuropathy. Dala are expressed a8 the mean = SEM. for 15 patients in ‘ach grovp. * Signfeanty diferent from ental group (no erage) (P< 0.05, win sioup) and # signifeanty efferent tom contol “group (a0. drugs) (P= 0.5, between groups}, as determined by two: way analys of variance wiih repeatad ‘easures, folowed by the Duncan's test. Pharmacokinetic data of vitamin Bs, Be Biz ‘Thiamine adminsteed orally has a dose- dependent cual ranepon mechanism namely ‘astve absorpton up tb concentfatons of 2 lt land passive dfusian with concentrations over 2 UM. Absorton is greatest n tha duodenal loop and: occurs toa lesser extent in the Upper and midele Sectone of the ‘small Intestine. There is vitally no absorgtion in the|stomach and in dstal secon of the small intestine. Absorotion of thamine takes place ater phosphoryation in tie epihatal call, ‘nd 2 cartier mechanism is aseurmed 0 66 involves in. passage through the intestinal Wal. Thiamine is exeroted with a haltife of 40h. The main excreton products ere thiamine carbonic aci, thiamine and otner ‘metaboltes not yet idriifeg. The greater the thiamine intake the more unchanged taamine is excreted via the lidneys within 43. The body stores approxmatey 20. mg. Because ihe high tumovers rate the reserve capacty is very mite (about & ys) Al_dervaives. of pyridoxine are. rapicly ‘bsarbed many inthe upper gastisintostnl tract and ‘re excreted with @. maximum between 2 and 5 h. In plasma pytdoxcl S-phosphate and pynidoxa! bind to ‘afbumin, ‘The functon ‘as 9 coenzyme. depends on Dhosphorlation af the Crl- OH group atthe & poston of pyridoxal to pyrdoxals phosphate Pyrioxal-sphosphate ia almost 86% protein bund in the blood. The bady slore betwen 40 and 150 mg of vitamin ‘By. Daly renal ‘excretion ranges trom 1.7 10 3.6 mg and the aly mover rate is 2.2 t0 2.4% The main ‘exciton product Is 4 pyrdesse acs Absorption ef vitamin Bie from the gasvontestnal tact takes place by two mechanisms. Visrin By i released by the gastic acid. and irmrstiay Bound to the Ininsc factor to form the lamin Eyeintinse factor complex. in addon, independent of the inns fector, vitamin xa may passively enter the bloodstream "by" an unepeciic mechanism, Aecording to studies in heallhy volunteers a meximum of 1.5 9 of vamin Biz administered orally is absorbed by the Intinsic factor pathway. When the oal dose is Increased, a saturetan pol fs reached in he inti facerdependont uptake ard there Ie ‘an increase in dusionncad absorption of ‘tain Big. The vtamia By contained Inthe body is stored in iver The daly requrement of vlamin Basis very low, i amounts to about 4 ig. The timover rate 2.5 bg per day ‘Vitamin Big fs mainly seeretad inthe bie snd for the most part is toabeorbed va te lenierahepatc creation the storage capacty of the body is exceeded by nigh doses, Paricuar with parenteral dases, the portion ‘which snot retaines Is excreted inte urine Thlemine has a very tow acute tocily in animals. Given ‘oral, inavenousiy” or inrapertonesly thiamine is extremly” safe having LD of 3710 molkg in rats [138 ‘There is no data about txity”of thiamine ster long-term adrnistaton spre degeneration inthe dorsal oot ganglia nin fhe Gasserian ganglia, degeneration of sensory nerve fers in peripheral nares, in areal columns. of the. spinal cord and descending spinal tract of the tiger nerve. Philips et Signs, but Stooge! examination revealed {oes of myelin in the dorsal nerve roots of lS dogs. No chronic toxiely was found in dogs (trad Reyes Gua et ab metaboite of vitamin Bn ras s S00 matkg [42]. Treatmant of rate with 02-20 mgt of mebiycabalamin during abe moths founé no tos du to Weatent [149 Final considerations ‘Several ‘Table 1. Summary of tudes on the antneclcepive or antalloynic effect of individual B amines armas Vitamin 8, Vitamin B, Vitamin 8, [Vitemin Bis ‘Nociceptive pain | Nociceptive pain | Noviceptive pain | Nociceptive pain Franga otal, | Zimmetmann etal, | Eschale ett, 200 (10) 1900 [347 1983 [80 : : “Juma etal > 190033)" Inflammatory pain | Inflammatory pain | Inflammatory pain | Inflammatory pain ‘Avaciogi et al Frangatal, | Zmmermann etal.| _ Eschalier etal, 2000 (a zoo 10) 1900 (39) 1983 80F Franga etal, | Granados-Sole etal, | Frengaetal, | Reyer Garcia, 201 {10F 2006 ft 2001 (10) 2003 (144) Reyes Garcia, - Reyes-Garca, ‘2003 1441" 2008 (144) Analgesic effects of B vitamins 2 a ‘Toble 1 continued, Neuropathic pain | Newropatic pain | Neuropaie pain | Newropathic pain Stoke etal, | GanadosSoioetat,| Wengefal, | suri tal, 2001 [14]" 2004 (217 2005/12)" 1985 (817 Wang fa, 5 Caran Saas ot, | Grane. Soo aa, 208 2h pubis eta | "0 ea Ceram Sais ofa, : Wang ofa, 2008 185) 2008 2" ane 5 ‘aramaiae ol, i 2006 [153] “Indicates sn antinociceptive or atalodynic effect found in hat poriular study. “Indicates that no antinociceptive or antslogyie elect was found in that parhcolar sty, Table 2. Summary of studes onthe antnosicoptve effet ofthe combination of 8 vtamine Injanimais Reference | Testeyetom [Combination ess Tee Fron 883¢B | Reta ofnacicoptan | wtp aris | eo Mamie lone or (10,15 20) 35 | Bocvealsaioton | — _,eBee8, | Dapanson one waked Sion Crees me | Oe te ‘sural nerves in rats ons ‘neurones: | Raters srdeons | —_ Sis Sepaen ean? masphereseral | age 8arae tence. ‘excitation by heat in 39499403 mang in thalamus and spinal rae eeas rk spc ©) Biasesner | Sis | Eanes motneal openssl sens nae ‘heal in rats sarsaon rig response 1365] ete on bc rise | agente panat aciny anettenn| 350 ance ngs ae rats SS+39109 mah from thalamus | 99 Hot plate test BBB ‘Clear antinociceptive 1 ‘Heat-coil test 167-667 mgikg ‘effect at the highest atpressuetex | “foooa® | Seaman ase \ ventng et nts 2 Gerardo Reyes Garcia a Tabie 2 continued Reference | __Testaystem Combination Results 148 | Wining testin mice Ba Reston of withing Bee response BytBet Bie 1000, §529 mata 70 ‘ee 26 wring BeBe “Aninocceptveofect ‘eatin mice ‘BiB Formaldehyde test | 20-200 mgtig Hotplate test for 7 days 100:100:3) $0 | Formainteatinrate |G BxtBie ‘atinciceptve eect, 204177 mika (0010071) ‘30d Byzin animals ‘Table 8. Summary of studies onthe antatodynic effet of the combination of vans By, By raternce | _Testeyston | Combination ‘oa | Sihanavetgaton | B0.8u TSITRS” | seems po wearin | praca veto of acto pea rae tgsten | 078rote, 28 a @ (5-66) in rats: aloo BeBaba | tion ermal typerigea ty cre | endvianinalore |" howe Sempron corset | By Be 100 eer | ETE | cngsem nmsny eee Fs ttheicttd win araatrenes | pxcnon2 mat sete for and 14 | Sent iony ae ea ss | Soracaretgaen | Snore, | Redicen facie (ieee | aseoommne se Analgesic effec 0 B ving 2 lc 4, Surmayy of sues on the arajesc ani anintonmoy etc of ne Etmbsvaion af onn ad ober age rats Reference [Test ion | ——Conbinaton Rane ‘a Chee" [anne (0 mgt, parce | Tacam ee Seon | ra pag Sid otoccnur oes aches | otssterat «mgt once Sa Te? Ihianhe + Dlseac "at wings |@y-6, 0 ge) —) Weapon mmee | te mongiarey oom owas) soma) 2 0 mg) be (6. Sake) Belin © mag ee setamizal (90 mga) B =| Terpressae | Br (10200 gt) — |“ vianns wa rotane > | cartageenin Bus (1-2.5 male) induce an antryperalgesic ‘est Diclofenac, ‘effect, but significantly increased i B vitamins + Diclofenac, p.o. ki induced by diclofenac Tor — ears] Bearsc te “ann Fteated he Inauced Porat weasel roporiey’? | anthyperagestefac st Pyperalgesia elofenac (1.8 mgkg), no. iciofenac 1a romain est | BeBe SETS gh. Svs ie GRASS inrats | 100808 Sor toe 008 | © eduadenmnecoseice | cs bapstens | Sytem ities fetien rales) | Keovee(Es2t0mah |S tarcn and elee Brana (08) KeorSac | nasser ne ie07 9b gs ook “noes ra ence . sete | Hasan anee Tas) romana} BRR GT aamaneaeee i irra | STaetabSponenane | Guess ie] oeotrac OT ematy | enter male | Pee tRetmetesye | Syme erat bowen Suen, | Stine aeh en suomre(srsis, | Gowurteoss sara ders SB, | mo leiettent ze cinta ety 7a] arabes BEG e tee eased Px ‘sclbaral| keopoten (io gg | apragese gon hyperalgesia Erbe Bun (100, -100:1 mg/kg) lemenatory aiiect ot inrats | +Ketoproten (1 maikg} po Ketoprofen [S| Fanaa [ Be ere ato. | __ Smee a (at sain | “comet iam i ae | seer GESI6 re) stiaclapt | a ‘Metamizo! (32-178 moka), | Synergitic interaction between acl Sa TOONO). | Brain mateo meen i ctneope (0) | (08!) rte e585) neta 28) a Interaction index (@ number close to indicates adative synergism, whie @ number close oro aletess sng potest a Gerad Reyer Gara ta Table 5. Summary of studies on the analgesic effect of the combination of @ vlamins and ‘other drug in models of neuropathic pin in anmmale Reference | Testayetem ‘Combination Results 02 | Spinal nerve | BSB (75-600 magn | ~ wisins reduced ale rolign dt | Soon ors rotor ‘atoayni soot 30%, inrais Gabapentin eed aut comaiiienon, 30%, rath rae rteraction Byante(o4) velveenB viamne and gabapentin (0), ‘abepenin 0 34) Tae) Spear aye, | Bese 600 mov |B vans reduced ace vgtion (SLs | 2031089 proponos pol | alodyi seat 30% inate ane 5 nk, cabaret about pa aytoniraiog) + ras teraction gabapentin (o>), elven B vomins and ‘abepenin (e003) TOS Spinal pene | BeBe Ba T5G00maRg |B warns reduced tate vgsten (St | S7o§AGlt pores So | © ios soot 8, ‘Dexamethason Dexaathaeane redid (32manG £0), about 638 Swamp 5) rai rterection dexamethasone (0.5) | between B isms and dexamethasone (0.17) 73 Neropattc ‘Conibneton reduced ‘rene neuropathy beter hen cuge ‘jeration index (a number case to 1 indeatesaddtive eynergim, while a number close to ‘eointeatos a steng patematon), Table 6, Summary of doube-ling placobe-contoled studles onthe analgesic efecto the combination ef vtamins in dabots patients Reference] Design] Treament() | Ouraon | Oignoaie [eect TH | Rapdraaaa Vierin G6, Biz| Sweets | Diabet or | —Signfaant ‘ouble |" combiacn, ‘2ecohate | improvement of Bind | im tetwaet then neuropathy | pain placebo. | |oralinea3) Restoration of Envi ‘pated sonsiily TE) Daa |Bavaaping Bo Swesls [Diabet — | Sian pacts, | Syanccsealanin feuppathy | "Score ana cenioied | "2 motiay vestry ral m2) percepibn TAS | “Doubs 300 mg ViamierB, | TE weeks [Type 1 daba Inpravernent ‘Bind | Soomp ey Be mg reper n| Ribg int Envios | _ ore (ards) * Aalgesi eee of 8 vitamins 2s “Toble 6 continued 3 | Ra | Ra aT we | aa [Ree : ei ig | nee bse eae ay? | one (| atics | PReaes Sy one a ase acne re ome SRR ‘ones | ous ® eae) os Bie [Pere TP alt Ee Sos ‘eat es sual ea ‘tr, sunny of nan ad pon bei see on anges oe fb eh mien men Son wes] Bes Tm [ovate | — ae nt ve | mn} acsnng RS oa bee oncaioted| _Gaynene aed neuropathy | nerve conduction Bee =e Ceeis oe TS a ape en aa cp eset ape 7 a Be | ae | eg ee ze, a oe samen | apo | anal, [ean soblno] = [RISA can eee | earn as | Seria, oe. | Bears y ane u renal 2% Safety good or aie otters, it an [ragga ea ee eres z 2 =, ae om | seh i ‘Oral (n=200) eee sues | eae ears | | page fen aS. Ea ain otto peiytouropaty| ato eee oatetten 6 Gera Reyes aren ea ‘Table &. Summary of contaled stuses on the anaigeste effect of the combination of 8 viamins and diclofenac in human beings tence] Bein [resin | Burana? Bagoate | Bet on 7 keer] Baars ee] Faia roam tories] Caos fom | "Saree SaasS) fre, efeetne| pe Socal | : ome, SEES) woe te wn Pores ire) act vides snus Saree |S) Case ewer | oe foe Saal | em, [MO | he| Sera Boe Saha) ioe sieges ean) Mag pas von Bret, aay 75 aes aT | eR See SSeewie| Tasewe |e femk | ya” | eet, Stel) ers, tee | gerse ty SS | Seer “ores, a ‘ee Sk caret air Cee ae ae Top itn Stag | ioc Foae ‘games ‘controlled | + 450mg By = eet Heme i Jame selon e Sota te Diciofenac fet ot Broeay cnt eats reas, "ST |RaeEgs)Dectens | Sizes Pema Pensa a Sora | cmarse, | aaregan | tongs tt iowy | «2 indtonan | ance” | Sangre plotstcy | uta | Bror surged |tonsitony | oxy Sreior stoma, | ‘oetense Pecamsten ion Soman reup an ‘SrgBe | newest) adGerae done Bo" | Erston stn Dicofenae | “post-surgery 50 mg (n=40) Aralgsi fet of 8 vitmine ” ACKNOWLEDGMENTS Authors greatly appreciate the biblographic assistance of 8 Se Héctor Vazquez, Nada L. (Garar-Salas is @ CONAGYT folow, eherences 1. | Woo. 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